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WO2024168065A1 - System comprising modified whole cell payloads for targeted delivery - Google Patents

System comprising modified whole cell payloads for targeted delivery Download PDF

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Publication number
WO2024168065A1
WO2024168065A1 PCT/US2024/014845 US2024014845W WO2024168065A1 WO 2024168065 A1 WO2024168065 A1 WO 2024168065A1 US 2024014845 W US2024014845 W US 2024014845W WO 2024168065 A1 WO2024168065 A1 WO 2024168065A1
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cell
cancer
cells
moiety
alkyl
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French (fr)
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José Manuel Mejía ONETO
Michael ZAKHARIAN
Jesse M. McFARLAND
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Tambo Inc
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Tambo Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors

Definitions

  • Certain cell-based immunotherapy approaches involve generating immune cells (activated T cells or natural killer cells) that can circulate long enough in patients to engage and destroy cancer cells through their natural cytotoxicity pathways.
  • Some of these approaches involve cancer vaccines, and others involve the genetic engineering of the immune cells to recognize leukemia biomarkers and the use of bispecific antibody T cell conjugates.
  • these approaches also have significant limitations, such as substantial production costs and limited number of bispecific antibodies on the surface of cells.
  • Bioorthogonal conjugation or click reactions are selective and orthogonal (non-interacting with) functionalities found in biological systems, and have found use in various applications in the fields of chemistry, chemical biology, molecular diagnostics, and medicine, where they can be used to facilitate the selective manipulation of molecules, cells, particles and surfaces, and the tagging and tracking of biomolecules in vitro and in vivo.
  • These reactions include the Staudinger ligation, the azide-cyclooctyne cycloaddition, and the inverse-electron-demand Diels-Alder reaction.
  • a system for targeted delivery of a live or whole cell to a treatment site comprising: a whole cell payload comprising a whole cell covalently or non-covalently linked to a first bioorthogonal moiety; and a therapeutic support composition comprising a biocompatible support covalently linked to a second bioorthogonal moiety; wherein the first and second bioorthogonal moieties comprise a complimentary reactive functional group pair.
  • the whole cell is a somatic cell.
  • the whole cell is a genetically modified/transgenic cell.
  • the whole cell is selected from the group consisting of an immune cell, bacterial cell, cardiomyocyte, gd T cell, cytokine induced killer, macrophage, neutrophil, natural killer T cell, primary cell, cytolytic T cell, killer cell, natural killer cell, monocyte, Atty Docket No.63XT-350609-WO Family 11.6 eosinophil, polymorphonuclear cell, granulocyte, mast cell, basophil, dendritic cell, B cell, T cell, antigen presenting cell, stem cell, cancer cell, transgenic cell, primary cell, cells from endocrine system, committed progenitors for the blood and immune system (various type), induced pluripotent stem cells, tumor infiltrating lymphocyte, lymphocyte-activated killer cell, pluripotent stem cell, totipotent stem cell, or multipotent stem cell.
  • an immune cell bacterial cell, cardiomyocyte, gd T cell, cytokine induced killer, macrophage, neutrophil, natural killer T cell, primary
  • the complimentary reactive functional group pair is selected from: (1) an azide and a cyclooctyne; (2) a thiol and a maleimide; (3) a hydrazine/hydrazine/HyNic or alkoxyamine and a monoaldehyde, dialdehyde or 4FB; (4) a tetrazine and a trans-cyclooctene, (5) an aniline and an o-methoxy or amino phenol; (6) a tetrazine and a substituted cyclopropene; (7) a trans-cyclooctene and a substituted cyclopropene; (8) a cyclooctyne and a substituted cyclopropene; (9) a nitrile imine and a substituted cyclopropene; and (10) a tetrazine and a (1R,8S)-9 ⁇ 3 -bicyclo[6
  • a method for treating cancer or enhancing or eliciting an immune response comprising administering to a subject in need thereof, a whole cell payload and a biocompatible support as described herein to the subject.
  • Administration of the biocompatible support can be prior to or after administration of the whole cell payload.
  • the cancer is metastatic.
  • the cancer is melanoma, renal cancer, prostate cancer, ovarian cancer, endometrial carcinoma, breast cancer, glioblastoma, lung cancer, soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical carcinoma, hepatocellular carcinoma, Kaposi’s sarcoma, Non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Wilm’s tumor/neuroblastoma, bladder cancer, thyroid adenocarcinoma, pancreatic neuroendocrine tumors, prostatic adenocarcinoma, nasopharyngeal carcinoma, or cutaneous T-cell lymphoma.
  • the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.
  • the cancer is a solid tumor.
  • the cancer is a lymphoma or leukemia.
  • the cancer is a hematolical malignancy.
  • FIG.2 shows the reaction scheme of Example 2 (Trans-cyclooctene-cell conjugate (double stranded DNA)). Atty Docket No.63XT-350609-WO Family 11.6 DETAILED DESCRIPTION [0013]
  • the following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. 1. Definitions [0014] It is appreciated that certain features, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment.
  • the conjunctive term “or” includes any and all combinations of one or more listed elements associated by the conjunctive term.
  • the phrase “an apparatus comprising A or B” may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B are present.
  • the phrases “at least one of A, B, ... and N” or “at least one of A, B, ... N, or combinations thereof” are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, ...
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.
  • alkyl as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 30 carbon atoms.
  • lower alkyl or “C 1- C 6 -alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • C 1 -C 3 - alkyl means a straight or Atty Docket No.63XT-350609-WO Family 11.6 branched chain hydrocarbon containing from 1 to 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, and n-decyl.
  • alkenyl as used herein, means a hydrocarbon chain containing from 2 to 30 carbon atoms with at least one carbon-carbon double bond.
  • the alkenyl group may be substituted or unsubstituted.
  • the alkenyl group may be substituted with an aryl group, such as a phenyl.
  • alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 30 carbon atoms, such as 2 to 20, or 2 to 10 carbon atoms and having at least 1 site of triple bond unsaturation.
  • alkyne also includes non-aromatic cycloalkyl groups of from 5 to 20 carbon atoms, such as from 5 to 10 carbon atoms, having single or multiple rings and having at least one triple bond.
  • alkynyl groups include, but are not limited to acetylenyl (-C ⁇ CH), and propargyl (-CH2C ⁇ CH), and cycloalkynyl moieties, such as, but not limited to, substituted or unsubstituted cyclooctyne moieties.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkylene refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 30 carbon atoms, for example, of 2 to 10 carbon atoms.
  • alkylene include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2CH2CH2-, and –CH2CH2CH2CH2CH2-.
  • amino acid refers to both natural and unnatural amino acids, protected natural and unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally encoded amino acids include 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine) and pyrrolidine and selenocysteine.
  • Amino acid analogs refer to compounds having the same basic chemical structure as a naturally occurring amino acid, i.e., by way of example only, an ⁇ -carbon attached to a hydrogen, carboxyl group, amino group, and R group.
  • Such analogs can have a modified R group (e.g., norleucine as an example) or retain a modified peptide backbone while retaining the same basic chemical structure as a natural amino acid.
  • amino acid analogs include citrulline, homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium, homophenylalanine, ornithine, Atty Docket No.63XT-350609-WO Family 11.6 formyl glycine, phenyl glycine, para-azidophenyl glycine, para-azidophenylalanine, para-acetophenylalanine, 4-(3-methyl-(1,2,4,5-tetrazine))-phenylglyine, and 4-(3-methyl-(1,2,4,5-tetrazine))-phenylalanine.
  • aryl refers to a phenyl group, or bicyclic aryl or tricyclic aryl fused ring systems.
  • Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a phenyl group.
  • Tricyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to two other phenyl groups.
  • Representative examples of bicyclic aryls include, but are not limited to, naphthyl.
  • tricyclic aryls include, but are not limited to, anthracenyl.
  • the monocyclic, bicyclic, and tricyclic aryls are connected to the parent molecular moiety through any carbon atom contained within the rings, and can be unsubstituted or substituted.
  • the term “azide” as used herein, refers to the functional group –N3.
  • the term “cycloalkyl” as used herein, refers to a carbocyclic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.
  • Cycloalkyl also includes carbocyclic ring systems in which a cycloalkyl group is appended to the parent molecular moiety and is fused to an aryl group as defined herein, a heteroaryl group as defined herein, or a heterocycle as defined herein.
  • cycloalkenyl as used herein, means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • cyclooctene refers to a substituted or unsubstituted non-aromatic cyclic alkyl group of 8 carbon atoms, having a single ring with a double bond.
  • cyclooctene groups include, but are not limited to, substituted or unsubstituted trans-cyclooctene (TCO).
  • TCO trans-cyclooctene
  • fluoroalkyl means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine.
  • Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3-trifluoropropyl.
  • alkoxyfluoroalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein. Atty Docket No.63XT-350609-WO Family 11.6 [0034]
  • fluoroalkoxy means at least one fluoroalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of fluoroalkyloxy include, but are not limited to, difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy.
  • halogen or “halo” as used herein, means Cl, Br, I, or F.
  • haloalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.
  • haloalkoxy as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
  • heteroalkyl as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, Si, O, P and N. The heteroatom may be oxidized.
  • Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, and alkyl sulfides.
  • heteroaryl refers to an aromatic monocyclic ring or an aromatic bicyclic ring system or an aromatic tricyclic ring system.
  • the aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N).
  • the five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds.
  • the bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • the tricyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to two of a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • monocyclic heteroaryl include, but are not limited to, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, and 2-oxo-1,2-dihydropyridinyl.
  • bicyclic heteroaryl include, but are not limited to, chromenyl, benzothienyl, benzodioxolyl, benzotriazolyl, quinolinyl, thienopyrrolyl, thienothienyl, imidazothiazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, imidazopyridine, benzooxadiazolyl, and benzopyrazolyl.
  • tricyclic heteroaryl include, but are not limited to, dibenzofuranyl and dibenzothienyl.
  • the monocyclic, bicyclic, and tricyclic heteroaryls are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
  • Atty Docket No.63XT-350609-WO Family 11.6 [0040]
  • the monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S.
  • the five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • the seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3- dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, 1,3-dimethylpyrimidine-2,4(1H,3H)-dione, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3]heptan-2-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro- 1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl.
  • Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • the monocyclic, Atty Docket No.63XT-350609-WO Family 11.6 bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
  • hydroxyl as used herein, means an –OH group.
  • hydroxyalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a hydroxyl group.
  • the term “HyNic” refers to hydrazinonicotinamide.
  • 4FB refers to “4-formylbenzamide”.
  • HyNic and 4FB are complimentary functional groups that readily react to form a arylhydrazone conjugate.
  • the number of carbon atoms in a hydrocarbyl substituent e.g., alkyl or cycloalkyl
  • Cx-Cy- or “Cx-y,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C1-C3-alkyl” and “C1-3alkyl” refer to an alkyl substituent containing from 1 to 3 carbon atoms.
  • tetrazine refers to a substituted or unsubstituted aromatic cyclic group of 2 carbon atoms and 4 nitrogen atoms, having a single ring with three double bonds.
  • tetrazine groups include 1,2,3,4-tetrazine and 1,2,4,5-tetrazine.
  • 1,2,4,5-tetrazine is referred to as a “Tz” group.
  • targeted delivery and “selectively delivering” refer to delivering an agent (e.g., whole cell payload) to an organ or tissue (or portion thereof) in need of treatment or diagnosis, without significant binding to other non-target organs or tissues (or portions thereof).
  • diagnostic agent refers to agents that assist in diagnosing conditions or diseases.
  • Representative diagnostic agents include imaging agents such as paramagnetic agents, optical probes, radionuclides, and the like.
  • Paramagnetic agents are imaging agents that are magnetic under an externally applied field. Examples of paramagnetic agents include, but are not limited to, iron particles including iron nanoparticles and iron microparticles.
  • Optical probes are fluorescent compounds that can be detected by excitation at one wavelength of radiation and detection at a second, different, wavelength of radiation.
  • Optical probes of the present disclosure include, but are not limited to, Cy5.5, Alexa 680, Cy5, DiD (1,1’- dioctadecyl-3,3,3’,3’-tetramethylindodicarbocyanine perchlorate) and DiR (1,1’-dioctadecyl-3,3,3’,3’- tetramethylindotricarbocyanine iodide).
  • Other optical probes include quantum dots. Radionuclides are elements that undergo detectable radioactive decay.
  • Representative organs and tissues for targeting include those that can be targeted by chemical or biological targeting agents, as well as those organs and tissues that cannot be targeted by chemical or biological targeting agents.
  • the term “implanting” refers to surgical implantation into a subject’s body.
  • the term “contacting” or “contact” refers to the process of bringing into contact at least two distinct species (e.g., two reagents or chemical compounds, or contact between the support composition and the whole cell payload) such that they can interact with each other, such as in a non-covalent or covalent binding interaction or binding reaction.
  • binding agent refers to an agent having a functional group capable of forming a covalent bond to a complementary functional group of another binding agent in a biological environment. Binding between binding agents in a biological environment may also be referred to as bioconjugation. Binding agents include bioorthogonal binding agents, which are binding agents having bioorthogonal functional groups.
  • Bioorthogonal functional groups of bioorthogonal binding agents selectively react with a complementary bioorthogonal functional group of another bioorthogonal binding partner. Selective reaction between bioorthogonal binding partners can minimize side reactions with other binding agents, biological compounds, or other non-complementary bioorthogonal binding agents or non-complementary bioorthogonal functional groups.
  • Bioorthogonal moieties or functional groups of bioorthogonal binding agents include, but are not limited to, an azide and alkyne for formation of a triazole via Click-chemistry reactions, trans- cyclooctene (TCO) and tetrazine (Tz) (e.g., 1,2,4,5-tetrazine), and others.
  • the binding agents useful in the present disclosure may have a high reactivity with the corresponding binding agent so that the reaction is rapid.
  • Atty Docket No.63XT-350609-WO Family 11.6 The term “functionalized” refers to a moiety having a functional group attached to the moiety, such as for example a moiety having a binding agent functional group (e.g., a bioorthogonal functional group) attached thereto.
  • administering refers to any suitable route of administration to a subject, such as, but not limited to, oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • the term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides (e.g., Br, Cl, I), sulfonate esters (e.g., triflate, mesylate, tosylate, and brosylate), and nitrophenols.
  • pharmaceutically effective amount” and “therapeutically effective amount” refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent or reduce the risk of the occurrence or reoccurrence of the disease or disorder or symptom(s) thereof.
  • a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or decrease the growth rate of the tumor.
  • the term “subject,” “patient,” or “organism” includes humans and mammals (e.g., mice, rats, pigs, cats, dogs, and horses). Typical subjects to which an agent(s) of the present disclosure may be administered may include mammals, particularly primates, especially humans. For veterinary applications, suitable subjects may include, for example, livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats.
  • suitable subjects may include mammals, such as rodents (e.g., mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like.
  • the term “treating” or “treatment” as used herein means the treating or treatment of a disease or medical condition or symptom(s) thereof in a patient, such as a mammal (particularly a human) that includes: (a) ameliorating the disease or medical condition or symptom(s) thereof, such as, eliminating or causing regression of the disease or medical condition or symptom(s) thereof in a patient; (b) suppressing the disease or medical condition or symptom(s) thereof, for example by, slowing or arresting the development of the Atty Docket No.63XT-350609-WO Family 11.6 disease or medical condition or symptom(s) thereof in a patient; or (c) alleviating a symptom of the disease or medical condition or symptom(s) thereof in a patient.
  • physiological conditions is meant to encompass those conditions compatible with living cells, e.g., predominantly aqueous conditions of a temperature, pH, salinity, etc. that are compatible with living cells.
  • groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the compounds may exist as stereoisomers wherein asymmetric or chiral centers are present.
  • the stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • R and S used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30.
  • Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art.
  • the present disclosure also includes isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • the compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors.
  • positron-emitting isotopes that can be incorporated are 11 C, 13 N, 15 O, and 18 F.
  • Isotopically-labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent.
  • B. Whole Cell Payloads [0067] Provided herein are a whole cell payloads for targeted delivery. The whole cell payloads are covalently or non-covalently linked to a first bioorthogonal moiety.
  • the first bioorthogonal moiety can be any bioorthogonal moiety, provided the first bioorthogonal moiety comprises a reactive functional group which is complimentary to the second bioorthogonal moiety.
  • the first bioorthogonal moiety is an azide, a cyclooctyne, a thiol, a maleimide, a hydrazine, a hydrazine, HyNic, an alkoxyamine, a monoaldehyde, a dialdehyde, 4FB, a tetrazine, a trans-cyclooctene, an aniline, an o-methoxy phenol, an amino phenol, a tetrazine, a substituted cyclopropene, a cyclooctyne, a nitrile imine, or a (1R,8S)-9 ⁇ 3 - bicyclo[6.1.0]non-4-yne.
  • first bioorthogonal moiety can be covalently or non-covalently linked to the whole cell.
  • first bioorthogonal moiety is covalently linked to the whole cell.
  • Suitable linking methods can comprise non-chemically modified whole cells such that the first bioorthogonal moiety Atty Docket No.63XT-350609-WO Family 11.6 is bonded to the whole cell via a functional group on the surface of the whole cell, such as an amino acid or other suitable functional group.
  • a functional group on the surface of the whole cell such as an amino acid or other suitable functional group.
  • Surface modification of whole cells via NHS esters (or N- hydroxysuccinimide) methodology is a well-used method.
  • the whole cell prior to attaching the bioorthogonal group, is modified first by methods, such as, metabolic glycoengineering, such as introducing azide groups onto the cell surface, provided the modification is done with minimal biological perturbation.
  • the first bioorthogonal moiety can be attached to an azide on the whole cell via a heterobifunctional crosslinker.
  • the first bioorthogonal moiety is non-covalently linked to whole cell.
  • Suitable linking methods can comprise a chemically modified whole cell or non-chemically modified whole cell such that the first bioorthogonal moiety is bound to the whole cell via a binding site on the surface of the whole cell, such as a DNA or RNA strand, or other suitable functional group.
  • the whole cell is modified with a DNA or RNA strand such that the first bioorthogonal moiety is bound to the whole cell via a complimentary DNA or RNA strand.
  • the whole cell can be a live cell, dead cell, or a mixture of live and dead cells.
  • Non-limiting examples of cells can include an immune cell, natural killer cell, a macrophage, a neutrophil, a T-cell, a natural killer T-cell (NKT cells), a stem cell, a cancer cell, an antigen presenting cell (APC), or a bacterial cell.
  • Cells used as a therapeutic agent may be primary cells from a sample from a subject, cells from a cell line, and/or transgenic cells. Cells may be eukaryotic or prokaryotic.
  • the cell is an effector cell.
  • effector cell relates to a cell that performs a specific function in response to a stimulus such as cells in the immune system.
  • effector cells are cells that induce cell death.
  • Non-limiting examples of effector cells include lymphocytes (such as T cells, including cytolytic T cells (CTLs)), killer cells, natural killer cells, macrophages, monocytes, eosinophils, neutrophils, polymorphonuclear cells, granulocytes, mast cells, and basophiles.
  • the cell is a cell involved in the cognitive and/or activation phases of an immune response, such as antigen presenting cells (APCs), including dendritic cells.
  • APCs antigen presenting cells
  • the whole cell is a somatic cell.
  • the whole cell is a genetically modified/transgenic cell.
  • Subjects from which cells may be derived include, but are not limited to, mammals, such as a human. Samples may be provided directly by the subject, or indirectly through one or more intermediaries, such as a sample collection service provider or a medical provider (e.g., a physician or nurse).
  • a sample collection service provider e.g., a physician or nurse.
  • a medical provider e.g., a physician or nurse.
  • samples from a subject from which cells may be derived include, without limitation, skin, heart, lung, kidney, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gall bladder, colon, intestine, brain, Atty Docket No.63XT-350609-WO Family 11.6 prostate, esophagus, thyroid, serum, saliva, urine, gastric and digestive fluid, tears, stool, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, sweat, mucus, earwax, oil, glandular secretions, spinal fluid, hair, fingernails, plasma, nasal swab or nasopharyngeal wash, spinal fluid, cerebral spinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk, and/or other excretions or body tissues.
  • lymphoid cells such as B cell, T cell (cytotoxic T cell, natural killer T cell, regulatory T cell, T helper cell), natural killer cell, cytokine induced killer (CIK) cells (see e. g.
  • myeloid cells such as granulocytes (basophil granulocyte, eosinophil granulocyte, neutrophil granulocyte/hypersegmented neutrophil), monocyte/macrophage, red blood cell (reticulocyte), mast cell, thrombocyte/megakaryocyte, dendritic cell; cells from the endocrine system, including thyroid (thyroid epithelial cell, parafollicular cell), para thyroid (parathyroid chief cell, oxyphil cell), adrenal (chromaffin cell), pineal (pinealocyte) cells; cells of the nervous system, including glial cells (astrocyte, microglia), magnocellular neurosecretory cell, stellate cell, Boettcher cell, and pituitary (gonadotropc, corticotropc, thyrotrope, somatotrope, lactotroph); cells of the respiratory system, including pneumocyte (type I pneumocyte, type II pneumocyte), Clara cell, goblet cell,
  • the cells can be healthy cells, or diseased cells.
  • the cells can be from a cancer condition such as epithelial cancer or carcinoma, including but not limited to, a carcinoma of the prostate, carcinoma of the breast, carcinoma of the colon, pancreatic carcinoma, lung carcinoma, skin carcinoma (melanoma), esophageal carcinoma, etc.; or the putative cell of origin (hepatocellular carcinoma, renal cell carcinoma, and small cell lung carcinoma, etc.).
  • Other cancer cells include myoepithelial cancers, sarcomas, gliomas, lymphomas, leukemias, carcinoids, and any other type of cancer.
  • Cells in other states or conditions of tissue may be used including but not limited to, autoimmune conditions, immune system related conditions (e.g., allergies, likely immune response to challenge), cells representative of conditions that contribute to or exhibit resistance to standard treatments, susceptibility or predisposition to a condition (e.g., susceptibility to diabetes, thyroid conditions, stroke, cardiovascular conditions, or liver quality, function, and degeneration, etc.).
  • the cell is a primary cell.
  • the cell is a mammalian cell.
  • the cell is a stem cell.
  • the cells are from a cell line.
  • cell lines include, but are not limited to, NK92, NK3.3, C8161, CCRF-CEM, MOLT, MIMCD-3, NHDF, HeLa-S3, Huhl, Huh4, Huh7, HUVEC, HASMC, HEKn, HEK, MiaPaCell, Panel, PC-3, TF1, CTLL-2, CIR, Rato, CV1, RPTE, A10, T24, J82, A375, ARH-77, Calul, SW 480, SW620, SKOV3, SK-UT, CaCo2, P388D1, SEM-K2, WEHI-231, HB56, TIB55, Jurkat, J45.01, LRMB, Bcl-1, BC-3, IC21, DLD2, Raw264.7, NRK, NRK-52E, MRC5, MEF, Hep G2, HeLa B, HeLa T4, COS, COS-1, COS-6, COS-M6A, BS-C-1 monkey kidney
  • the cell is a T-cell.
  • T-cells include all cells which express CD3, including T- cell subsets which also express CD4 and/or CD8.
  • T-cells include both naive and memory cells (e. g. TCM TEM and TEMRA), effector cells (e. g. CTLs or Tc cells), helper cells (e. g. Th1, Th2, Th3, Th9, Th7, TFH), regulatory cells (e.
  • the T cells are activated T-cells.
  • the cell is genetically modified or transgenic.
  • the genetically modified cell can be an immune or non-immune cell.
  • the cell is from a genetically modified cell-based therapy.
  • Genetically modified cell-based therapies include, but are not limited to CAR T, TCR, TIL, and adoptive NK therapies.
  • T cells can be obtained from a number of sources, including peripheral blood leukocytes, bone marrow, lymph node tissue, spleen tissue, and tumors.
  • peripheral blood leukocytes are obtained from an individual by leukopheresis.
  • Isolating T cells from peripheral blood leukocytes may include lysing the red blood cells and separate peripheral blood leukocytes from monocytes by, for example, centrifugation through, e. g., a PERCOLL®gradient.
  • a specific subpopulation of T cells, such as CD4 + or CD8 + T cells, can be further isolated by positive or negative selection techniques.
  • negative selection of a T cell population can be accomplished with a combination of antibodies directed to surface markers unique to the cells negatively selected.
  • One suitable technique includes cell sorting via negative magnetic immunoadherence, which utilizes a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected.
  • a monoclonal antibody cocktail typically includes antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD8.
  • the process of negative selection may be used to produce an essentially homogenous population of the desired T cell population.
  • the T-cell is an alpha/beta T-cell.
  • the T-cell is a delta/gamma T-cell.
  • a composition comprises a mixture of two or more (e. g.2, 3, 4, 5, or more) different kind of T-cells.
  • the linker conjugated to the T-cell is not associated with an activation domain.
  • the cell is a member of an enriched population of cells.
  • One or more desired cell types may be enriched by any suitable method, non-limiting examples of which include treating a population of cells to trigger expansion and/or differentiation to a desired cell type, treatment to stop the growth of undesired cell type(s), treatment to kill or lyse undesired cell type(s), purification of a desired cell type (e. g. purification on an affinity column to retain desired or undesired cell types on the basis of one or more cell surface markers).
  • the enriched population of cells is a population of cells enriched in gamma/delta T cells (yd T cells).
  • yd T cells may be enriched by any suitable method.
  • the percentage of yd T cells may be expanded in a population of hematolymphoid cells by first administering IL-12 and a ligand of CD2, followed by administering IL-2 and T cell mitogenic stimulus.
  • expanded y8 T cells can survive under culture conditions for a period of time which is greater than the period of time during which hematolymphoid cells in primary culture survive under the same conditions.
  • the enriched population of cells is a population of cells enriched in Cytokine Induced Killer (CIK) cells.
  • CIK Cytokine Induced Killer
  • CIK cells can be generated from peripheral blood mononuclear cells (PBMC) by in-vitro culture in presence of IFN-Y, OKT-3, and IL-2.
  • PBMC peripheral blood mononuclear cells
  • high dose Th1- type hormonal stimulation of a T-cells with IFN-1, OKT-3 and IL-2 is used to produce CIK AI cells as the enriched population of cells.
  • the CIK cells are CD3 + CD56 + cells.
  • a cell embodied in a subject complex or to which a linker is conjugated is a stem cell.
  • stem cell refers to a cell that is capable of differentiating into different, more specialized cell types.
  • a stem cell may be multi-potent, pluripotent, or totipotent.
  • a stem cell may be isolated from a subject, from a cell line, or induced from a non-pluripotent cell.
  • Embryonic stem cells may reside in the blastocyst and give rise to embryonic tissues, whereas somatic stem cells may reside in adult tissues for the purpose of tissue regeneration and repair.
  • the terms “pluripotent” and “pluripotency” refer to cells with the ability to give rise to progeny that can undergo differentiation, under appropriate conditions, into cell types that collectively exhibit characteristics associated with cell lineages from the three germ layers (endoderm, mesoderm, and ectoderm). Pluripotent stem cells can contribute to tissues of a prenatal, postnatal or adult organism.
  • a standard art accepted test such as the ability to form a teratoma in 8-12 week old SCID mice, can be used to establish the pluripotency of a cell population.
  • identification of various pluripotent stem cell characteristics can also be used to identify pluripotent cells.
  • human pluripotent stem cells may express at least some, and optionally all, of the markers from the following non- limiting list : SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, TRA-2-49/6E, ALP, Sox2, E-cadherin, UTF-1, Oct4, Lin28, Rexl, and Nanog.
  • iPSC induced pluripotent stem cell
  • a non-pluripotent cell can be a cell of lesser potency to self- renew and differentiate than a pluripotent stem cell.
  • Cells of lesser potency can be, but are not limited to, Atty Docket No.63XT-350609-WO Family 11.6 somatic stem cells, tissue specific progenitor cells, primary or secondary cells.
  • a somatic stem cell can be a hematopoietic stem cell, a mesenchymal stem cell, an epithelial stem cell, a skin stem cell or a neural stem cell.
  • Non-pluripotent cells can be reprogrammed to become iPSCs by the introduction of pluripotency genes or proteins, such as Oct4, Sox2, Lin28 and Nanog into the cell.
  • the genes or proteins may be introduced into the differentiated cells by any suitable technique, including plasmid transfection, viral transfection, or direct protein delivery.
  • the ancestor cells may be cultured. Cells expressing pluripotency markers may be isolated and/or purified to produce a population of iPS cells.
  • the cell is an embryonic stem cell (ESC), such as from an ESC cell line, non-limiting examples of which include CHB-1 to CHB-12, RUES1 to RUES3, HUES1 to HUES28, HUES45, HUES48, HUES49, HUES53, HUES62 to HUES66, WA01 (H1), WA07 (H7), WA09 (H9), WA13 (H13), WA14 (H14), NYUES1 to NYUES7, MFS5, and UCLA1 to UCLA3.
  • the cell is an immune cell.
  • the cell is a natural killer cell.
  • the cell is macrophage.
  • the cell is a neutrophil. [0087] In some embodiments, the cell is a T cell. [0088] In some embodiments, the cell is a gamma delta T cell. [0089] In some embodiments, the cell is a natural killer T cell. [0090] In some embodiments, the cell is a stem cell. [0091] In some embodiments, the cell is an antigen presenting cell. [0092] In some embodiments, the cell is a dendritic cell. [0093] In some embodiments, the cell is from a subject. In some embodiments, the cell is from a commercial or ex vivo cell line. In some embodiments, the cell is transgenic.
  • the cell is an effector cell, including but not limited to, a lymphocyte, such as a T cell, a cytolytic T cell, a cytotoxic T cell, a T helper cell, a killer cell, a natural killer cell, a cytokine induced killer cell, a macrophage, a monocyte, an eosinophil, a neutrophil, a polymorphonuclear cell, a granulocyte, a mast cell, or a basophil.
  • a lymphocyte such as a T cell, a cytolytic T cell, a cytotoxic T cell, a T helper cell, a killer cell, a natural killer cell, a cytokine induced killer cell, a macrophage, a monocyte, an eosinophil, a neutrophil, a polymorphonuclear cell, a granulocyte, a mast cell, or a basophil.
  • iPSC induced pluripotent stem cell
  • the cell is an embryo
  • the cell is a purified population of cells. In some embodiments, the cell is a mixture of different cell populations. [0098] The whole cell is covalently or non-covalently linked to a first bioorthogonal moiety. In some embodiments, the whole cell comprises from 10 – 1,000,000, or from 10 – 500,000, or from 10 – 100,000, or from 10 – 50,000, or from 10 – 10,000, or from 500 – 10,000, or from 10 – 5,000, or from 500 – 5,000, or from 10 – 1,000, or from 500 – 1,000, or about 1,000 bioorthogonal moieties.
  • the bioorthogonal moieties can be the same or different. In some embodiments, the bioorthogonal moieties are the same.
  • the whole cell comprises a first bioorthogonal moiety covalently bonded thereto, optionally via a linker. When live cells are employed, the percent viability of the sample can be determined after bonding to the first bioorthogonal moiety. In some embodiments, when live cells are employed, the percentage of live cells is greater than 80%, or 85%, or 90%, or 95%. [0100] In some embodiments, the first bioorthogonal moiety is covalently bonded to the whole cell via a linker.
  • the whole cell comprises a surface N-terminal amino acid, wherein the linker is covalently bonded to a N-terminal amino acid.
  • the first bioorthogonal moiety is covalently bonded to the whole cell via a cysteine or lysine residue on the whole cell.
  • the linker comprises one or more amino acids.
  • the linker comprises a polypeptide.
  • the linker comprises one or more of a hydrazone, a hydrazide, a disulfide, a N-succinimidyl-4-(2-pyridyldithio)pentanoate (SPP), a N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB), a 4-(4’-acetylphenoxy)butanoic acid (AcBut), one or more linear or branched, natural or unnatural amino acid, a valine-citrulline (Val-Cit) moiety, or a phenylalanine-lysine (Phe-Lys) moiety.
  • SPP N-succinimidyl-4-(2-pyridyldithio)pentanoate
  • SPDB N-succinimidyl-4-(2-pyridyldithio)butyrate
  • AcBut 4-(4’-acetyl
  • the linker comprises 1 to 100 linking atoms, from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms, or from 1 to 40 linking atoms, or from 1 to 30 linking atoms, or from 1 to 20 linking atoms, or from 1 to 10 linking atoms, or from 1 to 5 linking atoms, or from 5 to 30 linking atoms, or from 10 to 30 linking atoms, or from 5 to 40 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms.
  • the linker comprises one or more chain heteroatoms and one or more alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene moieties; Atty Docket No.63XT-350609-WO Family 11.6 wherein each alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene moiety may be independently optionally substituted with one to five substituents independently selected from oxo, halo, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl.
  • the linker is an alkylene linker optionally comprising one or more -O-, -S-, amine, ester, amide, carbamate, carbonate, thio-succinimide, or ketone functional group.
  • the first bioorthogonal moiety comprises a trans-cyclooctene moiety. In some embodiments, the first bioorthogonal moiety comprises a trans-cyclooctene moiety and the second bioorthogonal moiety comprises a tetrazine moiety.
  • the trans-cyclooctene moiety is of the formula: wherein: Atty Docket No.63XT-350609-WO Family 11.6
  • R 1A at each occurrence, is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy; q is 0, 1, or 2; q1 is 0 or 1;
  • R 1B at each occurrence, is independently selected from the group consisting of G 1 , OH, –NR 1c –C 1-4 alkylene–G 1 , –NR 1c –C 1-4 alkylene–N(R 1d ) 2 , –NR 1c –C 1-6 alkylene–N(C 1-4 alkyl) 3 + , –N(R 1c )CHR 1e CO 2 H, –N(R 1c )–C 1-6 alkylene–CO 2 H, –N(R 1f )–C 2-4
  • the trans-cyclooctene moiety is of the formula: ;
  • R 1A at each occurrence, is consisting of C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; q is 0, 1 or 2; q1 is 0 or 1;
  • R 1B at each occurrence, is independently selected from the group consisting of G 1 , OH, –NR 1c –C 1-4 alkylene–G 1 , –NR 1c –C 1-4 alkylene–N(R 1d ) 2 , –NR 1c –C 1-6 alkylene–N(C 1-4 alkyl) 3 + , –N(R 1c )CHR 1e CO 2 H, –N(R 1c )–C 1-6 alkylene–CO 2 H, –N(R 1f )–C 2-4 alkylene–(N(C 1-4
  • the trans-cyclooctene moiety is of the formula: ;
  • R 1A at each occurrence, is group consisting of C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; q is 0, 1 or 2; q1 is 0 or 1;
  • R 1B at each occurrence, is independently selected from the group consisting of G 1 , OH, –NR 1c –C1-4alkylene–G 1 , –NR 1c –C1-4alkylene–N(R 1d )2, –NR 1c –C1-6alkylene–N(C1-4alkyl)3 + , –N(R 1c )CHR 1e CO2H, –N(R 1c )–C1-6alkylene–CO2H, –N(R 1f )–C2-4alkylene–(N(C1-4alkylene–CO2H)–C2- 4alkylene)n–N(C1-4alkylene–CO2
  • the trans-cyclooctene moiety is of the formula: wherein: R 2 is -OH, 2-aminoethanesulfonic acid, an N-linked natural or unnatural amino acid, or an optionally substituted ethylenediamine; wherein R 2 may be optionally further substituted with a polyether.
  • the trans-cyclooctene moiety with a portion of the linker comprises a group capable of releasing the trans-cyclooctene moiety from the whole cell portion (such as upon tetrazine activation).
  • the trans-cyclooctene moiety linked to the whole cell portion via a linker having a -OC(O)- or -OC(O)NH- moiety at the attachments to the trans-cyclooctene moiety.
  • the trans-cyclooctene moiety with a linker portion having the Formula: ; Atty Docket No.63XT-350609-WO Family 11.6 wherein: R 2 is -OH, 2-aminoethanesulfonic acid, an N-linked natural or unnatural amino acid, or an optionally substituted ethylenediamine; wherein R 2 may be optionally further substituted with a polyether.
  • the remaining portion of the linker comprises an alkylene or polyether with an amino acid terminus for bonding to the whole cell portion.
  • the trans-cyclooctene moiety is of the .
  • the trans-cyclooctene moiety is of the .
  • the trans-cyclooctene moiety (optionally of the formula: 1-50, or 1-40, or 1-30, or 1-20, or 10-30, or 10-20, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
  • the trans-cyclooctene moiety is of the formula:
  • the whole cell payload is formulated for systemic administration.
  • Therapeutic Support Composition [0122] Provided is a system comprising a therapeutic support composition, wherein the therapeutic support composition comprises a biocompatible support covalently linked to a second bioorthogonal moiety.
  • the therapeutic support composition comprises a support. Supports may be biocompatible supports compositions, i.e., compatible with the subject’s body.
  • a support is non-toxic to the subject and does not substantially react with tissue or biological compounds in the subject.
  • the support can be a hydrogel, among others.
  • a support is capable of implantation into a subject’s body and supporting binding agents (e.g., tetrazine-containing group).
  • Representative supports include, but are not limited to polymers, viscous or non-viscous liquid materials, gels, hydrogels, polysaccharide hydrogels, a cross-linked polymer matrix, a metal, a ceramic, a plastic, a bone graft material, alginate, cellulose, chitosan, hyaluronic acid, chondroitin sulfate, heparin, and the like.
  • Hydrogels may be polysaccharide hydrogels, alginate, cellulose, hyaluronic acid, chitosan, chitosin, chitin, hyaluronic acid, chondroitin sulfate, heparin, and the like.
  • Other suitable sugar-based biomaterials Atty Docket No.63XT-350609-WO Family 11.6 include those described in Polymer Advanced Technology, 2014, 25, 448-460.
  • Polymers that may be used as the support can include, but are not limited to, polyphosphazenes, polyanhydrides, polyacetals, poly(ortho esters), polyphosphoesters, polycaprolactones, polyurethanes, polylactides, polycarbonates, polyamides, and polyethers, and blends/composites/co-polymers thereof.
  • Representative polyethers include, but are not limited to, poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), triblock Pluronic ([PEG]n-[PPG]m- [PEG]n), PEG diacrylate (PEGDA), and PEG dimethacrylate (PEGDMA).
  • the support can also include proteins and other poly(amino acids), such as collagen, gelatin, elastin and elastin-like polypeptides, albumin, fibrin, poly(gamma-glutamic acid), poly(L-lysine), poly(L-glutamic acid), poly(aspartic acid), and the like.
  • the support is a hydrogel.
  • the support is an alginate.
  • the support is chitin.
  • the support is a hyaluronic acid (e.g., a non-hydrogel hyaluronic acid substantially without crosslinks).
  • the support is chitosin.
  • the support is a particle.
  • Particles of the present disclosure can have a diameter that is 2 cm or less, such as 1.5 cm or less, or 1 cm or less, or 0.5 cm or less.
  • the particles can be nanoparticles or microparticles.
  • Nanoparticles include particles having average dimensions in the nanometer scale (e.g., 1000 nm or less).
  • Microparticles are particles having average dimensions in the micrometer scale (e.g., 1000 ⁇ m or less).
  • average is meant the arithmetic mean.
  • the nanoparticles have a diameter ranging from 1 nm to 1 ⁇ m, such as from 10 nm to 1 ⁇ m, or 25 nm to 1 ⁇ m, or 50 nm to 1 ⁇ m, or 75 nm to 1 ⁇ m, or 100 nm to 1 ⁇ m, or 150 nm to 1 ⁇ m, or 200 nm to 1 ⁇ m, or 250 nm to 1 ⁇ m, or 300 nm to 1 ⁇ m, or 350 nm to 1 ⁇ m, or 400 nm to 1 ⁇ m, or 450 nm to 1 ⁇ m, or 500 nm to 1 ⁇ m.
  • 1 nm to 1 ⁇ m such as from 10 nm to 1 ⁇ m, or 25 nm to 1 ⁇ m, or 50 nm to 1 ⁇ m, or 75 nm to 1 ⁇ m, or 100 nm to 1 ⁇ m, or 150 nm to 1 ⁇ m, or 200 nm to 1
  • the microparticles have a diameter ranging from 1 ⁇ m to 1 mm, such as from 10 ⁇ m to 1 mm, or 25 ⁇ m to 1 mm, or 50 ⁇ m to 1 mm, or 75 ⁇ m to 1 mm, or 100 ⁇ m to 1 mm, or 150 ⁇ m to 1 mm, or 200 ⁇ m to 1 mm, or 250 ⁇ m to 1 mm, or 300 ⁇ m to 1 mm, or 350 ⁇ m to 1 mm, or 400 ⁇ m to 1 mm, or 450 ⁇ m to 1 mm, or 500 ⁇ m to 1 mm.
  • 1 ⁇ m to 1 mm such as from 10 ⁇ m to 1 mm, or 25 ⁇ m to 1 mm, or 50 ⁇ m to 1 mm, or 75 ⁇ m to 1 mm, or 100 ⁇ m to 1 mm, or 150 ⁇ m to 1 mm, or 200 ⁇ m to 1 mm, or 250 ⁇ m to 1 mm, or 300 ⁇ m to 1
  • small particles on the order of 10-100 nm in diameter may be assembled to form larger complexes, such as clusters or assemblies on the order of 1-10 ⁇ m.
  • Particles of the present disclosure may be substantially spherical, such that the particles have a substantially circular cross-section.
  • Other particle shapes may also be used, such as, but not limited to, ellipsoid, cubic, cylindrical, conical, needle, or other irregular shapes.
  • a “particle” may take the form of any fabricated material, a molecule, cryptophan, a virus, a phage, etc.
  • the particle may be composed of a material, such as, but not limited to, a metal, a ceramic, a plastic, a glass, a composite, a polymer, a hydrogel, and the like.
  • the particles may be made of an inert material, such as alginate or iron oxide.
  • the particles may be magnetic and can be formed Atty Docket No.63XT-350609-WO Family 11.6 from a paramagnetic, super-paramagnetic or ferromagnetic material, or other material that responds to a magnetic field.
  • a particle may be of any shape, for example, spheres, rods, non-symmetrical shapes, etc.
  • the particles, or a group of several particles in a complex may be functionalized with a receptor that has a specific affinity to bind to or interact with a clinically relevant substrate.
  • the receptor may be inherent to the particle itself.
  • the particle itself may be a virus or a phage with an inherent affinity for certain substrates.
  • the particles can be functionalized by covalently or otherwise attaching or associating a receptor that specifically binds or otherwise recognizes a particular clinically relevant substrate.
  • the functionalized receptor can be an antibody, peptide, nucleic acid, phage, bacteria, virus, or any other molecule with a defined affinity for a target substrate.
  • Examples of material that may be used for the “particles” and/or “carrier” include polylactic acid, polyglycolic acid, PLGA polymers, alginates and alginate derivatives, gelatin, collagen, fibrin, hyaluronic acid, laminin rich gels, agarose, natural and synthetic polysaccharides, polyamino acids, polypeptides, polyesters, poly anhydrides, polyphosphazines, poly(vinyl alcohols), poly(alkylene oxides), poly(allylamines) (PAM), poly(acrylates), modified styrene polymers, pluronic polyols, poloxamers, poly(uronic acids), poly(vinylpyrrolidone) and copolymers or graft copolymers of any of the above.
  • the particles, or a group of several particles in a complex may be functionalized with a targeting agent (e.g., a ligand or antibody) that specifically binds (or substantially specifically binds) to a target (e.g., a target receptor or a cell surface target, such as a clinically relevant receptor or cell surface target (e.g., antigen)).
  • a targeting agent e.g., a ligand or antibody
  • the targeting agent may be attached directly to the particle itself.
  • the targeting agent can be an antibody, peptide, nucleic acid, phage, bacteria, virus, or any other molecule with a specific affinity for a target receptor or cell surface target.
  • the receptor or cell surface target is PD-1, CTLA-4, HER2/neu, HER1/EGFR, VEGFR, 4-1BB, GITR, or other cellular receptors or cell surface targets.
  • the targeting agent is a monoclonal antibody.
  • a monoclonal antibody can be an entire monoclonal antibody, or a fragment thereof (e.g., antigen-binding fragment (Fab)).
  • the targeting agent is an antibody, or antibody fragment, that targets one or more of CD25 (NCBI Gene ID 3559), CEA (NCBI Gene ID 634), CEACAM5 (NCBI Gene ID 1048), ASPH (NCBI Gene ID 444), EGFR (NCBI Gene ID 1956), EPCAM (NCBI Gene ID 4072), VEGFR (NCBI Gene ID 3791), PDGFR (NCBI Gene ID 5159), TROP2 (NCBI Gene ID 4070), Nectin4 (NCBI Gene ID 81607), PSMA (NCBI Gene ID 2346), BCMA (NCBI Gene ID 608), CD22 (NCBI Gene ID 933), CD20 (NCBI Gene ID 920), CD19 (NCBI Gene ID 930), CD79b (NCBI Gene ID 974), CD38 (NCBI Gene ID 952), CD45 (NCBI Gene ID 5788), Endoglin (NCBI Gene ID 2022), FGFR2 (NCBI Gene ID 14183), C4.4A (NCBI Gene ID Atty Docket No.
  • the support is a bone graft material, such as a bone graft substitute material.
  • a bone graft substitute material is a material structurally similar to bone.
  • a bone graft substitute material is bioresorbable such that the bone graft substitute material can dissolve or be absorbed in the body over time.
  • a bone graft substitute material can be osteoconductive, such that it facilitates blood vessel and new bone formation into the bone graft substitute material.
  • the bone graft substitute material is osteoinductive, such that it facilitates the formation of new bone through active recruitment of mesenchymal stem cells from the surrounding tissue.
  • growth factors such as bone morphogenetic proteins, may be included in the bone graft substitute material.
  • Bone graft substitute materials include, but are not limited to, hydroxyapatite, tricalcium phosphate, demineralized bone matrix, bovine collagen, calcium sulfate, calcium phosphate, cancellous bone chips, and the like, and combinations thereof.
  • Therapeutic support compositions of the present disclosure include a support and a first binding agent covalently linked to the support.
  • the binding agent may be attached to the support on a surface of the support, such as a solvent-accessible surface of the support (e.g., a surface of the support that is in contact with the surrounding solvent).
  • the binding agent is attached directly to the support.
  • the binding agent may be covalently attached to the surface of the support, e.g., through a covalent bond, such as an amide, amine, ester, carbamate, urea, thioether, thiocarbamate, thiocarbonate, thiourea, etc.
  • the binding agent is covalently attached to the support through an amide bond.
  • the binding agent may be linked to the support via a linker.
  • Any suitable linker can be used to link the binding agent to the support.
  • Representative linkers can have from 1 to 100 linking atoms, and can include ethylene-oxy groups, amines, esters, amides, carbamates, carbonates, and ketone functional groups.
  • linkers may have from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms.
  • linkers include, but are not limited to, those shown below: [0133]
  • the moiety, provided the second bioorthogonal moiety comprises a reactive functional group which is complimentary to the first bioorthogonal moiety.
  • the second bioorthogonal moiety is an azide, a cyclooctyne, a thiol, a maleimide, a hydrazine, a hydrazine, HyNic, an alkoxyamine, a monoaldehyde, a dialdehyde, 4FB, a tetrazine, a trans-cyclooctene, an aniline, an o-methoxy phenol, an amino phenol, a tetrazine, a substituted cyclopropene, a cyclooctyne, a nitrile imine, or a (1R,8S)-9 ⁇ 3 -bicyclo[6.1.0]non-4-yne.
  • the complimentary reactive functional group pair comprise a tetrazine moiety and a trans-cyclooctene moiety.
  • the second bioorthogonal moiety comprises a tetrazine moiety.
  • the first bioorthogonal moiety comprises a trans-cyclooctene moiety and the second bioorthogonal moiety comprises a tetrazine moiety.
  • the each R 20 is independently phenyl, pyrimidinyl, triazinyl, oxazolyl, isoxazole, imidazolyl, oxadiazolyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,3- d]pyrimidinyl, or 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl; wherein each is independently optionally substituted with one to three Z 1 .
  • linkers may have from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms.
  • the therapeutic support composition comprises units of formula: . Atty Docket No.63XT-350609-WO Family 11.6 [0142] In some embodiments, the therapeutic support compositions comprise units of formula: . the therapeutic support compositions comprise units of formula: . comprise substituted hyaluronic acid having units of formula (II): a linker of 1 to 100 linking atoms; and R 20 is as defined herein. Atty Docket No.63XT-350609-WO Family 11.6 . [0146] In still further is hydrogen or C1-4alkyl.
  • R 20 is hydrogen or C 1-4 alkyl.
  • the therapeutic support compositions comprise units of formula: or WO/2015/139025A1, and WO/2014/205126A1, the entire contents of each of which is incorporated herein by reference in their entirety.
  • the hyaluronic acid derivative includes a hyaluronic acid having a plurality of glucuronic acid units and a tetrazine-containing group linked or directly bonded to a glucuronic acid unit of the hyaluronic acid.
  • the hyaluronic acid may also have a plurality of N-acetylglucosamine units.
  • the N- acetylglucosamine units of the hyaluronic acid are not linked or conjugated to the tetrazine-containing group.
  • the tetrazine-containing group can be linked or directly bonded through a carboxylic acid of a glucuronic acid unit.
  • the tetrazine-containing group can be incorporated into the hyaluronic acid from about 0.1% to about 80% as measured by the % of carboxylic acids being linked or conjugated to the tetrazine- Atty Docket No.63XT-350609-WO Family 11.6 containing group, such as about 1% to about 75%, about 5% to about 75%, about 10% to about 50%, or about 40% to about 75% as measured by the % of carboxylic acids being linked or conjugated to the tetrazine-containing group.
  • D. Methods of Treatment [0152] Aspects of the present disclosure include methods for delivering a whole cell payload to a target location in a subject.
  • a target location e.g., an organ or tissue, or portion thereof
  • the target location or treatment site can be a stationary location (e.g., an organ or tissue, tumor, or portion thereof) or a systemic location (e.g., cells in the blood or other bodily fluid).
  • the whole cell payload is designed to target a treatment site in a subject via binding with the complimentary reactive functional group on the therapeutic support, and upon reaction of the first and second bioorthogonal moieties (e.g., contact of the TCO moiety with the tetrazine moiety), the whole cell is delivered to the treatment site in the subject.
  • the method comprises administering a therapeutic support composition to a subject in need thereof, followed by administering a whole cell payload.
  • the whole cell payload is administered systemically.
  • the whole cell payload is administered locally.
  • the therapeutic support composition is administered locally.
  • the whole cell payload is administered systemically.
  • the method includes administering to the subject a whole cell payload such that the whole cell is bound to the therapeutic support composition to form a support complex.
  • the whole cell payload may be administered systemically to the subject.
  • contact between the support composition and the whole cell payload occurs, such that the first bioorthogonal moiety and its complementary bioorthogonal moiety bind to one another to form a support complex, thereby selectively delivering the whole cell to the target location in the subject.
  • selective delivery of the whole cell payload results in a concentration of the whole cell at the target location that is greater than the concentration elsewhere in the subject (e.g., at non-targeted areas in the subject).
  • Atty Docket No.63XT-350609-WO Family 11.6 Provided herein is a method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of a whole cell payload as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutic support composition as described herein.
  • the cancer is metastatic.
  • the cancer is melanoma, renal cancer, prostate cancer, ovarian cancer, endometrial carcinoma, breast cancer, glioblastoma, lung cancer, soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical carcinoma, hepatocellular carcinoma, Kaposi’s sarcoma, Non-Hodgkin lymphoma, Hodgkin’s lymphoma, Wilm’s tumor/neuroblastoma, bladder cancer, thyroid adenocarcinoma, pancreatic neuroendocrine tumors, prostatic adenocarcinoma, nasopharyngeal carcinoma, or cutaneous T-cell lymphoma.
  • the approach can be used for the treatment and/or diagnosis of hematological malignancies such as myelodysplastic syndromes, acute myeloid leukemia, myeldysplastic syndromes, chronic myelogenous leukemia, chronic myelomonocytic leukemia, primary myelofibrosis, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy, plasma cell myeloma, follicular lymphoma, marginal zone lymphoma, classical Hodgkin lymphoma, monoclonal B-cell lymphocytosis, lymphoproliferative disorder NOS, T-cell lymphoma, precursor B-lymphoblastic leukemia, mantle cell lymphoma, plasmacytoma, Burkitt lymphoma, T-cell leukemia, hairy-cell leukemia, precursor T- lymphoblastic leukemia, nodular lymphocyte predominant Hodgkin lymph
  • the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.
  • the cancer is a solid tumor.
  • the cancer is a soft tissue sarcoma.
  • the soft tissue sarcoma is a fibrosarcoma, rhabdomyosarcoma, or Ewing’s sarcoma.
  • the method also comprises enhancing or eliciting an immune response.
  • the immune response is an increase in one or more of leukocytes, lymphocytes, monocytes, and eosinophils.
  • the method further comprising administering a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
  • an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
  • Anticancer agents, immunomodulatory agents, and their trans-cyclooctene prodrugs are known in the art. Atty Docket No.63XT-350609-WO Family 11.6 [0165] Indications for this approach include cancer, both hematological and solid cancers.
  • the approach can be used for the treatment and/or diagnosis of soft tissue sarcomas: rhabdomyosarcoma, fibrosarcoma, Ewing’s sarcoma, and all the different subtypes of soft tissue sarcoma as well as osteosarcoma.
  • the compositions can be for the treatment and/or diagnosis of pigmented vilonodular synovitis.
  • Compositions comprising the whole cell payload of the present disclosure find use in treatment and/or diagnosis of a condition or disease in a subject that is amenable to treatment or diagnosis by administration of a whole cell payload.
  • treatment is meant that at least an amelioration of the symptoms associated with the condition afflicting the subject is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., symptom, associated with the condition being treated.
  • amelioration also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the subject no longer suffers from the condition, or at least the symptoms that characterize the condition.
  • Treatment may include inhibition, that is, arresting the development or further development of clinical symptoms, e.g., mitigating or completely inhibiting an active disease.
  • Treatment may include relief, that is, causing the regression of clinical symptoms.
  • the term “treating” includes any or all of: reducing growth of a solid tumor, inhibiting replication of cancer cells, reducing overall tumor burden, prolonged survival, and ameliorating one or more symptoms associated with a cancer.
  • the subject to be treated can be one that is in need of therapy, where the subject to be treated is one amenable to treatment using a whole cell payload. Accordingly, a variety of subjects may be amenable to treatment as disclosed herein. Generally, such subjects are “mammals,” with humans being of interest.
  • Other subjects can include domestic pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats, horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease), as well as non- human primates (e.g., chimpanzees, and monkeys).
  • domestic pets e.g., dogs and cats
  • livestock e.g., cows, pigs, goats, horses, and the like
  • rodents e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease
  • non- human primates e.g., chimpanzees, and monkeys.
  • the whole cell payloads as described herein can be used for the treatment, prevention, and/or diagnosis of solid tumors, including but not limited to, melanoma (e.g., unresectable, metastatic melanoma), renal cancer (e.g., renal cell carcinoma), prostate cancer (e.g., metastatic castration resistant prostate cancer), ovarian cancer (e.g., epithelial ovarian cancer, such as metastatic epithelial ovarian cancer), endometrial carcinoma, breast cancer (e.g., triple negative breast cancer), glioblastoma (e.g., glioblastoma multiforme), lung cancer (e.g., non-small cell lung cancer), soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical
  • the disclosed approach lends itself well as an adjuvant / neoadjuvant system.
  • particles as disclosed herein could be placed during the biopsy; once the results from the study come back, the practitioner could deliver the appropriate cocktail to the desired site in the body. This would minimize the size of the tumor particularly in the context of a surgically resectable tumor. Then at the end of the surgery, the surgeon could place more particles around the surgical cavity and treat the patient with further doses of treatment (e.g., chemotherapy through the disclosed approach) to minimize the risk of any cancer cells that may have been missed in the surgical margins.
  • the disclosed methods may be used to treat or prevent cancer, including metastatic cancer.
  • Cancer is a group of related diseases that may include sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enablement of replicative immortality, induction of angiogenesis, and the activation of invasion and metastasis.
  • the disclosed methods may enhance or elicits an immune response against a cancer in the subject.
  • the immune response may lead to an increase in one or more of leukocytes, lymphocytes, monocytes, and eosinophils.
  • Cancer that may be treated by the disclosed methods, includes, but is not limited to, astrocytoma, adrenocortical carcinoma, appendix cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, brain stem cancer, brain stem glioma, breast cancer, cervical cancer, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, diffuse intrinsic pontine glioma, ductal cancer, endometrial cancer, ependymoma, Ewing’s sarcoma, esophageal cancer, eye cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, germ cell tumor, glioma, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, Kaposi’s sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer
  • the cancer that may be treated by the disclosed methods is melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.
  • the cancer is a solid tumor.
  • the cancer is a soft tissue carcinoma.
  • the cancer is afibrosarcoma.
  • the cancer is diffuse intrinsic pontine glioma.
  • the cancer is a metastatic cancer.
  • the methods can be used for the treatment, prevention, and/or diagnosis of solid tumors, including but not limited to, melanoma (e.g., unresectable, metastatic melanoma), renal cancer (e.g., renal cell carcinoma), prostate cancer (e.g., metastatic castration resistant prostate cancer), ovarian cancer (e.g., epithelial ovarian cancer, such as metastatic epithelial ovarian cancer), breast cancer (e.g., triple negative breast cancer), glioblastoma (e.g., glioblastoma multiforme), lung cancer (e.g., non-small cell lung cancer), soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, among others.
  • melanoma e.g., unresectable, metastatic melanoma
  • renal cancer e.g., renal cell carcinoma
  • prostate cancer e.g., metastatic castration resistant prostate cancer
  • ovarian cancer e
  • the disclosed methods may be used to treat or minimize the size of the tumor prior to surgical resection. This would minimize the size of the tumor particularly in the context of a surgically resectable tumor.
  • the disclosed whole cell payloads, or a system using the same may be administered during surgical resection.
  • the disclosed whole cell payloads, or a system using the same may be administered after surgical resection.
  • a therapeutic support composition as disclosed herein may be placed around the surgical cavity at the end of surgical resection and the subject may then be treated with further doses of whole cell payload to minimize the risk of any cancer cells that may have been missed in the surgical margins.
  • the disclosed methods may include multiple systemic doses of whole cell payload that focus at one location.
  • the disclosed methods may be used to deliver a whole cell payload to the site of a diffuse intrinsic pontine glioma (DIPG).
  • the disclosed methods may include delivering a whole cell payload systemically that are only activated at the tumor site.
  • the disclosed methods may be used as a neoadjuvant or adjuvant therapy.
  • Modes of Administration [0177] Methods of treatment may include any number of modes of admisteration.
  • Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, skin patches, skin creams, skin gels, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders.
  • a whole cell payload or composition comprising the same as disclosed herein disclosed herein may be dissolved or suspended in a physiologically acceptable diluent, such as water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • a physiologically acceptable diluent such as water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • Suitable oils may include, for example, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
  • a whole cell payload or composition comprising the same as disclosed herein may be administered in the form of an aqueous, lipid, oily or other kind of solution or suspension, or even administered in the form of liposomes or nano-suspensions.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • Therapeutic support compositions may be administered locally at the site of a tumor, such as by injection or implantation.
  • a whole cell payload, or composition comprising the same may be administered by any convenient route, in view of a subject’s condition and judgment of medical professionals.
  • Parenteral administration is a suitable means of administering a whole cell payload or composition comprising the same.
  • the amount administered to a subject can be initially determined based on guidance of a dose and/or dosage regimen.
  • the whole cell payload or composition comprising the same as disclosed herein can provide for targeted delivery and/or enhanced serum half-life of the bound drug, thus providing for at least one of reduced dose or reduced administrations in a dosage regimen.
  • the whole cell payload or composition comprising the same as disclosed herein can provide for reduced dose and/or reduced administration in a dosage regimen relative to the whole cell payload prior to being conjugated as described in the present disclosure.
  • a composition, or pharmaceutical formulation may be provided in unit dosage form.
  • the pharmaceutical formulation may be subdivided into unit doses containing appropriate quantities of the compositions of the present disclosure.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in pouches, vials or ampoules.
  • a kit comprising a whole cell payload or composition comprising the same as disclosed herein, and instructions for use thereof.
  • the kit further comprises a therapeutic support composition.
  • Compositions of the present disclosure can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc.
  • Suitable Atty Docket No.63XT-350609-WO Family 11.6 dosage ranges for the composition of the present disclosure include from 0.1 mg to 10,000 mg, or 1 mg to 1,000 mg, or 10 mg to 750 mg, or 25 mg to 500 mg, or 50 mg to 250 mg.
  • suitable dosages for the composition of the present disclosure include 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1,000 mg.
  • multiple doses are administered.
  • the frequency of administration can vary depending on any of a variety of factors, e.g., severity of the symptoms, condition of the subject, etc.
  • a whole cell payload or composition comprising the same as disclosed herein is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid).
  • the whole cell payload or composition comprising the same as disclosed herein can be administered at any suitable frequency, interval and duration.
  • a whole cell payload or composition comprising the same as disclosed herein can be administered once an hour, or two, three or more times an hour, once a day, or two, three, or more times per day, or once every 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, so as to provide the desired dosage level to the subject.
  • representative intervals include 5 min, 10 min, 15 min, 20 min, 30 min, 45 min and 60 minutes, as well as 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 20 hr, and 24 hours.
  • Administration can be administered once, twice, or three or more times, for an hour, for 1 to 6 hours, for 1 to 12 hours, for 1 to 24 hours, for 6 to 12 hours, for 12 to 24 hours, for a single day, for 1 to 7 days, for a single week, for 1 to 4 weeks, for a month, for 1 to 12 months, for a year or more, or even indefinitely.
  • the whole cell payload or composition comprising the same as disclosed herein of the present disclosure can be co-administered with another active agent.
  • Co-administration includes administering the whole cell payload or composition comprising the same and another active agent within 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 20 hr, or 24 hours of each other. Co-administration also includes administering simultaneously or approximately simultaneously (e.g., within about 1 min, 5 min, 10 min, 15 min, 20 min, or 30 minutes of each other), or sequentially in any order. In addition, the whole cell payload or composition comprising the same and another active agent can each be administered once a day, or two, three, or more times per day so as to provide the desired dosage level per day.
  • Co-administration can be accomplished by coimplantation or coinjection. Atty Docket No.63XT-350609-WO Family 11.6 [0190] In some embodiments, co-administration can be accomplished by co-formulation, e.g., preparing a single pharmaceutical formulation including both the whole cell payload or composition comprising the same and another active agent. In other embodiments, the whole cell payload or composition comprising the same and another active agent can be formulated separately and co-administered to the subject.
  • the invention provides a method of treating cancer or enhancing or eliciting an immune response comprising administering to a subject in need thereof: a therapeutically effective amount of a whole cell payload as described herein; a biocompatible support as described herein; and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
  • the disclosure also provides a pharmaceutical combination comprising a whole cell payload described herein, or composition thereof; a therapeutic support composition, as described herein; and an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof, for use in the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response.
  • a pharmaceutical combination comprising a whole cell payload described herein, or composition thereof; a therapeutic support composition, as described herein; and an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof, for use in the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response.
  • the disclosure also provides the use of a pharmaceutical combination comprising a whole cell payload described herein, or composition thereof; a therapeutic support composition; and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof for the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response.
  • an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof for the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response.
  • the components of the pharmaceutical combinations may be administered/used simultaneously, separately, or sequentially, and in any order, and the components may be administered separately or as a fixed combination.
  • the delay of progression or treatment of diseases according to the invention may comprise administration of the first active ingredient in free or pharmaceutically acceptable salt form and administration of the second active ingredient in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts or effective amounts, e.g., in daily dosages corresponding to the amounts described herein.
  • Atty Docket No.63XT-350609-WO Family 11.6 The individual active ingredients of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single dosage forms. The instant disclosure is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly.
  • a pharmaceutical combination defines either a fixed combination in one dosage unit form or separate dosages forms for the combined administration where the combined administration may be independently at the same time or at different times.
  • the whole cell payload and biocompatible support may be administered/used simultaneously (e.g., through coinjection or coimplantation), separately, or sequentially, followed by administration of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug.
  • the methods and uses in treating cancer include administering/localizing the whole cell payload at a tumor.
  • the administration of the whole cell payload, or composition thereof; the therapeutic support composition; and the additional therapeutic agent may inhibit the growth of the tumor.
  • Additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed whole cell payload. Sequential administration includes administration before or after the disclosed whole cell payload. An additional therapeutic agent may be administered before the disclosed whole cell payload. An additional therapeutic agent may be administered after the disclosed whole cell payload. An additional therapeutic agent may be administered at the same time as the disclosed whole cell payload. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed whole cell payload. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed whole cell payload.
  • administration of an additional therapeutic agent with a disclosed whole cell payload may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals.
  • the whole cell payload of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a whole cell payload of the present disclosure.
  • Anticancer agents include, but are not limited to, abiraterone acetate, Abitrexate (methotrexate), Abraxane (paclitaxel albumin-stabilized nanoparticle pormulation), ABVD, ABVE, ABVE- PC, AC, AC-T, Adcetris (brentuximab vedotin), ADE, ado-trastuzumab emtansine, Adriamycin (doxorubicin hydrochloride), Adrucil (fluorouracil), afatinib dimaleate, Afinitor (everolimus), Aldara (imiquimod), Atty Docket No.63XT-350609-WO Family 11.6 aldesleukin, alemtuzumab, Alimta (pemetrexed disodium), Aloxi (palonosetron hydrochloride), Ambochlorin (chlorambucil), aminolevulinic acid,
  • the anticancer agent may be a PBD dimer, calicheamicin, speromycin, tubulysin B, rhizoxin, dolastatin, didemnin B, camptothecin, CBI, temsirolimus, actinomycin D, epothilone B, taxol, cryptophycin, SN38, velcade, bruceantin, DAVLBH, DM1, phyllanthoside, Alimta, T2 Toxin, MMC, vantalanib, vinorelbine, brefeldin, sunitinib, daunomycin, semaxanib, tarceva, iressa, irinotecan, LY-541503, geldanomycin, gemcitabine, methotrexate, gleevec, topotecan, bleomycin, doxorubicin, cisplatin, N- mustards, etoposide, or 5-FU.
  • an anticancer agent is an anthracycline. In certain embodiments, anticancer agent is a taxane. In certain embodiments, anticancer agent is gemcitabine. In certain embodiments, anticancer agent is doxorubicin. In certain embodiments, anticancer agent is docetaxel. In certain embodiments, anticancer agent is SN38. In certain embodiments, anticancer agent is monomethyl auristatin E. In certain embodiments, an anticancer agent is an alkylating agent, antimetabolite (folate antagonist, purine antagonist, pyrimidine antagonist), antibiotic, taxane, vinca alkaloid, or campothecin analogue.
  • the whole cell payloads described herein may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein.
  • the synthesis of whole cell payloads described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. [0202] It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated.
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as Atty Docket No.63XT-350609-WO Family 11.6 suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and references cited therein.
  • the whole cell payloads of this disclosure may contain one or more chiral centers. Accordingly, if desired, such trans-cyclooctene-modified whole cells can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art.
  • racemic mixtures can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA).
  • a suspension of cells, such as gamma-delta T cells, (1e6 – 1e9 cells per mL) in aqueous buffer (50 mM potassium phosphate, 50 mM sodium chloride, 2 mM ethylenediaminetetraacetic acid disodium salt), pH 7.4 is cooled in an ice bucket.
  • a molar excess of trans-cyclooctene derivatized succinimidyl ester in dimethylacetamide (DMA) so that no more than 10% of the final solution is DMA %v/v.
  • the ratios of cells to NHS-PEG-TCO in the reaction mixture may be 1:1000, but includes ranges from 1:100 to 1:1e10.
  • the suspension is gently mixed and the reaction is allowed to proceed on ice (0.25 – 4 h) and, upon completion, quenched by the addition of an amine, such as ethanolamine.
  • the cells are collected by centrifugation and the supernatant discarded.
  • the cells are resuspended in fresh buffer and the steps are repeated at least three times to wash the cells and remove excess reagent.
  • the labeled cells are resuspended in phosphate buffered saline.
  • the labeling ratio (number of TCOs per cell) is determined by treatment of a sample of the cells with a tetrazine-linked fluorescent probe and the fluorescence signal per cell is measured, for example by flow cytometry.
  • the target labeling ratio may be ⁇ 1000 TCOs per cell, but includes ranges from 10 – 1,000,000 TCOs per cell.
  • the percent viability of the sample is also determined and the percentage of live cells should be greater than 90%.
  • Example 2 Trans-cyclooctene-cell conjugate (double stranded DNA) [0208] The reaction scheme of Example 2 is shown in FIG.2.
  • a solution of single-stranded oligonucleotide of defined sequence with an amine functional group at the 5’ end (1 mg/mL) in aqueous buffer (20 mM sodium bicarbonate, 2 mM ethylenediaminetetraacetic acid disodium salt), pH 8.0, is incubated with a molar excess of trans-cyclooctene derivatized succinimidyl ester in dimethylacetamide (DMA). The reaction is allowed to proceed at ambient temperature and, upon completion, purified by gel filtration column.
  • DMA dimethylacetamide
  • a solution of a complementary single-stranded oligonucleotide prepared with an activated ester at the 5’ end (1 mg/mL) in water is added to a suspension of cells, such as gd T cells, (1e6 – 1e9 cells/mL) in phosphate buffered saline and the reaction is allowed to proceed for up to 4 hours on ice. The excess reagent is removed by collection of the cells followed by washing the cells with phosphate buffered saline.
  • the solution of TCO-modified oligonucleotide is added to a suspension of oligonucleotide-modified cells to form the double-stranded oligonucleotide at 4 °C.
  • Excess reagent is removed by collection of the cells and washing with fresh buffer.
  • the labeling ratio is determined by treatment of a sample of the cells with a fluorescent probe and the fluorescence signal per cell is measured.
  • the target labeling ratio may be Atty Docket No.63XT-350609-WO Family 11.6 ⁇ 1000 TCOs per cell, but includes ranges from 10 – 1,000,000 TCOs per cell.
  • the percent viability of the sample is also determined and the percentage of live cells should be greater than 90%.
  • Example 3 Trans-cyclooctene-cell conjugate (host-guest interaction)
  • a 10 mM solution of reactive active ester in water is added to a suspension of as – buffered saline and the reaction is allowed to proceed for up to 4 hours on ice.
  • the excess reagent is removed by collection of the cells followed by washing the cells with phosphate buffered saline and the washed cells resuspended in phosphate buffered saline.
  • a solution of TCO-functionalized adamantane in DMA is added to a suspension of cyclodextrin- modified cells. The host-guest interaction is allowed to form on ice.
  • the excess reagent is removed by collection of the cells followed by washing the cells with phosphate buffered saline.
  • the labeling ratio is determined by treatment of a sample of the cells with a fluorescent probe and the fluorescence signal per cell is measured.
  • the target labeling ratio may be ⁇ 1000 TCOs per cell, but includes ranges from 10 – 1,000,000 TCOs per cell.
  • the percent viability of the sample is also determined and the percentage of live cells should be greater than 90%.
  • TCO-modified cells such as gd T cells or NK cells, as prepared in example 1
  • a murine tumor model such as NCI-N87 xenograft model in SCID mice.
  • TCO-modified cells or unmodified cells are resuspended in buffer, such as PBS, at approximately 1e9 cells per mL.
  • Tumor bearing mice are injected intratumorally with SQL70 (100 ⁇ L per mouse). Mice are randomized into groups and test groups receive IV injections of 10 ⁇ L per gram of TCO-cell solution while control groups receive identical injections of unmodified cells.
  • Tumor volumes and body weights are measured for all mice over the study period, such as three weeks.
  • TGI (%) [1-(Ti-T0)/ (Vi- V0)] ⁇ 100;
  • Ti is the average tumor volume of a treatment group on a given day
  • T0 is the average tumor Atty Docket No.63XT-350609-WO Family 11.6 volume of the treatment group on the day of treatment start
  • V i is the average tumor volume of the vehicle control group on the same day with T i
  • V 0 is the average tumor volume of the vehicle group on the day of treatment start.

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Abstract

The present disclosure relates generally to click modified whole cells which have applications, e.g., in the treatment of cancer and tumor growth.

Description

Atty Docket No.63XT-350609-WO Family 11.6 SYSTEM COMPRISING MODIFIED WHOLE CELL PAYLOADS FOR TARGETED DELIVERY CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Serial Number 63/483,909 filed February 8, 2023, the contents of which are hereby incorporated by reference in its entirety. FIELD [0002] The present disclosure relates generally to click modified whole cells which have applications, e.g., in the treatment of cancer and tumor growth. BACKGROUND [0003] Certain cell-based immunotherapy approaches involve generating immune cells (activated T cells or natural killer cells) that can circulate long enough in patients to engage and destroy cancer cells through their natural cytotoxicity pathways. Some of these approaches involve cancer vaccines, and others involve the genetic engineering of the immune cells to recognize leukemia biomarkers and the use of bispecific antibody T cell conjugates. However, these approaches also have significant limitations, such as substantial production costs and limited number of bispecific antibodies on the surface of cells. [0004] Bioorthogonal conjugation or click reactions are selective and orthogonal (non-interacting with) functionalities found in biological systems, and have found use in various applications in the fields of chemistry, chemical biology, molecular diagnostics, and medicine, where they can be used to facilitate the selective manipulation of molecules, cells, particles and surfaces, and the tagging and tracking of biomolecules in vitro and in vivo. These reactions include the Staudinger ligation, the azide-cyclooctyne cycloaddition, and the inverse-electron-demand Diels-Alder reaction. SUMMARY [0005] Provided herein is a system for targeted delivery of a live or whole cell to a treatment site, comprising: a whole cell payload comprising a whole cell covalently or non-covalently linked to a first bioorthogonal moiety; and a therapeutic support composition comprising a biocompatible support covalently linked to a second bioorthogonal moiety; wherein the first and second bioorthogonal moieties comprise a complimentary reactive functional group pair. [0006] In certain embodiments, the whole cell is a somatic cell. In certain embodiments, the whole cell is a genetically modified/transgenic cell. In certain embodiments, the whole cell is selected from the group consisting of an immune cell, bacterial cell, cardiomyocyte, gd T cell, cytokine induced killer, macrophage, neutrophil, natural killer T cell, primary cell, cytolytic T cell, killer cell, natural killer cell, monocyte, Atty Docket No.63XT-350609-WO Family 11.6 eosinophil, polymorphonuclear cell, granulocyte, mast cell, basophil, dendritic cell, B cell, T cell, antigen presenting cell, stem cell, cancer cell, transgenic cell, primary cell, cells from endocrine system, committed progenitors for the blood and immune system (various type), induced pluripotent stem cells, tumor infiltrating lymphocyte, lymphocyte-activated killer cell, pluripotent stem cell, totipotent stem cell, or multipotent stem cell. [0007] In certain embodiments, the complimentary reactive functional group pair is selected from: (1) an azide and a cyclooctyne; (2) a thiol and a maleimide; (3) a hydrazine/hydrazine/HyNic or alkoxyamine and a monoaldehyde, dialdehyde or 4FB; (4) a tetrazine and a trans-cyclooctene, (5) an aniline and an o-methoxy or amino phenol; (6) a tetrazine and a substituted cyclopropene; (7) a trans-cyclooctene and a substituted cyclopropene; (8) a cyclooctyne and a substituted cyclopropene; (9) a nitrile imine and a substituted cyclopropene; and (10) a tetrazine and a (1R,8S)-9λ3-bicyclo[6.1.0]non-4-yne. [0008] In some embodiments, provided is a method for treating cancer or enhancing or eliciting an immune response, comprising administering to a subject in need thereof, a whole cell payload and a biocompatible support as described herein to the subject. Administration of the biocompatible support can be prior to or after administration of the whole cell payload. [0009] In some embodiments, the cancer is metastatic. In some embodiments the cancer is melanoma, renal cancer, prostate cancer, ovarian cancer, endometrial carcinoma, breast cancer, glioblastoma, lung cancer, soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical carcinoma, hepatocellular carcinoma, Kaposi’s sarcoma, Non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Wilm’s tumor/neuroblastoma, bladder cancer, thyroid adenocarcinoma, pancreatic neuroendocrine tumors, prostatic adenocarcinoma, nasopharyngeal carcinoma, or cutaneous T-cell lymphoma. [0010] In some embodiments, the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a lymphoma or leukemia. In some embodiments, the cancer is a hematolical malignancy. BRIEF DESCRIPTION OF DRAWINGS [0011] FIG.1 shows the reaction scheme of Example 1 (Trans-cyclooctene-cell conjugate). [0012] FIG.2 shows the reaction scheme of Example 2 (Trans-cyclooctene-cell conjugate (double stranded DNA)). Atty Docket No.63XT-350609-WO Family 11.6 DETAILED DESCRIPTION [0013] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. 1. Definitions [0014] It is appreciated that certain features, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the invention are specifically embraced and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace subject matter that are, for example, compounds that are stable compounds (i.e., compounds that can be made, isolated, characterized, and tested for biological activity). In addition, all sub-combinations of the various embodiments and elements thereof (e.g., elements of the chemical groups listed in the embodiments describing such variables) are also specifically embraced and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein. A. Definitions [0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. [0016] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. Atty Docket No.63XT-350609-WO Family 11.6 [0017] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4. [0018] The conjunctive term “or” includes any and all combinations of one or more listed elements associated by the conjunctive term. For example, the phrase “an apparatus comprising A or B” may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B are present. The phrases “at least one of A, B, ... and N” or “at least one of A, B, ... N, or combinations thereof” are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, ... and N, that is to say, any combination of one or more of the elements A, B, ... or N including any one element alone or in combination with one or more of the other elements which may also include, in combination, additional elements not listed. [0019] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. [0020] The term “alkoxy” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy. [0021] The term “alkyl” as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 30 carbon atoms. The term “lower alkyl” or “C1-C6-alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1-C3- alkyl” means a straight or Atty Docket No.63XT-350609-WO Family 11.6 branched chain hydrocarbon containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, and n-decyl. [0022] The term “alkenyl” as used herein, means a hydrocarbon chain containing from 2 to 30 carbon atoms with at least one carbon-carbon double bond. The alkenyl group may be substituted or unsubstituted. For example, the alkenyl group may be substituted with an aryl group, such as a phenyl. [0023] The term “alkynyl,” as used herein, refers to straight or branched monovalent hydrocarbyl groups having from 2 to 30 carbon atoms, such as 2 to 20, or 2 to 10 carbon atoms and having at least 1 site of triple bond unsaturation. The term “alkyne” also includes non-aromatic cycloalkyl groups of from 5 to 20 carbon atoms, such as from 5 to 10 carbon atoms, having single or multiple rings and having at least one triple bond. Examples of such alkynyl groups include, but are not limited to acetylenyl (-C≡CH), and propargyl (-CH2C≡CH), and cycloalkynyl moieties, such as, but not limited to, substituted or unsubstituted cyclooctyne moieties. [0024] The term “alkoxyalkyl” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. [0025] The term “alkylene” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 30 carbon atoms, for example, of 2 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2CH2CH2-, and –CH2CH2CH2CH2CH2-. [0026] The term “amino acid” refers to both natural and unnatural amino acids, protected natural and unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally encoded amino acids include 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine) and pyrrolidine and selenocysteine. Amino acid analogs refer to compounds having the same basic chemical structure as a naturally occurring amino acid, i.e., by way of example only, an α-carbon attached to a hydrogen, carboxyl group, amino group, and R group. Such analogs can have a modified R group (e.g., norleucine as an example) or retain a modified peptide backbone while retaining the same basic chemical structure as a natural amino acid. Non-limiting examples of amino acid analogs include citrulline, homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium, homophenylalanine, ornithine, Atty Docket No.63XT-350609-WO Family 11.6 formyl glycine, phenyl glycine, para-azidophenyl glycine, para-azidophenylalanine, para-acetophenylalanine, 4-(3-methyl-(1,2,4,5-tetrazine))-phenylglyine, and 4-(3-methyl-(1,2,4,5-tetrazine))-phenylalanine. [0027] The term “aryl” as used herein, refers to a phenyl group, or bicyclic aryl or tricyclic aryl fused ring systems. Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a phenyl group. Tricyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to two other phenyl groups. Representative examples of bicyclic aryls include, but are not limited to, naphthyl. Representative examples of tricyclic aryls include, but are not limited to, anthracenyl. The monocyclic, bicyclic, and tricyclic aryls are connected to the parent molecular moiety through any carbon atom contained within the rings, and can be unsubstituted or substituted. [0028] The term “azide” as used herein, refers to the functional group –N3. [0029] The term “cycloalkyl” as used herein, refers to a carbocyclic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. “Cycloalkyl” also includes carbocyclic ring systems in which a cycloalkyl group is appended to the parent molecular moiety and is fused to an aryl group as defined herein, a heteroaryl group as defined herein, or a heterocycle as defined herein. [0030] The term “cycloalkenyl” as used herein, means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. [0031] The term “cyclooctene” as used herein, refers to a substituted or unsubstituted non-aromatic cyclic alkyl group of 8 carbon atoms, having a single ring with a double bond. Examples of such cyclooctene groups include, but are not limited to, substituted or unsubstituted trans-cyclooctene (TCO). [0032] The term “fluoroalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3-trifluoropropyl. [0033] The term “alkoxyfluoroalkyl” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein. Atty Docket No.63XT-350609-WO Family 11.6 [0034] The term “fluoroalkoxy” as used herein, means at least one fluoroalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkyloxy include, but are not limited to, difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy. [0035] The term “halogen” or “halo” as used herein, means Cl, Br, I, or F. [0036] The term “haloalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen. [0037] The term “haloalkoxy” as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. [0038] The term “heteroalkyl” as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, Si, O, P and N. The heteroatom may be oxidized. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, and alkyl sulfides. [0039] The term “heteroaryl” as used herein, refers to an aromatic monocyclic ring or an aromatic bicyclic ring system or an aromatic tricyclic ring system. The aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. The tricyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to two of a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Representative examples of monocyclic heteroaryl include, but are not limited to, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, and 2-oxo-1,2-dihydropyridinyl. Representative examples of bicyclic heteroaryl include, but are not limited to, chromenyl, benzothienyl, benzodioxolyl, benzotriazolyl, quinolinyl, thienopyrrolyl, thienothienyl, imidazothiazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, imidazopyridine, benzooxadiazolyl, and benzopyrazolyl. Representative examples of tricyclic heteroaryl include, but are not limited to, dibenzofuranyl and dibenzothienyl. The monocyclic, bicyclic, and tricyclic heteroaryls are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted. Atty Docket No.63XT-350609-WO Family 11.6 [0040] The term “heterocycle” or “heterocyclic” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3- dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, 1,3-dimethylpyrimidine-2,4(1H,3H)-dione, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3]heptan-2-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro- 1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, Atty Docket No.63XT-350609-WO Family 11.6 bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted. [0041] The term “hydroxyl” as used herein, means an –OH group. [0042] The term “hydroxyalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a hydroxyl group. [0043] The term “HyNic” refers to hydrazinonicotinamide. The term “4FB” refers to “4-formylbenzamide”. HyNic and 4FB are complimentary functional groups that readily react to form a arylhydrazone conjugate. [0044] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl or cycloalkyl) is indicated by the prefix “Cx-Cy-” or “Cx-y,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C3-alkyl” and “C1-3alkyl” refer to an alkyl substituent containing from 1 to 3 carbon atoms. The two conventions “Cx-Cy-” and “Cx-y” are used interchangeably and have the same meaning. [0045] The term “substituted” refers to a group that may be further substituted with one or more non- hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =O, =S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl. [0046] The term “tetrazine” refers to a substituted or unsubstituted aromatic cyclic group of 2 carbon atoms and 4 nitrogen atoms, having a single ring with three double bonds. Examples of tetrazine groups include 1,2,3,4-tetrazine and 1,2,4,5-tetrazine. As used herein, 1,2,4,5-tetrazine is referred to as a “Tz” group. [0047] The terms “targeted delivery” and “selectively delivering” refer to delivering an agent (e.g., whole cell payload) to an organ or tissue (or portion thereof) in need of treatment or diagnosis, without significant binding to other non-target organs or tissues (or portions thereof). [0048] The term “diagnostic agent” refers to agents that assist in diagnosing conditions or diseases. Representative diagnostic agents include imaging agents such as paramagnetic agents, optical probes, radionuclides, and the like. Paramagnetic agents are imaging agents that are magnetic under an externally applied field. Examples of paramagnetic agents include, but are not limited to, iron particles including iron nanoparticles and iron microparticles. Optical probes are fluorescent compounds that can be detected by excitation at one wavelength of radiation and detection at a second, different, wavelength of radiation. Atty Docket No.63XT-350609-WO Family 11.6 Optical probes of the present disclosure include, but are not limited to, Cy5.5, Alexa 680, Cy5, DiD (1,1’- dioctadecyl-3,3,3’,3’-tetramethylindodicarbocyanine perchlorate) and DiR (1,1’-dioctadecyl-3,3,3’,3’- tetramethylindotricarbocyanine iodide). Other optical probes include quantum dots. Radionuclides are elements that undergo detectable radioactive decay. Radionuclides useful in embodiments of the present disclosure include, but are not limited to, 3H, 11C, 13N, 18F, 19F, 60Co, 64Cu, 67Cu, 68Ga, 82Rb, 89Zr, 90Sr, 90Y, 99Tc, 99mTc, 111In, 123I, 124I, 125I, 129I, 131I, 137Cs, 177Lu, 186Re, 188Re, 211At, Rn, Ra, Th, U, Pu and 241Am. [0049] The terms “treatment site” and “targeted organ or tissue” refer to an organ or tissue that is being targeted for delivery of the whole cell payload. Representative organs and tissues for targeting include those that can be targeted by chemical or biological targeting agents, as well as those organs and tissues that cannot be targeted by chemical or biological targeting agents. [0050] The term “implanting” refers to surgical implantation into a subject’s body. [0051] The term “contacting” or “contact” refers to the process of bringing into contact at least two distinct species (e.g., two reagents or chemical compounds, or contact between the support composition and the whole cell payload) such that they can interact with each other, such as in a non-covalent or covalent binding interaction or binding reaction. It should be appreciated, however, the resulting complex or reaction product can be produced directly from an interaction or a reaction between the added reagents or from an intermediate from one or more of the added reagents or moieties, which can be produced in the contacting mixture. [0052] The term “binding agent” refers to an agent having a functional group capable of forming a covalent bond to a complementary functional group of another binding agent in a biological environment. Binding between binding agents in a biological environment may also be referred to as bioconjugation. Binding agents include bioorthogonal binding agents, which are binding agents having bioorthogonal functional groups. Bioorthogonal functional groups of bioorthogonal binding agents selectively react with a complementary bioorthogonal functional group of another bioorthogonal binding partner. Selective reaction between bioorthogonal binding partners can minimize side reactions with other binding agents, biological compounds, or other non-complementary bioorthogonal binding agents or non-complementary bioorthogonal functional groups. Bioorthogonal moieties or functional groups of bioorthogonal binding agents include, but are not limited to, an azide and alkyne for formation of a triazole via Click-chemistry reactions, trans- cyclooctene (TCO) and tetrazine (Tz) (e.g., 1,2,4,5-tetrazine), and others. The binding agents useful in the present disclosure may have a high reactivity with the corresponding binding agent so that the reaction is rapid. Atty Docket No.63XT-350609-WO Family 11.6 [0053] The term “functionalized” refers to a moiety having a functional group attached to the moiety, such as for example a moiety having a binding agent functional group (e.g., a bioorthogonal functional group) attached thereto. [0054] The term “administering” refers to any suitable route of administration to a subject, such as, but not limited to, oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. [0055] The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. [0056] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides (e.g., Br, Cl, I), sulfonate esters (e.g., triflate, mesylate, tosylate, and brosylate), and nitrophenols. [0057] The terms “pharmaceutically effective amount” and “therapeutically effective amount” refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent or reduce the risk of the occurrence or reoccurrence of the disease or disorder or symptom(s) thereof. In reference to tumorigenic proliferative disorders, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or decrease the growth rate of the tumor. [0058] As used herein, the term “subject,” “patient,” or “organism” includes humans and mammals (e.g., mice, rats, pigs, cats, dogs, and horses). Typical subjects to which an agent(s) of the present disclosure may be administered may include mammals, particularly primates, especially humans. For veterinary applications, suitable subjects may include, for example, livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats. For diagnostic or research applications, suitable subjects may include mammals, such as rodents (e.g., mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like. [0059] The term “treating” or “treatment” as used herein, means the treating or treatment of a disease or medical condition or symptom(s) thereof in a patient, such as a mammal (particularly a human) that includes: (a) ameliorating the disease or medical condition or symptom(s) thereof, such as, eliminating or causing regression of the disease or medical condition or symptom(s) thereof in a patient; (b) suppressing the disease or medical condition or symptom(s) thereof, for example by, slowing or arresting the development of the Atty Docket No.63XT-350609-WO Family 11.6 disease or medical condition or symptom(s) thereof in a patient; or (c) alleviating a symptom of the disease or medical condition or symptom(s) thereof in a patient. [0060] The term “physiological conditions” is meant to encompass those conditions compatible with living cells, e.g., predominantly aqueous conditions of a temperature, pH, salinity, etc. that are compatible with living cells. [0061] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. [0062] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. [0063] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. [0064] The compounds may exist as stereoisomers wherein asymmetric or chiral centers are present. The stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, Atty Docket No.63XT-350609-WO Family 11.6 “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM202JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods. [0065] It should be understood that the compounds may possess tautomeric forms as well as geometric isomers, and that these also constitute an aspect of the invention. [0066] The present disclosure also includes isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated are 11C, 13N, 15O, and 18F. Isotopically-labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent. B. Whole Cell Payloads [0067] Provided herein are a whole cell payloads for targeted delivery. The whole cell payloads are covalently or non-covalently linked to a first bioorthogonal moiety. The first bioorthogonal moiety can be any bioorthogonal moiety, provided the first bioorthogonal moiety comprises a reactive functional group which is complimentary to the second bioorthogonal moiety. In some embodiments, the first bioorthogonal moiety is an azide, a cyclooctyne, a thiol, a maleimide, a hydrazine, a hydrazine, HyNic, an alkoxyamine, a monoaldehyde, a dialdehyde, 4FB, a tetrazine, a trans-cyclooctene, an aniline, an o-methoxy phenol, an amino phenol, a tetrazine, a substituted cyclopropene, a cyclooctyne, a nitrile imine, or a (1R,8S)-9λ3- bicyclo[6.1.0]non-4-yne. [0068] Methods for modifying a whole cell with a bioorthogonal moiety are known in the art, where the first bioorthogonal moiety can be covalently or non-covalently linked to the whole cell. [0069] In some embodiments, the first bioorthogonal moiety is covalently linked to the whole cell. Suitable linking methods can comprise non-chemically modified whole cells such that the first bioorthogonal moiety Atty Docket No.63XT-350609-WO Family 11.6 is bonded to the whole cell via a functional group on the surface of the whole cell, such as an amino acid or other suitable functional group. Surface modification of whole cells via NHS esters (or N- hydroxysuccinimide) methodology is a well-used method. [0070] In some embodiments, prior to attaching the bioorthogonal group, the whole cell is modified first by methods, such as, metabolic glycoengineering, such as introducing azide groups onto the cell surface, provided the modification is done with minimal biological perturbation. For example, the first bioorthogonal moiety can be attached to an azide on the whole cell via a heterobifunctional crosslinker. [0071] In some embodiments, the first bioorthogonal moiety is non-covalently linked to whole cell. Suitable linking methods can comprise a chemically modified whole cell or non-chemically modified whole cell such that the first bioorthogonal moiety is bound to the whole cell via a binding site on the surface of the whole cell, such as a DNA or RNA strand, or other suitable functional group. In some embodiments, the whole cell is modified with a DNA or RNA strand such that the first bioorthogonal moiety is bound to the whole cell via a complimentary DNA or RNA strand. [0072] In some embodiments, the whole cell can be a live cell, dead cell, or a mixture of live and dead cells. Non-limiting examples of cells can include an immune cell, natural killer cell, a macrophage, a neutrophil, a T-cell, a natural killer T-cell (NKT cells), a stem cell, a cancer cell, an antigen presenting cell (APC), or a bacterial cell. Cells used as a therapeutic agent may be primary cells from a sample from a subject, cells from a cell line, and/or transgenic cells. Cells may be eukaryotic or prokaryotic. In some embodiments, the cell is an effector cell. In general, the term “effector cell” relates to a cell that performs a specific function in response to a stimulus such as cells in the immune system. In some embodiments, effector cells are cells that induce cell death. Non-limiting examples of effector cells include lymphocytes (such as T cells, including cytolytic T cells (CTLs)), killer cells, natural killer cells, macrophages, monocytes, eosinophils, neutrophils, polymorphonuclear cells, granulocytes, mast cells, and basophiles. In some embodiments, the cell is a cell involved in the cognitive and/or activation phases of an immune response, such as antigen presenting cells (APCs), including dendritic cells. [0073] In certain embodiments, the whole cell is a somatic cell. In certain embodiments, the whole cell is a genetically modified/transgenic cell. [0074] Subjects from which cells may be derived include, but are not limited to, mammals, such as a human. Samples may be provided directly by the subject, or indirectly through one or more intermediaries, such as a sample collection service provider or a medical provider (e.g., a physician or nurse). Examples of samples from a subject from which cells may be derived include, without limitation, skin, heart, lung, kidney, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gall bladder, colon, intestine, brain, Atty Docket No.63XT-350609-WO Family 11.6 prostate, esophagus, thyroid, serum, saliva, urine, gastric and digestive fluid, tears, stool, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, sweat, mucus, earwax, oil, glandular secretions, spinal fluid, hair, fingernails, plasma, nasal swab or nasopharyngeal wash, spinal fluid, cerebral spinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk, and/or other excretions or body tissues. Examples of cell types to which a linker may be conjugated include, but are not limited to, lymphoid cells, such as B cell, T cell (cytotoxic T cell, natural killer T cell, regulatory T cell, T helper cell), natural killer cell, cytokine induced killer (CIK) cells (see e. g. US20080241194); myeloid cells, such as granulocytes (basophil granulocyte, eosinophil granulocyte, neutrophil granulocyte/hypersegmented neutrophil), monocyte/macrophage, red blood cell (reticulocyte), mast cell, thrombocyte/megakaryocyte, dendritic cell; cells from the endocrine system, including thyroid (thyroid epithelial cell, parafollicular cell), para thyroid (parathyroid chief cell, oxyphil cell), adrenal (chromaffin cell), pineal (pinealocyte) cells; cells of the nervous system, including glial cells (astrocyte, microglia), magnocellular neurosecretory cell, stellate cell, Boettcher cell, and pituitary (gonadotropc, corticotropc, thyrotrope, somatotrope, lactotroph); cells of the respiratory system, including pneumocyte (type I pneumocyte, type II pneumocyte), Clara cell, goblet cell, dust cell; cells of the circulatory system, including myocardiocyte, pericyte; cells of the digestive system, including stomach (gastric chief cell, parietal cell), goblet cell, Paneth cell, G cells, D cells, ECL cells, I cells, K cells, S cells; enteroendocrine cells, including enterochromaffin cell, APUD cell, liver (hepatocyte, Kupffer cell), cartilage/bone/muscle; bone cells, including osteoblast, osteocyte, osteoclast, teeth (cementoblast, ameloblast); cartilage cells, including chondroblast, chondrocyte; skin cells, including trichocyte, keratinocyte, melanocyte (nevus cell); muscle cells, including myocyte; urinary system cells, including podocyte, juxta glomerular cell, intraglomerular mesangial cell/extraglomerular mesangial cell, kidney proximal tubule brush border cell, maculadensa cell; reproductive system cells, including spermatozoon, Sertoli cell, Leydig cell, ovum; and other cells, including adipocyte, fibroblast, tendon cell, epidermal keratinocyte (differentiating epidermal cell), epidermal basal cell (stem cell), keratinocyte of fingernails and toe nails, nail bed basal cell (stem cell), medullary hair shaft cell, cortical hair shaft cell, cuticular hair shaft cell, cuticular hair root sheath cell, hair root sheath cell of Huxley’s layer, hair root sheath cell of Henle’s layer, external hair root sheath cell, hair matrix cell (stem cell), wet stratified barrier epithelial cells, surface epithelial cell of stratified squamous epithelium of cornea, tongue, oral cavity, esophagus, anal canal, distal urethra and vagina, basal cell (stem cell) of epithelia of cornea, tongue, oral cavity, esophagus, anal canal, distal urethra and vagina, urinary epithelium cell (lining urinary bladder and urinary ducts), exocrine secretory epithelial cells, salivary gland mucous cell (polysaccharide-rich secretion), salivary gland serous cell (glycoprotein enzyme-rich secretion), Von Ebner’s gland cell in tongue (washes taste buds), mammary Atty Docket No.63XT-350609-WO Family 11.6 gland cell (milk secretion), lacrimal gland cell (tear secretion), ceruminous gland cell in ear (wax secretion), eccrine sweat gland dark cell (glycoprotein secretion), eccrine sweat gland clear cell (small molecule secretion), apocrine sweat gland cell (odoriferous secretion, sex-hormone sensitive), gland of Moll cell in eyelid (specialized sweat gland), sebaceous gland cell (lipid-rich sebum secretion), Bowman’s gland cell in nose (washes olfactory epithelium), Brunner’s gland cell in duo denum (enzymes and alkaline mucus), seminal vesicle cell (secretes seminal fluid components, including fructose for swimming sperm), prostate gland cell (secretes seminal fluid components), bulbourethral gland cell (mucus secretion), Bartholin’s gland cell (vaginal lubricant secretion), gland of Littre cell (mucus secretion), uterus endometrium cell (carbohydrate secretion), isolated goblet cell of respiratory and digestive tracts (mucus secretion), stomach lining mucous cell (mucus secretion), gastric gland zymogenic cell (pepsinogen secretion), gastric gland oxyntic cell (hydrochloric acid secretion), pancreatic acinar cell (bicarbonate and digestive enzyme secretion), Paneth cell of small intestine (lysozyme secretion), type II pneumocyte of lung (surfactant secretion), Clara cell of lung, hormone secreting cells, anterior pituitary cells, somatotropes, lactotropes, thyrotropes, gonadotropes, corticotropes, intermediate pituitary cell, magnocellular neurosecretory cells, gut and respiratory tract cells, thyroid gland cells, thyroid epithelial cell, parafollicular cell, parathyroid gland cells, parathyroid chief cell, oxyphil cell, adrenal gland cells, chromaffin cells, Leydig cell of testes, theca interna cell of ovarian follicle, corpus luteum cell of ruptured ovarian follicle, granulosa lutein cells, theca lutein cells, juxtaglomerular cell (renin secretion), macula densa cell of kidney, metabolism and storage cells, barrier function cells (lung, gut, exocrine glands and urogenital tract), kidney, type I pneumocyte (lining air space of lung), pancreatic duct cell (centroacinar cell), nonstriated duct cell (of sweat gland, salivary gland, mammary gland, etc.), duct cell (of seminal vesicle, prostate gland, etc.), epithelial cells lining closed internal body cavities, ciliated cells with propulsive function, extracellular matrix secretion cells, contractile cells; skeletal muscle cells, stem cell, heart muscle cells, blood and immune system cells, erythrocyte (red blood cell), megakaryocyte (platelet precursor), monocyte, connective tissue macro phage (various types), epidermal Langerhans cell, osteo clast (in bone), dendritic cell (in lymphoid tissues), micro glial cell (in central nervous system), neutrophil granulocyte, eosinophil granulocyte, basophil granulocyte, mast cell, helper T cell, suppressor T cell, cytotoxic T cell, natural killer T cell, B cell, natural killer cell, reticulocyte, stem cells and committed progenitors for the blood and immune system (various types), pluripotent stem cells, totipotent stem cells, induced pluripotent stem cells, adult stem cells, sensory transducer cells, autonomic neuron cells, sense organ and peripheral neuron supporting cells, central nervous system neurons and glial cells, lens cells, pigment cells, melanocyte, retinal pigmented epithelial cell, germ cells, oogonium/oocyte, spermatid, spermatocyte, spermatogonium cell (stem cell for spermatocyte), Atty Docket No.63XT-350609-WO Family 11.6 spermatozoon, nurse cells, ovarian follicle cell, Sertoli cell (in testis), thymus epithelial cell, interstitial cells, or interstitial kidney cells, or any combination thereof. [0075] The cells can be healthy cells, or diseased cells. For example the cells can be from a cancer condition such as epithelial cancer or carcinoma, including but not limited to, a carcinoma of the prostate, carcinoma of the breast, carcinoma of the colon, pancreatic carcinoma, lung carcinoma, skin carcinoma (melanoma), esophageal carcinoma, etc.; or the putative cell of origin (hepatocellular carcinoma, renal cell carcinoma, and small cell lung carcinoma, etc.). Other cancer cells include myoepithelial cancers, sarcomas, gliomas, lymphomas, leukemias, carcinoids, and any other type of cancer. Cells in other states or conditions of tissue may be used including but not limited to, autoimmune conditions, immune system related conditions (e.g., allergies, likely immune response to challenge), cells representative of conditions that contribute to or exhibit resistance to standard treatments, susceptibility or predisposition to a condition (e.g., susceptibility to diabetes, thyroid conditions, stroke, cardiovascular conditions, or liver quality, function, and degeneration, etc.). In some embodiments, the cell is a primary cell. In other embodiments, the cell is a mammalian cell. In some other embodiments, the cell is a stem cell. [0076] In some embodiments the cells are from a cell line. Examples of cell lines include, but are not limited to, NK92, NK3.3, C8161, CCRF-CEM, MOLT, MIMCD-3, NHDF, HeLa-S3, Huhl, Huh4, Huh7, HUVEC, HASMC, HEKn, HEK, MiaPaCell, Panel, PC-3, TF1, CTLL-2, CIR, Rato, CV1, RPTE, A10, T24, J82, A375, ARH-77, Calul, SW 480, SW620, SKOV3, SK-UT, CaCo2, P388D1, SEM-K2, WEHI-231, HB56, TIB55, Jurkat, J45.01, LRMB, Bcl-1, BC-3, IC21, DLD2, Raw264.7, NRK, NRK-52E, MRC5, MEF, Hep G2, HeLa B, HeLa T4, COS, COS-1, COS-6, COS-M6A, BS-C-1 monkey kidney epithelial, BALB/3T3 mouse embryo fibroblast, 3T3 Swiss, 3T3-L1, 132-d5 human fetal fibroblasts; 10.1 mouse fibroblasts, 293-T, 313, 721, 9L, A2780, A2780ADR, A2780cis, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1 cells, BEAS-2B, bEnd.3, BHK-21, BR 293, BxPC3, C3H-10T1/2, C6/36, Cal-27, CHO, CHO-7, CHO-IR, CHO-K1, CHO-K2, CHO T, CHO Dhfr-, COR-L23, COR-L23/CPR, COR-L23/5010, COR-L23/R23, COS-7, COV-434, CML T1, CMT, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6/AR1, EMT6/AR10.0, FM3, H1299, H69, HB54, HB55, HCA2, HEK-293, HeLa, Hepalclc7, HL-60, HMEC, HT-29, Jurkat, JY cells, K562 cells, Ku812, KCL22, KG1, KYO1, LNCap, Ma-Mel 1-48, MC-38, MCF-7, MCF 10A, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCK II, MDCK II, MOR/0.2R, MONO-MAC 6, MTD 1A, MyEnd, NCI-H69/CPR, NCI-H69/LX10, NCI-H69/LX20, NCI-H69/LX4, NIH- 3T3, NALM-1, NW-145, OPCN/OPCT cell lines, Peer, PNT -1A/PNT 2, RenCa, RIN 5F, RMA/RMAS, Saos-2 cells, Sf-9, SkBr3, T2, T-47D, T84, THP1 cell line, U373, US7, U937, VCap, Vero cells, WM39, WT-49, X63, YAC-1, YAR, and transgenic varieties thereof. Cell lines are available from a variety of Atty Docket No.63XT-350609-WO Family 11.6 sources known to those with skill in the art (see, e.g., the American Type Culture Collection (ATCC) (Manassas, Va.)) [0077] In some embodiments, the cell is a T-cell. T-cells include all cells which express CD3, including T- cell subsets which also express CD4 and/or CD8. T-cells include both naive and memory cells (e. g. TCM TEM and TEMRA), effector cells (e. g. CTLs or Tc cells), helper cells (e. g. Th1, Th2, Th3, Th9, Th7, TFH), regulatory cells (e. g. Treg, and Trl cells), NKT cells, tumor infiltrating lymphocytes (TILs), lymphocyte- activated killer cells (LAKS), aßT cells, yoT cells, and similar unique classes of the T-cell lineage. In some embodiments, the T cells are activated T-cells. [0078] In some embodiments, the cell is genetically modified or transgenic. The genetically modified cell can be an immune or non-immune cell. [0079] In some embodiments, the cell is from a genetically modified cell-based therapy. Genetically modified cell-based therapies include, but are not limited to CAR T, TCR, TIL, and adoptive NK therapies. Examples include Breyanzi (lisocabtagene maraleucel), Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (brexucabtagene autoleucel), Abecma (idecabtagene vicleucel), and Provenge (sipuleucel-T). [0080] T cells can be obtained from a number of sources, including peripheral blood leukocytes, bone marrow, lymph node tissue, spleen tissue, and tumors. In some embodiments, peripheral blood leukocytes are obtained from an individual by leukopheresis. Isolating T cells from peripheral blood leukocytes may include lysing the red blood cells and separate peripheral blood leukocytes from monocytes by, for example, centrifugation through, e. g., a PERCOLL®gradient. A specific subpopulation of T cells, such as CD4 + or CD8 + T cells, can be further isolated by positive or negative selection techniques. For example, negative selection of a T cell population can be accomplished with a combination of antibodies directed to surface markers unique to the cells negatively selected. One suitable technique includes cell sorting via negative magnetic immunoadherence, which utilizes a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected. For example, to isolate CD4 + cells, a monoclonal antibody cocktail typically includes antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD8. The process of negative selection may be used to produce an essentially homogenous population of the desired T cell population. In some embodiments, the T-cell is an alpha/beta T-cell. In some embodiments, the T-cell is a delta/gamma T-cell. In some embodiments, a composition comprises a mixture of two or more (e. g.2, 3, 4, 5, or more) different kind of T-cells. In some embodiments, the linker conjugated to the T-cell is not associated with an activation domain. Atty Docket No.63XT-350609-WO Family 11.6 [0081] In some embodiments, the cell is a member of an enriched population of cells. One or more desired cell types may be enriched by any suitable method, non-limiting examples of which include treating a population of cells to trigger expansion and/or differentiation to a desired cell type, treatment to stop the growth of undesired cell type(s), treatment to kill or lyse undesired cell type(s), purification of a desired cell type (e. g. purification on an affinity column to retain desired or undesired cell types on the basis of one or more cell surface markers). In some embodiment, the enriched population of cells is a population of cells enriched in gamma/delta T cells (yd T cells). yd T cells may be enriched by any suitable method. For example, the percentage of yd T cells may be expanded in a population of hematolymphoid cells by first administering IL-12 and a ligand of CD2, followed by administering IL-2 and T cell mitogenic stimulus. In some embodiments, expanded y8 T cells can survive under culture conditions for a period of time which is greater than the period of time during which hematolymphoid cells in primary culture survive under the same conditions. In some embodiments, the enriched population of cells is a population of cells enriched in Cytokine Induced Killer (CIK) cells. CIK cells can be generated from peripheral blood mononuclear cells (PBMC) by in-vitro culture in presence of IFN-Y, OKT-3, and IL-2. In some embodiments, high dose Th1- type hormonal stimulation of a T-cells with IFN-1, OKT-3 and IL-2 is used to produce CIK AI cells as the enriched population of cells. In some embodiments, the CIK cells are CD3 + CD56 + cells. [0082] In some embodiments, a cell embodied in a subject complex or to which a linker is conjugated is a stem cell. In general, “stem cell” refers to a cell that is capable of differentiating into different, more specialized cell types. A stem cell may be multi-potent, pluripotent, or totipotent. A stem cell may be isolated from a subject, from a cell line, or induced from a non-pluripotent cell. Embryonic stem cells may reside in the blastocyst and give rise to embryonic tissues, whereas somatic stem cells may reside in adult tissues for the purpose of tissue regeneration and repair. The terms “pluripotent” and “pluripotency” refer to cells with the ability to give rise to progeny that can undergo differentiation, under appropriate conditions, into cell types that collectively exhibit characteristics associated with cell lineages from the three germ layers (endoderm, mesoderm, and ectoderm). Pluripotent stem cells can contribute to tissues of a prenatal, postnatal or adult organism. A standard art accepted test, such as the ability to form a teratoma in 8-12 week old SCID mice, can be used to establish the pluripotency of a cell population. However, identification of various pluripotent stem cell characteristics can also be used to identify pluripotent cells. More specifically, human pluripotent stem cells may express at least some, and optionally all, of the markers from the following non- limiting list : SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, TRA-2-49/6E, ALP, Sox2, E-cadherin, UTF-1, Oct4, Lin28, Rexl, and Nanog. An “induced pluripotent stem cell” (iPSC) refers to a pluripotent stem cell artificially derived from a non-pluripotent cell. A non-pluripotent cell can be a cell of lesser potency to self- renew and differentiate than a pluripotent stem cell. Cells of lesser potency can be, but are not limited to, Atty Docket No.63XT-350609-WO Family 11.6 somatic stem cells, tissue specific progenitor cells, primary or secondary cells. Without limitation, a somatic stem cell can be a hematopoietic stem cell, a mesenchymal stem cell, an epithelial stem cell, a skin stem cell or a neural stem cell. Non-pluripotent cells can be reprogrammed to become iPSCs by the introduction of pluripotency genes or proteins, such as Oct4, Sox2, Lin28 and Nanog into the cell. The genes or proteins may be introduced into the differentiated cells by any suitable technique, including plasmid transfection, viral transfection, or direct protein delivery. Following introduction of the pluripotency genes or proteins, the ancestor cells may be cultured. Cells expressing pluripotency markers may be isolated and/or purified to produce a population of iPS cells. In some embodiments, the cell is an embryonic stem cell (ESC), such as from an ESC cell line, non-limiting examples of which include CHB-1 to CHB-12, RUES1 to RUES3, HUES1 to HUES28, HUES45, HUES48, HUES49, HUES53, HUES62 to HUES66, WA01 (H1), WA07 (H7), WA09 (H9), WA13 (H13), WA14 (H14), NYUES1 to NYUES7, MFS5, and UCLA1 to UCLA3. [0083] In some embodiments, the cell is an immune cell. [0084] In some embodiments, the cell is a natural killer cell. [0085] In some embodiments, the cell is macrophage. [0086] In some embodiments, the cell is a neutrophil. [0087] In some embodiments, the cell is a T cell. [0088] In some embodiments, the cell is a gamma delta T cell. [0089] In some embodiments, the cell is a natural killer T cell. [0090] In some embodiments, the cell is a stem cell. [0091] In some embodiments, the cell is an antigen presenting cell. [0092] In some embodiments, the cell is a dendritic cell. [0093] In some embodiments, the cell is from a subject. In some embodiments, the cell is from a commercial or ex vivo cell line. In some embodiments, the cell is transgenic. [0094] In some embodiments, the cell is an effector cell, including but not limited to, a lymphocyte, such as a T cell, a cytolytic T cell, a cytotoxic T cell, a T helper cell, a killer cell, a natural killer cell, a cytokine induced killer cell, a macrophage, a monocyte, an eosinophil, a neutrophil, a polymorphonuclear cell, a granulocyte, a mast cell, or a basophil. [0095] In some embodiments, the cell is an induced pluripotent stem cell (iPSC). [0096] In some embodiments, the cell is an embryonic stem cell. Atty Docket No.63XT-350609-WO Family 11.6 [0097] In some embodiments, the cell is a purified population of cells. In some embodiments, the cell is a mixture of different cell populations. [0098] The whole cell is covalently or non-covalently linked to a first bioorthogonal moiety. In some embodiments, the whole cell comprises from 10 – 1,000,000, or from 10 – 500,000, or from 10 – 100,000, or from 10 – 50,000, or from 10 – 10,000, or from 500 – 10,000, or from 10 – 5,000, or from 500 – 5,000, or from 10 – 1,000, or from 500 – 1,000, or about 1,000 bioorthogonal moieties. The bioorthogonal moieties can be the same or different. In some embodiments, the bioorthogonal moieties are the same. [0099] In some embodiments, the whole cell comprises a first bioorthogonal moiety covalently bonded thereto, optionally via a linker. When live cells are employed, the percent viability of the sample can be determined after bonding to the first bioorthogonal moiety. In some embodiments, when live cells are employed, the percentage of live cells is greater than 80%, or 85%, or 90%, or 95%. [0100] In some embodiments, the first bioorthogonal moiety is covalently bonded to the whole cell via a linker. [0101] In some embodiments, the whole cell comprises a surface N-terminal amino acid, wherein the linker is covalently bonded to a N-terminal amino acid. [0102] In some embodiments, the first bioorthogonal moiety is covalently bonded to the whole cell via a cysteine or lysine residue on the whole cell. [0103] In some embodiments, the linker comprises one or more amino acids. [0104] In some embodiments, the linker comprises a polypeptide. [0105] In some embodiments, the linker comprises one or more of a hydrazone, a hydrazide, a disulfide, a N-succinimidyl-4-(2-pyridyldithio)pentanoate (SPP), a N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB), a 4-(4’-acetylphenoxy)butanoic acid (AcBut), one or more linear or branched, natural or unnatural amino acid, a valine-citrulline (Val-Cit) moiety, or a phenylalanine-lysine (Phe-Lys) moiety. [0106] In some embodiments, the linker comprises 1 to 100 linking atoms, from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms, or from 1 to 40 linking atoms, or from 1 to 30 linking atoms, or from 1 to 20 linking atoms, or from 1 to 10 linking atoms, or from 1 to 5 linking atoms, or from 5 to 30 linking atoms, or from 10 to 30 linking atoms, or from 5 to 40 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms. [0107] In some embodiments, the linker comprises one or more chain heteroatoms and one or more alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene moieties; Atty Docket No.63XT-350609-WO Family 11.6 wherein each alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene moiety may be independently optionally substituted with one to five substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl. [0108] In some embodiments, the linker is an alkylene linker optionally comprising one or more -O-, -S-, amine, ester, amide, carbamate, carbonate, thio-succinimide, or ketone functional group. [0109] In some embodiments, the linker is of the formula: -Y10-(CH2)n’-Y20-(CH2)m''-Y30- wherein: each of Y10, Y20, and Y30 are independently a bond, -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -OC(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O)-, -OC(O)-, -OC(O)O-, alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; wherein each alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl; each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and n' and m'' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. [0110] In some embodiments, the first bioorthogonal moiety comprises a trans-cyclooctene moiety. In some embodiments, the first bioorthogonal moiety comprises a trans-cyclooctene moiety and the second bioorthogonal moiety comprises a tetrazine moiety. [0111] In some embodiments, the trans-cyclooctene moiety is of the formula:
Figure imgf000023_0001
wherein: Atty Docket No.63XT-350609-WO Family 11.6 R1A, at each occurrence, is independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; q is 0, 1, or 2; q1 is 0 or 1; R1B, at each occurrence, is independently selected from the group consisting of G1, OH, –NR1c–C1-4alkylene–G1, –NR1c–C1-4alkylene–N(R1d)2, –NR1c–C1-6alkylene–N(C1-4alkyl)3 +, –N(R1c)CHR1eCO2H, –N(R1c)–C1-6alkylene–CO2H, –N(R1f)–C2-4alkylene–(N(C1-4alkylene–CO2H)– C2-4alkylene)n–N(C1-4alkylene–CO2H)2, –N(R1c)CHR1eC(O)OC1-6alkyl, –N(R1c)–C1-6alkylene– C(O)OC1-6alkyl, –N(R1f)–C2-4alkylene–(N(C1-4alkylene–C(O)OC1-6alkyl)–C2-4alkylene)n–N(C1-4alkylene– C(O)OC1-6alkyl)2, –N(R1c)–C1-6alkylene–SO3H, –N(R1c)–(CH2CH2O)1-3–CH2CH2N((CH2CH2O)1-3– C1-6alkylene–CO2H)2, and –N(R1c)–CH(CH2O–(CH2CH2O)0-2–C1-6alkylene–CO2H)2; R1c and R1d, at each occurrence, are independently hydrogen or C1-4alkyl; R1e, at each occurrence, is independently –C1-4alkylene–CO2H, –C1-4alkylene–CONH2, or –C1-4alkylene–OH; R1f, at each occurrence, is independently hydrogen, C1-6alkyl, or C1-4alkylene–CO2H; n, at each occurrence, is independently 0, 1, 2, or 3; L2, at each occurrence, is independently selected from the group consisting of –C(O)– and C1-3alkylene; and G1, at each occurrence, is independently an optionally substituted heterocyclyl. [0112] In some embodiments, the trans-cyclooctene moiety is of the formula: ; R1A, at each occurrence, is
Figure imgf000024_0001
consisting of C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; q is 0, 1 or 2; q1 is 0 or 1; Atty Docket No.63XT-350609-WO Family 11.6 R1B, at each occurrence, is independently selected from the group consisting of G1, OH, –NR1c–C1-4alkylene–G1, –NR1c–C1-4alkylene–N(R1d)2, –NR1c–C1-6alkylene–N(C1-4alkyl)3 +, –N(R1c)CHR1eCO2H, –N(R1c)–C1-6alkylene–CO2H, –N(R1f)–C2-4alkylene–(N(C1-4alkylene–CO2H)–C2- 2,
Figure imgf000025_0001
R1e, at each occurrence, is independently –C1-4alkylene–CO2H, –C1-4alkylene–CONH2, or –C1-4alkylene–OH; R1f, at each occurrence, is independently hydrogen, C1-6alkyl, or C1-4alkylene–CO2H; n, at each occurrence, is independently 0, 1, 2, or 3; L2, at each occurrence, is independently selected from the group consisting of –C(O)– and C1-3alkylene; and G1, at each occurrence, is independently an optionally substituted heterocyclyl. [0113] In some embodiments, the trans-cyclooctene moiety is of the formula: ; R1A, at each occurrence, is
Figure imgf000025_0002
group consisting of C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; q is 0, 1 or 2; q1 is 0 or 1; R1B, at each occurrence, is independently selected from the group consisting of G1, OH, –NR1c–C1-4alkylene–G1, –NR1c–C1-4alkylene–N(R1d)2, –NR1c–C1-6alkylene–N(C1-4alkyl)3+, –N(R1c)CHR1eCO2H, –N(R1c)–C1-6alkylene–CO2H, –N(R1f)–C2-4alkylene–(N(C1-4alkylene–CO2H)–C2- 4alkylene)n–N(C1-4alkylene–CO2H)2, –N(R1c)CHR1eC(O)OC1-6alkyl, –N(R1c)–C1-6alkylene–C(O)OC1-6alkyl, Atty Docket No.63XT-350609-WO Family 11.6 –N(R1f)–C2-4alkylene–(N(C1-4alkylene–C(O)OC1-6alkyl)–C2-4alkylene)n–N(C1-4alkylene–C(O)OC1-6alkyl)2, –N(R1c)–C1-6alkylene–SO3H, –N(R1c)–(CH2CH2O)1-3–CH2CH2N((CH2CH2O)1-3–C1-6alkylene–CO2H)2, and –N(R1c)–CH(CH2O–(CH2CH2O)0-2–C1-6alkylene–CO2H)2; R1c and R1d, at each occurrence, are independently hydrogen or C1-4alkyl; R1e, at each occurrence, is independently –C1-4alkylene–CO2H, –C1-4alkylene–CONH2, or –C1-4alkylene–OH; R1f, at each occurrence, is independently hydrogen, C1-6alkyl, or C1-4alkylene–CO2H; n, at each occurrence, is independently 0, 1, 2, or 3; L2, at each occurrence, is independently selected from the group consisting of –C(O)– and C1-3alkylene; and G1, at each occurrence, is independently an optionally substituted heterocyclyl. [0114] In some embodiments, the trans-cyclooctene moiety is of the formula: wherein:
Figure imgf000026_0001
R2 is -OH, 2-aminoethanesulfonic acid, an N-linked natural or unnatural amino acid, or an optionally substituted ethylenediamine; wherein R2 may be optionally further substituted with a polyether. [0115] In some embodiments, the trans-cyclooctene moiety with a portion of the linker comprises a group capable of releasing the trans-cyclooctene moiety from the whole cell portion (such as upon tetrazine activation). In some embodiments, the trans-cyclooctene moiety linked to the whole cell portion via a linker having a -OC(O)- or -OC(O)NH- moiety at the attachments to the trans-cyclooctene moiety. In some embodiments, the trans-cyclooctene moiety with a linker portion having the Formula: ;
Figure imgf000026_0002
Atty Docket No.63XT-350609-WO Family 11.6 wherein: R2 is -OH, 2-aminoethanesulfonic acid, an N-linked natural or unnatural amino acid, or an optionally substituted ethylenediamine; wherein R2 may be optionally further substituted with a polyether. In some embodiments, the remaining portion of the linker comprises an alkylene or polyether with an amino acid terminus for bonding to the whole cell portion. [0116] In some embodiments, the trans-cyclooctene moiety is of the .
Figure imgf000027_0001
[0117] In some embodiments, the trans-cyclooctene moiety is of the .
Figure imgf000027_0002
[0118] In some embodiments, the trans-cyclooctene moiety is of the . [0119] In some embodiments, the trans-cyclooctene moiety (optionally
Figure imgf000027_0003
of the formula: 1-50, or 1-40, or 1-30, or 1-20, or 10-30, or 10-20, or
Figure imgf000027_0004
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. [0120] In some embodiments, the trans-cyclooctene moiety is of the formula:
Atty Docket No.63XT-350609-WO Family 11.6 OH O O O O , , .
Figure imgf000028_0001
(e.g., a trans-cyclooctene-modified whole cell) as disclosed herein, and a pharmaceutically acceptable carrier. In some embodiments, the whole cell payload is formulated for systemic administration. C. Therapeutic Support Composition [0122] Provided is a system comprising a therapeutic support composition, wherein the therapeutic support composition comprises a biocompatible support covalently linked to a second bioorthogonal moiety. [0123] In some embodiments, the therapeutic support composition comprises a support. Supports may be biocompatible supports compositions, i.e., compatible with the subject’s body. In some instances, a support is non-toxic to the subject and does not substantially react with tissue or biological compounds in the subject. For example, the support can be a hydrogel, among others. A support is capable of implantation into a subject’s body and supporting binding agents (e.g., tetrazine-containing group). Representative supports include, but are not limited to polymers, viscous or non-viscous liquid materials, gels, hydrogels, polysaccharide hydrogels, a cross-linked polymer matrix, a metal, a ceramic, a plastic, a bone graft material, alginate, cellulose, chitosan, hyaluronic acid, chondroitin sulfate, heparin, and the like. Supports also include particles, such as nanoparticles, microparticles, and the like. [0124] Hydrogels may be polysaccharide hydrogels, alginate, cellulose, hyaluronic acid, chitosan, chitosin, chitin, hyaluronic acid, chondroitin sulfate, heparin, and the like. Other suitable sugar-based biomaterials Atty Docket No.63XT-350609-WO Family 11.6 include those described in Polymer Advanced Technology, 2014, 25, 448-460. Polymers that may be used as the support can include, but are not limited to, polyphosphazenes, polyanhydrides, polyacetals, poly(ortho esters), polyphosphoesters, polycaprolactones, polyurethanes, polylactides, polycarbonates, polyamides, and polyethers, and blends/composites/co-polymers thereof. Representative polyethers include, but are not limited to, poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), triblock Pluronic ([PEG]n-[PPG]m- [PEG]n), PEG diacrylate (PEGDA), and PEG dimethacrylate (PEGDMA). The support can also include proteins and other poly(amino acids), such as collagen, gelatin, elastin and elastin-like polypeptides, albumin, fibrin, poly(gamma-glutamic acid), poly(L-lysine), poly(L-glutamic acid), poly(aspartic acid), and the like. [0125] In some embodiments, the support is a hydrogel. In some embodiments, the support is an alginate. In some embodiments, the support is chitin. In some embodiments, the support is a hyaluronic acid (e.g., a non-hydrogel hyaluronic acid substantially without crosslinks). In some embodiments, the support is chitosin. [0126] In certain embodiments, the support is a particle. Particles of the present disclosure can have a diameter that is 2 cm or less, such as 1.5 cm or less, or 1 cm or less, or 0.5 cm or less. For example, the particles can be nanoparticles or microparticles. Nanoparticles include particles having average dimensions in the nanometer scale (e.g., 1000 nm or less). Microparticles are particles having average dimensions in the micrometer scale (e.g., 1000 μm or less). By “average” is meant the arithmetic mean. In some embodiments, the nanoparticles have a diameter ranging from 1 nm to 1 μm, such as from 10 nm to 1 μm, or 25 nm to 1 μm, or 50 nm to 1 μm, or 75 nm to 1 μm, or 100 nm to 1 μm, or 150 nm to 1 μm, or 200 nm to 1 μm, or 250 nm to 1 μm, or 300 nm to 1 μm, or 350 nm to 1 μm, or 400 nm to 1 μm, or 450 nm to 1 μm, or 500 nm to 1 μm. In other embodiments, the microparticles have a diameter ranging from 1 μm to 1 mm, such as from 10 μm to 1 mm, or 25 μm to 1 mm, or 50 μm to 1 mm, or 75 μm to 1 mm, or 100 μm to 1 mm, or 150 μm to 1 mm, or 200 μm to 1 mm, or 250 μm to 1 mm, or 300 μm to 1 mm, or 350 μm to 1 mm, or 400 μm to 1 mm, or 450 μm to 1 mm, or 500 μm to 1 mm. In further embodiments, small particles on the order of 10-100 nm in diameter may be assembled to form larger complexes, such as clusters or assemblies on the order of 1-10 μm. Particles of the present disclosure may be substantially spherical, such that the particles have a substantially circular cross-section. Other particle shapes may also be used, such as, but not limited to, ellipsoid, cubic, cylindrical, conical, needle, or other irregular shapes. [0127] A “particle” may take the form of any fabricated material, a molecule, cryptophan, a virus, a phage, etc. The particle may be composed of a material, such as, but not limited to, a metal, a ceramic, a plastic, a glass, a composite, a polymer, a hydrogel, and the like. For example, the particles may be made of an inert material, such as alginate or iron oxide. In some examples, the particles may be magnetic and can be formed Atty Docket No.63XT-350609-WO Family 11.6 from a paramagnetic, super-paramagnetic or ferromagnetic material, or other material that responds to a magnetic field. Further, a particle may be of any shape, for example, spheres, rods, non-symmetrical shapes, etc. The particles, or a group of several particles in a complex, may be functionalized with a receptor that has a specific affinity to bind to or interact with a clinically relevant substrate. The receptor may be inherent to the particle itself. For example, the particle itself may be a virus or a phage with an inherent affinity for certain substrates. Additionally or alternatively, the particles can be functionalized by covalently or otherwise attaching or associating a receptor that specifically binds or otherwise recognizes a particular clinically relevant substrate. The functionalized receptor can be an antibody, peptide, nucleic acid, phage, bacteria, virus, or any other molecule with a defined affinity for a target substrate. Examples of material that may be used for the “particles” and/or “carrier” include polylactic acid, polyglycolic acid, PLGA polymers, alginates and alginate derivatives, gelatin, collagen, fibrin, hyaluronic acid, laminin rich gels, agarose, natural and synthetic polysaccharides, polyamino acids, polypeptides, polyesters, poly anhydrides, polyphosphazines, poly(vinyl alcohols), poly(alkylene oxides), poly(allylamines) (PAM), poly(acrylates), modified styrene polymers, pluronic polyols, poloxamers, poly(uronic acids), poly(vinylpyrrolidone) and copolymers or graft copolymers of any of the above. These examples do not limit their concentration, their cross-linking with different agents, their method of administration, their tailored degradation profiles and other characteristics known to those skilled in the art. [0128] The particles, or a group of several particles in a complex, may be functionalized with a targeting agent (e.g., a ligand or antibody) that specifically binds (or substantially specifically binds) to a target (e.g., a target receptor or a cell surface target, such as a clinically relevant receptor or cell surface target (e.g., antigen)). The targeting agent may be attached directly to the particle itself. The targeting agent can be an antibody, peptide, nucleic acid, phage, bacteria, virus, or any other molecule with a specific affinity for a target receptor or cell surface target. In some instances, the receptor or cell surface target is PD-1, CTLA-4, HER2/neu, HER1/EGFR, VEGFR, 4-1BB, GITR, or other cellular receptors or cell surface targets. [0129] In some embodiments, the targeting agent is a monoclonal antibody. A monoclonal antibody can be an entire monoclonal antibody, or a fragment thereof (e.g., antigen-binding fragment (Fab)). In certain embodiments, the targeting agent is an antibody, or antibody fragment, that targets one or more of CD25 (NCBI Gene ID 3559), CEA (NCBI Gene ID 634), CEACAM5 (NCBI Gene ID 1048), ASPH (NCBI Gene ID 444), EGFR (NCBI Gene ID 1956), EPCAM (NCBI Gene ID 4072), VEGFR (NCBI Gene ID 3791), PDGFR (NCBI Gene ID 5159), TROP2 (NCBI Gene ID 4070), Nectin4 (NCBI Gene ID 81607), PSMA (NCBI Gene ID 2346), BCMA (NCBI Gene ID 608), CD22 (NCBI Gene ID 933), CD20 (NCBI Gene ID 920), CD19 (NCBI Gene ID 930), CD79b (NCBI Gene ID 974), CD38 (NCBI Gene ID 952), CD45 (NCBI Gene ID 5788), Endoglin (NCBI Gene ID 2022), FGFR2 (NCBI Gene ID 14183), C4.4A (NCBI Gene ID Atty Docket No.63XT-350609-WO Family 11.6 27076), Claudin-18.2 (NCBI Gene ID 51208), MMP9 (NCBI Gene ID 4318), Folate receptor (NCBI Gene ID 2348), DLL3 (NCBI Gene ID 10683), CD138 (NCBI Gene ID 6382), CD56 (NCBI Gene ID 4684), CD37 (NCBI Gene ID 951), CD74 (NCBI Gene ID 972), mesothelin (NCBI Gene ID 10232), IL-6R (NCBI Gene ID 3570), SLAMF7 (NCBI Gene ID 57823), BAFF (NCBI Gene ID 10673), MUC1 (NCBI Gene ID 4582), GPC3 (NCBI Gene ID 2719), HER2 (NCBI Gene ID 2064), HER3 (NCBI Gene ID 2065), CD30 (NCBI Gene ID 943), CD33 (NCBI Gene ID 945), CD123 (NCBI Gene ID 3563), GPNMB (NCBI Gene ID 10457), cMET (NCBI Gene ID 4233), CD142 (NCBI Gene ID 2152), NaPi2B (NCBI Gene ID 10568), GCC (NCBI Gene ID 2984), STEAP1 (NCBI Gene ID 26872), MUC16 (NCBI Gene ID 94025), CD70 (NCBI Gene ID 970), CD44 (NCBI Gene ID 960), vWF (NCBI Gene ID 7450), TNF (NCBI Gene ID 7124), IL-6R (NCBI Gene ID 3570), BCMA (NCBI Gene ID 608), ADAMTS5 (NCBI Gene ID 11096), CX3CR1 (NCBI Gene ID 1524), CXCR4 (NCBI Gene ID 7852), TfR1 (NCBI Gene ID 7037), VEGFR (NCBI Gene ID 3791), or PSMA (NCBI Gene ID 2346). [0130] Other compounds or molecules, such as fluorophores or autofluorescent or luminescent markers, which may assist in detecting the particles (e.g., in vivo detection), may also be attached to the particles. The ligands and/or detectable labels may be attached directly to the particle or attached to the particle through bioorthogonal functional groups as described herein. [0131] In certain embodiments, the support is a bone graft material, such as a bone graft substitute material. A bone graft substitute material is a material structurally similar to bone. In some instances, a bone graft substitute material is bioresorbable such that the bone graft substitute material can dissolve or be absorbed in the body over time. A bone graft substitute material can be osteoconductive, such that it facilitates blood vessel and new bone formation into the bone graft substitute material. In some instances, the bone graft substitute material is osteoinductive, such that it facilitates the formation of new bone through active recruitment of mesenchymal stem cells from the surrounding tissue. For example, growth factors, such as bone morphogenetic proteins, may be included in the bone graft substitute material. Bone graft substitute materials include, but are not limited to, hydroxyapatite, tricalcium phosphate, demineralized bone matrix, bovine collagen, calcium sulfate, calcium phosphate, cancellous bone chips, and the like, and combinations thereof. [0132] Therapeutic support compositions of the present disclosure include a support and a first binding agent covalently linked to the support. The binding agent may be attached to the support on a surface of the support, such as a solvent-accessible surface of the support (e.g., a surface of the support that is in contact with the surrounding solvent). In some cases, the binding agent is attached directly to the support. For example, the binding agent may be covalently attached to the surface of the support, e.g., through a covalent bond, such as an amide, amine, ester, carbamate, urea, thioether, thiocarbamate, thiocarbonate, thiourea, etc. Atty Docket No.63XT-350609-WO Family 11.6 In some instances, the binding agent is covalently attached to the support through an amide bond. In other instances, the binding agent may be linked to the support via a linker. Any suitable linker can be used to link the binding agent to the support. Representative linkers can have from 1 to 100 linking atoms, and can include ethylene-oxy groups, amines, esters, amides, carbamates, carbonates, and ketone functional groups. For example, linkers may have from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms. Representative linkers include, but are not limited to, those shown below: [0133] The
Figure imgf000032_0001
moiety, provided the second bioorthogonal moiety comprises a reactive functional group which is complimentary to the first bioorthogonal moiety. In some embodiments, the second bioorthogonal moiety is an azide, a cyclooctyne, a thiol, a maleimide, a hydrazine, a hydrazine, HyNic, an alkoxyamine, a monoaldehyde, a dialdehyde, 4FB, a tetrazine, a trans-cyclooctene, an aniline, an o-methoxy phenol, an amino phenol, a tetrazine, a substituted cyclopropene, a cyclooctyne, a nitrile imine, or a (1R,8S)-9λ3-bicyclo[6.1.0]non-4-yne. [0134] In some embodiments, the complimentary reactive functional group pair comprise a tetrazine moiety and a trans-cyclooctene moiety. In some embodiments, the second bioorthogonal moiety comprises a tetrazine moiety. In some embodiments, the first bioorthogonal moiety comprises a trans-cyclooctene moiety and the second bioorthogonal moiety comprises a tetrazine moiety. [0135] In some embodiments, the second bioorthogonal moiety comprises a tetrazine moiety of formula: ;
Figure imgf000032_0002
Atty Docket No.63XT-350609-WO Family 11.6 wherein: R20 is selected from the group consisting of hydrogen, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR'R", C(=O)O-R', C(=O)S-R', C(=S)OR', C(=S)SR', C(=O)NR'R", C(=S)NR'R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S)R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with one to three Z1; R' and R" at each occurrence are independently selected from hydrogen, aryl and alkyl; R''' at each occurrence is independently selected from aryl and alkyl; R30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy; haloalkoxy, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; Ra, R31a and R31b are each independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each Z1 is independently selected from halo, oxo, cyano, nitro, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, heteroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR' R", C(=O)O-R', C(=O)S-R', C(=S)O-R', C(=S)S-R', C(=O)NR'R", C(=S)NR'R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S)R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; and t is 0, 1, 2, 3, or 4. [0136] In certain embodiments, the each R20 is independently phenyl, pyrimidinyl, triazinyl, oxazolyl, isoxazole, imidazolyl, oxadiazolyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,3- d]pyrimidinyl, or 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl; wherein each is independently optionally substituted with one to three Z1. [0137] In certain embodiments, the therapeutic support compositions comprise a support and a tetrazine moiety of formula: Atty Docket No.63XT-350609-WO Family 11.6 ; wherein R20 is
Figure imgf000034_0001
halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF3, CF2-R', NO2, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR' R", C(=O)O-R', C(=O)S-R', C(=S)O-R', C(=S)S-R', C(=O)NR'R", C(=S)NR' R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S) R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; R' and R" at each occurrence are independently selected from hydrogen, aryl and alkyl; and R''' at each occurrence is independently selected from aryl and alkyl; R30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; haloalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; Ra, R31a and R31b are each independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; and t is 0, 1, 2, 3, or 4. [0138] In certain embodiments, the therapeutic support compositions have formula:
Figure imgf000034_0002
wherein R20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF3, CF2-R', NO2, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR' R", C(=O)O-R', C(=O)S-R', C(=S)O-R', C(=S)S-R', C(=O)NR'R", C(=S)NR' R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S) R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; R' and R" at each occurrence are independently selected from hydrogen, aryl and alkyl; R''' at each occurrence is independently selected from Atty Docket No.63XT-350609-WO Family 11.6 aryl and alkyl; and R22 is a linker of 1 to 100 linking atoms, and can include ethylene-oxy groups, amines, esters, amides, carbamates, carbonates, and ketone functional groups. For example, linkers may have from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms. [0139] In certain embodiments, the therapeutic support compositions have formula: ;
Figure imgf000035_0001
wherein R20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF3, CF2-R', NO2, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR' R", C(=O)O-R', C(=O)S-R', C(=S)O-R', C(=S)S-R', C(=O)NR'R", C(=S)NR' R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S) R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; R' and R" at each occurrence are independently selected from hydrogen, aryl and alkyl; R''' at each occurrence is independently selected from aryl and alkyl; R30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; haloalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; Ra, R31a and R31b are each independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; and t is 0, 1, 2, 3, or 4. [0140] In certain embodiments, the therapeutic support compositions comprise substituted alginate having units of formula:
Atty Docket No.63XT-350609-WO Family 11.6
Figure imgf000036_0001
wherein R20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF3, CF2-R', NO2, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR' R", C(=O)O-R', C(=O)S-R', C(=S)O-R', C(=S)S-R', C(=O)NR'R", C(=S)NR' R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S) R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; R' and R" at each occurrence are independently selected from hydrogen, aryl and alkyl; and R''' at each occurrence is independently selected from aryl and alkyl. [0141] In certain embodiments, the therapeutic support composition comprises units of formula: .
Figure imgf000036_0002
Atty Docket No.63XT-350609-WO Family 11.6 [0142] In some embodiments, the therapeutic support compositions comprise units of formula: .
Figure imgf000037_0001
the therapeutic support compositions comprise units of formula: .
Figure imgf000037_0002
comprise substituted hyaluronic acid having units of formula (II):
Figure imgf000037_0003
a linker of 1 to 100 linking atoms; and R20 is as defined herein.
Figure imgf000037_0004
Atty Docket No.63XT-350609-WO Family 11.6 .
Figure imgf000038_0001
[0146] In still further is hydrogen or C1-4alkyl. [0147] Compounds of formula (II)
Figure imgf000038_0002
(II-A):
Figure imgf000038_0003
wherein R20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF3, CF2-R', NO2, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR' R", C(=O)O-R', C(=O)S-R', C(=S)O-R', C(=S)S-R', C(=O)NR'R", C(=S)NR' R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S) R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; R' and R" at each occurrence are Atty Docket No.63XT-350609-WO Family 11.6 independently selected from hydrogen, aryl and alkyl; and R''' at each occurrence is independently selected from aryl and alkyl. In further embodiments according to formula (II-A), R20 is hydrogen or C1-4alkyl. [0148] In some embodiments, the therapeutic support compositions comprise units of formula: or
Figure imgf000039_0001
WO/2015/139025A1, and WO/2014/205126A1, the entire contents of each of which is incorporated herein by reference in their entirety. [0150] The hyaluronic acid derivative includes a hyaluronic acid having a plurality of glucuronic acid units and a tetrazine-containing group linked or directly bonded to a glucuronic acid unit of the hyaluronic acid. The hyaluronic acid may also have a plurality of N-acetylglucosamine units. In certain embodiments, the N- acetylglucosamine units of the hyaluronic acid are not linked or conjugated to the tetrazine-containing group. [0151] The tetrazine-containing group can be linked or directly bonded through a carboxylic acid of a glucuronic acid unit. The tetrazine-containing group can be incorporated into the hyaluronic acid from about 0.1% to about 80% as measured by the % of carboxylic acids being linked or conjugated to the tetrazine- Atty Docket No.63XT-350609-WO Family 11.6 containing group, such as about 1% to about 75%, about 5% to about 75%, about 10% to about 50%, or about 40% to about 75% as measured by the % of carboxylic acids being linked or conjugated to the tetrazine-containing group. D. Methods of Treatment [0152] Aspects of the present disclosure include methods for delivering a whole cell payload to a target location in a subject. By using the system as described herein, selective delivery of the whole cell payload can be achieved to a target location (e.g., an organ or tissue, or portion thereof), without targeting other locations in the subject (e.g., other organs or tissues, or portions thereof) that do not need treatment. The target location or treatment site can be a stationary location (e.g., an organ or tissue, tumor, or portion thereof) or a systemic location (e.g., cells in the blood or other bodily fluid). [0153] The whole cell payload is designed to target a treatment site in a subject via binding with the complimentary reactive functional group on the therapeutic support, and upon reaction of the first and second bioorthogonal moieties (e.g., contact of the TCO moiety with the tetrazine moiety), the whole cell is delivered to the treatment site in the subject. [0154] In certain embodiments, the method comprises administering a therapeutic support composition to a subject in need thereof, followed by administering a whole cell payload. In certain embodiments, the whole cell payload is administered systemically. In certain embodiments, the whole cell payload is administered locally. In certain embodiments, the therapeutic support composition is administered locally. In certain embodiments, the therapeutic support composition is administered locally and the whole cell payload is administered systemically. Due to the localized administration to a desired location in the subject, the therapeutic support composition will localize the whole cell payload at the desired target location. [0155] In certain embodiments, the method includes administering to the subject a whole cell payload such that the whole cell is bound to the therapeutic support composition to form a support complex. For example, the whole cell payload may be administered systemically to the subject. Upon administration of the whole cell payload to the subject, contact between the support composition and the whole cell payload occurs, such that the first bioorthogonal moiety and its complementary bioorthogonal moiety bind to one another to form a support complex, thereby selectively delivering the whole cell to the target location in the subject. In some embodiments, selective delivery of the whole cell payload results in a concentration of the whole cell at the target location that is greater than the concentration elsewhere in the subject (e.g., at non-targeted areas in the subject). Atty Docket No.63XT-350609-WO Family 11.6 [0156] Provided herein is a method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of a whole cell payload as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutic support composition as described herein. [0157] In some embodiments, the cancer is metastatic. In some embodiments the cancer is melanoma, renal cancer, prostate cancer, ovarian cancer, endometrial carcinoma, breast cancer, glioblastoma, lung cancer, soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical carcinoma, hepatocellular carcinoma, Kaposi’s sarcoma, Non-Hodgkin lymphoma, Hodgkin’s lymphoma, Wilm’s tumor/neuroblastoma, bladder cancer, thyroid adenocarcinoma, pancreatic neuroendocrine tumors, prostatic adenocarcinoma, nasopharyngeal carcinoma, or cutaneous T-cell lymphoma. [0158] In certain embodiments, the approach can be used for the treatment and/or diagnosis of hematological malignancies such as myelodysplastic syndromes, acute myeloid leukemia, myeldysplastic syndromes, chronic myelogenous leukemia, chronic myelomonocytic leukemia, primary myelofibrosis, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy, plasma cell myeloma, follicular lymphoma, marginal zone lymphoma, classical Hodgkin lymphoma, monoclonal B-cell lymphocytosis, lymphoproliferative disorder NOS, T-cell lymphoma, precursor B-lymphoblastic leukemia, mantle cell lymphoma, plasmacytoma, Burkitt lymphoma, T-cell leukemia, hairy-cell leukemia, precursor T- lymphoblastic leukemia, nodular lymphocyte predominant Hodgkin lymphoma, as well as others. [0159] In some embodiments, the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer. [0160] In some embodiments, the cancer is a solid tumor. [0161] In some embodiments, the cancer is a soft tissue sarcoma. [0162] In some embodiments, the soft tissue sarcoma is a fibrosarcoma, rhabdomyosarcoma, or Ewing’s sarcoma. [0163] In some embodiments, the method also comprises enhancing or eliciting an immune response. In some embodiments the immune response is an increase in one or more of leukocytes, lymphocytes, monocytes, and eosinophils. [0164] In some embodiments, the method further comprising administering a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof. Anticancer agents, immunomodulatory agents, and their trans-cyclooctene prodrugs are known in the art. Atty Docket No.63XT-350609-WO Family 11.6 [0165] Indications for this approach include cancer, both hematological and solid cancers. In certain embodiments, the approach can be used for the treatment and/or diagnosis of soft tissue sarcomas: rhabdomyosarcoma, fibrosarcoma, Ewing’s sarcoma, and all the different subtypes of soft tissue sarcoma as well as osteosarcoma. The compositions can be for the treatment and/or diagnosis of pigmented vilonodular synovitis. [0166] Compositions comprising the whole cell payload of the present disclosure find use in treatment and/or diagnosis of a condition or disease in a subject that is amenable to treatment or diagnosis by administration of a whole cell payload. By “treatment” is meant that at least an amelioration of the symptoms associated with the condition afflicting the subject is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., symptom, associated with the condition being treated. As such, treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the subject no longer suffers from the condition, or at least the symptoms that characterize the condition. Treatment may include inhibition, that is, arresting the development or further development of clinical symptoms, e.g., mitigating or completely inhibiting an active disease. Treatment may include relief, that is, causing the regression of clinical symptoms. For example, in the context of cancer, the term “treating” includes any or all of: reducing growth of a solid tumor, inhibiting replication of cancer cells, reducing overall tumor burden, prolonged survival, and ameliorating one or more symptoms associated with a cancer. [0167] The subject to be treated can be one that is in need of therapy, where the subject to be treated is one amenable to treatment using a whole cell payload. Accordingly, a variety of subjects may be amenable to treatment as disclosed herein. Generally, such subjects are “mammals,” with humans being of interest. Other subjects can include domestic pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats, horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease), as well as non- human primates (e.g., chimpanzees, and monkeys). [0168] In certain embodiments, the whole cell payloads as described herein can be used for the treatment, prevention, and/or diagnosis of solid tumors, including but not limited to, melanoma (e.g., unresectable, metastatic melanoma), renal cancer (e.g., renal cell carcinoma), prostate cancer (e.g., metastatic castration resistant prostate cancer), ovarian cancer (e.g., epithelial ovarian cancer, such as metastatic epithelial ovarian cancer), endometrial carcinoma, breast cancer (e.g., triple negative breast cancer), glioblastoma (e.g., glioblastoma multiforme), lung cancer (e.g., non-small cell lung cancer), soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical carcinoma, hepatocellular carcinoma, Atty Docket No.63XT-350609-WO Family 11.6 Kaposi’s sarcoma, Non-Hodgkin lymphoma, Hodgkin lymphoma, Wilm’s tumor/neuroblastoma, bladder cancer, thyroid adenocarcinoma, pancreatic neuroendocrine tumors, prostatic adenocarcinoma, nasopharyngeal carcinoma, cutaneous T-cell lymphoma, among others. The disclosed approach lends itself well as an adjuvant / neoadjuvant system. For example, particles as disclosed herein could be placed during the biopsy; once the results from the study come back, the practitioner could deliver the appropriate cocktail to the desired site in the body. This would minimize the size of the tumor particularly in the context of a surgically resectable tumor. Then at the end of the surgery, the surgeon could place more particles around the surgical cavity and treat the patient with further doses of treatment (e.g., chemotherapy through the disclosed approach) to minimize the risk of any cancer cells that may have been missed in the surgical margins. Cancer [0169] The disclosed methods may be used to treat or prevent cancer, including metastatic cancer. Cancer is a group of related diseases that may include sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enablement of replicative immortality, induction of angiogenesis, and the activation of invasion and metastasis. The disclosed methods may enhance or elicits an immune response against a cancer in the subject. The immune response may lead to an increase in one or more of leukocytes, lymphocytes, monocytes, and eosinophils. [0170] Cancer that may be treated by the disclosed methods, includes, but is not limited to, astrocytoma, adrenocortical carcinoma, appendix cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, brain stem cancer, brain stem glioma, breast cancer, cervical cancer, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, diffuse intrinsic pontine glioma, ductal cancer, endometrial cancer, ependymoma, Ewing’s sarcoma, esophageal cancer, eye cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, germ cell tumor, glioma, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, Kaposi’s sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, macroglobulinemia, melanoma, mesothelioma, mouth cancer, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary cancer, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue carcinoma, soft tissue sarcoma, solid tumor, squamous cell carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma, thyroid cancer, trophoblastic tumor, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilm’s tumor. Atty Docket No.63XT-350609-WO Family 11.6 [0171] In some embodiments, the cancer that may be treated by the disclosed methods is melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a soft tissue carcinoma. In some embodiments, the cancer is afibrosarcoma. In some embodiments, the cancer is diffuse intrinsic pontine glioma. In some embodiments, the cancer is a metastatic cancer. [0172] In certain embodiments, the methods can be used for the treatment, prevention, and/or diagnosis of solid tumors, including but not limited to, melanoma (e.g., unresectable, metastatic melanoma), renal cancer (e.g., renal cell carcinoma), prostate cancer (e.g., metastatic castration resistant prostate cancer), ovarian cancer (e.g., epithelial ovarian cancer, such as metastatic epithelial ovarian cancer), breast cancer (e.g., triple negative breast cancer), glioblastoma (e.g., glioblastoma multiforme), lung cancer (e.g., non-small cell lung cancer), soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, among others. [0173] The disclosed methods may be used to treat or minimize the size of the tumor prior to surgical resection. This would minimize the size of the tumor particularly in the context of a surgically resectable tumor. The disclosed whole cell payloads, or a system using the same, may be administered during surgical resection. The disclosed whole cell payloads, or a system using the same, may be administered after surgical resection. [0174] A therapeutic support composition as disclosed herein may be placed around the surgical cavity at the end of surgical resection and the subject may then be treated with further doses of whole cell payload to minimize the risk of any cancer cells that may have been missed in the surgical margins. [0175] The disclosed methods may include multiple systemic doses of whole cell payload that focus at one location. [0176] The disclosed methods may be used to deliver a whole cell payload to the site of a diffuse intrinsic pontine glioma (DIPG). The disclosed methods may include delivering a whole cell payload systemically that are only activated at the tumor site. The disclosed methods may be used as a neoadjuvant or adjuvant therapy. Modes of Administration [0177] Methods of treatment may include any number of modes of admisteration. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, skin patches, skin creams, skin gels, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. Atty Docket No.63XT-350609-WO Family 11.6 [0178] For parenteral administration, a whole cell payload or composition comprising the same as disclosed herein disclosed herein may be dissolved or suspended in a physiologically acceptable diluent, such as water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. Suitable oils may include, for example, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil. For parenteral administration, a whole cell payload or composition comprising the same as disclosed herein may be administered in the form of an aqueous, lipid, oily or other kind of solution or suspension, or even administered in the form of liposomes or nano-suspensions. [0179] The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. [0180] Therapeutic support compositions may be administered locally at the site of a tumor, such as by injection or implantation. A whole cell payload, or composition comprising the same, may be administered by any convenient route, in view of a subject’s condition and judgment of medical professionals. Parenteral administration is a suitable means of administering a whole cell payload or composition comprising the same. [0181] The amount administered to a subject can be initially determined based on guidance of a dose and/or dosage regimen. In general, the whole cell payload or composition comprising the same as disclosed herein can provide for targeted delivery and/or enhanced serum half-life of the bound drug, thus providing for at least one of reduced dose or reduced administrations in a dosage regimen. Thus, the whole cell payload or composition comprising the same as disclosed herein can provide for reduced dose and/or reduced administration in a dosage regimen relative to the whole cell payload prior to being conjugated as described in the present disclosure. [0182] A composition, or pharmaceutical formulation, may be provided in unit dosage form. In such form the pharmaceutical formulation may be subdivided into unit doses containing appropriate quantities of the compositions of the present disclosure. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in pouches, vials or ampoules. [0183] In some embodiments, provided is a kit comprising a whole cell payload or composition comprising the same as disclosed herein, and instructions for use thereof. [0184] In some embodiments, the kit further comprises a therapeutic support composition. [0185] Compositions of the present disclosure can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc. Suitable Atty Docket No.63XT-350609-WO Family 11.6 dosage ranges for the composition of the present disclosure include from 0.1 mg to 10,000 mg, or 1 mg to 1,000 mg, or 10 mg to 750 mg, or 25 mg to 500 mg, or 50 mg to 250 mg. For instance, suitable dosages for the composition of the present disclosure include 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1,000 mg. [0186] In some embodiments, multiple doses are administered. The frequency of administration can vary depending on any of a variety of factors, e.g., severity of the symptoms, condition of the subject, etc. For example, in some embodiments, a whole cell payload or composition comprising the same as disclosed herein is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid). [0187] The whole cell payload or composition comprising the same as disclosed herein can be administered at any suitable frequency, interval and duration. For example, a whole cell payload or composition comprising the same as disclosed herein can be administered once an hour, or two, three or more times an hour, once a day, or two, three, or more times per day, or once every 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, so as to provide the desired dosage level to the subject. When the whole cell payload or composition comprising the same as disclosed herein is administered more than once a day, representative intervals include 5 min, 10 min, 15 min, 20 min, 30 min, 45 min and 60 minutes, as well as 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 20 hr, and 24 hours. Administration can be administered once, twice, or three or more times, for an hour, for 1 to 6 hours, for 1 to 12 hours, for 1 to 24 hours, for 6 to 12 hours, for 12 to 24 hours, for a single day, for 1 to 7 days, for a single week, for 1 to 4 weeks, for a month, for 1 to 12 months, for a year or more, or even indefinitely. [0188] The whole cell payload or composition comprising the same as disclosed herein of the present disclosure can be co-administered with another active agent. Co-administration includes administering the whole cell payload or composition comprising the same and another active agent within 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 20 hr, or 24 hours of each other. Co-administration also includes administering simultaneously or approximately simultaneously (e.g., within about 1 min, 5 min, 10 min, 15 min, 20 min, or 30 minutes of each other), or sequentially in any order. In addition, the whole cell payload or composition comprising the same and another active agent can each be administered once a day, or two, three, or more times per day so as to provide the desired dosage level per day. [0189] Co-administration can be accomplished by coimplantation or coinjection. Atty Docket No.63XT-350609-WO Family 11.6 [0190] In some embodiments, co-administration can be accomplished by co-formulation, e.g., preparing a single pharmaceutical formulation including both the whole cell payload or composition comprising the same and another active agent. In other embodiments, the whole cell payload or composition comprising the same and another active agent can be formulated separately and co-administered to the subject. [0191] The whole cell payload or composition comprising the same and the active agent can be present in a formulation in any suitable weight ratio, such as from 1:100 to 100:1 (w/w), or 1:50 to 50:1, or 1:25 to 25:1, or 1:10 to 10:1, or 1:5 to 5:1 (w/w). The whole cell payload or composition comprising the same and the other active agent can be present in any suitable weight ratio, such as 1:100 (w/w), 1:75, 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1, 75:1, or 100:1 (w/w). Combination Therapies [0192] In one aspect, the invention provides a method of treating cancer or enhancing or eliciting an immune response comprising administering to a subject in need thereof: a therapeutically effective amount of a whole cell payload as described herein; a biocompatible support as described herein; and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof. [0193] The disclosure also provides a pharmaceutical combination comprising a whole cell payload described herein, or composition thereof; a therapeutic support composition, as described herein; and an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof, for use in the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response. [0194] The disclosure also provides the use of a pharmaceutical combination comprising a whole cell payload described herein, or composition thereof; a therapeutic support composition; and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof for the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response. [0195] In the methods and uses described herein, the components of the pharmaceutical combinations may be administered/used simultaneously, separately, or sequentially, and in any order, and the components may be administered separately or as a fixed combination. For example, the delay of progression or treatment of diseases according to the invention may comprise administration of the first active ingredient in free or pharmaceutically acceptable salt form and administration of the second active ingredient in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts or effective amounts, e.g., in daily dosages corresponding to the amounts described herein. Atty Docket No.63XT-350609-WO Family 11.6 The individual active ingredients of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single dosage forms. The instant disclosure is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly. Thus, a pharmaceutical combination, as used herein, defines either a fixed combination in one dosage unit form or separate dosages forms for the combined administration where the combined administration may be independently at the same time or at different times. As a further example, the whole cell payload and biocompatible support may be administered/used simultaneously (e.g., through coinjection or coimplantation), separately, or sequentially, followed by administration of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug. [0196] In certain embodiments, the methods and uses in treating cancer include administering/localizing the whole cell payload at a tumor. The administration of the whole cell payload, or composition thereof; the therapeutic support composition; and the additional therapeutic agent may inhibit the growth of the tumor. [0197] Additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed whole cell payload. Sequential administration includes administration before or after the disclosed whole cell payload. An additional therapeutic agent may be administered before the disclosed whole cell payload. An additional therapeutic agent may be administered after the disclosed whole cell payload. An additional therapeutic agent may be administered at the same time as the disclosed whole cell payload. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed whole cell payload. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed whole cell payload. In some embodiments, administration of an additional therapeutic agent with a disclosed whole cell payload may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals. When used in combination with one or more other active ingredients, the whole cell payload of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a whole cell payload of the present disclosure. Anticancer agents [0198] Exemplary anti-cancer agents include, but are not limited to, abiraterone acetate, Abitrexate (methotrexate), Abraxane (paclitaxel albumin-stabilized nanoparticle pormulation), ABVD, ABVE, ABVE- PC, AC, AC-T, Adcetris (brentuximab vedotin), ADE, ado-trastuzumab emtansine, Adriamycin (doxorubicin hydrochloride), Adrucil (fluorouracil), afatinib dimaleate, Afinitor (everolimus), Aldara (imiquimod), Atty Docket No.63XT-350609-WO Family 11.6 aldesleukin, alemtuzumab, Alimta (pemetrexed disodium), Aloxi (palonosetron hydrochloride), Ambochlorin (chlorambucil), aminolevulinic acid, anastrozole, aprepitant, Aredia (pamidronate disodium), Arimidex (anastrozole), Aromasin (exemestane), Arranon (nelarabine), arsenic trioxide, Arzerra (ofatumumab), asparaginase erwinia chrysanthemi, Avastin (bevacizumab), axitinib, azacitidine, BEACOPP, bendamustine hydrochloride, BEP, bevacizumab, bexarotene, Bexaar (tositumomab andi 131 tositumomab), bicalutamide, bleomycin, bortezomib, Bosulif (bosutinib), bosutinib, brentuximab vedotin, busulfan, Busulfex (busulfan), cabazitaxel, cabozantinib- S-malate, CAF, Campath (alemtuzumab), Camptosar (irinotecan hydrochloride), capecitabine, CAPOX, carboplatin, carboplatin-taxol, carfilzomib, Casodex (bicalutamide), CeeNU (lomustine), Cerubidine (daunorubicin hydrochloride), Cervarix (recombinant HPV bivalent vaccine), cetuximab, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, Clafen (cyclophosphamide), clofarabine, Clofarex (clofarabine), Clolar (clofarabine), CMF, Cometriq (cabozantinib-S-malate), COPP, COPP-ABV, Cosmegen (dactinomycin), crizotinib, CVP, cyclophosphamide, Cyfos (ifosfamide), cytarabine, cytarabine liposomal, Cytosar-U (cytarabine), Cytoxan (cyclophosphamide), dabrafenib, dacarbazine, Dacogen (decitabine), dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, DepoCyt (liposomal cytarabine), DepoFoam (liposomal cytarabine), dexrazoxane hydrochloride, docetaxel, Doxil (doxorubicin hydrochloride liposome), doxorubicin hydrochloride, doxorubicin hydrochloride liposome, Dox-SL (doxorubicin hydrochloride liposome), DTIC-Dome (dacarbazine), Efudex (fluorouracil), Elitek (rasburicase), Ellence (epirubicin hydrochloride), Eloxatin (oxaliplatin), eltrombopag olamine, Emend (aprepitant), enzalutamide, epirubicin hydrochloride, EPOCH, Erbitux (cetuximab), eribulin mesylate, Erivedge (vismodegib), erlotinib hydrochloride, Erwinaze (asparaginase erwinia chrysanthemi), Etopophos (etoposide phosphate), etoposide, etoposide phosphate, Evacet (doxorubicin hydrochloride liposome), everolimus, Evista (raloxifene hydrochloride), exemestane, Fareston (toremifene), Faslodex (fulvestrant), FEC, Femara (letrozole), filgrastim, Fludara (fludarabine phosphate), fludarabine phosphate, Fluoroplex (fluorouracil), fluorouracil, Folex (methotrexate), Folex PFS (methotrexate), Folfiri, Folfiri- bevacizumab, Folfiri-cetuximab, Folfirinox, Folfox (leucovorin, fluorouracil, oxaliplatin), Folotyn (pralatrexate), FU-LV, fulvestrant, Gardasil (recombinant HPV quadrivalent vaccine), Gazyva (obinutuzumab), gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine- oxaliplatin, gemtuzumab ozogamicin, Gemzar (gemcitabine hydrochloride), Gilotrif (afatinib dimaleate), Gleevec (imatinib mesylate), glucarpidase, goserelin acetate, Halaven (eribulin mesylate), Herceptin (trastuzumab), HPV bivalent vaccine, recombinant, HPV quadrivalent vaccine, Hycamtin (topotecan hydrochloride), Hyper-CVAD, ibritumomab tiuxetan, ibrutinib, ICE, Iclusig (ponatinib hydrochloride), Ifex (ifosfamide), Ifosf amide, Ifosfamidum (ifosfamide), imatinib mesylate, Imbruvica (ibrutinib), imiquimod, Inlyta (axitinib), Intron A (recombinant interferon alfa- 2b), ipilimumab, Iressa (gefitinib), irinotecan Atty Docket No.63XT-350609-WO Family 11.6 hydrochloride, Istodax (romidepsin), ixabepilone, Ixempra (ixabepilone), Jakafi (ruxolitinib phosphate), Jevtana (cabazitaxel), Kadcyla (ado-trastuzumab emtansine), Keoxifene (raloxifene hydrochloride), Kepivance (palifermin), Kyprolis (carfilzomib), lapatinib ditosylate, lenalidomide, letrozole, leucovorin calcium, Leukeran (chlorambucil), leuprolide acetate, Levulan (aminolevulinic acid), Linfolizin (chlorambucil), LipoDox (doxorubicin hydrochloride liposome), liposomal cytarabine, lomustine, Lupron (leuprolide acetate), Lupron Depot (leuprolide acetate), Lupron Depot-Ped (leuprolide acetate), Lupron Depot- 3 Month (leuprolide acetate), Lupron Depot-4 Month (leuprolide acetate), Marqibo (vincristine sulfate liposome), Matulane (procarbazine hydrochloride), mechlorethamine hydrochloride, Megace (megestrol acetate), megestrol acetate, Mekinist (trametinib), mercaptopurine, mesna, Mesnex (mesna), Methazolastone (temozolomide), methotrexate, Methotrexate LPF (methotrexate), Mexate (methotrexate), Mexate-AQ (methotrexate), mitomycin C, Mitozytrex (mitomycin C), MOPP, Mozobil (plerixafor), Mustargen (mechlorethamine hydrochloride), Mutamycin (mitomycin C), Myleran (busulfan), Mylosar (azacitidine), Mylotarg (gemtuzumab ozogamicin), Navelbine (vinorelbine tartrate), nelarabine, Neosar (cyclophosphamide), Neupogen (filgrastim), Nexavar (sorafenib tosylate), nilotinib, Nolvadex (tamoxifen citrate), Nplate (romiplostim), obinutuzumab, ofatumumab, omacetaxine mepesuccinate, Oncaspar (pegaspargase), Ontak (denileukin diftitox), OEPA, OPPA, oxaliplatin, paclitaxel, palifermin, palonosetron hydrochloride, pamidronate disodium, panitumumab, Paraplat (carboplatin), Paraplatin (carboplatin), pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, pemetrexed disodium, Perjeta (pertuzumab), pertuzumab, plerixafor, pomalidomide, Pomalyst (pomalidomide), ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, Proleukin (aldesleukin), Prolia (denosumab), Promacta (eltrombopag olamine), Provenge (sipuleucel-T), Purinethol (mercaptopurine), radium 223 dichloride, raloxifene hydrochloride, rasburicase, R-CHOP, R-CVP, recombinant HPV bivalent vaccine, recombinant HPV quadrivalent vaccine, recombinant interferon alfa- 2b, regorafenib, Revlimid (lenalidomide), Rheumatrex (methotrexate), rituximab, romidepsin, romiplostim, Rubidomycin (daunorubicin hydrochloride), ruxolitinib phosphate, Sclerosol Intrapleural Aerosol (talc), sipuleucel-T, sorafenib tosylate, Sprycel (dasatinib), Stanford V, Sterile Talc Powder (talc), Steritalc (talc), Stivarga (regorafenib), sunitinib malate, Sutent (sunitinib malate), Sylatron (peginterferon alfa- 2b), Synovir (thalidomide), Synribo (omacetaxine mepesuccinate), Tafinlar (dabrafenib), talc, tamoxifen citrate, Tarabine PFS (cytarabine), Tarceva (erlotinib hydrochloride), Targretin (bexarotene), Tasigna (nilotinib), Taxotere (docetaxel), Temodar (temozolomide), temozolomide, temsirolimus, thalidomide, Thalomid (thalidomide), Toposar (etoposide), topotecan hydrochloride, toremifene, Torisel (temsirolimus), tositumomab and I-131 iodine tositumomab, Totect (dexrazoxane hydrochloride), trametinib, trastuzumab, Treanda (bendamustine hydrochloride), Trisenox (arsenic trioxide), Tykerb (lapatinib ditosylate), vandetanib, VAMP, Vectibix (panitumumab), Atty Docket No.63XT-350609-WO Family 11.6 VelP, Velban (vinblastine sulfate), Velcade (bortezomib), Velsar (vinblastine sulfate), vemurafenib, VePesid (etoposide), Viadur (leuprolide acetate), vinblastine sulfate, vincristine sulfate, vincristine sulfate liposome, vinorelbine tartrate, vismodegib, Voraxaze (glucarpidase), vorinostat, Votrient (pazopanib hydrochloride), Wellcovorin (leucovorin calcium), Xalkori (crizotinib), Xeloda (capecitabine), xelox, Xofigo (radium 223 dichloride), Xtandi (enzalutamide), Yervoy (ipilimumab), Zaltrap (ziv-Aflibercept), Zelboraf (vemurafenib), Zevalin (ibritumomab tiuxetan), Zinecard (dexrazoxane hydrochloride), ziv-aflibercept, Zoladex (goserelin acetate), zoledronic acid, and Zolinza (vorinostat). [0199] The anticancer agent may be a PBD dimer, calicheamicin, speromycin, tubulysin B, rhizoxin, dolastatin, didemnin B, camptothecin, CBI, temsirolimus, actinomycin D, epothilone B, taxol, cryptophycin, SN38, velcade, bruceantin, DAVLBH, DM1, phyllanthoside, Alimta, T2 Toxin, MMC, vantalanib, vinorelbine, brefeldin, sunitinib, daunomycin, semaxanib, tarceva, iressa, irinotecan, LY-541503, geldanomycin, gemcitabine, methotrexate, gleevec, topotecan, bleomycin, doxorubicin, cisplatin, N- mustards, etoposide, or 5-FU. [0200] In certain embodiments, an anticancer agent is an anthracycline. In certain embodiments, anticancer agent is a taxane. In certain embodiments, anticancer agent is gemcitabine. In certain embodiments, anticancer agent is doxorubicin. In certain embodiments, anticancer agent is docetaxel. In certain embodiments, anticancer agent is SN38. In certain embodiments, anticancer agent is monomethyl auristatin E. In certain embodiments, an anticancer agent is an alkylating agent, antimetabolite (folate antagonist, purine antagonist, pyrimidine antagonist), antibiotic, taxane, vinca alkaloid, or campothecin analogue. Synthetic Methods [0201] The whole cell payloads described herein may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of whole cell payloads described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. [0202] It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0203] Additionally, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as Atty Docket No.63XT-350609-WO Family 11.6 suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and references cited therein. [0204] Furthermore, the whole cell payloads of this disclosure may contain one or more chiral centers. Accordingly, if desired, such trans-cyclooctene-modified whole cells can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0205] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). EXAMPLES [0206] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Atty Docket No.63XT-350609-WO Family 11.6 Example 1 Trans-cyclooctene-cell conjugate [0207] The reaction scheme of Example 1 is shown in FIG.1. A suspension of cells, such as gamma-delta T cells, (1e6 – 1e9 cells per mL) in aqueous buffer (50 mM potassium phosphate, 50 mM sodium chloride, 2 mM ethylenediaminetetraacetic acid disodium salt), pH 7.4 is cooled in an ice bucket. To the mixture is added a molar excess of trans-cyclooctene derivatized succinimidyl ester in dimethylacetamide (DMA) so that no more than 10% of the final solution is DMA %v/v. The ratios of cells to NHS-PEG-TCO in the reaction mixture may be 1:1000, but includes ranges from 1:100 to 1:1e10. The suspension is gently mixed and the reaction is allowed to proceed on ice (0.25 – 4 h) and, upon completion, quenched by the addition of an amine, such as ethanolamine. The cells are collected by centrifugation and the supernatant discarded. The cells are resuspended in fresh buffer and the steps are repeated at least three times to wash the cells and remove excess reagent. Finally, the labeled cells are resuspended in phosphate buffered saline. The labeling ratio (number of TCOs per cell) is determined by treatment of a sample of the cells with a tetrazine-linked fluorescent probe and the fluorescence signal per cell is measured, for example by flow cytometry. The target labeling ratio may be ~1000 TCOs per cell, but includes ranges from 10 – 1,000,000 TCOs per cell. The percent viability of the sample is also determined and the percentage of live cells should be greater than 90%. Example 2 Trans-cyclooctene-cell conjugate (double stranded DNA) [0208] The reaction scheme of Example 2 is shown in FIG.2. A solution of single-stranded oligonucleotide of defined sequence with an amine functional group at the 5’ end (1 mg/mL) in aqueous buffer (20 mM sodium bicarbonate, 2 mM ethylenediaminetetraacetic acid disodium salt), pH 8.0, is incubated with a molar excess of trans-cyclooctene derivatized succinimidyl ester in dimethylacetamide (DMA). The reaction is allowed to proceed at ambient temperature and, upon completion, purified by gel filtration column. [0209] A solution of a complementary single-stranded oligonucleotide prepared with an activated ester at the 5’ end (1 mg/mL) in water is added to a suspension of cells, such as gd T cells, (1e6 – 1e9 cells/mL) in phosphate buffered saline and the reaction is allowed to proceed for up to 4 hours on ice. The excess reagent is removed by collection of the cells followed by washing the cells with phosphate buffered saline. [0210] The solution of TCO-modified oligonucleotide is added to a suspension of oligonucleotide-modified cells to form the double-stranded oligonucleotide at 4 °C. Excess reagent is removed by collection of the cells and washing with fresh buffer. The labeling ratio is determined by treatment of a sample of the cells with a fluorescent probe and the fluorescence signal per cell is measured. The target labeling ratio may be Atty Docket No.63XT-350609-WO Family 11.6 ~1000 TCOs per cell, but includes ranges from 10 – 1,000,000 TCOs per cell. The percent viability of the sample is also determined and the percentage of live cells should be greater than 90%. Example 3 Trans-cyclooctene-cell conjugate (host-guest interaction) [0211] A 10 mM solution of reactive active ester in water is
Figure imgf000054_0001
added to a suspension of as – buffered saline and the reaction is allowed to proceed for up to 4 hours on ice. The excess reagent is removed by collection of the cells followed by washing the cells with phosphate buffered saline and the washed cells resuspended in phosphate buffered saline. [0212] A solution of TCO-functionalized adamantane in DMA is added to a suspension of cyclodextrin- modified cells. The host-guest interaction is allowed to form on ice. The excess reagent is removed by collection of the cells followed by washing the cells with phosphate buffered saline. The labeling ratio is determined by treatment of a sample of the cells with a fluorescent probe and the fluorescence signal per cell is measured. The target labeling ratio may be ~1000 TCOs per cell, but includes ranges from 10 – 1,000,000 TCOs per cell. The percent viability of the sample is also determined and the percentage of live cells should be greater than 90%. Example 4 Effects of TCO-modified cells on tumor growth in a mouse model (prophetic example) [0213] The effect of TCO-modified cells, such as gd T cells or NK cells, as prepared in example 1, is tested in a murine tumor model, such as NCI-N87 xenograft model in SCID mice. TCO-modified cells or unmodified cells (control) are resuspended in buffer, such as PBS, at approximately 1e9 cells per mL. Tumor bearing mice are injected intratumorally with SQL70 (100 µL per mouse). Mice are randomized into groups and test groups receive IV injections of 10 µL per gram of TCO-cell solution while control groups receive identical injections of unmodified cells. Tumor volumes and body weights are measured for all mice over the study period, such as three weeks. [0214] The tumor volumes are expressed in mm3 using the formula: V = 0.5 a x b2 where a and b are the long and short diameters of the tumor, respectively. The tumor volumes are plotted for each group and the percent tumor growth inhibition is calculated for each group using the formula: TGI (%) = [1-(Ti-T0)/ (Vi- V0)] ×100; Ti is the average tumor volume of a treatment group on a given day, T0 is the average tumor Atty Docket No.63XT-350609-WO Family 11.6 volume of the treatment group on the day of treatment start, Vi is the average tumor volume of the vehicle control group on the same day with Ti, and V0 is the average tumor volume of the vehicle group on the day of treatment start. [0215] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. [0216] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. [0217] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. [0218] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

Atty Docket No.63XT-350609-WO Family 11.6 WHAT IS CLAIMED IS: 1. A system for targeted delivery of a live cell to a treatment site, comprising: a whole cell payload comprising a whole cell covalently or non-covalently linked to a first bioorthogonal moiety; and a therapeutic support composition comprising a biocompatible support covalently linked to a second bioorthogonal moiety; wherein the first and second bioorthogonal moieties comprise a complimentary reactive functional group pair. 2. The system of claim 1, wherein the whole cell is selected from the group consisting of a immune cell, bacterial cell, cardiomyocyte, gd T cell, cytokine induced killer, macrophage, neutrophil, natural killer T cell, primary cell, cytolytic T cell, killer cell, natural killer cell, monocyte, eosinophil, polymorphonuclear cell, granulocyte, mast cell, basophil, dendritic cell, B cell, T cell, antigen presenting cell, stem cell, cancer cell, transgenic cell, primary cell, cells from endocrine system, committed progenitors for the blood and immune system (various type), induced pluripotent stem cells, tumor infiltrating lymphocyte, lymphocyte- activated killer cell, pluripotent stem cell, totipotent stem cell, or multipotent stem cell. 3. The system of claim 1, wherein the whole cell is a primary cell from a sample from a subject. 4. The system of claim 1, wherein the whole cell is from an ex vivo cell line. 5. The system of claim 1, wherein the whole cell is a transgenic cell. 6. The system of claim 1, wherein the whole cell is eukaryotic. 7. The system of claim 1, wherein the whole cell is prokaryotic. 8. The system of claim 1, wherein the whole cell is an effector cell. 9. The system of any preceding claim, wherein complimentary reactive functional group pair is selected from: (1) an azide and a cyclooctyne; (2) a thiol and a maleimide; (3) a hydrazine/hydrazine/HyNic or alkoxyamine and a monoaldehyde, dialdehyde or 4FB; (4) a tetrazine and a trans-cyclooctene; (5) an aniline and an o-methoxy or amino phenol; (6) a tetrazine and a substituted cyclopropene; (7) a trans-cyclooctene and a substituted cyclopropene; (8) a cyclooctyne and a substituted cyclopropene; (9) a nitrile imine and a substituted cyclopropene; and (10) a tetrazine and a (1R,8S)-9λ3-bicyclo[6.1.0]non-4-yne. 10. The system of any preceding claim, wherein the complimentary reactive functional group pair comprise a tetrazine moiety and a trans-cyclooctene moiety. 11. The system of any preceding claim, wherein the first bioorthogonal moiety comprises a trans- cyclooctene moiety and the second bioorthogonal moiety comprises a tetrazine moiety. Atty Docket No.63XT-350609-WO Family 11.6 12. The system of any preceding claim, wherein the first bioorthogonal moiety comprises a trans- cyclooctene moiety of formula: wherein: 1A
Figure imgf000057_0001
R , at each occurrence, is the group consisting of C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; q is 0, 1, or 2; q1 is 0 or 1; R1B, at each occurrence, is independently selected from the group consisting of G1, OH, –NR1c–C1-4alkylene–G1, –NR1c–C1-4alkylene–N(R1d)2, –NR1c–C1-6alkylene–N(C1-4alkyl)3+, 4alkylene–(N(C1-4alkylene–CO2H)– 6alkyl, –N(R1c)–C1-6alkylene– 6alkyl)–C2-4alkylene)n–N(C1-4alkylene–
Figure imgf000057_0002
C(O)OC1-6alkyl)2, –N(R1c)–C1-6alkylene–SO3H, –N(R1c)–(CH2CH2O)1-3–CH2CH2N((CH2CH2O)1-3– C1-6alkylene–CO2H)2, and –N(R1c)–CH(CH2O–(CH2CH2O)0-2–C1-6alkylene–CO2H)2; R1c and R1d, at each occurrence, are independently hydrogen or C1-4alkyl; R1e, at each occurrence, is independently –C1-4alkylene–CO2H, –C1-4alkylene–CONH2, or –C1-4alkylene–OH; R1f, at each occurrence, is independently hydrogen, C1-6alkyl, or C1-4alkylene–CO2H; n, at each occurrence, is independently 0, 1, 2, or 3; L2, at each occurrence, is independently selected from the group consisting of –C(O)– and C1-3alkylene; and G1, at each occurrence, is independently an optionally substituted heterocyclyl. 13. The system of any preceding claim, wherein the first bioorthogonal moiety comprises a trans- cyclooctene moiety of formula: wherein:
Figure imgf000057_0003
Atty Docket No.63XT-350609-WO Family 11.6 R2 is -OH, 2-aminoethanesulfonic acid, an N-linked natural or unnatural amino acid, or an optionally substituted ethylenediamine; wherein R2 may be optionally further substituted with a polyether. 14. The system of any preceding claim, wherein the first bioorthogonal moiety comprises a trans- cyclooctene moiety of formula: OH O O O O , .
Figure imgf000058_0001
a trans- cyclooctene moiety with a linker of 1-30. 16. The system of any preceding
Figure imgf000058_0002
administration. 17. The system of any preceding claim, wherein the second bioorthogonal moiety comprises a tetrazine moiety of formula: ; wherein:
Figure imgf000058_0003
Atty Docket No.63XT-350609-WO Family 11.6 R20 is selected from the group consisting of hydrogen, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR'R", C(=O)O-R', C(=O)S-R', C(=S)OR', C(=S)SR', C(=O)NR'R", C(=S)NR'R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S)R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with one to three Z1; R' and R" at each occurrence are independently selected from hydrogen, aryl and alkyl; R''' at each occurrence is independently selected from aryl and alkyl; R30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; haloalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; Ra, R31a and R31b are each independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each Z1 is independently selected from halo, oxo, cyano, nitro, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, heteroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, OR', SR', C(=O)R', C(=S)R', OC(=O)R"', SC(=O)R'", OC(=S)R"', SC(=S)R"', S(=O)R', S(=O)2R"', S(=O)2NR' R", C(=O)O-R', C(=O)S-R', C(=S)O-R', C(=S)S-R', C(=O)NR'R", C(=S)NR'R'', NR'R", NR'C(=O)R", NR'C(=S)R'', NR'C(=O)OR'', NR'C(=S)OR'', NR'C(=O)SR", NR'C(=S)SR", OC(=O)NR'R", SC(=O)NR'R", OC(=S)R'R''', SC(=S)R'R'', NR'C(=O)NR"R", and NR'C(=S)NR"R''; and t is 0, 1, 2, 3, or 4. 18. The system of claim 17, wherein each R20 is independently phenyl, pyrimidinyl, triazinyl, oxazolyl, isoxazole, imidazolyl, oxadiazolyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,3- d]pyrimidinyl, or 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl; wherein is independently optionally substituted with one to three Z1. 19. The system of any preceding claim, wherein the biocompatible support is a polymer, viscous or non- viscous liquid material, gel, hydrogel, polysaccharide hydrogel, a cross-linked polymer matrix, a metal, a ceramic, a plastic, a bone graft material, alginate, cellulose, chitosan, hyaluronic acid, chondroitin sulfate, heparin, particle, nanoparticle, microparticle, alginate, cellulose, hyaluronic acid, chitosan, chitosin, chitin, hyaluronic acid, or chondroitin sulfate. 20. The system of any one of claims 11-19, wherein the tetrazine moiety is bonded to the biocompatible support via a linker. 21. The system of any one of claims 11-20, wherein the trans-cyclooctene moiety is covalently linked to the whole cell via a linker. 22. The system of claim 20 or 21, wherein the linker comprises one or more amino acids. Atty Docket No.63XT-350609-WO Family 11.6 23. The system of any one of claims 20-22, wherein the linker comprises one or more of a hydrazone, a hydrazide, a disulfide, a polyethylene glycol (PEG), a N-succinimidyl-4-(2-pyridyldithio)pentanoate (SPP), a N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB), a 4-(4’-acetylphenoxy)butanoic acid (AcBut), one or more linear or branched, natural or unnatural amino acid, a valine-citrulline (Val-Cit) moiety, or a phenylalanine-lysine (Phe-Lys) moiety. 24. The system of any one of claims 20-23, wherein the linker comprises 1 to 100 linking atoms, from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms, or from 1 to 40 linking atoms, or from 1 to 30 linking atoms, or from 1 to 20 linking atoms, or from 1 to 10 linking atoms, or from 1 to 5 linking atoms, or from 5 to 30 linking atoms, or from 10 to 30 linking atoms, or from 5 to 40 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms. 25. The system of any one of claims 20-24, wherein the linker comprises one or more chain heteroatoms and one or more alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene moieties; wherein each alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene moiety, may be independently optionally substituted with one to five substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl. 26. The system of any one of claims 20-25, wherein the linker is an alkylene linker optionally comprising one or more -O-, -S-, amine, ester, amide, carbamate, carbonate, thio-succinimide, or ketone functional group. 27. The system of any one of claims 20-26, wherein the linker is of the formula: -Y10-(CH2)n’-Y20-(CH2)m''-Y30- wherein: each of Y10, Y20, and Y30 are independently a bond, -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -OC(O)NR110-, -C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O)-, -OC(O)-, -OC(O)O-, alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; wherein each alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl; each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and n' and m'' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. Atty Docket No.63XT-350609-WO Family 11.6 28. A method of treating cancer or enhancing or eliciting an immune response, the method comprising administering to a subject in need thereof, the system of any one of claims 1-27. 29. The method of claim 28, wherein the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, endometrial carcinoma, breast cancer , glioblastoma, lung cancer, soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical carcinoma, hepatocellular carcinoma, Kaposi’s sarcoma, non-Hodgkin’s lymphoma, Hodgkins lymphoma, Wilm’s tumor/neuroblastoma, bladder cancer, thyroid adenocarcinoma, pancreatic neuroendocrine tumors, Prostatic adenocarcinoma, Nasopharyngeal carcinoma, or cutaneous T-cell lymphoma. 30. The method of claim 28, wherein the cancer is a solid tumor. 31. The method of claim 28, wherein the cancer is a soft tissue sarcoma. 32. The method of claim 28, wherein the cancer is a hematological malignancy. 33. The method of claim 32, wherein the hematological malignancy is myelodysplastic syndrome, acute myeloid leukemia, myelodysplastic syndromes, chronic myelogenous leukemia, chronic myelomonocytic leukemia, primary myelofibrosis, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy, plasma cell myeloma, follicular lymphoma, marginal zone lymphoma, classical Hodgkin lymphoma, monoclonal B-cell lymphocytosis, lymphoproliferative disorder NOS, T-cell lymphoma, precursor B-lymphoblastic leukemia, mantle cell lymphoma, plasmacytoma, Burkitt lymphoma, T-cell leukemia, hairy-cell leukemia, precursor T-lymphoblastic leukemia, or nodular lymphocyte predominant Hodgkin lymphoma. 34. The method of claim 28, wherein the immune response is an increase in one or more of leukocytes, lymphocytes, monocytes, and eosinophils.
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