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WO2025188914A1 - Tyrosine phosphatase inhibitor 1 (tpi-1) derivatives - Google Patents

Tyrosine phosphatase inhibitor 1 (tpi-1) derivatives

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Publication number
WO2025188914A1
WO2025188914A1 PCT/US2025/018599 US2025018599W WO2025188914A1 WO 2025188914 A1 WO2025188914 A1 WO 2025188914A1 US 2025018599 W US2025018599 W US 2025018599W WO 2025188914 A1 WO2025188914 A1 WO 2025188914A1
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Prior art keywords
tpi
derivative
pro
inflammatory agent
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/018599
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French (fr)
Other versions
WO2025188914A8 (en
Inventor
Harry Stylli
Lei Shi
Yuan Liu
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Mdx Management LLC
Original Assignee
Mdx Management LLC
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Publication of WO2025188914A1 publication Critical patent/WO2025188914A1/en
Publication of WO2025188914A8 publication Critical patent/WO2025188914A8/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/38—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups having unsaturation outside the aromatic rings
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    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07K16/241—Tumor Necrosis Factors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
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    • C07—ORGANIC CHEMISTRY
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    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
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    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
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Definitions

  • TPI-1 tyrosine phosphatase inhibitor 1
  • TPI-1 for inhibition of protein tyrosine phosphatases, such as Src homology protein tyrosine phosphatase 1 (SHP-1), in treatment of cancer was disclosed in WO 2008/002641.
  • SHP-1 Src homology protein tyrosine phosphatase 1
  • TPI-1 SUMMARY OF THE INVENTION
  • Such derivatives include a compound of the formula: 1 sf-6609919 Attorney Docket No.245162001140 [0007] where R C is R CA or -C 1 -C 4 alkyl-R CA , where R CA is -COOH, -NH 2 , or -OH; or a pharmaceutically acceptable salt thereof.
  • Such derivatives also include perdeuterated TPI-1: [0009] or pharmaceutically acceptable salts thereof.
  • Such derivatives also include a compound of the formula: 2 sf-6609919 Attorney Docket No.245162001140 [0011] where R C is R CA or -C1-C4 alkyl-R CA , where R CA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. [0012] The features of any of the embodiments recited above and herein are combinable with any of the other embodiments recited above and herein where appropriate and practical. BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIG. 1A-FIG.
  • FIG. 1E show the results of in vitro assays of perdeuterated TPI-1 (dTPI-1) for inhibition of SHP-1 activity in macrophages.
  • FIG. 1A shows the study system. Human monocyte-derived macrophages without or with cancer cells surrounding were stimulated with TLR agonist (aTLR) R848 and IFN ⁇ ⁇ dTPI-1. The presence of cancer cells was to ligate macrophage surface inhibitory receptors (iRs), of which cytoplasmic domain phosphorylation in ITIMs led to SHP-1 activation.
  • FIG. 1B shows the results of protein tyrosine phosphatase (PTP) activity assays.
  • FIG. 1A shows the study system. Human monocyte-derived macrophages without or with cancer cells surrounding were stimulated with TLR agonist (aTLR) R848 and IFN ⁇ ⁇ dTPI-1. The presence of cancer cells was to ligate macrophage surface inhibitory receptors (iRs), of which cytoplasmic
  • FIG. 1C shows the results of flow cytometric assay, demonstrating inhibition of SHP-1 by dTPI-1 unleashed macrophage antigen presentation inhibited by the cancer environment.
  • FIG. 1D shows cytokine profiling by ELISA of IL-6, TNF ⁇ , and IL-10 of human monocyte-derived macrophages with or without cancer cells, with or without R848/IFN ⁇ , and with or without dTPI-1 treatment.
  • FIG. 1E shows cytokine profiling by ELISA of TNF ⁇ as a function of dTPI concentration.
  • FIGS. 2A-2B show the results of R848 or dTPI-1 treatment, alone or in combination, in a murine metastatic melanoma model.
  • FIG. 2A shows the experimental scheme.
  • FIG. 2B shows lung images of melanoma prior to treatment (d12) and after different treatments.
  • 3 sf-6609919 Attorney Docket No.245162001140 [0015]
  • FIG. 3A-3D show the results of dTPI-1 treatment in a murine lung cancer model.
  • FIG. 3A shows the experimental design. Controls (ctl.) were mice treated with topical non-drug lotion; anti-PD-1 ( ⁇ PD-1) was given to mice with topical non-drug lotion treatment.
  • Topical drugs were TLR agonists (aTLR: PolyI;C, R848 and LPS) + dTPI-1, mixed in lotion, or Sting activator (aSting: MSA-2, ADU-S100, cGAMP) + dTPI-1, together mixed in lotion.
  • FIG. 3B shows that LLC tumor burden changes post treatments recorded as bioluminescence images.
  • FIG. 3C shows tumor microenvironment (TME) analyses of MHC-I, MHC-II, CD80, and CD86 expression by flow cytometry.
  • FIG. 3D shows flow cytometric analysis of cell populations in the TME. [0016] FIGS.
  • FIG. 4A-4D show the results of experiments assaying Ester and Amide conjugated R848-TPI-1 compounds for activation of macrophages in the presence of a cancer environment.
  • FIG. 4A shows the study system of human monocyte-derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ⁇ TPI-1 or Ester or Amide conjugated R848-TPI-1 compounds.
  • FIG. 4B shows schematics of R848 and TPI-1 monomers and ester conjugate and amide conjugated R848-TPI-1 compounds.
  • FIG. 4A-4D show the results of experiments assaying Ester and Amide conjugated R848-TPI-1 compounds for activation of macrophages in the presence of a cancer environment.
  • FIG. 4A shows the study system of human monocyte-derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ⁇ TPI-1 or Ester or Amide conjugated R848-TPI-1
  • FIG. 4C shows the results of ELISAs assaying macrophage proinflammatory (TNF ⁇ and IL-6) or anti-inflammatory (IL- 10) response stimulated by R848 ⁇ TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells.
  • FIG. 4D shows the results of flow cytometry measuring macrophage expression of cell surface antigen presentation machinery following stimulation with R848 ⁇ TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells. All monomer and conjugate compounds in FIGS. 4C-4D were used at 1 ⁇ M.
  • FIG. 4E shows the dose-dependent effects of Ester and Amide conjugated R848-TPI-1 compounds on activation of macrophage production of TNF ⁇ , as measured by ELISA.
  • the amide curve is the upper curve and the ester curve is the lower curve [0017]
  • FIGS. 5A-5D show dose-dependent efficacies of R848-TPI-1 Ester and Amide conjugated compounds treating KPC pancreatic cancer.
  • FIG. 5A shows the experimental design. KPC cells were engrafted (5 ⁇ 10 5 , s.c.) into the right flank of C57BL6 mice. After tumors reached 200 mm 3 , mice were treated daily with escalated doses of R848-TPI-1 Ester and Amide conjugated compounds.
  • FIG. 5B shows KPC tumor volume changes over time (in days) following treatments.
  • FIG. 5C shows TME analyses of MHC-I, MHC-II, CD80, and CD86- expressing populations by flow cytometry on post-treatment d2.
  • FIG. 5D shows TME analyses of various cell types by flow cytometry on post-treatment d5. 4 sf-6609919 Attorney Docket No.245162001140 [0018]
  • FIGS. 6A-6D show the results of dTPI-1 treatment in a murine lung cancer model (LLC).
  • FIG. 6A shows the experimental design. LLC lung cancer were engrafted (5 ⁇ 10 5 , s.c.) into the right flank of C57BL6 mice.
  • FIG. 6B shows bioluminescence images of LLC tumor burden changes post treatments.
  • FIG. 6C shows the tumor volume over time post-treatment (in days) for LLC treated with the control, ester-conjugated R848-TPI-1, or amide-conjugated R848-TPI-1.
  • TEE tumor microenvironment
  • the term “individual,” “subject,” or “patient” is used synonymously herein to describe a mammal, including humans.
  • An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate.
  • the individual is human.
  • an individual suffers from a disease, such as cancer.
  • the individual is in need of treatment.
  • a “reference” as used herein refers to any sample, standard, or level that is used for comparison purposes.
  • a reference may be obtained from a healthy and/or non-diseased sample. In some examples, a reference may be obtained from an untreated sample.
  • a reference is obtained from a non-diseased or non-treated sample of an individual. In some examples, a reference is obtained from one or more healthy individuals who are not the individual or individual.
  • the term “intermittent” or “intermittently” in the context of dosing refers to a non-continuous dosing regimen. In some cases, “intermittent” dosing refers to a dosing where a) a therapeutic agent is administered less than 12 consecutive days (e.g., less than 11, 10, 9, 8, 7, 6, 5, 4 and 3 days), and b) the therapeutic agent is administered at least two times, and the two administrations are separated by at least one day (i.e., Day 1 and Day 3).
  • the therapeutic agent is administered daily for no more than three consecutive days, and at least twice that is separated by at least one day.
  • the term “cycle” in the context of dosing refers to a time period during which there is at least one administration of a therapeutic agent.
  • Day 1 of a cycle is defined as the day when the first administration of a therapeutic agent happens during that time period.
  • Day 1 of the cycle is defined as the day of the first administration of the multiple daily consecutive administrations.
  • the last day of the cycle is defined as the day before the next non-consecutive administration of the therapeutic agent happens.
  • the cycles do not have to have the same length of time.
  • the first cycle can have five days
  • the second cycle can have seven days.
  • Each cycle may have different numbers of administrations of the therapeutic agent.
  • the first cycle which may have five days
  • the second cycle which may have seven days
  • immunogenic is the ability to elicit an immune response, e.g., via T-cells, B cells, or both.
  • treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • treatment is a reduction of pathological consequence of the disease.
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • “delaying” the development of cancer means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that “delays” development of cancer is a method that reduces probability of disease development in a given 6 sf-6609919 Attorney Docket No.245162001140 time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of individuals.
  • Cancer development can be detectable using standard methods, including, but not limited to, computerized axial tomography (CAT Scan), Magnetic Resonance Imaging (MRI), abdominal ultrasound, clotting tests, arteriography, or biopsy. Development may also refer to cancer progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • the term “simultaneous administration,” as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes.
  • the first and second therapies may be contained in the same composition (e.g., a composition comprising both a first and second therapy) or in separate compositions (e.g., a first therapy in one composition and a second therapy is contained in another composition).
  • the term “sequential administration” means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first therapy or the second therapy may be administered first.
  • the first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.
  • the term “concurrent administration” means that the administration of the first therapy and that of a second therapy in a combination therapy overlap with each other.
  • pharmaceutically acceptable or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • a “small molecule” refers to a molecule with a molecular weight less than about 900 Dalton.
  • a “small organic molecule” refers to an organic molecule with a molecular weight less than about 900 Dalton. 7 sf-6609919 Attorney Docket No.245162001140 [0032] It is understood that embodiments of the application described herein include “consisting” and/or “consisting essentially of” embodiments. [0033] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. [0034] As used herein, reference to “not” a value or parameter generally means and describes “other than” a value or parameter.
  • the method is not used to treat cancer of type X means the method is used to treat cancer of types other than X.
  • the term “about X-Y” used herein has the same meaning as “about X to about Y.”
  • the singular forms “a,” “an,” and “the” as used herein include plural referents unless the context clearly dictates otherwise.
  • Alkyl refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms).
  • Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”), having 1 to 10 carbon atoms (a “C1-C10 alkyl”), having 6 to 10 carbon atoms (a “C6-C10 alkyl”), having 1 to 6 carbon atoms (a “C1-C6 alkyl”), having 2 to 6 carbon atoms (a “C2-C6 alkyl”), or having 1 to 4 carbon atoms (a “C1-C4 alkyl”).
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • Alkylene as used herein refers to the same residues as alkyl, but having bivalency.
  • Particular alkylene groups are those having 1 to 20 carbon atoms (a “C1-C20 alkylene”), having 1 to 10 carbon atoms (a “C1-C10 alkylene”), having 6 to 10 carbon atoms (a “C6-C10 alkylene”), having 1 to 6 carbon atoms (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C 1 -C 3 alkylene”).
  • alkylene examples include, but are not limited to, groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH 2 CH(CH 3 )-), butylene (-CH 2 (CH 2 ) 2 CH 2 -), isobutylene (-CH 2 CH(CH 3 )CH 2 -), pentylene (-CH 2 (CH 2 ) 3 CH 2 -), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like.
  • groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH 2 CH(CH 3 )-), butylene (-CH 2 (CH 2 ) 2 CH 2 -), iso
  • An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations.
  • Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 6 to 10 carbon atoms (a “C6-C10 alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”).
  • alkenyl group examples include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex- 1-enyl, hex-2-enyl, hex-3-enyl, and the like.
  • Alkenylene refers to the same residues as alkenyl, but having bivalency.
  • Particular alkenylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenylene”), having 2 to 10 carbon atoms (a “C2-C10 alkenylene”), having 6 to 10 carbon atoms (a “C6-C10 alkenylene”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkenylene”), 2 to 4 carbon atoms (a “C 2 -C 4 alkenylene”) or 2 to 3 carbon atoms (a “C2-C3 alkenylene”).
  • Alkynyl refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms).
  • Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynyl”), having 6 to 10 carbon atoms (a “C6-C10 alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”).
  • alkynyl group examples include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3- ynyl, and the like.
  • Alkynylene refers to the same residues as alkynyl, but having bivalency.
  • Particular alkynylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynylene”), having 2 to 10 carbon atoms (a “C2-C10 alkynylene”), having 6 to 10 carbon atoms (a “C6-C10 alkynylene”), having 2 to 6 carbon atoms (a “C2-C6 alkynylene”), 2 to 4 carbon atoms (a “C2- C4 alkynylene”) or 2 to 3 carbon atoms (a “C2-C3 alkynylene”).
  • alkynylene examples include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C ⁇ C-), propynylene (-C ⁇ CCH2-), and the like. 9 sf-6609919 Attorney Docket No.245162001140 [0043] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl.
  • a cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof.
  • Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl").
  • Cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
  • Cycloalkylene refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkylene”), having 3 to 6 carbon atoms (a “C3-C6 cycloalkylene”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkylene”).
  • Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like.
  • a cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms.
  • cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans- 1,2-cyclopropylene), or a mixture thereof.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.
  • Cycloalkenylene refers to the same residues as cycloalkenyl, but having bivalency.
  • Aryl or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic.
  • Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C6-C14 aryl”).
  • An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • “Arylene” as used herein refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a “C6-C14 arylene”).
  • “Heteroaryl” as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur.
  • particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heteroaryl group having more than one ring where at least one ring is non- aromatic may be connected to the parent structure at either an aromatic ring position or at a non- aromatic ring position.
  • a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • a heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
  • Heteroarylene refers to the same residues as heteroaryl, but having bivalency. 11 sf-6609919 Attorney Docket No.245162001140
  • Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like.
  • a heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof, but excludes heteroaryl groups.
  • the heterocyclyl group may be optionally substituted independently with one or more substituents described herein.
  • Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10- membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • perhaloalkyl An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.”
  • a preferred perhaloalkyl group is trifluoromethyl (-CF3).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • An example of a perhaloalkoxy group is trifluoromethoxy (–OCF3).
  • “D” refers to deuterium ( 2 H).
  • “T” refers to tritium ( 3 H).
  • a group in which each hydrogen is replaced with deuterium is referred to as “perdeuterated.”
  • a group in which each hydrogen is replaced with tritium is referred to as “pertritiated.”
  • the disclosure includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds.
  • Isotopologues can have isotopic replacements at any or at all locations in a structure, or can have atoms present in natural abundance at any or all locations in a structure.
  • “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted. [0062] It is understood that an optionally substituted moiety can be substituted with more than five substituents, if permitted by the number of valences available for substitution on the moiety. For example, a propyl group can be substituted with seven halogen atoms to provide a perhalopropyl group. The substituents may be the same or different.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or 13 sf-6609919 Attorney Docket No.245162001140 pharmaceuticals to an individual.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
  • excipient as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • excipient including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • substantially pure intends a composition that contains no more than 10% impurity, such as a composition comprising less than 9%, 7%, 5%, 3%, 1%, 0.5% impurity.
  • 14 sf-6609919 Attorney Docket No.245162001140
  • any terms not directly defined herein shall be understood to have the meanings commonly associated with them as understood within the art of the invention.
  • TPI-1 The compound 2-(2,5-dichlorophenyl)benzoquinone (which is also referred to as 2-(2,5- dichlorophenyl)cyclohexa-2,5-diene-1,4-dione, Tyrosine Phosphatase Inhibitor 1 or TPI-1; CAS Registry No. 79756-69-7) is an inhibitor of SHP-1.
  • TPI-1 has the following structure: .
  • TPI-1 can be derivatized with a functional group for facile attachment to other compounds, for use in conjugate compounds.
  • a carboxyl group can be introduced at the 3-position of the dichlorophenyl ring to provide: 15 sf-6609919 Attorney Docket No.245162001140 [0071] which can be readily coupled to an amino or hydroxy group on another molecule, such as a therapeutic molecule, or a linker to another molecule.
  • Derivatives and analogs of TPI-1 include compounds of the following structure: [0072] where R C is R CA or -C1-C4 alkyl-R CA , where R CA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. [0073] Various methods for preparing TPI-1 analogs are available.
  • an R C - substituted 2,5-dichloroaniline is suitably protected on its R C group (the protected R C group is indicated as R CP in the scheme below). Then the amino group is converted to the corresponding diazonium ion and coupled with quinone to give the TPI-1 scaffold.
  • R C group is indicated as R CP in the scheme below.
  • the amino group is converted to the corresponding diazonium ion and coupled with quinone to give the TPI-1 scaffold.
  • An example of the experimental conditions that can be adapted for this reaction is shown in the synthesis in Jones et al., Journal of Organic Chemistry 58(8):2035 (1993) for 2-(4-carboxyphenyl)-3,6-dichloro- 2,5-cyclohexadiene-1,4-dione. The Jones et al.
  • reaction can be adapted to preparation of carboxylic acid-functionalized TPI-1 derivatives by replacing the 2,5-dichloro-2,5- cyclohexadiene-1,4-dione reagent with 1,4-benzoquinone, and replacing the 4-aminobenzoic acid reagent with 2-amino-3,6-dichlorobenzoic acid, 3-amino-3,6-dichlorobenzoic acid, or 4- 16 sf-6609919 Attorney Docket No.245162001140 amino-3,6-dichlorobenzoic acid, to yield 2-(2-carboxy-3,6-dichlorophenyl)-2,5-cyclohexadiene- 1,4-dione, 2-(5-carboxy-3,6-dichlorophenyl)-2,5-cyclohexadiene-1,4-dione, or 2-(4-carboxy- 3,6-dichlorophenyl)-2,5-cyclohexadiene
  • 2-amino-3,6-dichlorobenzoic acid can be replaced by 2-(2-amino-3,6-dichlorophenyl)acetic acid, 3-(2-amino-3,6-dichlorophenyl)propanoic acid, etc., and similarly for the other positional isomers.
  • Deprotection affords the TPI-1 analog ready for conjugation to a linker or PIA.
  • carbamates or cleavable alkyl groups where R CA -NH2
  • silyl ethers, cleavable alkyl groups, or esters where R CA -OH.
  • an approach through Pd-catalyzed biaryl coupling may be utilized.
  • An R C substituted 2,5-dichloroaniline is suitably protected on its R C group (the protected R C group is 17 sf-6609919 Attorney Docket No.245162001140 indicated as R CP in the scheme below).
  • the amino group is converted to a halide through a diazonium intermediate using t-butyl nitrite and copper halide (CuX2, e.g., CuBr2) (Sandmeyer reaction).
  • CuX2 t-butyl nitrite and copper halide
  • Pd-catalyst and 2,5-dimethoxyphenyl boronic acid provides the biaryl structure of TPI-1.
  • Oxidative conditions, such as ceric ammonium nitrate, give the quinone.
  • Deprotection affords the TPI-1 analog ready for conjugation to a linker or PIA.
  • Perdeuterated TPI-1 has the following structure, where D is deuterium (i.e., 2H):
  • D is deuterium (i.e., 2H):
  • Other deuterated forms of TPI-1 can also be prepared and used, by selecting suitably deuterated starting materials (e.g., appropriately deuterated benzoquinone; appropriately deuterated 2,5-dichloroaniline).
  • suitably deuterated starting materials e.g., appropriately deuterated benzoquinone; appropriately deuterated 2,5-dichloroaniline.
  • the available positions for deuteration include the 3, 4, and 6 positions of the benzoquinone moiety of TPI-1 and the 3’, 4’, and 6’ positions of the dichlorobenzene moiety of TPI-1, as shown in the following numbered structure.
  • the various deuterated compounds (d 1 , d 2 , d 3 , d 4 , d 5 , d 6 ) are expected to be effective for inhibiting SHP-1 and treating cancer (e.g., via systemic administration, e.g., in a topical application).
  • the deuterated TPI-1 is TPI-1-d 1 .
  • the TPI-1-d1 is selected from TPI-1-3-d1, TPI-1-4-d1, TPI-1-6-d1, TPI-1-3’-d1, TPI-1-4’-d1, or TPI- 1-6’-d 1 .
  • the deuterated TPI-1 is TPI-1-d 2 .
  • the TPI-1-d2 is selected from TPI-1-3,4-d2, TPI-3,6-d2, TPI-1-3,3’-d2, TPI-1-3,4’-d2, TPI-3,6’-d2, TPI-1-4,6-d2, TPI-1-4,3’-d2, TPI-1-4,4’-d2, TPI-4,6’-d2, TPI-1-6,3’-d2, TPI-1-6,4’-d2, TPI-6,6’- d 2 , TPI-1-3’,4’-d 2 , TPI-3,6’-d 2 , or TPI-4’,6’-d 2 .
  • the deuterated TPI-1 is TPI-1-d 3 .
  • the TPI-1-d3 is selected from TPI-1-3,4,6-d3, TPI-1-3,4,3'-d3, TPI-1-3,4,4’-d3, TPI-1-3,6,3’-d 3 , TPI-1-3,6,4’-d 3 , TPI-1-3,6,6’-d 3 , TPI-1-3,6,6’-d 3 , TPI-1-3,3’,4’-d 3 , TPI-1-3,3’,6’-d 3 , TPI-1-3,4’,6’- d 3 , TPI-1-4,6,3’-d 3 , TPI-1-4,6,4’-d 3 , TPI-1-4,6,6’-d 3 , TPI-1-4,3’,4’-d 3 , TPI-1-4,6,6’-d 3 , TPI-1-4,3’,4’-d 3 , TPI-1-4,6,6’-d 3 , T
  • the deuterated TPI-1 is TPI-1-d 4 .
  • the TPI- 1-d 4 is selected from TPI-1-3,4,6,3’-d 4 , TPI-1-3,4,6,4'-d 4 , TPI-1-3,4,6,6’-d 4 , TPI-1-3,4,3’,4’-d 4 , TPI-1-3,4,3’,6’-d4, TPI-1-3,4,4’6’-d4, TPI-1-3,6,3’,4’-d4, TPI-1-3,6,3’,6’-d4, TPI-1-3,6,4’,6’-d4, TPI-1-4,6,3’,4’-d4, TPI-1-4,6,3’,6’-d4, TPI-1-4,6,4’,6’-d4, TPI-1-3,3’,4’,6’-d4, TPI-1-4,3’,6’-d4, TPI-1-4,6,4’,6’-d4, TPI-1-3,3’,4’,6’-
  • the deuterated TPI-1 is TPI-1-d 5 .
  • the TPI- 1-d 5 is selected from TPI-1-3,4,6,3’,4’-d 5 , TPI-1-3,4,6,3’,6’-d 5 , TPI-1-3,4,6,4’,6’-d 5 , TPI-1- 4,6,3’,4’,6’-d5, TPI-1-3,6,3’,4’,6’-d5, or TPI-3,4,3’,4’,6’-d6.
  • the deuterated TPI-1 is TPI-1-d 6 , i.e., perdeuterated TPI-1, or TPI-1-3,4,6,3’,4’,6’-d 6 .
  • Deuterated and perdeuterated TPI-1 can also be functionalized as described above for conjugation, as a compound of the formula: [0085] where R C is R CA or -C1-C4 alkyl-R CA , where R CA is -COOH, -NH 2 , or -OH; or a pharmaceutically acceptable salt thereof.
  • Deuterated and perdeuterated TPI-1 derivatives can be prepared by using appropriately deuterated compounds in the synthetic preparations of the TPI-1 derivatives disclosed herein.
  • TPI-1 derivatives are disclosed in Kundu et al., J Immunol. 2010 Jun 1; 184(11): 6529–6536; see for example, FIG. 6 of Kundu et al.
  • Methods of treatment [0087]
  • the present application in one aspect provides methods of treating a cancer by administering a TPI-1 derivative.
  • the TPI-1 derivative can be administered in combination with a pro-inflammatory agent.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently.
  • the TPI-1 derivative or TPI-1 21 sf-6609919 Attorney Docket No.245162001140 derivative-pro-inflammatory agent combination is administered daily for no more than two or three consecutive days, and optionally for at least two administrations which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises systemically administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • the method comprises locally administering (e.g., intratumorally administering) the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination.
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, and wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously or subcutaneously).
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally.
  • the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination is administered systemically and intratumorally.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered locally (e.g., topically). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination.
  • the pro-inflammatory agent of the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • the pro-inflammatory agent of the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine (e.g., IFN-gamma).
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (e.g., where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is a TLR agonist, e.g., R848), and wherein the method comprises intravenous or subcutaneous administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, optionally wherein the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is administered intermittently.
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination e.g., where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is a TLR agonist, e.g., R848
  • the method comprises intravenous or subcutaneous administration
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice 23 sf-6609919 Attorney Docket No.245162001140 where the administrations are separated by at least one day.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times.
  • at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered twice (e.g., two consecutive days) every seven to twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered three times (e.g., three consecutive days) every ten to twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at an interval of no more than once every two days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the method further comprises locally (e.g., intratumorally or locally) administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is e.g., a TLR agonist, e.g., R848), and wherein the method comprises intravenous or subcutaneous administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, optionally wherein the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is administered intermittently.
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is e.g., a TLR agonist, e.g., R848
  • the method comprises intravenous or subcutaneous administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, further optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle is about three to about twenty days long.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least twice (e.g., at least two consecutive days) in each cycle.
  • the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for at least three times (e.g., at least three consecutive days) in each cycle.
  • the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the method further comprises locally (e.g., intratumorally or locally) administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination into the individual.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ 25 sf-6609919 Attorney Docket No.245162001140 antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • the pro-inflammatory agent of the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • a method of treating a cancer comprising intravenously, subcutaneously and/or intratumorally administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 5 days, and optionally wherein the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice (e.g., at least 3, 4, 5, or 6 times).
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at an interval of no more than twice every seven to twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered at an interval of no more than three times every seven to twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for a period of at least fourteen to twenty days at an interval of about 1-3 times every seven to twenty days.
  • the TPI-1 26 sf-6609919 Attorney Docket No.245162001140 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least about 2, 3, 4, 5, or 6 times in a period of about fourteen to about forty days (e.g., about fourteen to about twenty days).
  • the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days).
  • the method further comprises locally (e.g., intratumorally or locally) administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination into the individual.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise an agent or can be selected from the group consisting of R848, 3M- 852A, Motolimod, Bropirimine and Vesatolimod.
  • a method of treating a cancer comprising intravenously, subcutaneously and/or intratumorally administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848), wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 5 days (e.g., for no more than 5, 4, or 3 days), and wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently.
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a T
  • the TPI-1 derivative or TPI-1 derivative-pro- 27 sf-6609919 Attorney Docket No.245162001140 inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least twice (e.g., at least two consecutive days) in each cycle.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least three times (e.g., at least three consecutive days) in each cycle.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the method further comprises locally (e.g., intratumorally or locally) administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination into the individual.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro- 28 sf-6609919 Attorney Docket No.245162001140 inflammatory agent can comprise or be selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod).
  • a method of treating a cancer comprising administering (e.g., intravenously, subcutaneously and/or intratumorally) to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848) and immune cells (such as any of the immune cells described herein).
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • administering e.g., intravenously, subcutaneously and/or intratumorally
  • a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848
  • immune cells such as any of the immune cells described herein.
  • a method of treating a cancer comprising administering (e.g., intravenously, subcutaneously and/or intratumorally) to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848), and immune cells.
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • administering e.g., intravenously, subcutaneously and/or intratumorally
  • a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848)
  • the immune cells are derived from the same individual.
  • the immune cells comprise T cells (e.g., CAR-T cells).
  • the immune cells comprise NK cells (e.g., CAR-NK cells).
  • the immune cells comprise neutrophils (e.g., CAR-expressing neutrophils cells).
  • the immune cells comprise antigen presenting cells (APCs).
  • the immune cells are engineered to express a chimeric receptor that specifically binds to a tumor antigen.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day.
  • the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times.
  • at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination administration.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination and the immune cells are administered within 7, 6, 5, 4, 3, 2 or 1 day. In some embodiments, the TPI-1 derivative or TPI-1 derivative- 29 sf-6609919 Attorney Docket No.245162001140 pro-inflammatory agent combination and the immune cells are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of each other. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination and the immune cells are administered simultaneously. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination and the immune cells are administered concurrently.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination and the immune cells are administered sequentially.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise or be selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod).
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory compound of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be a TLR agonist, e.g., R848), wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (e.g., at least 3, 4, or 5 times).
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent 30 sf-6609919 Attorney Docket No.245162001140 combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for at least once (e.g., at least twice or three time) in each cycle and wherein each cycle has about three to about twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously or subcutaneously) and/or locally (e.g., intratumorally).
  • the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is a TLR agonist, and the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and/or Pam3CSK4.
  • the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, optionally wherein the TLR agonist comprises a diacylated lipopeptide, a hot shock protein, HMGB1, uric acid, fibronectin, and/or ECM protein.
  • the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and/or CBLB612.
  • the TLR agonist activates TLR3, optionally wherein the TLR agonist comprises dsRNA, Poly I:C, PolyICIC, Poly-IC12U, IPH302, ARNAX, and/or MPLA (Monophosphoryl Lipid A).
  • the TLR agonist activates TLR4, optionally wherein the TLR agonist comprises LPS, lipoteichoic acid beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, FP20, G100, and/or GLA-SE.
  • the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and/or M-VM3.
  • the TLR agonist activates TLR6.
  • the TLR agonist activates TLR7 or TLR8, optionally wherein the TLR agonist comprises ssRNA, CpG-A, poly G10, poly G3, and/or 324 BDB001. In some embodiments, the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and/or R848. In some embodiments, the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and/or R848.
  • the TLR agonist activates TLR9, optionally wherein the TLR agonist comprises unmethylated CpG 31 sf-6609919 Attorney Docket No.245162001140 DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and/or ODN M362.
  • the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam3CSK4.
  • the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises toxoplasma gondii profilin.
  • the TLR agonist activates TLR12. In some embodiments, the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV. In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and/or TLR9. In some embodiments, the TLR agonist activates TLR1. In some embodiments, the TLR agonist activates TLR2. In some embodiments, the TLR agonist activates TLR3. In some embodiments, the TLR agonist activates TLR4. In some embodiments, the TLR agonist activates TLR7. In some embodiments, the TLR agonist activates TLR8. In some embodiments, the TLR agonist activates TLR9.
  • the TLR agonist activates TLR9, TLR4 and TLR7/8.
  • the TLR agonist comprises CpG, polyI:C and/or R848.
  • the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically.
  • the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered intratumorally.
  • the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • a method of treating a cancer comprising administering a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises a TLR agonist (e.g., R848), optionally wherein the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7 and TLR8.
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises a TLR agonist (e.g., R848), optionally wherein the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7 and TLR8.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent 32 sf-6609919 Attorney Docket No.245162001140 combination is administered intermittently.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times.
  • at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (e.g., at least three, four, five or six times).
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least two cycles (e.g., at least three cycles). In some embodiments, each cycle has about seven to about twenty days.
  • the TLR agonist of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination activates a TLR on a macrophage, optionally wherein the TLR comprises TLR9.
  • the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9).
  • the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4 and TLR7/8).
  • the TLR agonist comprises CpG, polyI:C and/or R848.
  • the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be a STING activator (e.g., cGAMP, e.g., MSA-2), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times).
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be a STING activator (e.g., cGAMP, e.g., MSA-2), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally).
  • the STING activator of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is a cyclic-guanosine monophosphate- adenosine monophosphate (cGAMP, e.g., 3’3’ cGAMP, e.g., 2’3’ cGAMP), a bacterial vector (e.g., SYNB1891, STACT-TREX-1), a CDN compound (e.g., ADU-S100, BI-STING, BMS- 986301, GSK532, JNJ-4412, MK-1454, SB11285, 3’3’-cyclic AIMP), a non-CDN small molecule (e.g., ALG-031048, E7755, J
  • the TPI-1 derivative or 34 sf-6609919 Attorney Docket No.245162001140 TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti- TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • an anti-TNF ⁇ antibody optionally wherein the anti- TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be a PAMP/DAMP activator), optionally wherein the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times).
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro- 35 sf-6609919 Attorney Docket No.245162001140 inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally).
  • the pro-inflammatory agent is a PAMP activator.
  • the PAMP activator is triacyl lipopeptides, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porins, lipoarabinomannan, double-stranded RNA, poly(I:C), trypanosomal lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single-stranded RNA, resiquimod, bacterial/viral DNA, CpG DNA, ureobacteria, or toxoplasma LPS.
  • the pro-inflammatory agent is a DAMP activator.
  • the DAMP activator is defensins, HSP60, HSP70, messenger RNA, low-molecular-weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, or unmethylated CpG DNA.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally.
  • the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti- TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • an anti-TNF ⁇ antibody optionally wherein the anti- TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory compound of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise a checkpoint inhibitor (e.g., an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times).
  • a checkpoint inhibitor e.g., an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent
  • the TPI-1 derivative or 36 sf-6609919 Attorney Docket No.245162001140 TPI-1 derivative-pro-inflammatory agent combination is administered intermittently.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times.
  • at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally).
  • the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG/PVRL2, CEACAM1, CEACAM 5/6, FAK, CCL2/CCR2, LIF, CD47/SIRP ⁇ , CSF-1(M- CSF)/CSF-1R, IL-1/IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine.
  • the checkpoint inhibitor comprises or is lipilimumab, Cemiplimab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO-201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, Lanotuzumab (MCS110), LY3022855, SNDX-6352, Emactuzumab (RG7155), Pexidartinib (PLX3397),
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is 37 sf-6609919 Attorney Docket No.245162001140 administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • an anti-TNF ⁇ antibody optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination can comprise a pro-inflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and/or TNF ⁇ ), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered at least twice (at least three, four, five, or six times).
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination can comprise a pro-inflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and/or TNF ⁇ ), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration is separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., 38 sf-6609919 Attorney Docket No.245162001140 subcutaneously) and/or locally (e.g., intratumorally).
  • the pro- inflammatory cytokine of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination promotes the M1 macrophages.
  • the pro-inflammatory cytokine comprises or is TNF, IFN ⁇ , and/or GM-CSF.
  • the pro- inflammatory cytokine comprises IFN ⁇ .
  • the pro-inflammatory cytokine comprises IL-1.
  • the pro-inflammatory cytokine comprises TNF-a. In some embodiments, the pro-inflammatory cytokine comprises IL-6. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • an anti-TNF ⁇ antibody optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • a method of treating a cancer comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise a chemotherapeutic agent (e.g., azathioprine), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times).
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise a chemotherapeutic agent (e.g., azathioprine), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times).
  • chemotherapeutic agent e.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice.
  • the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally).
  • the chemotherapeutic agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is an alkylating agent.
  • the alkylating agent is selected from the group consisting of nitrogen mustard (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkyl sulfonate (e.g., busulfan), and ethyleneimine (e.g., thiotepa).
  • nitrogen mustard e.g., endamustine, cyclophosphamide, ifosfamide
  • nitrosoureas e.g., carmustine, lomustine
  • platinum analogs e.g., carboplatin, cisplatin, oxaliplatin
  • triazenes e.g., dacar
  • the chemotherapeutic agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is an antimetabolite.
  • the antimetabolite is selected from the group consisting of icytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (prodrug of 5-FU)).
  • icytidine analogs e.g., azacitidine, decitabine, cytarabine, gemcitabine
  • folate antagonists e.g., methotrexate, pemetrexed
  • purine analogs e.g., cladribine, clofarabine, nelarabine
  • the chemotherapeutic agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is an antimicrotubular agent.
  • the antimicrotubular agent is selected from the group consisting of topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin).
  • topoisomerase II inhibitors e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone
  • the chemotherapeutic agent of the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination is hydroxyurea, tretinoin, arsenic trioxide, or a proteasome inhibitor (e.g., bortezomib).
  • the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered systemically.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered 40 sf-6609919 Attorney Docket No.245162001140 intratumorally.
  • the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti- TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • the present application also provides a method of modulating monocytes or macrophages derived from an individual having a cancer, comprising contacting the monocytes or macrophages with a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination as described herein.
  • the monocytes or macrophages are derived from the same individual.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination e.g., comprising TPI-1 or an analog or a derivative thereof
  • is administered at least two times such as at least 3, 4, 5, or 6 times).
  • the method comprises administering the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination (e.g., comprising TPI-1 or an analog or a derivative thereof) at an interval of no more than once every two days for at least twice (such as at least three times, four times, five times, or six times).
  • the method comprises administering the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination (e.g., comprising TPI-1 or an analog or a derivative thereof) at an interval of no more than once every three days for at least twice (such as at least three times, four times, five times, or six times).
  • the method comprises administering the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination (e.g., TPI-1 or an analog or a derivative thereof) for at least two cycles.
  • the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination e.g., comprising TPI-1 or an analog or a derivative thereof
  • each cycle has about three to about 50 days (e.g., about 3-40 days, about 3-30 days, about 3-20 days, about 3-15 days, about 3-10 days, or about 2-10 days).
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., orally, intravenously, subcutaneously, intraperitoneally). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered locally (e.g., intratumorally). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered both systemically and locally (e.g., intratumorally). [0108] Local administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise topical administration.
  • Topical dosage forms available to treat mammals include solids (dusting powders), semisolids (creams, ointments, pastes, and gels), and liquids (solutions, suspension concentrates, suspoemulsions, emulsifiable concentrates, paints, and tinctures).
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, intestinal, intranasal, or intraocular administration.
  • the compounds can also be administered in sustained or controlled release dosage forms, including transdermal (e.g., electrotransport) patches, creams, lotions, pastes, patches, ointments, sprays, gels, isotonic aqueous solutions (e.g., eyedrops), or microneedles and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • transdermal e.g., electrotransport
  • isotonic aqueous solutions e.g., eyedrops
  • microneedles and the like for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination formulation is sterile.
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is complexe
  • the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination modulates a monocyte or macrophage (e.g., a monocyte or macrophage derived from the individual to be treated) in vitro.
  • TME Tumor microenvironment
  • SHP-1 signaling [0113] Src homology region 2 (SH-2) domain-containing phosphatase 1 (SHP-1) is a non- receptor tyrosine phosphatase.
  • SHP-1 is encoded by the PTPN6 gene (on chromosome 12p13).
  • SHP-1 As there are two promoter regions, one on exon 1 (active in cells of non-hematopoietic lineage) and one on exon 2 (active in cells of hematopoietic lineage), there are two forms of SHP-1 which have different N-terminal sequences, but which both have phosphatase activity. Both promoters may be active in epithelial cancer cells, giving rise to alternative SHP-1 transcripts. Form I of SHP-1 is primarily found in the nucleus, while form II is primarily found in the cytoplasm, and presumably they have different substrates. [0114] SHP-1 is a 595 amino acid protein.
  • N-SH2 and C-SH2 have two tandem N-terminal SH2 domains (N-SH2 and C-SH2), and a classic catalytic protein tyrosine phosphatase (PTP) domain.
  • the C-terminal tail has multiple sites for phosphorylation.
  • Structural analysis of SHP-1 indicates that its N-SH2 is bound to and auto-inhibits the catalytic site in its inactive state.
  • phosphotyrosine residues bind to the SH2 domains, the electrostatic interactions between N-SH2 and the catalytic site is disrupted, allowing the enzyme to become active.
  • substrate interaction plays a role in regulating the activity of SHP-1.
  • Phosphorylation of amino acids Tyr536, Tyr564 and Ser591 also increase SHP-1 activity.
  • Ser591 may also play a role in down-regulating SHP-1 activity, via phosphorylation by protein kinase C (PKC) or mitogen-activated protein kinases (MAPKs).
  • PLC protein kinase C
  • MAPKs mitogen-activated protein kinases
  • Motheaten mice (me/me or me v /me v ) which are genetically deficient in SHP-1 show abnormal immune function, including hyperactivation of immune cells, and such mice have shortened life spans. Depletion of SHP-1 in adult wild-type mice also caused pathology, including enlarged spleens and inflammation of the lungs. Thus, approaches to treatment of cancer by inhibition of SHP-1 require careful balancing of the need for normal SHP-1 activity versus preventing abnormal SHP-1 activity. 43 sf-6609919 Attorney Docket No.245162001140 [0117] Inhibitors of SHP-1 phosphatase activity include TPI-1, suramine, NSC-87877, and sodium stibogluconate.
  • CRS cytokine release syndrome
  • the methods described herein can further comprises administration of an agent that reduces systemic inflammation (including, for example, an agent that reduces inflammatory cytokine cascade or cytokine storm), in order to curb down systemic inflammation and reduce adverse toxicity.
  • agents that reduce systemic inflammation include, but are not limited to, inhibitors of TNF ⁇ , IL6, IL10, and IFN ⁇ .
  • the agent that reduces systemic inflammation is administered simultaneously with the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination. In some embodiments, the agent that reduces systemic inflammation is administered sequentially (e.g., prior to or after) with the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the administration of the agent that reduces systemic inflammation follows the same dosing schedule as the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the agent that reduces systemic inflammation is administered at a sub- therapeutic dose, namely, at a dose that is lower than an effective amount for treating a disease when administered alone.
  • the administration of the agent that reduces systemic inflammation allows more frequent administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (e.g., daily, once every two days, once every three days, etc.).
  • the agent that reduces systemic inflammation can include any anti-inflammatory agent known in the art, including inhibitors of or antagonists to pro-inflammatory agents.
  • the agent can be an inhibitor or antagonist, including but not limited to, a small molecule 44 sf-6609919 Attorney Docket No.245162001140 inhibitor, a neutralizing antibody, a receptor blockade antibody, a soluble receptor, a targeting short interfering RNA (siRNA), a chemical inhibitor of mRNA stability, derivatives thereof, and any combination thereof, including combinations of agents targeting one or more molecules (e.g., targeting via the inhibition of TNF ⁇ alone, IL6 alone, TNF ⁇ and IL6 in combination).
  • Anti-TNF ⁇ antagonist [0121] TNF ⁇ , a major proinflammatory cytokine, is secreted by activated macrophages, monocytes and lymphocytes.
  • TNF ⁇ inhibitor e.g., an anti-TNF ⁇ antagonist (e.g., in the context where the proinflammatory agent is not TNF ⁇ ) in addition to the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • the TNF ⁇ inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNF ⁇ receptor blockade antibody, a soluble TNF ⁇ receptor, a TNF ⁇ -targeting short interfering RNA (siRNA), a chemical inhibitor of TNF ⁇ mRNA stability, an inhibitor of TNF ⁇ converting enzyme (TACE), and derivatives thereof.
  • the TNF ⁇ inhibitor is an anti-TNF ⁇ neutralizing antibody.
  • the TNF ⁇ inhibitor is an anti-TNF ⁇ receptor blockade antibody.
  • the anti-TNF ⁇ antibody is a monoclonal antibody.
  • anti-TNF ⁇ antibody is a chimeric, humanized, and/or fully human antibody.
  • Suitable antibodies for use in the methods provided herein include, but are not limited to, Remicade® (Infliximab (Centocor)), and those antibodies described, for example, in U.S. Patent No. 6,835,823; 6,790,444; 6,284,471; 6,277,969; 5,919,452; 5,698,195; 5,656,272; and 5,223,395 and in EP Patent No. 0610201, the contents of each of which are hereby incorporated by reference in their entirety, or antibodies that bind to the same epitope as Remicade®.
  • anti-TNF ⁇ antibodies for use in the methods provided herein are, by way of non-limiting example, Humira (Adalimumab (Abbott Laboratories, Esai)) as described in U.S. Patent No. 6,090,382; 6,258,562; or 6,509,015 and related patents and applications, the contents of which are hereby incorporated by reference in their entirety; SimponiTM (Golimimab, CNTO 148 (Centocor)) as described in PCT Publication No.
  • Humira Adalimumab (Abbott Laboratories, Esai)
  • SimponiTM Golimimab, CNTO 148 (Centocor)
  • the TNF ⁇ inhibitor e.g., anti-TNF ⁇ antagonist
  • the TNF ⁇ inhibitor is a fusion protein.
  • Suitable fusion proteins for use in the methods provided herein include, but are not limited to, Enbrel (Etanercept (Amgen)) and other fusion proteins or fragments thereof described in U.S. Patent No.
  • the TNF ⁇ inhibitor e.g., anti-TNF ⁇ antagonist
  • the TNF ⁇ inhibitor is a modified antibody antagonist or a non-antibody-based antagonist.
  • Such antagonists include advanced antibody therapeutics, such as antibody fragments including, but not limited to, CimziaTM (Certolizumab pegol, CDP870 (Enzon)), bispecific antibodies, Nanobodies® such as ABX 0402 (Ablynx), immunotoxins, and radiolabeled therapeutics; peptide therapeutics; gene therapies, particularly intrabodies; oligonucleotide therapeutics such as aptamer therapeutics, antisense therapeutics, interfering RNA therapeutics; and small molecules such as LMP-420 (LeukoMed) as described in EP Patent No. 0767793, and related patents and applications, the contents of which are hereby incorporated by reference in their entirety.
  • advanced antibody therapeutics such as antibody fragments including, but not limited to, CimziaTM (Certolizumab pegol, CDP870 (Enzon)), bispecific antibodies, Nanobodies® such as ABX 0402 (Ablynx), immunotoxins, and radiolabeled therapeutics; peptide therapeutics;
  • the TNF ⁇ inhibitor (e.g., an anti-TNF ⁇ antibody) is administered within two weeks, 10 days, or one week prior to the administration of a TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination described herein.
  • Exemplary TNF ⁇ inhibitors such an anti-TNF ⁇ antibody is usually stable for at least one or two weeks.
  • the TNF ⁇ inhibitor (e.g., an anti-TNF ⁇ antibody) is administered concurrently or simultaneously with the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • the TNF ⁇ inhibitor (e.g., an anti-TNF ⁇ antibody) is administered immediately after (e.g., within 1 hour or 30 minutes) the administration of the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination.
  • the TNF ⁇ inhibitor is administered systemically.
  • the TNF ⁇ inhibitor is administered at least once a week, once every five days, once every three days, or daily.
  • the TNF ⁇ inhibitor is administered intermittently.
  • the TNF ⁇ inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days. In some embodiments, the individual does not develop cytokine release syndrome or pro-inflammatory organ damage.
  • administering does not compromise or weakly compromises tumor clearance.
  • an “anti-IL6 antagonist” or “IL6 inhibitor” refers to an agent that inhibits or blocks IL6 biological activity via binding to IL6 or IL6 receptor.
  • the anti-IL6 antagonist is an antibody.
  • the anti-IL6 antagonist is an antibody that binds IL6 receptor.
  • Antibodies that bind IL-6 receptor include tocilizumab (including intravenous, i.v., and subcutaneous, s.c., formulations thereof) (Chugai, Roche, Genentech), satralizumab (Chugai, Roche, Genentech), sarilumab (Sanofi, Regeneron), NI-1201 (Novimmune and Tiziana), and vobarilizumab (Ablynx).
  • the anti-IL6 antagonist is a monoclonal antibody that binds IL6.
  • Antibodies that bind IL-6 include sirukumab (Centecor, Janssen), olokizumab (UCB), clazakizumab (BMS and Alder), siltuximab (Janssen), and EBI- 031 (Eleven Biotherapeutics and Roche).
  • the IL6 antagonist is olamkicept.
  • the IL6 inhibitor is administered systemically. In some embodiments, the IL6 inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the IL6 inhibitor is administered intermittently.
  • the IL6 inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days.
  • Pro-inflammatory agents used in the TPI-1 derivative-pro-inflammatory agent combinations [0129] Infection and tissue injury are the two classic instigators of inflammation. See e.g., Medzhitov, Nature. 2008 Jul 24;454(7203):428-35.
  • the pro-inflammatory agents that can be used in the TPI-1 derivative-pro-inflammatory agent combinations described herein include at least two overlapping categories: 1) an agent or therapy of any kind or sort that can promote an inflammation (e.g., by promoting one or more pro-inflammatory cytokines or chemokines, inhibiting one or more anti-inflammatory cytokines or chemokines, recruiting macrophages, NK cells, neutrophils, effector T cells, or B cells to the tissue or activating any of these cells, or suppressing regulatory/suppressive immune cells such as regulatory T cells or MDSC), and 2) an agent or therapy that can cause damage of cancer cells (e.g., necrosis of cancer cells).
  • an agent or therapy of any kind or sort that can promote an inflammation (e.g., by promoting one or more pro-inflammatory cytokines or chemokines, inhibiting one or more anti-inflammatory cytokines or chemokines, recruiting macrophages, NK cells, neutrophils, effector T cells, or B cells to the tissue or activ
  • the pro-inflammatory agent triggers a pro-inflammatory signal on macrophages.
  • the pro-inflammatory agent activates a TLR, a TNFR, or ITAM-R. See Lionel et al., Eur J Immunol. 2011 Sep; 41(9): 2477–2481.
  • the pro-inflammatory can activate a pro-inflammatory signal on macrophages via a direct manner or indirect manner.
  • a TLR agonist which directly activates TLR on macrophages
  • a radiotherapy which indirectly activates a pro-inflammatory signal on macrophages, when used with a SHP-1 inhibitor both demonstrated remarkable anti-tumor effects.
  • the pro-inflammatory agent comprises an agent selected from the group consisting of TLR agonists, STING activators, PAMP/DAMP activators, checkpoint inhibitors, pro-inflammatory cytokines or chemokines, chemotherapeutic agents, and bacterial components.
  • the pro-inflammatory agent comprises an agent selected from the group consisting of TLR agonists, STING activators, PAMP/DAMP activators, pro- inflammatory cytokines or chemokines, and bacterial components.
  • the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a cytokine (e.g., IFN-gamma).
  • TLR agonists e.g., R848
  • cytokine e.g., IFN-gamma
  • TLR agonists e.g., the pro-inflammatory agent comprises or is a TLR agonist.
  • TLRs play a vital role in activating immune responses. TLRs recognize conserved pathogen-associated molecular patterns (PAMPs) expressed on a wide array of microbes, as well as endogenous DAMPs released from stressed or dying cells.
  • PAMPs pathogen-associated molecular patterns
  • TLR1, -2, -4, -5, -6, and -10 are expressed on the cell surface, whereas TLR3, -7, -8, and -9 are situated on endosomal membranes within the cell.
  • TLR1 and TLR2 can heterodimerize to recognize a variety of bacterial lipid structures and cell wall components, such as triacylated lipoproteins, lipoteichoic acid, and ⁇ -glucans.
  • TLR2 also heterodimerizes with TLR6 to bind diacylated lipopeptides. Additionally, TLR2 can bind various endogenous DAMPs, such as HSPs, HMGB1, uric acid, fibronectin, and other extracellular matrix proteins.
  • TLR1 and TLR6 can heterodimerize with TLR10; however, the TLR agonist recognized by this dimer remains to be identified.
  • TLR3 recognizes viral dsRNA, as well as synthetic analogs of dsRNA, such as ligand Poly I:C.
  • TLR4 binds LPS in complex with lipid A binding protein, CD14, and myeloid differentiation protein 2, MD2 as well as recognizing various DAMPs. Endogenous TLR4 ligands, which have been described, include ⁇ -defensin 2, fibronectin extra domain A EDA, HMGB1, Snapin, and tenascin C.
  • TLR5 recognizes bacterial flagellin
  • TLR7 and TLR8 bind viral ssRNA
  • TLR9 interacts with unmethylated CpG DNA from bacteria and some viruses. Additional TLRs have been identified more recently in mice based on sequence homology of the highly conserved TIR domain.
  • TLR10 is a surface receptor whose natural ligand remains unknown.
  • TLR11, -12, and -13 are present in mice but not in humans.
  • TLR11 was shown to bind a T. gondii profilin and uropathogenic Escherichia coli.
  • the ligand for TLR12 has not yet been identified, whereas TLR13 is an endosomal receptor that recognizes VSV.
  • TLR signaling can act as a double-edged sword in cancer. It was found that TLR stimulation of cancer cells can lead to either tumor progression or inhibition. For example, Stimulation of TLR 2, 4, and 7/8 was found to lead to tumor progression via production of immunosuppressive cytokines, increased cell proliferation and resistance to apoptosis. R848- stimulation of TLR7/8 overexpressing pancreatic cancer cell line resulted in increased cell proliferation and reduced chemosensitivity.
  • the TLR agonist activates any of the TLRs.
  • the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and/or Pam 3 CSK 4 .
  • the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, optionally wherein the TLR agonist comprises a diacylated lipopeptide, a hot shock protein, HMGB1, uric acid, fibronectin, and/or ECM protein.
  • the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and/or CBLB612.
  • the TLR agonist activates TLR3, optionally wherein the TLR agonist comprises dsRNA, Poly I:C, PolyICIC, Poly-IC12U, IPH302, ARNAX, and/or MPLA.
  • the TLR agonist activates TLR4, optionally wherein the TLR agonist comprises LPS, lipoteichoic acid beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, FP20, G100, and/or GLA-SE.
  • the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and/or M-VM3. [0144] In some embodiments, the TLR agonist activates TLR6. [0145] In some embodiments, the TLR agonist activates TLR7 or TLR8, optionally wherein the TLR agonist comprises ssRNA, CpG-A, poly G10, poly G3, and/or 324 BDB001. [0146] In some embodiments, the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and/or R848.
  • the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and/or R848.
  • the TLR agonist activates TLR9, optionally wherein the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and/or ODN M362.
  • the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam 3 CSK 4 .
  • the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises toxoplasma gondii profilin.
  • the TLR agonist activates TLR12.
  • the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV.
  • the TLR agonist activates a TLR on a macrophage.
  • the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and/or TLR9. [0155] In some embodiments, the TLR comprises TLR1, TLR4, and/or TLR9. In some embodiments, the TLR comprises TLR9. [0156] In some embodiments, the TLR comprises TLR2, TLR4, TLR7, and/or TLR8. [0157] In some embodiments, the TLR agonist comprises CpG. In some embodiments, the TLR agonist comprises polyI:C. In some embodiments, the TLR agonist comprises CpG and/or polyI:C. In some embodiments, the TLR agonist comprises CpG, polyI:C and/or R848.
  • the TLR agonist is R848, 3M-852A, Motolimod, Bropirimine or Vesatolimod. In some embodiments, the TLR agonist is R848.
  • Radiopharmaceuticals [0159] In some embodiments, the pro-inflammatory agent is a radiopharmaceutical. Examples of radiopharmaceuticals that can be used are disclosed in, e.g., Sgouros et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19, 589–608 (2020). STING activator [0160] In some embodiments, the pro-inflammatory agent comprises or is a STING activator.
  • Stimulator of IFN genes is a pattern recognition receptor (PRR) that recognizes cytosolic DNA in the form of cyclic dinucleotides (CDNs), such as the bacterial product cyclic-guanosine monophosphate-adenosine monophosphate (3’3’ cGAMP).
  • CDNs cyclic dinucleotides
  • cGAMP c- GMP-AMP synthase
  • cGAS converts ATP and GTP into the metazoan-specific CDN 2’3’-cGAMP for STING recognition and activation.
  • 50 sf-6609919 Attorney Docket No.245162001140 STING is a transmembrane protein that exists as dimers anchored within the endoplasmic reticulum membrane and forms a V-shaped pocket that enables cytosolic CDN binding. Ligand binding results in significant conformational changes in the C-terminal domain of STING, mediating its transport to Golgi compartments.
  • STING recruits TANK-binding kinase 1 (TBK1), which facilitates IRF3 phosphorylation, nuclear translocation and the strong induction of transcription of type I IFNs (e.g., IFN- ⁇ ).
  • TNF tumor necrosis factor
  • STING also triggers a robust pro- inflammatory cytokine response [e.g., tumor necrosis factor (TNF)] by activating Nuclear Factor-kappa B (NF- ⁇ B) and this part of the pathway can be mediated independent of TBK1 via a closely related homologue protein, IKK ⁇ .
  • TNF- ⁇ B Nuclear Factor-kappa B
  • the STING activator is a cyclic-guanosine monophosphate- adenosine monophosphate (cGAMP, e.g., 3’3’ cGAMP, e.g., 2’3’ cGAMP).
  • the STING activator is a bacterial vector (e.g., SYNB1891, STACT-TREX-1).
  • the STING activator is a CDN compound (e.g., ADU-S100, BI- STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3’3’-cyclic AIMP).
  • the STING activator is a non-CDN small molecule (e.g., ALG- 031048, E7755, JNJ-‘6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI- 10001).
  • the STING activator is a nanovaccine (e.g., PC7A NP, cCAMP- NP, ONM-500). [0167] In some embodiments, the STING activator is an antibody-drug conjugate (e.g., XMT- 2056, CRD-5500). 51 sf-6609919 Attorney Docket No.245162001140 [0168] In some embodiments, the STING activator is the compound SR-717 of the formula: . [0169] In some embodiments, the STING activator is the compound MSA-2 of the formula: . [0170] In some embodiments, the STING activator is the compound SNX-281 of the formula: .
  • the STING activator is the compound alpha-mangostin of the [0172] In some embodiments, the STING activator is the compound DMXAA of the formula: . [0173] Other exemplary STING activators can be found in Amougezar et al., Cancers (Basel). 2021 May 30;13(11):2695, which is incorporated by reference here by its entirety. PAMP/DAMP activators [0174] In some embodiments, the pro-inflammatory agent comprises or is a PAMP/DAMP activator.
  • the organism senses microbial infection through innate receptors encoded in the genome, called pattern-recognition receptors, including the Toll-like receptors (TLRs), the nucleotide-binding and oligomerization domain (NOD)-like receptors, and retinoic acid– inducible gene I (RIG-I)-like receptors.
  • TLRs Toll-like receptors
  • NOD nucleotide-binding and oligomerization domain
  • RIG-I retinoic acid– inducible gene I
  • the pro-inflammatory agent is a PAMP activator.
  • Exemplary PAMP activator includes triacyl lipopeptides, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porins, lipoarabinomannan, double- stranded RNA, poly(I:C), trepanosomal lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial/viral DNA, CpG DNA, ureobacteria, and toxoplasma LPS.
  • the pro-inflammatory agent is a DAMP activator.
  • Examplary DAMP activator includes defensins, HSP60, HSP70, messenger RNA, low-molecular-weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, and unmethylated CpG DNA.
  • Chemotherapeutic agent [0178]
  • the pro-inflammatory agent comprises or is a chemotherapeutic agent.
  • the chemotherapeutic agent is an alkylating agent.
  • alkylating agents include nitrogen mustard (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkyl sulfonate (e.g., busulfan), and ethyleneimine (e.g., thiotepa).
  • the chemotherapeutic agent is an antimetabolite.
  • Exemplary antimetabolites include cytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (prodrug of 5-FU)).
  • the chemotherapeutic agent is an antimicrotubular agent.
  • antimmicrotubular agents include topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin).
  • topoisomerase II inhibitors e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone
  • topoisomerase I inhibitors e.g., irinotecan, topotecan
  • taxanes e.g., paclitaxel,
  • chemotherapeutic agents include hydroxyurea, tretinoin, arsenic trioxide, and proteasome inhibitors (e.g., bortezomib). 54 sf-6609919 Attorney Docket No.245162001140 Pro-inflammatory cytokines [0183]
  • the pro-inflammatory agent is a pro-inflammatory cytokine.
  • the pro-inflammatory cytokine promotes the M1 macrophages. See e.g., Duque et al., Front Immunol. 2014; 5: 491.
  • the pro- inflammatory cytokine comprises or is TNF, IFN ⁇ , and/or GM-CSF.
  • the pro-inflammatory cytokine comprises IL-6, TNF ⁇ , a cytokine from IL-1 family (e.g., IL-1 ⁇ , IL-1 ⁇ , IL-18, IL-33 and IL-36), and/or IFN ⁇ .
  • the pro-inflammatory cytokine comprises a cytokine from IL-1 family.
  • the pro-inflammatory cytokine comprises any one or more of IL- 1 ⁇ , IL-1 ⁇ , IL-18, IL-33, and IL-36. See e.g., Sims, J., Smith, D. The IL-1 family: regulators of immunity. Nat Rev Immunol 10, 89–102 (2010).
  • the pro-inflammatory agent is a checkpoint inhibitor.
  • Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). See e.g., Marin-Acevedo et al., J Hematol Oncol 14, 45 (2021).
  • the checkpoint inhibitor targets CLTA-4, PD-1 or PD-L1 (e.g., an antibody targeting CTLA-4, PD-1 or PD-L1).
  • the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG/PVRL2, CEACAM1, CEACAM 5/6, FAK, CCL2/CCR2, LIF, CD47/SIRP ⁇ , CSF-1(M-CSF)/CSF-1R, IL-1/IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine.
  • the checkpoint inhibitor comprises or is lipilimumab, Cemiplimab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO-201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, Lanotuzumab (MCS110), LY3022855, SNDX-6352, Emactuzumab (RG7155), Pexidartinib (PL
  • ATR inhibitors such as berzosertib
  • ATR inhibitors such as berzosertib
  • TPI-1 derivatives TPI-1 derivatives
  • berzosertib TPI-1 derivatives
  • TPI-1 derivatives TPI-1 derivatives.
  • a tyrosine kinase inhibitor can be in combination with TPI-1 derivatives.
  • the tyrosine kinase inhibitors referred to herein are agents of any kind or sort that inhibits the expression or activation of tyrosine kinase.
  • the tyrosine kinase inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%) of the tyrosine kinase activity. In some embodiments, the tyrosine kinase inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%) of the tyrosine kinase expression. [0195] In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling.
  • the diazonium salt solution is added slowly to an aqueous solution of 1,4- benzoquinone-d4 and sodium acetate.
  • the precipitate is filtered off and washed with water to give 2-(2,5-dichlorophenyl)-1,4-benzoquinone-d6.
  • Compound (2-4) is then activated using 1.25 eq. HATU and 2.4 eq. DIPEA in DMF at room temperature for 15 minutes, followed by addition of nucleophile (2-5) (1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4- amine) (1.05 eq).
  • Examples B1-B3 describe perdeuterated TPI-1 (dTPI-1) assayed in vitro for the capability to inhibit SHP-1 in macrophages within a tumor environment, and the ability to unleash proinflammatory responses in vivo in the TME when combined with TLR agonists (e.g. R848, LPS, PolyI:C, etc.), Sting activators (e.g. MSA-2, ADU-S100, cGAMP), as well as other inflammatory factors or means, thereby inducing intratumoral antigen presentation and activation of T cell immunity against cancer.
  • TLR agonists e.g. R848, LPS, PolyI:C, etc.
  • Sting activators e.g. MSA-2, ADU-S100, cGAMP
  • other inflammatory factors or means thereby inducing intratumoral antigen presentation and activation of T cell immunity against cancer.
  • Examples B4 and B5 describe experiments using 61 sf-6609919 Attorney Docket No.245162001140 R848-TPI-1 Ester and Amide conjugates chemically formed by linking the TLR7/8 agonist R848 with TPI-1 through an Ester or Amide bond. These experiments demonstrate that R848- TPI-1 Ester and Amide conjugates possess properties of both R848, which through TLR7/8 triggers proinflammatory response, and TPI-1, which inhibits SHP-1 activity.
  • TME tumor microenvironment
  • simultaneous activation of intratumoral macrophages (TAM) while inhibiting SHP-1 activity is required for skewing TAM toward proinflammatory activation and antigen presentation, which leads to activation of T cell immunity and elimination of cancer.
  • Example B-1 In vitro assays of dTPI-1 for the capability to inhibit SHP-1 in macrophages within a tumor environment
  • Human monocytes-derived macrophages in culture were stimulated with TLR agonist R848 (1 ⁇ g/ml) and IFN ⁇ (40ng/ml), in the absence or the presence of human renal cancer cells (TK10) and dTPI-1.
  • TLR agonist R848 (1 ⁇ g/ml) and IFN ⁇ (40ng/ml)
  • TK10 human renal cancer cells
  • cells were lysed in 1% Triton containing PBS, followed by assaying protein tyrosine phosphatase activity in supernatants using pNPP as the substrate.
  • FIGS. 1B-1E Results are shown in FIGS. 1B-1E.
  • FIG. 1A shows the study system. Human monocyte-derived macrophages without or with cancer cells surrounding were stimulated with TLR agonist (aTLR) R848 and IFN ⁇ ⁇ dTPI-1.
  • TLR agonist aTLR
  • FIG. 1B shows the results of protein tyrosine phosphatase (PTP) activity assays. Strong SHP-1 activity (labeled) was induced in macrophages by aTLR stimulation plus cancer cell ligating macrophage iRs. As shown, dTPI-1 dose-dependently inhibited SHP-1 activity induced by aTLR with cancer cell ligation.
  • FIG. 1C shows inhibition of SHP-1 by dTPI-1 unleashed macrophage antigen presentation inhibited by the cancer environment.
  • FIG. 1D shows inhibition of SHP-1 by dTPI-1 also unleashed macrophage proinflammatory cytokine production inhibited by 62 sf-6609919 Attorney Docket No.245162001140 the cancer environment.
  • FIG. 1E shows the dose-dependent effect of dTPI-1 for unleashing proinflammatory cytokine (TNF ⁇ ) production.
  • Example B-2 R848 and/or dTPI-1 treatment in a murine metastatic melanoma model [0207] Lung metastases of B16 melanoma were established in syngeneic mice C57BL6. After melanoma were formed in lungs (day 12), mice were treated with TLR agonists (aTLR: R848 and polyI:C), dTPI-1, or aTLR and dTPI-1 combination. A dose of prophylactic anti- TNF ⁇ was given to mice 3h before treatments to ameliorate treatment-associated CRS. FIG.
  • FIG. 2A shows the experimental scheme.
  • Results are shown in FIG. 2B, which are lung images of melanoma prior to treatment (d12) and after different treatments. None of the single treatment with either R848 or dTPI-1 suppressed melanoma progression. However, the combination of R848 or dTPI-1 effectively controlled the disease, even inducing regression of melanoma in lungs.
  • Example B-3 Topical and/or systemic treatment using dTPI-1 in a murine lung cancer model
  • Murine lung cancer (LLC-luc) was engrafted into syngeneic C57BL6 mice in a multi-point cutaneous/subcutaneous manner into the dorsal skinfold.
  • FIG. 3A shows the experimental design.
  • the treatments include: i) Control treatment (ctl.); mice were given topical non-drug lotion (vehicle) only. ii) ⁇ PD-1; anti-PD-1 mAb (100 ⁇ g, i.p., once every 3 days) was given to mice with topical non-drug lotion treatment. iii) Topical treatments with TLR agonists (aTLR) + dTPI-1 + ⁇ PD-1.
  • aTLR TLR agonists
  • TLR agonists Resiquimod (R848) and PolyI:C, together with dTPI-1 were prepared in Johnson’s lotion, each at 100 ⁇ g/ml, topical application 2x per day, each 100-200 ⁇ l lotion.
  • Anti-PD- 1 mAb 100 ⁇ g, i.p., once every 3 days) 63 sf-6609919 Attorney Docket No.245162001140 iv) Topical treatments with Stine activators (aSting) + dTPI-1 + ⁇ PD-1.
  • Stine activators including MSA-2, ADU-S100 and cGAMP were prepared in Johnson’s lotion, each at 5mg/ml , together with dTPI-1 prepared at 100 ⁇ g/ml in lotion, were given as topical application, 2x per day, each 100-200 ⁇ l lotion.
  • a dose of anti-TNF ⁇ was given to mice 3h before the first dose of topical therapies for prophylactic neutralization of TNF ⁇ to ameliorate treatment-associated CRS.
  • Results are shown in FIGS. 3B-3D.
  • FIG. 3B are bioluminescence images that show that LLC tumor burden changes post treatment. In FIGS.
  • TME analyses revealed that aTLR+dTPI-1 or aStine+TPI-1 treatments skewed intratumoral macrophages toward the proinflammatory phenotype with elevated expression of antigen presentation machinery (FIG. 3C), resulting in increased CD8 T cells (Tc) and reduction of MDSC in the TME (FIG. 3D) [0213]
  • LLC lung cancer strongly resisted anti-PD-1 immune checkpoint inhibitor; however, treatment to this cancer with TLR agonists or Sting activators combined with dTPI-1 achieved strong anti-cancer immunity, leading to clearance of the malignant lesions.
  • TAM intratumoral macrophages
  • Example B-4 In vitro testing R848-TPI-1 Ester and Amide conjugates for proinflammatory activation of macrophages in a cancer environment [0214] Human monocytes-derived macrophages were treated with R848-TPI-1 Ester and Amide conjugates (1 ⁇ M each), in the absence or presence of ovarian cancer cells (OVCAR5).
  • FIG. 4A shows the study system: human monocyte-derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ⁇ TPI-1 or Ester (Compound 1-6) or Amide (Compound 2-6) conjugated R848-TPI-1 compounds.
  • FIG. 5 shows the study system: human monocyte-derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ⁇ TPI-1 or Ester (Compound 1-6) or Amide (Compound 2-6) conjugated R848-TPI-1 compounds.
  • FIG. 4B shows schematics of R848 and TPI-1 monomers and ester conjugate and amide conjugated R848-TPI-1 compounds.
  • 64 sf-6609919 Attorney Docket No.245162001140 [0215] Results are in FIGS. 4C-4E.
  • FIG. 4C shows the results of assaying macrophage proinflammatory (TNF ⁇ and IL-6) or anti-inflammatory (IL-10) response stimulated by R848 ⁇ TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells.
  • TNF ⁇ and IL-6 macrophage proinflammatory
  • IL-10 anti-inflammatory
  • Ester and Amide conjugated R848-TPI-1 compounds resembled R848 + TPI-1, capable of skewing macrophages toward proinflammatory direction with high production of TNF ⁇ and IL-6 and low IL-10 even in the presence of cancer cell ligation.
  • FIG. 4D shows macrophage expression of cell surface antigen presentation machinery following stimulation with R848 ⁇ TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells.
  • FIG. 4E shows the dose-dependent effects of Ester and Amide conjugated R848- TPI-1 compounds on activation of macrophage production of TNF ⁇ (in FIG. 4E, the amide curve is the upper curve and the ester curve is the lower curve).
  • R848 treatment induced the typical proinflammatory response in macrophages, resulting in high production of TNF ⁇ and IL-6 and low IL-10.
  • mice were treated with R848-TPI-1 Ester or Amide conjugated compound daily in a dose escalation manner (FIG. 5A). Prior to treatment (3h), prophylactic anti-TNF ⁇ was given to prevent treatment-associated CRS. [0221] Results are in FIG. 5B-5D, which show dose-dependent efficacies of R848-TPI-1 Ester and Amide conjugated compounds treating KPC pancreatic cancer.
  • FIG. 5B shows KPC tumor volume changes over time (in days) following treatments.
  • FIG. 5B shows KPC tumor volume changes over time (in days) following treatments.
  • TME analyses on d2 revealed that treatments with R848-TPI-1 conjugated compounds skewed intratumoral macrophages (TAM) toward the proinflammatory phenotype with elevated expression of antigen presentation machinery, suggesting that TAM mediated antigen presentation and induced anti- cancer T cell immunity.
  • TME analyses on d5 revealed significant increases in CD8 T cells (Tc) and NK cells, while immunosuppressive components including MDSC were reduced.
  • Model-2 LLC lung cancer
  • Murine lung cancer (LLC-luc) was s.c. engrafted into the right flank of syngeneic C57BL6 mice. After cancer formation, mice were treated with either with anti-PD-1 ( ⁇ PD-1, 100ug, i.p. every 3 days), or R848-TPI-1 Ester compound (3mg/kg, s.c.
  • FIG. 6A A dose of anti-TNF ⁇ was given to 66 sf-6609919 Attorney Docket No.245162001140 mice 3h before the first dose of topical therapies for prophylactic neutralization of TNF ⁇ to ameliorate treatment-associated CRS.
  • the experimental design is shown in FIG. 6A.
  • Results are shown in FIG. 6B-6D.
  • FIG. 6B shows bioluminescence images of LLC tumor burden changes post treatments.
  • FIG. 6C shows that tumor volume (mm 3 ) shrunk over time post-treatment over 13 days after LLC was treated with ester-conjugated R848-TPI-1 or amide-conjugated R848-TPI-1, but not when treated with the control.
  • FIG. 6D TME analyses revealed that both Ester and Amide treatments combined with ⁇ PD-1 significantly increased CD8 T cells (Tc), which attributed to tumor elimination.
  • Tc CD8 T cells

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Abstract

Derivatives, including deuterated derivatives, of the SHP-1 inhibitor compound 2-(2,5- dichlorophenyl)benzoquinone (which is also referred to as 2-(2,5-dichlorophenyl)cyclohexa-2,5- diene- 1,4-dione, Tyrosine Phosphatase Inhibitor 1 or TPI-1; CAS Registry No. 79756-69-7) are provided. The TPI-1 derivatives can be used in treatment of diseases such as cancer.

Description

Attorney Docket No.245162001140 TYROSINE PHOSPHATASE INHIBITOR 1 (TPI-1) DERIVATIVES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This patent application claims priority benefit of United States Provisional Patent Application No. 63/562,140, filed March 6, 2024; United States Provisional Patent Application No. 63/562,133, filed March 6, 2024; United States Provisional Patent Application No. 63/562,250, filed March 6, 2024; and United States Provisional Patent Application No. 63/562,237, filed March 6, 2024. The entire contents of those applications are hereby incorporated by reference herein. FIELD OF THE INVENTION [0002] The disclosure relates to derivatives of 2-(2,5-dichlorophenyl)-2,5-cyclohexadiene- 1,4-dione (tyrosine phosphatase inhibitor 1; TPI-1) for use in preparation of medicaments and compounds for treatment of diseases such as cancer. BACKGROUND OF THE INVENTION [0003] The compound 2-(2,5-dichlorophenyl)-2,5-cyclohexadiene-1,4-dione is known as tyrosine phosphatase inhibitor 1 (TPI-1). A synthesis of 2-(2,5-dichlorophenyl)-2,5- cyclohexadiene-1,4-dione was disclosed in Schimmelschmidt, K., Annalen der Chemie, Justus Liebigs (1950), 566, 184-206. Use of TPI-1 for inhibition of protein tyrosine phosphatases, such as Src homology protein tyrosine phosphatase 1 (SHP-1), in treatment of cancer was disclosed in WO 2008/002641. [0004] The instant disclosure provides derivatives of TPI-1 for use in preparation of medicaments and compounds for the treatment of diseases such as cancer. SUMMARY OF THE INVENTION [0005] Provided are derivatives of TPI-1, which can be used in preparing medicaments and compounds for treatment of diseases such as cancer. [0006] Such derivatives include a compound of the formula: 1 sf-6609919 Attorney Docket No.245162001140 [0007] where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. [0008] Such derivatives also include perdeuterated TPI-1: [0009] or pharmaceutically acceptable salts thereof. [0010] Such derivatives also include a compound of the formula: 2 sf-6609919 Attorney Docket No.245162001140 [0011] where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. [0012] The features of any of the embodiments recited above and herein are combinable with any of the other embodiments recited above and herein where appropriate and practical. BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIG. 1A-FIG. 1E show the results of in vitro assays of perdeuterated TPI-1 (dTPI-1) for inhibition of SHP-1 activity in macrophages. FIG. 1A shows the study system. Human monocyte-derived macrophages without or with cancer cells surrounding were stimulated with TLR agonist (aTLR) R848 and IFNγ ± dTPI-1. The presence of cancer cells was to ligate macrophage surface inhibitory receptors (iRs), of which cytoplasmic domain phosphorylation in ITIMs led to SHP-1 activation. FIG. 1B shows the results of protein tyrosine phosphatase (PTP) activity assays. FIG. 1C shows the results of flow cytometric assay, demonstrating inhibition of SHP-1 by dTPI-1 unleashed macrophage antigen presentation inhibited by the cancer environment. FIG. 1D shows cytokine profiling by ELISA of IL-6, TNFα, and IL-10 of human monocyte-derived macrophages with or without cancer cells, with or without R848/IFNγ, and with or without dTPI-1 treatment. FIG. 1E shows cytokine profiling by ELISA of TNFα as a function of dTPI concentration. [0014] FIGS. 2A-2B show the results of R848 or dTPI-1 treatment, alone or in combination, in a murine metastatic melanoma model. FIG. 2A shows the experimental scheme. FIG. 2B shows lung images of melanoma prior to treatment (d12) and after different treatments. 3 sf-6609919 Attorney Docket No.245162001140 [0015] FIG. 3A-3D show the results of dTPI-1 treatment in a murine lung cancer model. FIG. 3A shows the experimental design. Controls (ctl.) were mice treated with topical non-drug lotion; anti-PD-1 (αPD-1) was given to mice with topical non-drug lotion treatment. Topical drugs were TLR agonists (aTLR: PolyI;C, R848 and LPS) + dTPI-1, mixed in lotion, or Sting activator (aSting: MSA-2, ADU-S100, cGAMP) + dTPI-1, together mixed in lotion. FIG. 3B shows that LLC tumor burden changes post treatments recorded as bioluminescence images. FIG. 3C shows tumor microenvironment (TME) analyses of MHC-I, MHC-II, CD80, and CD86 expression by flow cytometry. FIG. 3D shows flow cytometric analysis of cell populations in the TME. [0016] FIGS. 4A-4D show the results of experiments assaying Ester and Amide conjugated R848-TPI-1 compounds for activation of macrophages in the presence of a cancer environment. FIG. 4A shows the study system of human monocyte-derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ± TPI-1 or Ester or Amide conjugated R848-TPI-1 compounds. FIG. 4B shows schematics of R848 and TPI-1 monomers and ester conjugate and amide conjugated R848-TPI-1 compounds. FIG. 4C shows the results of ELISAs assaying macrophage proinflammatory (TNFα and IL-6) or anti-inflammatory (IL- 10) response stimulated by R848 ± TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells. FIG. 4D shows the results of flow cytometry measuring macrophage expression of cell surface antigen presentation machinery following stimulation with R848 ± TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells. All monomer and conjugate compounds in FIGS. 4C-4D were used at 1μM. FIG. 4E shows the dose-dependent effects of Ester and Amide conjugated R848-TPI-1 compounds on activation of macrophage production of TNFα, as measured by ELISA. In FIG. 4E, the amide curve is the upper curve and the ester curve is the lower curve [0017] FIGS. 5A-5D show dose-dependent efficacies of R848-TPI-1 Ester and Amide conjugated compounds treating KPC pancreatic cancer. FIG. 5A shows the experimental design. KPC cells were engrafted (5 × 105, s.c.) into the right flank of C57BL6 mice. After tumors reached 200 mm3, mice were treated daily with escalated doses of R848-TPI-1 Ester and Amide conjugated compounds. FIG. 5B shows KPC tumor volume changes over time (in days) following treatments. FIG. 5C shows TME analyses of MHC-I, MHC-II, CD80, and CD86- expressing populations by flow cytometry on post-treatment d2. FIG. 5D shows TME analyses of various cell types by flow cytometry on post-treatment d5. 4 sf-6609919 Attorney Docket No.245162001140 [0018] FIGS. 6A-6D show the results of dTPI-1 treatment in a murine lung cancer model (LLC). FIG. 6A shows the experimental design. LLC lung cancer were engrafted (5 × 105, s.c.) into the right flank of C57BL6 mice. After tumor stably formed (>200 mm3), the mice were treated with anti-PD-1 (αPD-1, 100ug, i.p. every 3 days), R848-TPI-1 Ester compound (3mg/kg) + αPD-1, or R848-TPI-1 Amide compound (3mg/kg) + αPD-1. FIG. 6B shows bioluminescence images of LLC tumor burden changes post treatments. FIG. 6C shows the tumor volume over time post-treatment (in days) for LLC treated with the control, ester-conjugated R848-TPI-1, or amide-conjugated R848-TPI-1. FIG. 6D shows tumor microenvironment (TME) analyses by flow cytometry of cell populations post-treatment with αPD-1, ester-conjugated R848-TPI-1 + αPD-1, and amide-conjugated R848-TPI-1 + αPD-1. DETAILED DESCRIPTION OF THE INVENTION Definitions [0019] In general, terms used in the claims and the specification are intended to be construed as having the plain meaning understood by a person of ordinary skill in the art. Certain terms are defined below to provide additional clarity. In case of conflict between the plain meaning and the provided definitions, the provided definitions are to be used. [0020] The term “individual,” “subject,” or “patient” is used synonymously herein to describe a mammal, including humans. An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is human. In some embodiments, an individual suffers from a disease, such as cancer. In some embodiments, the individual is in need of treatment. [0021] A “reference” as used herein, refers to any sample, standard, or level that is used for comparison purposes. A reference may be obtained from a healthy and/or non-diseased sample. In some examples, a reference may be obtained from an untreated sample. In some examples, a reference is obtained from a non-diseased or non-treated sample of an individual. In some examples, a reference is obtained from one or more healthy individuals who are not the individual or individual. [0022] As used herein, the term “intermittent” or “intermittently” in the context of dosing refers to a non-continuous dosing regimen. In some cases, “intermittent” dosing refers to a dosing where a) a therapeutic agent is administered less than 12 consecutive days (e.g., less than 11, 10, 9, 8, 7, 6, 5, 4 and 3 days), and b) the therapeutic agent is administered at least two times, and the two administrations are separated by at least one day (i.e., Day 1 and Day 3). In some 5 sf-6609919 Attorney Docket No.245162001140 embodiments, the therapeutic agent is administered daily for no more than three consecutive days, and at least twice that is separated by at least one day. [0023] As used herein, the term “cycle” in the context of dosing refers to a time period during which there is at least one administration of a therapeutic agent. Day 1 of a cycle is defined as the day when the first administration of a therapeutic agent happens during that time period. When there are multiple daily consecutive administrations of the therapeutic agent, Day 1 of the cycle is defined as the day of the first administration of the multiple daily consecutive administrations. The last day of the cycle is defined as the day before the next non-consecutive administration of the therapeutic agent happens. The cycles do not have to have the same length of time. For example, the first cycle can have five days, and the second cycle can have seven days. Each cycle may have different numbers of administrations of the therapeutic agent. For example, the first cycle, which may have five days, may have one administration of the therapeutic agent, and the second cycle, which may have seven days, may have two administrations of the therapeutic agent. [0024] As used herein the term “immunogenic” is the ability to elicit an immune response, e.g., via T-cells, B cells, or both. [0025] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. Also encompassed by “treatment” is a reduction of pathological consequence of the disease. The methods of the invention contemplate any one or more of these aspects of treatment. [0026] As used herein, “delaying” the development of cancer means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. A method that “delays” development of cancer is a method that reduces probability of disease development in a given 6 sf-6609919 Attorney Docket No.245162001140 time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of individuals. Cancer development can be detectable using standard methods, including, but not limited to, computerized axial tomography (CAT Scan), Magnetic Resonance Imaging (MRI), abdominal ultrasound, clotting tests, arteriography, or biopsy. Development may also refer to cancer progression that may be initially undetectable and includes occurrence, recurrence, and onset. [0027] The term “simultaneous administration,” as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes. When the first and second therapies are administered simultaneously, the first and second therapies may be contained in the same composition (e.g., a composition comprising both a first and second therapy) or in separate compositions (e.g., a first therapy in one composition and a second therapy is contained in another composition). [0028] As used herein, the term “sequential administration” means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first therapy or the second therapy may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits. [0029] As used herein, the term “concurrent administration” means that the administration of the first therapy and that of a second therapy in a combination therapy overlap with each other. [0030] As used herein, by “pharmaceutically acceptable” or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. [0031] As used herein, a “small molecule” refers to a molecule with a molecular weight less than about 900 Dalton. A “small organic molecule” refers to an organic molecule with a molecular weight less than about 900 Dalton. 7 sf-6609919 Attorney Docket No.245162001140 [0032] It is understood that embodiments of the application described herein include “consisting” and/or “consisting essentially of” embodiments. [0033] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. [0034] As used herein, reference to “not” a value or parameter generally means and describes “other than” a value or parameter. For example, the method is not used to treat cancer of type X means the method is used to treat cancer of types other than X. [0035] The term “about X-Y” used herein has the same meaning as “about X to about Y.” [0036] The singular forms “a,” “an,” and “the” as used herein include plural referents unless the context clearly dictates otherwise. [0037] “Alkyl” as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”), having 1 to 10 carbon atoms (a “C1-C10 alkyl”), having 6 to 10 carbon atoms (a “C6-C10 alkyl”), having 1 to 6 carbon atoms (a “C1-C6 alkyl”), having 2 to 6 carbon atoms (a “C2-C6 alkyl”), or having 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, n-nonyl, n-decyl, and the like. [0038] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 20 carbon atoms (a “C1-C20 alkylene”), having 1 to 10 carbon atoms (a “C1-C10 alkylene”), having 6 to 10 carbon atoms (a “C6-C10 alkylene”), having 1 to 6 carbon atoms (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like. [0039] “Alkenyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon 8 sf-6609919 Attorney Docket No.245162001140 atoms). An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 6 to 10 carbon atoms (a “C6-C10 alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl group include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex- 1-enyl, hex-2-enyl, hex-3-enyl, and the like. [0040] “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkenylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenylene”), having 2 to 10 carbon atoms (a “C2-C10 alkenylene”), having 6 to 10 carbon atoms (a “C6-C10 alkenylene”), having 2 to 6 carbon atoms (a “C2-C6 alkenylene”), 2 to 4 carbon atoms (a “C2-C4 alkenylene”) or 2 to 3 carbon atoms (a “C2-C3 alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH2-), 1,4-but-1-enylene (-CH=CH-CH2CH2-), 1,4-but-2-enylene (-CH2CH=CHCH2-), 1,6-hex-1-enylene (-CH=CH-(CH2)3CH2-), and the like. [0041] “Alkynyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynyl”), having 6 to 10 carbon atoms (a “C6-C10 alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3- ynyl, and the like. [0042] “Alkynylene” as used herein refers to the same residues as alkynyl, but having bivalency. Particular alkynylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynylene”), having 2 to 10 carbon atoms (a “C2-C10 alkynylene”), having 6 to 10 carbon atoms (a “C6-C10 alkynylene”), having 2 to 6 carbon atoms (a “C2-C6 alkynylene”), 2 to 4 carbon atoms (a “C2- C4 alkynylene”) or 2 to 3 carbon atoms (a “C2-C3 alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH2-), and the like. 9 sf-6609919 Attorney Docket No.245162001140 [0043] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. [0044] “Cycloalkylene” as used herein refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkylene"), having 3 to 6 carbon atoms (a “C3-C6 cycloalkylene”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkylene"). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms. When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis- or trans- to each other. For example, cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans- 1,2-cyclopropylene), or a mixture thereof. [0045] “Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic non- aromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like. [0046] “Cycloalkenylene” as used herein refers to the same residues as cycloalkenyl, but having bivalency. 10 sf-6609919 Attorney Docket No.245162001140 [0047] “Aryl” or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C6-C14 aryl”). An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position. [0048] “Arylene” as used herein refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a “C6-C14 arylene”). [0049] “Heteroaryl” as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryl group having more than one ring where at least one ring is non- aromatic may be connected to the parent structure at either an aromatic ring position or at a non- aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom. [0050] “Heteroarylene” as used herein refers to the same residues as heteroaryl, but having bivalency. 11 sf-6609919 Attorney Docket No.245162001140 [0051] “Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof, but excludes heteroaryl groups. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10- membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. [0052] “Heterocyclylene” as used herein refers to the same residues as heterocyclyl, but having bivalency. [0053] “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (–OCF3). [0054] “Carbonyl” refers to the group C=O. 12 sf-6609919 Attorney Docket No.245162001140 [0055] “Thiocarbonyl” refers to the group C=S. [0056] “Oxo” refers to the moiety =O. [0057] “D” refers to deuterium (2H). [0058] “T” refers to tritium (3H). [0059] A group in which each hydrogen is replaced with deuterium is referred to as “perdeuterated.” A group in which each hydrogen is replaced with tritium is referred to as “pertritiated.” [0060] Unless a specific isotope of an element is indicated in a formula, the disclosure includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds. Isotopologues can have isotopic replacements at any or at all locations in a structure, or can have atoms present in natural abundance at any or all locations in a structure. [0061] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted. [0062] It is understood that an optionally substituted moiety can be substituted with more than five substituents, if permitted by the number of valences available for substitution on the moiety. For example, a propyl group can be substituted with seven halogen atoms to provide a perhalopropyl group. The substituents may be the same or different. [0063] As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. [0064] “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or 13 sf-6609919 Attorney Docket No.245162001140 pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. [0065] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. [0066] Unless otherwise stated, "substantially pure" intends a composition that contains no more than 10% impurity, such as a composition comprising less than 9%, 7%, 5%, 3%, 1%, 0.5% impurity. 14 sf-6609919 Attorney Docket No.245162001140 [0067] It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. [0068] Any terms not directly defined herein shall be understood to have the meanings commonly associated with them as understood within the art of the invention. Certain terms are discussed herein to provide additional guidance to the practitioner in describing the compositions, devices, methods, and the like of aspects of the invention, and how to make or use them. It will be appreciated that the same thing may be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. No significance is to be placed upon whether or not a term is elaborated or discussed herein. Some synonyms or substitutable methods, materials and the like are provided. Recital of one or a few synonyms or equivalents does not exclude use of other synonyms or equivalents, unless it is explicitly stated. Use of examples, including examples of terms, is for illustrative purposes only and does not limit the scope and meaning of the aspects of the invention herein. [0069] The compound 2-(2,5-dichlorophenyl)benzoquinone (which is also referred to as 2-(2,5- dichlorophenyl)cyclohexa-2,5-diene-1,4-dione, Tyrosine Phosphatase Inhibitor 1 or TPI-1; CAS Registry No. 79756-69-7) is an inhibitor of SHP-1. TPI-1 has the following structure: . [0070] TPI-1 can be derivatized with a functional group for facile attachment to other compounds, for use in conjugate compounds. For example, a carboxyl group can be introduced at the 3-position of the dichlorophenyl ring to provide: 15 sf-6609919 Attorney Docket No.245162001140 [0071] which can be readily coupled to an amino or hydroxy group on another molecule, such as a therapeutic molecule, or a linker to another molecule. Derivatives and analogs of TPI-1 include compounds of the following structure: [0072] where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. [0073] Various methods for preparing TPI-1 analogs are available. In one such method, an RC- substituted 2,5-dichloroaniline is suitably protected on its RC group (the protected RC group is indicated as RCP in the scheme below). Then the amino group is converted to the corresponding diazonium ion and coupled with quinone to give the TPI-1 scaffold. An example of the experimental conditions that can be adapted for this reaction is shown in the synthesis in Jones et al., Journal of Organic Chemistry 58(8):2035 (1993) for 2-(4-carboxyphenyl)-3,6-dichloro- 2,5-cyclohexadiene-1,4-dione. The Jones et al. reaction can be adapted to preparation of carboxylic acid-functionalized TPI-1 derivatives by replacing the 2,5-dichloro-2,5- cyclohexadiene-1,4-dione reagent with 1,4-benzoquinone, and replacing the 4-aminobenzoic acid reagent with 2-amino-3,6-dichlorobenzoic acid, 3-amino-3,6-dichlorobenzoic acid, or 4- 16 sf-6609919 Attorney Docket No.245162001140 amino-3,6-dichlorobenzoic acid, to yield 2-(2-carboxy-3,6-dichlorophenyl)-2,5-cyclohexadiene- 1,4-dione, 2-(5-carboxy-3,6-dichlorophenyl)-2,5-cyclohexadiene-1,4-dione, or 2-(4-carboxy- 3,6-dichlorophenyl)-2,5-cyclohexadiene-1,4-dione, respectively. Should a longer linker be desired between the TPI-1 derivative and the molecule conjugated through the carboxylic acid, 2-amino-3,6-dichlorobenzoic acid can be replaced by 2-(2-amino-3,6-dichlorophenyl)acetic acid, 3-(2-amino-3,6-dichlorophenyl)propanoic acid, etc., and similarly for the other positional isomers. Deprotection affords the TPI-1 analog ready for conjugation to a linker or PIA. Suitable protecting group approaches for RCA include esters where RCA = -COOH, carbamates or cleavable alkyl groups where RCA = -NH2, and silyl ethers, cleavable alkyl groups, or esters where RCA = -OH. [0074] Alternatively, an approach through Pd-catalyzed biaryl coupling may be utilized. An RC substituted 2,5-dichloroaniline is suitably protected on its RC group (the protected RC group is 17 sf-6609919 Attorney Docket No.245162001140 indicated as RCP in the scheme below). The amino group is converted to a halide through a diazonium intermediate using t-butyl nitrite and copper halide (CuX2, e.g., CuBr2) (Sandmeyer reaction). Treatment of the aryl halide with Pd-catalyst and 2,5-dimethoxyphenyl boronic acid provides the biaryl structure of TPI-1. Oxidative conditions, such as ceric ammonium nitrate, give the quinone. Deprotection affords the TPI-1 analog ready for conjugation to a linker or PIA. Suitable protecting group approaches for the RCA group include esters where RCA = -COOH, carbamates or cleavable alkyl groups where RCA = -NH2, and silyl ethers, cleavable alkyl groups, or esters where RCA = -OH. 18 sf-6609919 Attorney Docket No.245162001140 [0075] In addition to TPI-1 functionalized for conjugation, perdeuterated TPI-1 can be used in methods in place of TPI-1 at natural isotopic abundance. Perdeuterated TPI-1 has the following structure, where D is deuterium (i.e., 2H): [0076] Other deuterated forms of TPI-1 can also be prepared and used, by selecting suitably deuterated starting materials (e.g., appropriately deuterated benzoquinone; appropriately deuterated 2,5-dichloroaniline). The available positions for deuteration include the 3, 4, and 6 positions of the benzoquinone moiety of TPI-1 and the 3’, 4’, and 6’ positions of the dichlorobenzene moiety of TPI-1, as shown in the following numbered structure. 19 sf-6609919 Attorney Docket No.245162001140 [0077] In addition to the perdeuterated compound (i.e., TPI-1-d6), there are 62 possible deuterated compounds with deuterium at one, two, three, four, or five positions out of the 3, 4, 6, 3’, 4’, and 6’ positions on TPI-1, which are all provided herein. (The compound without any specific deuteration will have deuterium at natural isotopic abundance.) In view of the results demonstrated in Examples, the various deuterated compounds (d1, d2, d3, d4, d5, d6) are expected to be effective for inhibiting SHP-1 and treating cancer (e.g., via systemic administration, e.g., in a topical application). [0078] In some embodiments, the deuterated TPI-1 is TPI-1-d1. In some embodiments, the TPI-1-d1 is selected from TPI-1-3-d1, TPI-1-4-d1, TPI-1-6-d1, TPI-1-3’-d1, TPI-1-4’-d1, or TPI- 1-6’-d1. [0079] In some embodiments, the deuterated TPI-1 is TPI-1-d2. In some embodiments, the TPI-1-d2 is selected from TPI-1-3,4-d2, TPI-3,6-d2, TPI-1-3,3’-d2, TPI-1-3,4’-d2, TPI-3,6’-d2, TPI-1-4,6-d2, TPI-1-4,3’-d2, TPI-1-4,4’-d2, TPI-4,6’-d2, TPI-1-6,3’-d2, TPI-1-6,4’-d2, TPI-6,6’- d2, TPI-1-3’,4’-d2, TPI-3,6’-d2, or TPI-4’,6’-d2. [0080] In some embodiments, the deuterated TPI-1 is TPI-1-d3. In some embodiments, the TPI-1-d3 is selected from TPI-1-3,4,6-d3, TPI-1-3,4,3'-d3, TPI-1-3,4,4’-d3, TPI-1-3,4,6’-d3, TPI- 1-3,6,3’-d3, TPI-1-3,6,4’-d3, TPI-1-3,6,6’-d3, TPI-1-3,3’,4’-d3, TPI-1-3,3’,6’-d3, TPI-1-3,4’,6’- d3, TPI-1-4,6,3’-d3, TPI-1-4,6,4’-d3, TPI-1-4,6,6’-d3, TPI-1-4,3’,4’-d3, TPI-1-4,3’,6’-d3, TPI-1- 4,4’,6’-d3, TPI-1-6,3’,4’-d3, TPI-1-6,3’,6’-d3, TPI-1-6,4’,6’-d3, or TPI-1-3’,4’,6’-d3. [0081] In some embodiments, the deuterated TPI-1 is TPI-1-d4. In some embodiments, the TPI- 1-d4 is selected from TPI-1-3,4,6,3’-d4, TPI-1-3,4,6,4'-d4, TPI-1-3,4,6,6’-d4, TPI-1-3,4,3’,4’-d4, TPI-1-3,4,3’,6’-d4, TPI-1-3,4,4’6’-d4, TPI-1-3,6,3’,4’-d4, TPI-1-3,6,3’,6’-d4, TPI-1-3,6,4’,6’-d4, TPI-1-4,6,3’,4’-d4, TPI-1-4,6,3’,6’-d4, TPI-1-4,6,4’,6’-d4, TPI-1-3,3’,4’,6’-d4, TPI-1-4,3’,4’,6’- d4, or TPI-1-6,3’,4’,6’-d4. 20 sf-6609919 Attorney Docket No.245162001140 [0082] In some embodiments, the deuterated TPI-1 is TPI-1-d5. In some embodiments, the TPI- 1-d5 is selected from TPI-1-3,4,6,3’,4’-d5, TPI-1-3,4,6,3’,6’-d5, TPI-1-3,4,6,4’,6’-d5, TPI-1- 4,6,3’,4’,6’-d5, TPI-1-3,6,3’,4’,6’-d5, or TPI-3,4,3’,4’,6’-d6. [0083] In some embodiments, the deuterated TPI-1 is TPI-1-d6, i.e., perdeuterated TPI-1, or TPI-1-3,4,6,3’,4’,6’-d6. [0084] Deuterated and perdeuterated TPI-1 can also be functionalized as described above for conjugation, as a compound of the formula: [0085] where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. Deuterated and perdeuterated TPI-1 derivatives can be prepared by using appropriately deuterated compounds in the synthetic preparations of the TPI-1 derivatives disclosed herein. [0086] Other analogs of TPI-1 that can be used in the methods disclosed herein are disclosed in Kundu et al., J Immunol. 2010 Jun 1; 184(11): 6529–6536; see for example, FIG. 6 of Kundu et al. Methods of treatment [0087] The present application in one aspect provides methods of treating a cancer by administering a TPI-1 derivative. The TPI-1 derivative can be administered in combination with a pro-inflammatory agent. [0088] In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 21 sf-6609919 Attorney Docket No.245162001140 derivative-pro-inflammatory agent combination is administered daily for no more than two or three consecutive days, and optionally for at least two administrations which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises systemically administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the method comprises locally administering (e.g., intratumorally administering) the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination. [0089] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, and wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously or subcutaneously). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered locally (e.g., topically). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- 22 sf-6609919 Attorney Docket No.245162001140 inflammatory agent combination is administered at an interval of no more than once every two days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days. In some embodiments, the method further comprises locally (e.g., intratumorally or topically) administering TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination into the individual. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination. In some embodiments, the pro-inflammatory agent of the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod. In some embodiments, the pro-inflammatory agent of the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine (e.g., IFN-gamma). [0090] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (e.g., where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is a TLR agonist, e.g., R848), and wherein the method comprises intravenous or subcutaneous administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, optionally wherein the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice 23 sf-6609919 Attorney Docket No.245162001140 where the administrations are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered twice (e.g., two consecutive days) every seven to twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered three times (e.g., three consecutive days) every ten to twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at an interval of no more than once every two days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the method further comprises locally (e.g., intratumorally or locally) administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod. 24 sf-6609919 Attorney Docket No.245162001140 [0091] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is e.g., a TLR agonist, e.g., R848), and wherein the method comprises intravenous or subcutaneous administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, optionally wherein the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, further optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle is about three to about twenty days long. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for at least twice (e.g., at least two consecutive days) in each cycle. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for at least three times (e.g., at least three consecutive days) in each cycle. In some embodiments, the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the method further comprises locally (e.g., intratumorally or locally) administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination into the individual. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti- TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 25 sf-6609919 Attorney Docket No.245162001140 antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the pro-inflammatory agent of the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod. [0092] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising intravenously, subcutaneously and/or intratumorally administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 5 days, and optionally wherein the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice (e.g., at least 3, 4, 5, or 6 times). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered at an interval of no more than twice every seven to twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered at an interval of no more than three times every seven to twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for a period of at least fourteen to twenty days at an interval of about 1-3 times every seven to twenty days. In some embodiments, the TPI-1 26 sf-6609919 Attorney Docket No.245162001140 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least about 2, 3, 4, 5, or 6 times in a period of about fourteen to about forty days (e.g., about fourteen to about twenty days). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises locally (e.g., intratumorally or locally) administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination into the individual. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise an agent or can be selected from the group consisting of R848, 3M- 852A, Motolimod, Bropirimine and Vesatolimod. [0093] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising intravenously, subcutaneously and/or intratumorally administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848), wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 5 days (e.g., for no more than 5, 4, or 3 days), and wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- 27 sf-6609919 Attorney Docket No.245162001140 inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least twice (e.g., at least two consecutive days) in each cycle. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least three times (e.g., at least three consecutive days) in each cycle. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the method further comprises locally (e.g., intratumorally or locally) administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination into the individual. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro- 28 sf-6609919 Attorney Docket No.245162001140 inflammatory agent can comprise or be selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod). [0094] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering (e.g., intravenously, subcutaneously and/or intratumorally) to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro- inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848) and immune cells (such as any of the immune cells described herein). In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering (e.g., intravenously, subcutaneously and/or intratumorally) to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be, e.g., a TLR agonist, e.g., R848), and immune cells. In some embodiments, the immune cells are derived from the same individual. In some embodiments, the immune cells comprise monocytes or macrophages. In some embodiments, the immune cells comprise T cells (e.g., CAR-T cells). In some embodiments, the immune cells comprise NK cells (e.g., CAR-NK cells). In some embodiments, the immune cells comprise neutrophils (e.g., CAR-expressing neutrophils cells). In some embodiments, the immune cells comprise antigen presenting cells (APCs). In some embodiments, the immune cells are engineered to express a chimeric receptor that specifically binds to a tumor antigen. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination administration. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination and the immune cells are administered within 7, 6, 5, 4, 3, 2 or 1 day. In some embodiments, the TPI-1 derivative or TPI-1 derivative- 29 sf-6609919 Attorney Docket No.245162001140 pro-inflammatory agent combination and the immune cells are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of each other. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination and the immune cells are administered simultaneously. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination and the immune cells are administered concurrently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination and the immune cells are administered sequentially. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise or be selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod). [0095] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory compound of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can be a TLR agonist, e.g., R848), wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (e.g., at least 3, 4, or 5 times). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent 30 sf-6609919 Attorney Docket No.245162001140 combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for at least once (e.g., at least twice or three time) in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously or subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is a TLR agonist, and the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and/or Pam3CSK4. In some embodiments, the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, optionally wherein the TLR agonist comprises a diacylated lipopeptide, a hot shock protein, HMGB1, uric acid, fibronectin, and/or ECM protein. In some embodiments, the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and/or CBLB612. In some embodiments, the TLR agonist activates TLR3, optionally wherein the TLR agonist comprises dsRNA, Poly I:C, PolyICIC, Poly-IC12U, IPH302, ARNAX, and/or MPLA (Monophosphoryl Lipid A). In some embodiments, the TLR agonist activates TLR4, optionally wherein the TLR agonist comprises LPS, lipoteichoic acid beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, FP20, G100, and/or GLA-SE. In some embodiments, the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and/or M-VM3. In some embodiments, the TLR agonist activates TLR6. In some embodiments, the TLR agonist activates TLR7 or TLR8, optionally wherein the TLR agonist comprises ssRNA, CpG-A, poly G10, poly G3, and/or 324 BDB001. In some embodiments, the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and/or R848. In some embodiments, the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and/or R848. In some embodiments, the TLR agonist activates TLR9, optionally wherein the TLR agonist comprises unmethylated CpG 31 sf-6609919 Attorney Docket No.245162001140 DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and/or ODN M362. In some embodiments, the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam3CSK4. In some embodiments, the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises toxoplasma gondii profilin. In some embodiments, the TLR agonist activates TLR12. In some embodiments, the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV. In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and/or TLR9. In some embodiments, the TLR agonist activates TLR1. In some embodiments, the TLR agonist activates TLR2. In some embodiments, the TLR agonist activates TLR3. In some embodiments, the TLR agonist activates TLR4. In some embodiments, the TLR agonist activates TLR7. In some embodiments, the TLR agonist activates TLR8. In some embodiments, the TLR agonist activates TLR9. In some embodiments, the TLR agonist activates TLR9, TLR4 and TLR7/8. In some embodiments, the TLR agonist comprises CpG, polyI:C and/or R848. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered intratumorally. In some embodiments, the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. [0096] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises a TLR agonist (e.g., R848), optionally wherein the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7 and TLR8. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent 32 sf-6609919 Attorney Docket No.245162001140 combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (e.g., at least three, four, five or six times). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least two cycles (e.g., at least three cycles). In some embodiments, each cycle has about seven to about twenty days. In some embodiments, the TLR agonist of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination activates a TLR on a macrophage, optionally wherein the TLR comprises TLR9. In some embodiments, the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9). In some embodiments, the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4 and TLR7/8). In some embodiments, the TLR agonist comprises CpG, polyI:C and/or R848. In some embodiments, the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. 33 sf-6609919 Attorney Docket No.245162001140 [0097] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination can be a STING activator (e.g., cGAMP, e.g., MSA-2), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the STING activator of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is a cyclic-guanosine monophosphate- adenosine monophosphate (cGAMP, e.g., 3’3’ cGAMP, e.g., 2’3’ cGAMP), a bacterial vector (e.g., SYNB1891, STACT-TREX-1), a CDN compound (e.g., ADU-S100, BI-STING, BMS- 986301, GSK532, JNJ-4412, MK-1454, SB11285, 3’3’-cyclic AIMP), a non-CDN small molecule (e.g., ALG-031048, E7755, JNJ-‘6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI-10001), a nanovaccine (e.g., PC7A NP, cCAMP-NP, ONM-500) or an antibody- drug conjugate (e.g., XMT-2056, CRD-5500). In some embodiments, the TPI-1 derivative or 34 sf-6609919 Attorney Docket No.245162001140 TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti- TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. [0098] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination can be a PAMP/DAMP activator), optionally wherein the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro- 35 sf-6609919 Attorney Docket No.245162001140 inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the pro-inflammatory agent is a PAMP activator. In some embodiments, the PAMP activator is triacyl lipopeptides, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porins, lipoarabinomannan, double-stranded RNA, poly(I:C), trypanosomal lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single-stranded RNA, resiquimod, bacterial/viral DNA, CpG DNA, ureobacteria, or toxoplasma LPS. In some embodiments, the pro-inflammatory agent is a DAMP activator. In some embodiments, the DAMP activator is defensins, HSP60, HSP70, messenger RNA, low-molecular-weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, or unmethylated CpG DNA. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti- TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. [0099] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory compound of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise a checkpoint inhibitor (e.g., an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times). In some embodiments, the TPI-1 derivative or 36 sf-6609919 Attorney Docket No.245162001140 TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG/PVRL2, CEACAM1, CEACAM 5/6, FAK, CCL2/CCR2, LIF, CD47/SIRPα, CSF-1(M- CSF)/CSF-1R, IL-1/IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine. In some embodiments, the checkpoint inhibitor comprises or is lipilimumab, Cemiplimab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO-201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, Lanotuzumab (MCS110), LY3022855, SNDX-6352, Emactuzumab (RG7155), Pexidartinib (PLX3397), CAN04, Canakinumab (ACZ885), BMS- 986253, Pepinemab (VX15/2503), Trebananib, FP-1305, Enapotamab vedotin(EnaV), or Bavituximab. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is 37 sf-6609919 Attorney Docket No.245162001140 administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. [0100] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination can comprise a pro-inflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and/or TNFα), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered at least twice (at least three, four, five, or six times). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration is separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered systemically (e.g., intravenously, e.g., 38 sf-6609919 Attorney Docket No.245162001140 subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the pro- inflammatory cytokine of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination promotes the M1 macrophages. In some embodiments, the pro-inflammatory cytokine comprises or is TNF, IFNγ, and/or GM-CSF. In some embodiments, the pro- inflammatory cytokine comprises IFNγ. In some embodiments, the pro-inflammatory cytokine comprises IL-1. In some embodiments, the pro-inflammatory cytokine comprises TNF-a. In some embodiments, the pro-inflammatory cytokine comprises IL-6. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. [0101] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination, where the pro-inflammatory agent of the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination can comprise a chemotherapeutic agent (e.g., azathioprine), optionally wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least twice (at least three, four, five, or six times). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered intermittently. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered at least three, four, or five times. In some embodiments, at least two TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, 39 sf-6609919 Attorney Docket No.245162001140 each of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administrations is separated by at least one day from the preceding or following TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination administration. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination to the individual for at least two cycles, wherein the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the chemotherapeutic agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is an alkylating agent. In some embodiments, the alkylating agent is selected from the group consisting of nitrogen mustard (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkyl sulfonate (e.g., busulfan), and ethyleneimine (e.g., thiotepa). In some embodiments, the chemotherapeutic agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is an antimetabolite. In some embodiments, the antimetabolite is selected from the group consisting of icytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (prodrug of 5-FU)). In some embodiments, the chemotherapeutic agent of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is an antimicrotubular agent. In some embodiments, the antimicrotubular agent is selected from the group consisting of topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin). In some embodiments, the chemotherapeutic agent of the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination is hydroxyurea, tretinoin, arsenic trioxide, or a proteasome inhibitor (e.g., bortezomib). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered systemically. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered 40 sf-6609919 Attorney Docket No.245162001140 intratumorally. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti- TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. [0102] The present application also provides a method of modulating monocytes or macrophages derived from an individual having a cancer, comprising contacting the monocytes or macrophages with a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination as described herein. In some embodiments, the monocytes or macrophages are derived from the same individual. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. [0103] In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (e.g., comprising TPI-1 or an analog or a derivative thereof) is administered at least two times (such as at least 3, 4, 5, or 6 times). [0104] In some embodiments, the method comprises administering the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination (e.g., comprising TPI-1 or an analog or a derivative thereof) at an interval of no more than once every two days for at least twice (such as at least three times, four times, five times, or six times). [0105] In some embodiments, the method comprises administering the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination (e.g., comprising TPI-1 or an analog or a derivative thereof) at an interval of no more than once every three days for at least twice (such as at least three times, four times, five times, or six times). 41 sf-6609919 Attorney Docket No.245162001140 [0106] In some embodiments, the method comprises administering the TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination (e.g., TPI-1 or an analog or a derivative thereof) for at least two cycles. In some embodiments, the TPI-1 derivative or TPI-1 derivative- pro-inflammatory agent combination (e.g., comprising TPI-1 or an analog or a derivative thereof) is administered for at least once (e.g., for twice, three times, four times) in each cycle. In some embodiments, each cycle has about three to about 50 days (e.g., about 3-40 days, about 3-30 days, about 3-20 days, about 3-15 days, about 3-10 days, or about 2-10 days). [0107] In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered systemically (e.g., orally, intravenously, subcutaneously, intraperitoneally). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination is administered locally (e.g., intratumorally). In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is administered both systemically and locally (e.g., intratumorally). [0108] Local administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination can comprise topical administration. Topical administration can include, but is not limited to, the application of a cream, a lotion, a paste, a patch, an ointment, a spray, a gel, an isotonic aqueous solution (e.g., an eyedrop), or a microneedle. In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is comprised in: a) a nanoparticle (e.g., lipid nanoparticle), a microparticle, and/or a liposome, and/or b) a slow- release formulation. Topical dosage forms available to treat mammals (e.g., humans) include solids (dusting powders), semisolids (creams, ointments, pastes, and gels), and liquids (solutions, suspension concentrates, suspoemulsions, emulsifiable concentrates, paints, and tinctures). [0109] Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, intestinal, intranasal, or intraocular administration. The compounds can also be administered in sustained or controlled release dosage forms, including transdermal (e.g., electrotransport) patches, creams, lotions, pastes, patches, ointments, sprays, gels, isotonic aqueous solutions (e.g., eyedrops), or microneedles and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. [0110] In embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination formulation is sterile. [0111] In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination is complexed with a delivery vehicle before being administered into the individual. In some embodiments, the delivery vehicle promotes the delivery into the tumor. 42 sf-6609919 Attorney Docket No.245162001140 [0112] In some embodiments, the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination modulates a monocyte or macrophage (e.g., a monocyte or macrophage derived from the individual to be treated) in vitro. Tumor microenvironment (TME) immunosuppression and SHP-1 signaling [0113] Src homology region 2 (SH-2) domain-containing phosphatase 1 (SHP-1) is a non- receptor tyrosine phosphatase. SHP-1 is encoded by the PTPN6 gene (on chromosome 12p13). As there are two promoter regions, one on exon 1 (active in cells of non-hematopoietic lineage) and one on exon 2 (active in cells of hematopoietic lineage), there are two forms of SHP-1 which have different N-terminal sequences, but which both have phosphatase activity. Both promoters may be active in epithelial cancer cells, giving rise to alternative SHP-1 transcripts. Form I of SHP-1 is primarily found in the nucleus, while form II is primarily found in the cytoplasm, and presumably they have different substrates. [0114] SHP-1 is a 595 amino acid protein. It has two tandem N-terminal SH2 domains (N-SH2 and C-SH2), and a classic catalytic protein tyrosine phosphatase (PTP) domain. The C-terminal tail has multiple sites for phosphorylation. Structural analysis of SHP-1 indicates that its N-SH2 is bound to and auto-inhibits the catalytic site in its inactive state. When phosphotyrosine residues bind to the SH2 domains, the electrostatic interactions between N-SH2 and the catalytic site is disrupted, allowing the enzyme to become active. Thus, substrate interaction plays a role in regulating the activity of SHP-1. Phosphorylation of amino acids Tyr536, Tyr564 and Ser591 also increase SHP-1 activity. Ser591 may also play a role in down-regulating SHP-1 activity, via phosphorylation by protein kinase C (PKC) or mitogen-activated protein kinases (MAPKs). [0115] SHP-1 activity in solid cancers and blood cancers is altered, and this alteration may be due to mutations or changes in epigenetic regulation. SHP-1 is involved in multiple signal transduction pathways related to development and progression of cancer. Presumably, disruption of the normal, highly regulated phosphorylation patterns involved in SHP-1 regulation is a factor in SHP-1’s role in cancer. [0116] Inhibition of SHP-1, however, can also cause deleterious effects. Motheaten mice (me/me or mev/mev) which are genetically deficient in SHP-1 show abnormal immune function, including hyperactivation of immune cells, and such mice have shortened life spans. Depletion of SHP-1 in adult wild-type mice also caused pathology, including enlarged spleens and inflammation of the lungs. Thus, approaches to treatment of cancer by inhibition of SHP-1 require careful balancing of the need for normal SHP-1 activity versus preventing abnormal SHP-1 activity. 43 sf-6609919 Attorney Docket No.245162001140 [0117] Inhibitors of SHP-1 phosphatase activity include TPI-1, suramine, NSC-87877, and sodium stibogluconate. Sodium stibogluconate entered Phase I clinical trials for malignant melanoma, but showed severe side effects. To date, no SHP-1 inhibitors have progressed to Phase II trials. An agent that reduces systemic inflammation [0118] In some cases, individuals develop systemic inflammation, i.e., cytokine release syndrome (CRS) after receiving (e.g.) immunotherapeutic treatment, however the inflammatory disorder is not fully understood. CRS can be induced by direct target cell lysis and the consecutive release of cytokines like TNFα or IFNγ, or by activation of T cells due to therapeutic stimuli that is followed by subsequent cytokine release. These cytokines trigger a chain reaction due to the activation of innate immune cells like macrophages and endothelial cells, which then induces further cytokine release. In particular, IL6, IL10, and IFNγ are most commonly found to be elevated in patients with CRS. [0119] The methods described herein can further comprises administration of an agent that reduces systemic inflammation (including, for example, an agent that reduces inflammatory cytokine cascade or cytokine storm), in order to curb down systemic inflammation and reduce adverse toxicity. The agents that reduce systemic inflammation include, but are not limited to, inhibitors of TNFα, IL6, IL10, and IFNγ. In some embodiments, the agent that reduces systemic inflammation is administered simultaneously with the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination. In some embodiments, the agent that reduces systemic inflammation is administered sequentially (e.g., prior to or after) with the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the administration of the agent that reduces systemic inflammation follows the same dosing schedule as the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the agent that reduces systemic inflammation is administered at a sub- therapeutic dose, namely, at a dose that is lower than an effective amount for treating a disease when administered alone. In some embodiments, the administration of the agent that reduces systemic inflammation allows more frequent administration of the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination (e.g., daily, once every two days, once every three days, etc.). [0120] The agent that reduces systemic inflammation can include any anti-inflammatory agent known in the art, including inhibitors of or antagonists to pro-inflammatory agents. For example, the agent can be an inhibitor or antagonist, including but not limited to, a small molecule 44 sf-6609919 Attorney Docket No.245162001140 inhibitor, a neutralizing antibody, a receptor blockade antibody, a soluble receptor, a targeting short interfering RNA (siRNA), a chemical inhibitor of mRNA stability, derivatives thereof, and any combination thereof, including combinations of agents targeting one or more molecules (e.g., targeting via the inhibition of TNFα alone, IL6 alone, TNFα and IL6 in combination). Anti-TNFα antagonist [0121] TNFα, a major proinflammatory cytokine, is secreted by activated macrophages, monocytes and lymphocytes. Administration of an anti-TNFα antibody to an individual who has been administered with a TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination may alleviate toxicity caused by systemic inflammation without compromising the efficacy of the therapeutic agent. [0122] The methods of the present application therefore in some embodiments comprises administration of TNFα inhibitor, e.g., an anti-TNFα antagonist (e.g., in the context where the proinflammatory agent is not TNFα) in addition to the TPI-1 derivative or TPI-1 derivative-pro- inflammatory agent combination. In some embodiments, the TNFα inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNFα receptor blockade antibody, a soluble TNFα receptor, a TNFα-targeting short interfering RNA (siRNA), a chemical inhibitor of TNFα mRNA stability, an inhibitor of TNFα converting enzyme (TACE), and derivatives thereof. In some embodiments, the TNFα inhibitor is an anti-TNFα neutralizing antibody. In some embodiments, the TNFα inhibitor is an anti-TNFα receptor blockade antibody. In some embodiments, the anti-TNFα antibody is a monoclonal antibody. In some embodiments, anti-TNFα antibody is a chimeric, humanized, and/or fully human antibody. [0123] Suitable antibodies for use in the methods provided herein include, but are not limited to, Remicade® (Infliximab (Centocor)), and those antibodies described, for example, in U.S. Patent No. 6,835,823; 6,790,444; 6,284,471; 6,277,969; 5,919,452; 5,698,195; 5,656,272; and 5,223,395 and in EP Patent No. 0610201, the contents of each of which are hereby incorporated by reference in their entirety, or antibodies that bind to the same epitope as Remicade®. Others suitable anti-TNFα antibodies for use in the methods provided herein are, by way of non- limiting example, Humira (Adalimumab (Abbott Laboratories, Esai)) as described in U.S. Patent No. 6,090,382; 6,258,562; or 6,509,015 and related patents and applications, the contents of which are hereby incorporated by reference in their entirety; Simponi™ (Golimimab, CNTO 148 (Centocor)) as described in PCT Publication No. WO 02/12502 and related patents and applications, the contents of which are hereby incorporated by reference in their entirety; 45 sf-6609919 Attorney Docket No.245162001140 ART621 (Arana Therapeutics), SSS 07 (Epitopmics and 3SBio) or antibodies that bind to the same epitope as Humira, Simponi, ART621, or SSS 07. [0124] In some embodiments, the TNFα inhibitor, e.g., anti-TNFα antagonist, is a fusion protein. Suitable fusion proteins for use in the methods provided herein include, but are not limited to, Enbrel (Etanercept (Amgen)) and other fusion proteins or fragments thereof described in U.S. Patent No. 5,712,155, PCT Publication No. WO 91/03553, and related patents and applications, the contents of which are hereby incorporated by reference in their entirety. [0125] In some embodiments, the TNFα inhibitor, e.g., anti-TNFα antagonist, is a modified antibody antagonist or a non-antibody-based antagonist. Such antagonists include advanced antibody therapeutics, such as antibody fragments including, but not limited to, Cimzia™ (Certolizumab pegol, CDP870 (Enzon)), bispecific antibodies, Nanobodies® such as ABX 0402 (Ablynx), immunotoxins, and radiolabeled therapeutics; peptide therapeutics; gene therapies, particularly intrabodies; oligonucleotide therapeutics such as aptamer therapeutics, antisense therapeutics, interfering RNA therapeutics; and small molecules such as LMP-420 (LeukoMed) as described in EP Patent No. 0767793, and related patents and applications, the contents of which are hereby incorporated by reference in their entirety. [0126] In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered within two weeks, 10 days, or one week prior to the administration of a TPI-1 derivative or TPI- 1 derivative-pro-inflammatory agent combination described herein. Exemplary TNFα inhibitors such an anti-TNFα antibody is usually stable for at least one or two weeks. In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered concurrently or simultaneously with the TPI-1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered immediately after (e.g., within 1 hour or 30 minutes) the administration of the TPI- 1 derivative or TPI-1 derivative-pro-inflammatory agent combination. In some embodiments, the TNFα inhibitor is administered systemically. In some embodiments, the TNFα inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days. In some embodiments, the individual does not develop cytokine release syndrome or pro-inflammatory organ damage. In some embodiments, administration of the TNFα inhibitor does not compromise or weakly compromises tumor clearance. 46 sf-6609919 Attorney Docket No.245162001140 Anti-IL6 antagonist [0127] An “anti-IL6 antagonist” or “IL6 inhibitor” refers to an agent that inhibits or blocks IL6 biological activity via binding to IL6 or IL6 receptor. In some embodiments, the anti-IL6 antagonist is an antibody. In one embodiment, the anti-IL6 antagonist is an antibody that binds IL6 receptor. Antibodies that bind IL-6 receptor include tocilizumab (including intravenous, i.v., and subcutaneous, s.c., formulations thereof) (Chugai, Roche, Genentech), satralizumab (Chugai, Roche, Genentech), sarilumab (Sanofi, Regeneron), NI-1201 (Novimmune and Tiziana), and vobarilizumab (Ablynx). In one embodiment, the anti-IL6 antagonist is a monoclonal antibody that binds IL6. Antibodies that bind IL-6 include sirukumab (Centecor, Janssen), olokizumab (UCB), clazakizumab (BMS and Alder), siltuximab (Janssen), and EBI- 031 (Eleven Biotherapeutics and Roche). In one embodiment, the IL6 antagonist is olamkicept. [0128] In some embodiments, the IL6 inhibitor is administered systemically. In some embodiments, the IL6 inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the IL6 inhibitor is administered intermittently. In some embodiments, the IL6 inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days. Pro-inflammatory agents used in the TPI-1 derivative-pro-inflammatory agent combinations [0129] Infection and tissue injury are the two classic instigators of inflammation. See e.g., Medzhitov, Nature. 2008 Jul 24;454(7203):428-35. The pro-inflammatory agents that can be used in the TPI-1 derivative-pro-inflammatory agent combinations described herein include at least two overlapping categories: 1) an agent or therapy of any kind or sort that can promote an inflammation (e.g., by promoting one or more pro-inflammatory cytokines or chemokines, inhibiting one or more anti-inflammatory cytokines or chemokines, recruiting macrophages, NK cells, neutrophils, effector T cells, or B cells to the tissue or activating any of these cells, or suppressing regulatory/suppressive immune cells such as regulatory T cells or MDSC), and 2) an agent or therapy that can cause damage of cancer cells (e.g., necrosis of cancer cells). [0130] In some embodiments, the pro-inflammatory agent triggers a pro-inflammatory signal on macrophages. In some embodiments, the pro-inflammatory agent activates a TLR, a TNFR, or ITAM-R. See Lionel et al., Eur J Immunol. 2011 Sep; 41(9): 2477–2481. The pro-inflammatory can activate a pro-inflammatory signal on macrophages via a direct manner or indirect manner. For example, a TLR agonist, which directly activates TLR on macrophages, or a radiotherapy which indirectly activates a pro-inflammatory signal on macrophages, when used with a SHP-1 inhibitor both demonstrated remarkable anti-tumor effects. 47 sf-6609919 Attorney Docket No.245162001140 [0131] In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of TLR agonists, STING activators, PAMP/DAMP activators, checkpoint inhibitors, pro-inflammatory cytokines or chemokines, chemotherapeutic agents, and bacterial components. [0132] In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of TLR agonists, STING activators, PAMP/DAMP activators, pro- inflammatory cytokines or chemokines, and bacterial components. [0133] In some embodiments, the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a cytokine (e.g., IFN-gamma). TLR agonists [0134] In some embodiments, the pro-inflammatory agent comprises or is a TLR agonist. [0135] TLRs play a vital role in activating immune responses. TLRs recognize conserved pathogen-associated molecular patterns (PAMPs) expressed on a wide array of microbes, as well as endogenous DAMPs released from stressed or dying cells. TLR1, -2, -4, -5, -6, and -10 are expressed on the cell surface, whereas TLR3, -7, -8, and -9 are situated on endosomal membranes within the cell. TLR1 and TLR2 can heterodimerize to recognize a variety of bacterial lipid structures and cell wall components, such as triacylated lipoproteins, lipoteichoic acid, and β-glucans. TLR2 also heterodimerizes with TLR6 to bind diacylated lipopeptides. Additionally, TLR2 can bind various endogenous DAMPs, such as HSPs, HMGB1, uric acid, fibronectin, and other extracellular matrix proteins. It has also been suggested that TLR1 and TLR6 can heterodimerize with TLR10; however, the TLR agonist recognized by this dimer remains to be identified. TLR3 recognizes viral dsRNA, as well as synthetic analogs of dsRNA, such as ligand Poly I:C. TLR4 binds LPS in complex with lipid A binding protein, CD14, and myeloid differentiation protein 2, MD2 as well as recognizing various DAMPs. Endogenous TLR4 ligands, which have been described, include β-defensin 2, fibronectin extra domain A EDA, HMGB1, Snapin, and tenascin C. TLR5 recognizes bacterial flagellin, TLR7 and TLR8 bind viral ssRNA, whereas TLR9 interacts with unmethylated CpG DNA from bacteria and some viruses. Additional TLRs have been identified more recently in mice based on sequence homology of the highly conserved TIR domain. TLR10 is a surface receptor whose natural ligand remains unknown. TLR11, -12, and -13 are present in mice but not in humans. TLR11 was shown to bind a T. gondii profilin and uropathogenic Escherichia coli. The ligand for TLR12 has not yet been identified, whereas TLR13 is an endosomal receptor that recognizes VSV. See e.g., Kaczanowska et al., J Leukoc Biol. 2013 Jun;93(6):847-63. 48 sf-6609919 Attorney Docket No.245162001140 [0136] TLR signaling can act as a double-edged sword in cancer. It was found that TLR stimulation of cancer cells can lead to either tumor progression or inhibition. For example, Stimulation of TLR 2, 4, and 7/8 was found to lead to tumor progression via production of immunosuppressive cytokines, increased cell proliferation and resistance to apoptosis. R848- stimulation of TLR7/8 overexpressing pancreatic cancer cell line resulted in increased cell proliferation and reduced chemosensitivity. On the other hand, stimulation of TLR 2, 3, 4, 5, 7/8, and 9, often combined with chemo- or immunotherapy, can lead to tumor inhibition via different pathways. See e.g., Grimmig et al., Int J Oncol. (2015) 47:857–66; Urban-Wojciuk et al., Front Immunol. 2019; 10: 2388. [0137] In some embodiments, the TLR agonist activates any of the TLRs. [0138] In some embodiments, the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and/or Pam3CSK4. [0139] In some embodiments, the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, optionally wherein the TLR agonist comprises a diacylated lipopeptide, a hot shock protein, HMGB1, uric acid, fibronectin, and/or ECM protein. [0140] In some embodiments, the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and/or CBLB612. [0141] In some embodiments, the TLR agonist activates TLR3, optionally wherein the TLR agonist comprises dsRNA, Poly I:C, PolyICIC, Poly-IC12U, IPH302, ARNAX, and/or MPLA. [0142] In some embodiments, the TLR agonist activates TLR4, optionally wherein the TLR agonist comprises LPS, lipoteichoic acid beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, FP20, G100, and/or GLA-SE. [0143] In some embodiments, the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and/or M-VM3. [0144] In some embodiments, the TLR agonist activates TLR6. [0145] In some embodiments, the TLR agonist activates TLR7 or TLR8, optionally wherein the TLR agonist comprises ssRNA, CpG-A, poly G10, poly G3, and/or 324 BDB001. [0146] In some embodiments, the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and/or R848. [0147] In some embodiments, the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and/or R848. [0148] In some embodiments, the TLR agonist activates TLR9, optionally wherein the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and/or ODN M362. 49 sf-6609919 Attorney Docket No.245162001140 [0149] In some embodiments, the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam3CSK4. [0150] In some embodiments, the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises toxoplasma gondii profilin. [0151] In some embodiments, the TLR agonist activates TLR12. [0152] In some embodiments, the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV. [0153] In some embodiments, the TLR agonist activates a TLR on a macrophage. [0154] In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and/or TLR9. [0155] In some embodiments, the TLR comprises TLR1, TLR4, and/or TLR9. In some embodiments, the TLR comprises TLR9. [0156] In some embodiments, the TLR comprises TLR2, TLR4, TLR7, and/or TLR8. [0157] In some embodiments, the TLR agonist comprises CpG. In some embodiments, the TLR agonist comprises polyI:C. In some embodiments, the TLR agonist comprises CpG and/or polyI:C. In some embodiments, the TLR agonist comprises CpG, polyI:C and/or R848. [0158] In some embodiments, the TLR agonist is R848, 3M-852A, Motolimod, Bropirimine or Vesatolimod. In some embodiments, the TLR agonist is R848. Radiopharmaceuticals [0159] In some embodiments, the pro-inflammatory agent is a radiopharmaceutical. Examples of radiopharmaceuticals that can be used are disclosed in, e.g., Sgouros et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19, 589–608 (2020). STING activator [0160] In some embodiments, the pro-inflammatory agent comprises or is a STING activator. [0161] Stimulator of IFN genes (STING, also known as TMEM173, MITA, MPYS or ERIS) is a pattern recognition receptor (PRR) that recognizes cytosolic DNA in the form of cyclic dinucleotides (CDNs), such as the bacterial product cyclic-guanosine monophosphate-adenosine monophosphate (3’3’ cGAMP). In addition to bacterial components, other forms of DNA from viruses, or the host cell, that find their way into the cytosol are recognized by an enzyme c- GMP-AMP (cGAMP) synthase (cGAS). Upon cytosolic DNA binding, cGAS converts ATP and GTP into the metazoan-specific CDN 2’3’-cGAMP for STING recognition and activation. 50 sf-6609919 Attorney Docket No.245162001140 STING is a transmembrane protein that exists as dimers anchored within the endoplasmic reticulum membrane and forms a V-shaped pocket that enables cytosolic CDN binding. Ligand binding results in significant conformational changes in the C-terminal domain of STING, mediating its transport to Golgi compartments. At the Golgi, STING recruits TANK-binding kinase 1 (TBK1), which facilitates IRF3 phosphorylation, nuclear translocation and the strong induction of transcription of type I IFNs (e.g., IFN-β). STING also triggers a robust pro- inflammatory cytokine response [e.g., tumor necrosis factor (TNF)] by activating Nuclear Factor-kappa B (NF-κB) and this part of the pathway can be mediated independent of TBK1 via a closely related homologue protein, IKK^. See e.g., Peng et al., Front Immunol. 2022 Feb 25;13:794776; Amougezar et al., Cancers (Basel). 2021 May 30;13(11):2695. [0162] In some embodiments, the STING activator is a cyclic-guanosine monophosphate- adenosine monophosphate (cGAMP, e.g., 3’3’ cGAMP, e.g., 2’3’ cGAMP). [0163] In some embodiments, the STING activator is a bacterial vector (e.g., SYNB1891, STACT-TREX-1). [0164] In some embodiments, the STING activator is a CDN compound (e.g., ADU-S100, BI- STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3’3’-cyclic AIMP). [0165] In some embodiments, the STING activator is a non-CDN small molecule (e.g., ALG- 031048, E7755, JNJ-‘6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI- 10001). [0166] In some embodiments, the STING activator is a nanovaccine (e.g., PC7A NP, cCAMP- NP, ONM-500). [0167] In some embodiments, the STING activator is an antibody-drug conjugate (e.g., XMT- 2056, CRD-5500). 51 sf-6609919 Attorney Docket No.245162001140 [0168] In some embodiments, the STING activator is the compound SR-717 of the formula: . [0169] In some embodiments, the STING activator is the compound MSA-2 of the formula: . [0170] In some embodiments, the STING activator is the compound SNX-281 of the formula: . 52 sf-6609919 Attorney Docket No.245162001140 [0171] In some embodiments, the STING activator is the compound alpha-mangostin of the [0172] In some embodiments, the STING activator is the compound DMXAA of the formula: . [0173] Other exemplary STING activators can be found in Amougezar et al., Cancers (Basel). 2021 May 30;13(11):2695, which is incorporated by reference here by its entirety. PAMP/DAMP activators [0174] In some embodiments, the pro-inflammatory agent comprises or is a PAMP/DAMP activator. [0175] The organism senses microbial infection through innate receptors encoded in the genome, called pattern-recognition receptors, including the Toll-like receptors (TLRs), the nucleotide-binding and oligomerization domain (NOD)-like receptors, and retinoic acid– inducible gene I (RIG-I)-like receptors. These receptors recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, fungi, and viruses, but also bind damage- associated molecular patterns (DAMPs), which are molecules released by sterile injury. Thus, 53 sf-6609919 Attorney Docket No.245162001140 PAMPs and DAMPs that bind to the same type of receptors initiate identical intracellular pathways terminating in identical effector functions. See e.g., Alisi et al., Hepatology. 2011 Nov;54(5):1500-2. [0176] In some embodiments, the pro-inflammatory agent is a PAMP activator. Exemplary PAMP activator includes triacyl lipopeptides, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porins, lipoarabinomannan, double- stranded RNA, poly(I:C), trepanosomal lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial/viral DNA, CpG DNA, ureobacteria, and toxoplasma LPS. [0177] In some embodiments, the pro-inflammatory agent is a DAMP activator. Examplary DAMP activator includes defensins, HSP60, HSP70, messenger RNA, low-molecular-weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, and unmethylated CpG DNA. Chemotherapeutic agent [0178] In some embodiments, the pro-inflammatory agent comprises or is a chemotherapeutic agent. [0179] In some embodiments, the chemotherapeutic agent is an alkylating agent. Exemplary alkylating agents include nitrogen mustard (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkyl sulfonate (e.g., busulfan), and ethyleneimine (e.g., thiotepa). [0180] In some embodiments, the chemotherapeutic agent is an antimetabolite. Exemplary antimetabolites include cytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (prodrug of 5-FU)). [0181] In some embodiments, the chemotherapeutic agent is an antimicrotubular agent. Exemplary antimmicrotubular agents include topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin). [0182] Other exemplary chemotherapeutic agents include hydroxyurea, tretinoin, arsenic trioxide, and proteasome inhibitors (e.g., bortezomib). 54 sf-6609919 Attorney Docket No.245162001140 Pro-inflammatory cytokines [0183] In some embodiments, the pro-inflammatory agent is a pro-inflammatory cytokine. [0184] In some embodiments, the pro-inflammatory cytokine promotes the M1 macrophages. See e.g., Duque et al., Front Immunol. 2014; 5: 491. In some embodiments, the pro- inflammatory cytokine comprises or is TNF, IFNγ, and/or GM-CSF. [0185] In some embodiments, the pro-inflammatory cytokine comprises IL-6, TNFα, a cytokine from IL-1 family (e.g., IL-1α, IL-1β, IL-18, IL-33 and IL-36), and/or IFNγ. [0186] In some embodiments, the pro-inflammatory cytokine comprises a cytokine from IL-1 family. In some embodiments, the pro-inflammatory cytokine comprises any one or more of IL- 1α, IL-1β, IL-18, IL-33, and IL-36. See e.g., Sims, J., Smith, D. The IL-1 family: regulators of immunity. Nat Rev Immunol 10, 89–102 (2010). Checkpoint inhibitors [0187] In some embodiments, the pro-inflammatory agent is a checkpoint inhibitor. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). See e.g., Marin-Acevedo et al., J Hematol Oncol 14, 45 (2021). [0188] In some embodiments, the checkpoint inhibitor targets CLTA-4, PD-1 or PD-L1 (e.g., an antibody targeting CTLA-4, PD-1 or PD-L1). [0189] In some embodiments, the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG/PVRL2, CEACAM1, CEACAM 5/6, FAK, CCL2/CCR2, LIF, CD47/SIRPα, CSF-1(M-CSF)/CSF-1R, IL-1/IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine. [0190] In some embodiments, the checkpoint inhibitor comprises or is lipilimumab, Cemiplimab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO-201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, Lanotuzumab (MCS110), LY3022855, SNDX-6352, Emactuzumab (RG7155), Pexidartinib (PLX3397), CAN04, Canakinumab (ACZ885), BMS- 55 sf-6609919 Attorney Docket No.245162001140 986253, Pepinemab (VX15/2503), Trebananib, FP-1305, Enapotamab vedotin(EnaV), or Bavituximab. ATR Inhibitors [0191] In some embodiments, inhibitors of the ataxia telangiectasia and Rad3-related protein (ATR inhibitors; ATRi), such as berzosertib, can be used in combination with TPI-1 derivatives. Tyrosine Kinase Inhibitors [0192] In some embodiments, a tyrosine kinase inhibitor can be in combination with TPI-1 derivatives. [0193] The tyrosine kinase inhibitors referred to herein are agents of any kind or sort that inhibits the expression or activation of tyrosine kinase. [0194] In some embodiments, the tyrosine kinase inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%) of the tyrosine kinase activity. In some embodiments, the tyrosine kinase inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%) of the tyrosine kinase expression. [0195] In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. 56 sf-6609919 Attorney Docket No.245162001140 EXAMPLES [0196] The disclosure is further illustrated by the following non-limiting synthetic (S) and biological (B) examples. SYNTHETIC EXAMPLES Example S-1 Preparation of Perdeuterated 2-(2,5-Dichlorophenyl)-1,4-Benzoquinone (dTPI-1) [0197] The procedure for coupling 1,4-benzoquinone with 1,4-dichlorobenzene to prepare 2- (2,5-dichlorophenyl)cyclohexa-2,5-diene-1,4-dione (i.e., 2-(2,5-dichlorophenyl)-1,4- benzoquinone) of Itahara, T., J. Org. Chem. 1985, 50, 5546-5550 is modified for preparation of the deuterated compound. A solution containing 1,4-benzoquinone, 1,4-dichlorobenzene, and palladium acetate in acetic acid is refluxed under nitrogen for 14 hours. The reaction mixture is evaporated and the residue is purified on a silica gel column eluted with benzene to give 2-(2,5- dichlorophenyl)-1,4-benzoquinone. [0198] 2-(2,5-dichlorophenyl)-1,4-benzoquinone-d6 (dTPI-1) is prepared by using perdeuterated starting materials. 1-4 benzoquinone-d4 (CAS Registry No. 2237-14-1) is commercially available from vendors such as Sigma-Aldrich or Clearsynth (Eliot, Maine). 1,4- 57 sf-6609919 Attorney Docket No.245162001140 dichlorobenzene-d4 (CAS Registry No. 3855-82-1) is also commercially available from vendors such as Sigma-Aldrich or Santa Cruz Biotechnology (Dallas, Texas). Example S-2 Alternative procedure for preparation of Perdeuterated 2-(2,5-Dichlorophenyl)-1,4- Benzoquinone (dTPI-1) [0199] An alternative procedure for preparing 2-(2,5-dichlorophenyl)-1,4-benzoquinone-d6 is adapted from Termentzi A. et al., European Journal of Medicinal Chemistry 45 (2010) 5833- 5847. This procedure utilizes a diazotized intermediate. The starting materials for the reaction are 2,5-dichloroaniline-3,4,6-d3 (CAS Registry No.783321-80-2, available from Clearsynth) and 1-4 benzoquinone-d4. 58 sf-6609919 Attorney Docket No.245162001140 [0200] A solution of NaNO2 in water is added to a solution of 2,5-dichloroaniline-3,4,6-d3 in 9% aqueous hydrochloric acid solution and is stirred at 0°C to 5°C for 90 minutes to form the diazonium salt. The diazonium salt solution is added slowly to an aqueous solution of 1,4- benzoquinone-d4 and sodium acetate. The precipitate is filtered off and washed with water to give 2-(2,5-dichlorophenyl)-1,4-benzoquinone-d6. S-3 R848-linker-TPI-1 ester conjugate (1-6): 4-((2-((1-(4-amino-2-(ethoxymethyl)-1H- imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)amino)-4-oxobutyl 2,5- dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxylate [0201] 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxylic acid (1-1) (TPI-1 functionalized with a carboxylic acid group) (1.25 eq.) is added to a solution of 1.4 eq. 59 sf-6609919 Attorney Docket No.245162001140 hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) and 2 eq. diisopropylethylamine (DIPEA) in dimethylformamide (DMF) at 0°C. After 30 minutes, the alcohol t-butyl 4-hydroxybutanoate (1-2) is added. The reaction proceeds for 30 minutes to form 4-(t-butoxy)-4-oxobutyl 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxylate (1-3). The t-butyl group is removed using trifluoroacetic acid (TFA) in dichloromethane (DCM) to give 4-((2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carbonyl)oxy)butanoic acid (1-4). Compound (1-4) is then activated using 1.25 eq. HATU and 2.4 eq. DIPEA in DMF at room temperature for 15 minutes, followed by addition of nucleophile (1-5) (1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4- amine) (1.05 eq). The reaction proceeds at 0°C for 15 minutes to give (1-6), 4-((2-((1-(4-amino- 2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)amino)-4- oxobutyl 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxylate. S-4 60 sf-6609919 Attorney Docket No.245162001140 R848-linker-TPI-1 amide conjugate (2-6): N-(4-((2-((1-(4-amino-2-(ethoxymethyl)-1H- imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)amino)-4-oxobutyl)-2,5- dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxamide [0202] 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxylic acid (2-1) (TPI-1 functionalized with a carboxylic acid group) is added to a solution of HATU and DIPEA in DMF at 0°C. After 30 minutes, the amine t-butyl 4-aminobutanoate (2-2) is added. The reaction affords t-butyl 4-(2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxamido)butanoate (2-3). The t-butyl group is removed using trifluoroacetic acid (TFA) in dichloromethane (DCM) to give 4-(2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxamido)butanoic acid (2-4). Compound (2-4) is then activated using 1.25 eq. HATU and 2.4 eq. DIPEA in DMF at room temperature for 15 minutes, followed by addition of nucleophile (2-5) (1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4- amine) (1.05 eq). The reaction proceeds at 0°C for 10 minutes to give (2-6), N-(4-((2-((1-(4- amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2- yl)oxy)ethyl)amino)-4-oxobutyl)-2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxamide. BIOLOGICAL EXAMPLES [0203] Examples B1-B3 describe perdeuterated TPI-1 (dTPI-1) assayed in vitro for the capability to inhibit SHP-1 in macrophages within a tumor environment, and the ability to unleash proinflammatory responses in vivo in the TME when combined with TLR agonists (e.g. R848, LPS, PolyI:C, etc.), Sting activators (e.g. MSA-2, ADU-S100, cGAMP), as well as other inflammatory factors or means, thereby inducing intratumoral antigen presentation and activation of T cell immunity against cancer. Examples B4 and B5 describe experiments using 61 sf-6609919 Attorney Docket No.245162001140 R848-TPI-1 Ester and Amide conjugates chemically formed by linking the TLR7/8 agonist R848 with TPI-1 through an Ester or Amide bond. These experiments demonstrate that R848- TPI-1 Ester and Amide conjugates possess properties of both R848, which through TLR7/8 triggers proinflammatory response, and TPI-1, which inhibits SHP-1 activity. In the tumor microenvironment (TME), simultaneous activation of intratumoral macrophages (TAM) while inhibiting SHP-1 activity is required for skewing TAM toward proinflammatory activation and antigen presentation, which leads to activation of T cell immunity and elimination of cancer. Example B-1 In vitro assays of dTPI-1 for the capability to inhibit SHP-1 in macrophages within a tumor environment [0204] Human monocytes-derived macrophages in culture were stimulated with TLR agonist R848 (1μg/ml) and IFNγ (40ng/ml), in the absence or the presence of human renal cancer cells (TK10) and dTPI-1. The study system is shown in FIG. 1A. The ratio of macrophage: TK10 =1:3. After 20min of stimulation, cells were lysed in 1% Triton containing PBS, followed by assaying protein tyrosine phosphatase activity in supernatants using pNPP as the substrate. To study how dTPI-1 affects macrophage expression of the cell surface antigen presentation machinery and production of inflammatory cytokines, the macrophage and TK10 co-culture after stimulation with R848 ± dTPI-1 were cultured overnight (18h), followed by detecting macrophage surface MHC-I and -II, CD80, CD86, and CD40. Cell culture medium was collected, in which macrophage secreted cytokines were detected by ELISA. [0205] Results are shown in FIGS. 1B-1E. FIG. 1A shows the study system. Human monocyte-derived macrophages without or with cancer cells surrounding were stimulated with TLR agonist (aTLR) R848 and IFNγ ± dTPI-1. The presence of cancer cells was to ligate macrophage surface inhibitory receptors (iRs), of which cytoplasmic domain phosphorylation in ITIMs led to SHP-1 activation. FIG. 1B shows the results of protein tyrosine phosphatase (PTP) activity assays. Strong SHP-1 activity (labeled) was induced in macrophages by aTLR stimulation plus cancer cell ligating macrophage iRs. As shown, dTPI-1 dose-dependently inhibited SHP-1 activity induced by aTLR with cancer cell ligation. FIG. 1C shows inhibition of SHP-1 by dTPI-1 unleashed macrophage antigen presentation inhibited by the cancer environment. The presence of cancer cell ligation abrogated aTLR induced macrophage antigen presentation, whereas inhibition of SHP-1 by dTPI-1 reversed it. FIG. 1D shows inhibition of SHP-1 by dTPI-1 also unleashed macrophage proinflammatory cytokine production inhibited by 62 sf-6609919 Attorney Docket No.245162001140 the cancer environment. FIG. 1E shows the dose-dependent effect of dTPI-1 for unleashing proinflammatory cytokine (TNFα) production. [0206] These results demonstrate that dTPI-1 dose-dependently inhibited macrophage iRs ligation-induced activation of SHP-1 upon TLR agonist stimulation, confirming dTPI-1 is an effective SHP-1 inhibitor. These studies show that inhibition of SHP-1 overcomes cancer cells- imposed inhibition on macrophages, unleashing macrophage proinflammatory response and antigen presentation within a tumor environment. Example B-2 R848 and/or dTPI-1 treatment in a murine metastatic melanoma model [0207] Lung metastases of B16 melanoma were established in syngeneic mice C57BL6. After melanoma were formed in lungs (day 12), mice were treated with TLR agonists (aTLR: R848 and polyI:C), dTPI-1, or aTLR and dTPI-1 combination. A dose of prophylactic anti- TNFα was given to mice 3h before treatments to ameliorate treatment-associated CRS. FIG. 2A shows the experimental scheme. [0208] Results are shown in FIG. 2B, which are lung images of melanoma prior to treatment (d12) and after different treatments. None of the single treatment with either R848 or dTPI-1 suppressed melanoma progression. However, the combination of R848 or dTPI-1 effectively controlled the disease, even inducing regression of melanoma in lungs. Example B-3 Topical and/or systemic treatment using dTPI-1 in a murine lung cancer model [0209] Murine lung cancer (LLC-luc) was engrafted into syngeneic C57BL6 mice in a multi-point cutaneous/subcutaneous manner into the dorsal skinfold. Lung cancer lesions were formed in 10-15 days and were traced by bioluminescence imaging. Topical and/or systemic treatments started when tumors were well formed. [0210] FIG. 3A shows the experimental design. The treatments include: i) Control treatment (ctl.); mice were given topical non-drug lotion (vehicle) only. ii) αPD-1; anti-PD-1 mAb (100μg, i.p., once every 3 days) was given to mice with topical non-drug lotion treatment. iii) Topical treatments with TLR agonists (aTLR) + dTPI-1 + αPD-1. TLR agonists Resiquimod (R848) and PolyI:C, together with dTPI-1, were prepared in Johnson’s lotion, each at 100μg/ml, topical application 2x per day, each 100-200μl lotion. Anti-PD- 1 mAb (100μg, i.p., once every 3 days) 63 sf-6609919 Attorney Docket No.245162001140 iv) Topical treatments with Stine activators (aSting) + dTPI-1 + αPD-1. Stine activators including MSA-2, ADU-S100 and cGAMP were prepared in Johnson’s lotion, each at 5mg/ml , together with dTPI-1 prepared at 100μg/ml in lotion, were given as topical application, 2x per day, each 100-200μl lotion. [0211] A dose of anti-TNFα was given to mice 3h before the first dose of topical therapies for prophylactic neutralization of TNFα to ameliorate treatment-associated CRS. [0212] Results are shown in FIGS. 3B-3D. FIG. 3B are bioluminescence images that show that LLC tumor burden changes post treatment. In FIGS. 3C-3D, TME analyses revealed that aTLR+dTPI-1 or aStine+TPI-1 treatments skewed intratumoral macrophages toward the proinflammatory phenotype with elevated expression of antigen presentation machinery (FIG. 3C), resulting in increased CD8 T cells (Tc) and reduction of MDSC in the TME (FIG. 3D) [0213] In conclusion, LLC lung cancer strongly resisted anti-PD-1 immune checkpoint inhibitor; however, treatment to this cancer with TLR agonists or Sting activators combined with dTPI-1 achieved strong anti-cancer immunity, leading to clearance of the malignant lesions. TME analyses suggest that the effects of TLR agonists or Sting activators plus dTPI-1 were through activate intratumoral macrophages (TAM) for proinflammatory response and antigen presentation that activate strong anti-cancer T cell immunity. Example B-4 In vitro testing R848-TPI-1 Ester and Amide conjugates for proinflammatory activation of macrophages in a cancer environment [0214] Human monocytes-derived macrophages were treated with R848-TPI-1 Ester and Amide conjugates (1μM each), in the absence or presence of ovarian cancer cells (OVCAR5). Parallel treatments were performed using non-conjugated compounds R848 and TPI-1 (1μM each) to compare their effects to Ester Conjugate (Compound 1-6 of Example S-1) and Amide Conjugate (Compound 2-6 of Example S-2). The presence of cancer cells (OVCAR5) serves to ligate macrophage iRs and activate SHP-1, which drives negative regulation to suppress proinflammatory response. FIG. 4A shows the study system: human monocyte-derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ± TPI-1 or Ester (Compound 1-6) or Amide (Compound 2-6) conjugated R848-TPI-1 compounds. FIG. 4B shows schematics of R848 and TPI-1 monomers and ester conjugate and amide conjugated R848-TPI-1 compounds. 64 sf-6609919 Attorney Docket No.245162001140 [0215] Results are in FIGS. 4C-4E. FIG. 4C shows the results of assaying macrophage proinflammatory (TNFα and IL-6) or anti-inflammatory (IL-10) response stimulated by R848 ± TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells. As shown, Ester and Amide conjugated R848-TPI-1 compounds resembled R848 + TPI-1, capable of skewing macrophages toward proinflammatory direction with high production of TNFα and IL-6 and low IL-10 even in the presence of cancer cell ligation. FIG. 4D shows macrophage expression of cell surface antigen presentation machinery following stimulation with R848 ± TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells. As shown, treatment with Ester and Amide conjugated R848-TPI-1 resembled R848 + TPI-1 and enabled macrophages to overcome cancer cell- imposed inhibition, leading to elevation of cell surface MHC-I and –II, CD40, CD80 and CD86 expression. FIG. 4E shows the dose-dependent effects of Ester and Amide conjugated R848- TPI-1 compounds on activation of macrophage production of TNFα (in FIG. 4E, the amide curve is the upper curve and the ester curve is the lower curve). [0216] As shown, in the absence of cancer cells, R848 treatment induced the typical proinflammatory response in macrophages, resulting in high production of TNFα and IL-6 and low IL-10. However, the presence of cancer cells skewed R848-induced macrophage activation towards anti-inflammatory direction with high IL-10, while diminishing TNFα and IL-6. This was because cancer cells mediated ligation of macrophage surface inhibitory receptors (iRs) and activation of SHP-1, which then mediated master negative-regulation that suppresses proinflammatory response. Addition of TPI-1 (R848 + TPI-1) to inhibit SHP-1 abrogated negative regulation, unleashing R848-induced proinflammatory response and antigen presentation. [0217] Treating macrophages with R848-TPI-1 Ester and Amide conjugates led to high production of TNFα and IL-6 and low IL-10 in the presence of cancer cells. These results suggest that both R848-TPI-1 Ester and Amide conjugates resembled R848 + TPI-1, not only did it activate TLR7/8 proinflammatory pathway but it also abrogated SHP-1 mediated negative regulation. [0218] Conclusion: Treating macrophages with R848 in the presence of cancer cells failed to induce proinflammatory response (but enhanced anti-inflammatory IL-10 production), whereas treatment with R848 + TPI-1 enabled macrophages to overcome the presence of cancer cell ligation and unleashed TLR-triggered potent proinflammatory response. Treating R848 + TPI-1 also unleashed macrophage antigen presentation in the presence of cancer cell environment. 65 sf-6609919 Attorney Docket No.245162001140 [0219] Both R848-TPI-1 Ester and Amide conjugates demonstrated effects that resemble R848 + TPI-1, enabling macrophages to drive proinflammatory response and antigen presentation in the presence of cancer cell ligation. Example B-5 Topical and/or systemic treatment using dTPI-1 in a murine lung cancer model Model-1: KPC pancreatic ductal adenocarcinoma. [0220] KPC pancreatic ductal adenocarcinoma were established in the flank area of syngeneic mice C57BL6. After tumors were stably formed (> 200mm3), mice were treated with R848-TPI-1 Ester or Amide conjugated compound daily in a dose escalation manner (FIG. 5A). Prior to treatment (3h), prophylactic anti-TNFα was given to prevent treatment-associated CRS. [0221] Results are in FIG. 5B-5D, which show dose-dependent efficacies of R848-TPI-1 Ester and Amide conjugated compounds treating KPC pancreatic cancer. FIG. 5B shows KPC tumor volume changes over time (in days) following treatments. In FIG. 5C, TME analyses on d2 revealed that treatments with R848-TPI-1 conjugated compounds skewed intratumoral macrophages (TAM) toward the proinflammatory phenotype with elevated expression of antigen presentation machinery, suggesting that TAM mediated antigen presentation and induced anti- cancer T cell immunity. In FIG. 5D, TME analyses on d5 revealed significant increases in CD8 T cells (Tc) and NK cells, while immunosuppressive components including MDSC were reduced. [0222] Conclusions: These results show that treating KPC tumors with R848-TPI-1 Ester or Amide conjugated compound dose-dependently induced strong immunity response in vivo, effectively restraining cancer progression or having induced tumor regression. TME analyses confirmed that R848-TPI-1 conjugates had induced TAM proinflammatory activation and the capacity of immunogenic antigen presentation, leading to reprogramming of the TME and increases in CD8 T cells and NK cells, while reducing immunosuppressive MDSC, together contributing to tumor suppression. Model-2: LLC lung cancer [0223] Murine lung cancer (LLC-luc) was s.c. engrafted into the right flank of syngeneic C57BL6 mice. After cancer formation, mice were treated with either with anti-PD-1 (αPD-1, 100ug, i.p. every 3 days), or R848-TPI-1 Ester compound (3mg/kg, s.c. daily) + αPD-1, or R848-TPI-1 Amide compound (3mg/kg, s.c. daily) + αPD-1. A dose of anti-TNFα was given to 66 sf-6609919 Attorney Docket No.245162001140 mice 3h before the first dose of topical therapies for prophylactic neutralization of TNFα to ameliorate treatment-associated CRS. The experimental design is shown in FIG. 6A. [0224] Results are shown in FIG. 6B-6D. FIG. 6B shows bioluminescence images of LLC tumor burden changes post treatments. FIG. 6C shows that tumor volume (mm3) shrunk over time post-treatment over 13 days after LLC was treated with ester-conjugated R848-TPI-1 or amide-conjugated R848-TPI-1, but not when treated with the control. In FIG. 6D, TME analyses revealed that both Ester and Amide treatments combined with αPD-1 significantly increased CD8 T cells (Tc), which attributed to tumor elimination. [0225] Conclusion: Both R848-TPI-1 Ester compound and Amide compound induced strong anti-cancer T cell immunity against lung cancer. The effects by R848-TPI-1 compounds are likely synergistic with immune check point inhibitor anti-PD-1. [0226] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety. Web sites referenced using “World-Wide-Web” at the beginning of the Uniform Resource Locator (URL) can be accessed by replacing “World-Wide-Web” with www. [0227] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention. 67 sf-6609919

Claims

Attorney Docket No.245162001140 CLAIMS What is claimed is: 1. A compound of the formula: where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, where RC is RCA and RCA is -COOH, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1 of the formula: or a pharmaceutically acceptable salt thereof. 68 sf-6609919 Attorney Docket No.245162001140 4. The compound of claim 1, where RC is RCA and RCA is -NH2, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, where RC is RCA and RCA is -OH, or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1, where RC is -C1-C4 alkyl-RCA and RCA is -COOH, or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, where RC is -C1-C4 alkyl-RCA and RCA is -NH2, or a pharmaceutically acceptable salt thereof. 8. The compound of claim 1, where RC is -C1-C4 alkyl-RCA and RCA is -OH, or a pharmaceutically acceptable salt thereof. 9. A compound of the formula: or a pharmaceutically acceptable salt thereof. 69 sf-6609919 Attorney Docket No.245162001140 10. A compound of the formula: where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. 11. The compound of claim 10, where RC is RCA and RCA is -COOH, or a pharmaceutically acceptable salt thereof. 12. The compound of claim 10 of the formula: or a pharmaceutically acceptable salt thereof. 70 sf-6609919 Attorney Docket No.245162001140 13. The compound of claim 10, where RC is RCA and RCA is -NH2, or a pharmaceutically acceptable salt thereof. 14. The compound of claim 10, where RC is RCA and RCA is -OH, or a pharmaceutically acceptable salt thereof. 15. The compound of claim 10, where RC is -C1-C4 alkyl-RCA and RCA is -COOH, or a pharmaceutically acceptable salt thereof. 16. The compound of claim 10, where RC is -C1-C4 alkyl-RCA and RCA is -NH2, or a pharmaceutically acceptable salt thereof. 17. The compound of claim 10, where RC is -C1-C4 alkyl-RCA and RCA is -OH, or a pharmaceutically acceptable salt thereof. 18. A composition comprising the compound of any one of claims 1-17, and a pharmaceutically acceptable carrier. 19. A composition comprising a) the compound of any one of claims 1-17, and b) a pro- inflammatory agent or therapy. 20. The composition of claim 19, wherein the pro-inflammatory agent or therapy comprises an agent or therapy selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy (e.g., a radiopharmaceutical), a PAMP/DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, an antibody-drug conjugate, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. 21. A composition comprising a) the compound of any one of claims 1-17, and b) a lymphocyte activating agent or therapy. 22. The composition of claim 21, wherein the the lymphocyte activating agent or therapy is selected from the group consisting of: a cytokine, a chemokine, a metabolism-modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a 71 sf-6609919 Attorney Docket No.245162001140 bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a T cell activating antibody, a bispecific T cell engager (BiTE), an antibody-drug conjugate, a small molecule, a calcium ionophore, and any combination thereof. 23. The composition of any one of claims 19-22, wherein the compound and the pro- inflammatory agent or the lymphocyte activating agent are associated. 24. The composition of claim 23, wherein the compound and the pro-inflammatory agent or the lymphocyte activating agent are fused via a linker, optionally wherein the linker is a cleavable linker, further optionally wherein the linker is a pH sensitive linker. 25. The composition of claim 23, wherein the compound and the pro-inflammatory agent or the lymphocyte activating agent are covalently conjugated, optionally wherein the compound and the pro-inflammatory agent or the lymphocyte activating agent are covalently conjugated via an ester bond or via an amide bond. 26. The composition of any one of claims 18-25, wherein the pro-inflammatory agent comprises a checkpoint inhibitor, optionally the checkpoint inhibitor is an anti-PD-1 antibody. 27. The composition of any one of claims 18-26, wherein the pro-inflammatory agent omprises a TLR agonist, optionally wherein the TLR agonist comprises CpG, R848, and/or Poly I:C. 28. The composition of any one of claims 18-27, wherein the pro-inflammatory agent comprises a STING activator, optionally wherein the STING activator comprises 2’3’-cGAMP. 29. The composition of any one of claims 21-28, wherein the composition comprises a cytokine, optionally wherein the cytokine is IL-2, IL-4, IL-7, and/or IL-15, and/or functional derivatives thereof. 30. The composition of any one of claims 18-29, wherein the pro-inflammatory agent or therapy comprises a radiation therapy, optionally wherein the radiation therapy comprises a radiopharmaceutical. 72 sf-6609919 Attorney Docket No.245162001140 31. A method of treating a disease or condition in an individual, comprising administering the compound or composition of any one of claims 1-30. 32. The method of claim 31, wherein the individual has an ongoing inflammation. 33. The method of claim 31 or claim 32, wherein the disease or condition is a cancer, optionally wherein the cancer is a solid tumor, further optionally where the cancer is a late stage cancer. 34. The method of any one of claims 31-33, wherein the method comprises administering an TNFa inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor. 35. The method of any one of claims 27-34, wherein the method comprises administering a TNFα inhibitor, optionally wherein the TNFα inhibitor comprises an anti-TNFα antibody, optionally wherein the TNFα inhibitor is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. 36. The method of claim 35, wherein the TNFα inhibitor is administered to the individual prior to the administration of the compound or composition or within about 3 hours post the administration of the compound or composition, optionally wherein the TNFα inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the compound or composition. 37. The method of claim 36, wherein the individual is a human. 73 sf-6609919
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