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WO2025170888A1 - Combinaison de l'inhibiteur d'axl slc-391 et d'un inhibiteur de pd-1 destinée à être utilisée dans le traitement du cancer du sang - Google Patents

Combinaison de l'inhibiteur d'axl slc-391 et d'un inhibiteur de pd-1 destinée à être utilisée dans le traitement du cancer du sang

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Publication number
WO2025170888A1
WO2025170888A1 PCT/US2025/014420 US2025014420W WO2025170888A1 WO 2025170888 A1 WO2025170888 A1 WO 2025170888A1 US 2025014420 W US2025014420 W US 2025014420W WO 2025170888 A1 WO2025170888 A1 WO 2025170888A1
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Prior art keywords
cells
inhibitor
combination
treatment
acid
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Yehyeon AHN
Min Chen
Xiaoyan Jiang
Zaihui Zhang
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Signalchem Lifesciences Corp
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Signalchem Lifesciences Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present disclosure provides a combination therapy in the treatment of blood cancer, particularly acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • AML Acute myeloid leukemia
  • LSCs leukemic stem cells
  • blasts myeloid precursors
  • An accumulation of rapid growth of abnormal cells severely disrupts normal hematopoiesis, and thus results in bone marrow failure.
  • AML is a highly heterogeneous malignancy with complicated genetic mutations, and treatment of AML is one of most challenging hematopoietic malignancies.
  • FIG. 1A-1C show SCL-391 treatment reduces the growth of AML cells and increases T-cell populations when co-cultured with activated PBMC.
  • FIG. 1A - MV4-11- GFP + cells were cultured with or without SLC-391 (0.05 pM, 0.1 pM, and 0.2 pM) or PBMCs at the effector: target ratio 5:1. Viable GFP + cells were counted under fluorescent microscope at 3, 5 and 7 days after treatment, and the percentage of viable cells was normalized to untreated condition.
  • FIG. IB Immunofluore scent photos were taken under a fluorescent microscope in MV4-11-GFP + cells under the treatment condition indicated.
  • FIG. 1C The same cells were harvested after 7 days in culture and stained with antibodies to detect total CD3 + T cells, CD4 + and CD8 + T cells in each treatment condition by flow cytometry. The differences among each treatment condition were normalized to PBMC treatment only condition. Data shown are the mean ⁇ SEM of measurements for at least three experimental replicates. P-values were calculated using 1- way ANOVA with Tukey’s correction for multiple comparisons using GraphPad Prism.
  • FIG. 2B Total CD3 + , CD3 + CD4 + and CD3 + CD8 + T cells were analyzed by flow cytometry and fold changes were shown as relative to PBMC treatment only condition.
  • FIG. 2C The percentage of CD3 + /PD1 + cells was analyzed via flow cytometry under each treatment condition.
  • FIG. 2D - PD-L1 expression in MV4-11-GFP + cells was analyzed after 5 or 7 days of treatment by flow cytometry. The mean fluorescence intensity was then calculated under each treatment condition.
  • FIG. 2E CD3'CD56 + NK cells were analyzed under each treatment condition by flow cytometry and the fold change was normalized to PBMC treatment only condition.
  • MV411-GFP+ cells were treated with SLC-391 (0.05 pM, O.lpM, or 0.2pM) alone, PEM (O.lpg/ml, 1 pg/ml, or 10 pg/ml) alone, or with a combination of both PEM and SLC-391.
  • Viable GFP+ cells were measured by counting beads via FACS analysis after 5 days in culture (bar graph). Synergistic effects among different treatment conditions were calculated based on various concentrations of either SLC-391 or PEM by SynergyFinder software.
  • synergy scores including the Loewe synergy score (left tensor) and HSA score (right tensor), were also determined. A score more than 10 or lower than -10 was classified as synergistic or antagonistic, respectively; a score between -10 and 10 was considered additive. Data shown are the mean ⁇ SEM of measurements for at least three experimental replicates. P- values were calculated using 1-way ANOVA with Tukey’s correction for multiple comparisons using GraphPad Prism.
  • FIG. 4A-4G show combination treatment of SLC-391 and PEM inhibits the growth of AML stem/ progenitor cells and increases functional T-cells when co-cultured with PBMC.
  • FIG. 4A Pre- violet labeled CD34 + primary AML cells were cultured in the presence of SLC-391 (0.2 pM), anti-PDl(10pg/ml), alone or in combination, with or without PBMC for 7 days in six-growth factors supplementary medium. Cells were harvested and AccruCheck counting beads were added to each tube to calculate the remaining viable AML cells in each condition by flow cytometry analysis. Viable cells from each treatment were normalized to untreated condition.
  • FIG. 4A Pre- violet labeled CD34 + primary AML cells were cultured in the presence of SLC-391 (0.2 pM), anti-PDl(10pg/ml), alone or in combination, with or without PBMC for 7 days in six-growth factors supplementary medium. Cells were harvested and AccruCheck counting beads were added to each tube to calculate
  • FIG. 4B The fold change in CD3 + , CD3 + CD4 + and CD3 + CD8 + cells under PBMC co-culture condition was analyzed and normalized to PBMC treatment only condition.
  • FIG. 4C The PD1 + CD3 + cells were compared among each group and the mean fluorescence intensity (MFI) was normalized to PBMC treatment only condition. Representative blots under each treatment condition are shown, as assessed by flow cytometry.
  • FIG. 4D The PD-L1 expression of primary AML cells was analyzed via flow cytometry analysis and the MFI under each treatment condition was normalized to the level of unstained control.
  • FIG. 4E The percentage of CD8 + IFN-Y + cells was determined via intracellular staining and representative blots under each treatment condition are shown. The concentration of IFN-y (pg/mL) in culture medium was measured using the LEGENDplex cytokine array kit.
  • FIG. 4F Heat map of each cytokine concentration with hierarchical clustering of the samples used for cytokine array assay. The row z-scores were used to display changes in cytokine concentration across all samples for different treatment conditions.
  • FIG. 4G Absolute concentrations of TNFa, sFasL and TIM3 (pg/mL) detected in co-cultured AML patient cells are shown.
  • FIG. 5A-5G show combination treatment of SLC-391 and PEM decreases leukemia burden and enhances survival of mice in a humanized PDX model.
  • FIG. 5A - Schematic of experimental design using a preclinical transplant model.
  • CD34 + cord blood (CB) cells were intravenously (IV) injected into sub-lethal irradiated NSG mice at 4 weeks of age (0.4xl0 5 /mouse) and engraftment levels in peripheral blood (PB) were monitored via flow cytometry analysis.
  • PB peripheral blood
  • MV4-11 cells carrying a luciferase reporter and GFP marker were IV injected into the humanized immune mice (0.5xl0 6 /mouse).
  • FIG. 5B Engraftment levels of human CD45 + , CD3 + , CD3’CD56 + (NK), HLR-DR + CD123 + (pDC) and other cell populations were determined at week 8 and week 12 after transplantation of CD34 + CB cells into mice.
  • FIG. 5C Bioluminescence images of mice after three weeks treatment and representative images from each group are presented.
  • FIG. 5D Three to four mice from each group were then sacrificed and images and weights of spleen from each mouse are shown.
  • FIG. 5B Engraftment levels of human CD45 + , CD3 + , CD3’CD56 + (NK), HLR-DR + CD123 + (pDC) and other cell populations were determined at week 8 and week 12 after transplantation of CD34 + CB cells into mice.
  • FIG. 5C Bioluminescence images of mice after three weeks treatment and representative images from each group are presented.
  • FIG. 5D Three to four mice from each group were then sacrificed and images and weights of spleen from each mouse are shown.
  • FIG. 5E Engraftment levels of AML cells (CD45 + GFP + ) and CB-derived CD45 + GFP" cells from hematological tissues including PB, spleen and BM are shown with representative flow cytometry plots.
  • FIG. 5G Immunohistological staining was performed to evaluate the number of leukemic cells, CD3+ cells, and CD8+ cells for mice receiving combination treatment of SLC-391 and PEM. Spleens of treated mice were harvested and fixed in 10% formalin.
  • the fixed tissues were further individually processed for Haemotoxylin and Eosin staining and IHC staining of anti-human CD3, CD8, and PDL1 antibodies.
  • the representative 40X imaging of each treated mouse is shown.
  • the percentage of CD3-positive, CD8-positive, and PDL1 -positive cells from each treatment condition are shown in the bar graph wherein the cell numbers were manually counted and calculated based on the total 4000 cells in each field. P-values were calculated using logrank test.
  • FIG. 6A-6B show combination treatment of SLC-391 and PEM increased CD3 + T cells and other immune cell populations in a PDX model.
  • a combination treatment of AXE inhibitor with PD-1 inhibitor enhances anti-leukemic activity by reducing or eliminating the tumor-induced immunosuppression in AME.
  • PD-1 inhibitor e.g., an anti-PD-1 antibody
  • various embodiments of the present disclosure are directed to combination therapies utilizing an AXE inhibitor in combination with an PD- 1 inhibitor for treating blood cancer, in particular, acute myeloid leukemia.
  • AXL is a receptor tyrosine kinase of the TAM family including TRYO3, AXL, and MER (Graham et al., 2014; Schoumacher and Burbridge, 2017; Zhu et al., 2019). TAM family members are overexpressed in many solid tumors, enhancing survival and resistance to apoptosis.
  • growth arrest-specific gene 6 GAS6
  • GAS6 growth arrest-specific gene 6
  • AXL plays a critical role in mediating migration and invasiveness of cancer cells.
  • AML patient cells express increased levels of AXL protein as compared to normal individuals, and highly increased AXL activity has been reported in AML stem/progenitor cells, including patients harboring mixed-lineage leukemia (MLL) fusion, a poor prognostic group (Niu et al., 2021).
  • MML mixed-lineage leukemia
  • SLC-391 can also sensitize AML stem/progenitor cells to venetoclax, a BH3-mimetic and selective BCL-2 inhibitor (Delbridge et al., 2016; DiNardo et al., 2019), with strong synergistic effects in vitro and in patient-derived xenografts (PDX) models (Niu et al., 2021).
  • PDX patient-derived xenografts
  • inhibitory checkpoint molecules such as programmed death-ligand 1 (PD-L1)
  • AML patient cells have been demonstrated in AML patient cells as compared to healthy donors, which contribute to immune exhaustion and possibly AML disease relapse (Abaza and Zeidan, 2022; Williams et al., 2019).
  • the PD-L1 blocking peptide can impede the binding between PD-1 and PD- Ll, disrupting the inhibitory signals on natural killer (NK) cells and T cells, leading to greater antitumor responses (Pardoll, 2012; Sharma and Allison, 2015).
  • NK natural killer
  • the blockade of immune checkpoints such as PD-1, can enhance antitumor immunity and the potential to produce enduring clinical responses.
  • any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
  • the term “about” means ⁇ 20% of the indicated range, value, or structure, unless otherwise indicated. It should be understood that the terms “a” and “an” as used herein refer to “one or more" of the enumerated components.
  • a “functional portion” or “functional fragment” refers to a polypeptide or polynucleotide that comprises only a domain, portion or fragment of a parent or reference compound, and the polypeptide or encoded polypeptide retains at least 50% activity associated with the domain, portion or fragment of the parent or reference compound, preferably at least 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% level of activity of the parent polypeptide, or provides a biological benefit (e.g., effector function).
  • a biological benefit e.g., effector function
  • Antigen refers to an immunogenic molecule that provokes an immune response. This immune response may involve antibody production, activation of specific immunologically-competent cells, activation of complement, antibody dependent cytotoxicity, or any combination thereof.
  • An antigen immunogenic molecule
  • An antigen may be, for example, a peptide, glycopeptide, polypeptide, glycopolypeptide, polynucleotide, polysaccharide, lipid, or the like. It is readily apparent that an antigen can be synthesized, produced recombinantly, or derived from a biological sample. Exemplary biological samples that can contain one or more antigens include tissue samples, stool samples, cells, biological fluids, or combinations thereof. Antigens can be produced by cells that have been modified or genetically engineered to express an antigen.
  • the epitope can be comprised of consecutive amino acids (e.g., a linear epitope), or can be comprised of amino acids from different parts or regions of the protein that are brought into proximity by protein folding (e.g., a discontinuous or conformational epitope), or non-contiguous amino acids that are in close proximity irrespective of protein folding.
  • antigen binding site or “antigen binding moiety” are used interchangeably herein and refer to the part of the antibody and/or immunoglobulin molecule that participates in binding to an antigen and/or epitope.
  • the antigen binding site is formed by amino acid residues of the N-terminal variable ("V") regions of the heavy ("H") and light (“L”) chains.
  • V N-terminal variable
  • H heavy
  • L light
  • hypervariable regions are three highly divergent stretches within the V regions of the heavy and light chains which are interposed between "framework regions,” ("FR"), which are relatively conserved flanking stretches.
  • FR refers to amino acid sequences which are naturally found between and adjacent to hypervariable regions in immunoglobulins.
  • the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three-dimensional space to form an antigen-binding surface.
  • the antigen-binding surface is complementary to the three-dimensional surface of a bound antigen.
  • Antigen-binding sites can exist in an intact antibody, in an antigenbinding fragment of an antibody that retains the antigen-binding surface, or in a recombinant polypeptide such as an scFv, using a peptide linker to connect the heavy chain variable domain to the light chain variable domain in a single polypeptide.
  • An antigen binding site can comprise an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).
  • antibody encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies, bifunctional antibodies), antibody fusion proteins, antibodies that for heterodimers in engineered proteins, and antibody fragments so long as they exhibit the desired antigen-binding activity.
  • Numbering of CDR and framework regions may be according to any known method or scheme, such as the Kabat, Chothia, EU, IMGT, and AHo numbering schemes (see, e.g., Kabat et al., "Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services, Public Health Service National Institutes of Health, 1991, 5 th ed.; Chothia and Lesk, J. Mol. Biol. 796:901-917 (1987)); Lefranc et al., Dev. Comp. Immunol. 27:55, 2003; Honegger and Pliickthun, J. Mol. Bio. 309:657-670 (2001)).
  • Kabat et al. Kabat et al., "Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services, Public Health Service National Institutes of Health, 1991, 5 th ed.; Chothia and Lesk, J. Mol. Biol. 796:901-917 (19
  • Equivalent residue positions can be annotated and for different molecules to be compared using Antigen receptor Numbering and Receptor Classification (ANARCI) software tool (2016, Bioinformatics 15:298-300).
  • the CDRs of an antigen-binding site can be determined according to known methods, such as the Kabat, Chothia, EU, IMGT, and AHo as described above.
  • the CDRs determined under these definitions typically include overlapping or subsets of amino acid residues when compared against each other.
  • the heavy chain CDRs and light chain CDRs of an antibody can be defined using different numbering conventions. For example, in certain embodiments, the heavy chain CDRs are defined according to Chothia, supra, and the light CDRs are defined according to Kabat, supra.
  • CDRH1, CDRH2 and CDRH3 denote the heavy chain CDRs
  • CDRL1, CDRL2 and CDRL3 denote the light chain CDRs.
  • PD-L1 also known as “programmed death-ligand 1” or CD274 in humans
  • CD274 refers to the protein of UniProt Accession No. Q0GN75 (human) and related isoforms and orthologs.
  • inhibit refers the reduction of a specified activity (e.g., immune suppression or tumor growth). Unless specified otherwise, an activity can be considered inhibited if the activity is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%, as measured by the methods disclosed herein or known in the art.
  • a specified activity e.g., immune suppression or tumor growth.
  • an activity can be considered inhibited if the activity is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%, as measured by the methods disclosed herein or known in the art.
  • ‘Mammal” or “mammalian subject” includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
  • “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the disclosure with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the disclosure may be true solvates, while in other cases, the compound of the disclosure may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • a “pharmaceutical composition” refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • “Therapeutically effective amount” refers to that amount of a compound of the disclosure which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a disease or condition in the mammal, preferably a human.
  • the amount of a compound of the disclosure which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or disorder of interest, and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;
  • Described herein in more detail are therefore methods for treating blood cancer in a patient in need thereof, the method comprising concomitantly administering one or more AXL inhibitors with one or more PD- 1 inhibitor.
  • the resulting therapeutic effects are surprisingly greater than the mere additive effects of monotherapies using each type of inhibitors alone.
  • Such a synergistic combination is further accompanied by low toxicity.
  • the AXL inhibitors suitable for the combination therapy disclosed are aminopyridine derivatives, known for being TAM family kinase inhibitors. See e.g., US Pat. No. 10,233,176, which is incorporated herein by reference in its entirety.
  • the AXL inhibitor is 3-(5-(cyclopropylmethyl)-l,3,4-oxadiazol-2- yl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine (referred to herein as “Compound A” or “SLC-391”):
  • PD-1 Programmed cell death protein 1
  • CD279 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting selftolerance by suppressing T cell inflammatory activity.
  • PD-1 refers to the protein of UniProt Accession No. Q15116 (human) and related isoforms and orthologs.
  • PD-1 inhibitors are a class of drugs that block PD-1 and promote activation of the immune system to attack tumors and are used to treat certain types of cancer.
  • a PD- 1 inhibitor is an anti-PD- 1 antibody that blocks the interaction of PD- 1 with a PD-1 ligand, such as PD-L1.
  • anti-PD- 1 antibodies include pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP- 514 (MEDI0680), acrixolimab, and toripalimab.
  • a PD-1 inhibitor is anti-PD-Ll antibody that blocks the interaction of PD-L1 with PD-1.
  • anti- PD-L1 antibodies include Atezolizumab, Avelumab, and Durvalumab.
  • combination therapy refers to the administration of one or more AXL inhibitor, (e.g., Compound A), in combination with the administration of one or more PD-1 inhibitor (e.g., pembrolizumab). Unless stated otherwise, “combination therapy” may include simultaneous or sequential administration of the AXL inhibitor and the PD-1 inhibitor, in any order, in any dosage forms.
  • AXL inhibitor e.g., Compound A
  • PD-1 inhibitor e.g., pembrolizumab
  • the antiproliferative effect of a combination therapy of the invention may be assessed by administering the active ingredients of the combination therapy to a cultured tumor cell line.
  • administration of an active ingredient may be simply achieved by contacting the cells in culture with the active ingredient in amounts effective to inhibit cell proliferation.
  • the antiproliferative effect of a combination therapy of the invention may be assessed by administering the active ingredients of the combination therapy to an animal in an approved in vivo model for cell proliferation.
  • the combination therapies of the invention can be tested for the treatment of AML by testing the combination therapy in a xenograft in SCID or nu/nu mouse model using human AXL-expressing AML leukemia cell lines.
  • Selection of the preferred prophylactically or therapeutically effective dose of an active ingredient used in the combination therapies of the invention can be determined (e.g., by clinical trials) by a skilled artisan based upon the consideration of several factors, including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; and the severity of the metastatic cancer.
  • a therapeutically effective daily dose for a AXL inhibitor may be, for a 70 kg mammal, from about 0.001 mg/kg (z.e., 0.07 mg) to about 300 mg/kg (z.e., 21.0 gm); preferably a therapeutically effective dose is from about 0.01 mg/kg (i.e., 0.7 mg) to about 100 mg/kg (i.e., 7.0 gm); more preferably a therapeutically effective dose is from about 0.1 mg/kg (i.e., 7 mg) to about 50 mg/kg (i.e., 3.5 gm); and more preferably a therapeutically effective dose is from about 0.5 mg/kg (i.e., 35 mg) to about 25 mg/kg (i.e., 1.75 gm).
  • the AXL inhibitor is administered to a patient concomitantly with a PD- 1 inhibitor useful for the treatment of cancer.
  • a PD- 1 inhibitor useful for the treatment of cancer.
  • the term “concomitantly” or “concurrently,” is not limited to the administration of the active ingredients i.e., the AXL inhibitor and the PD-1 inhibitor) at exactly the same time, but rather it is meant that the AXL inhibitor and the PD-1 inhibitor are administered to a patient in a sequence and within a time interval such that the AXL inhibitor can act together with PD-1 inhibitor to provide a synergistic benefit than if they were administered otherwise.
  • the chemotherapeutic agents in particular cytotoxic agents, are used at lower doses.
  • Such dosing regimens encompass the chronic daily administration of relatively low doses for extended periods of time.
  • the use of lower doses of the chemotherapeutic agent can minimize toxic side effects and eliminate rest periods.
  • the active ingredients are administered by chronic low-dose or continuous infusion ranging from about 24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3 weeks to about 1 month to about 2 months, to about 3 months, to about 4 months, to about 5 months, to about 6 months.
  • the scheduling of such dose regimens can be optimized by the skilled oncologist.
  • compositions of the disclosure can be prepared by combining a compound of the disclosure with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi- solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • compositions of the disclosure are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the disclosure in aerosol form may hold a plurality of dosage units.
  • cytokines were detected in co-cultured media obtained from MV4-11-GFP + cells co-cultured with PBMCs and treated with either SLC-391 or PEM, alone or in combination, using a LEGENDplex multiplex assay; in particular, enhanced production of IFN-y after the combination treatment was observed (up to 15-fold, P ⁇ 0.001, FIG. 3B).
  • Other immune active cytokines, such as TNF-a also displayed significantly increased concentrations with treatment of SLC-391 alone or SLC- 391 in combination with PEM when co-cultured with activated PBMCs in comparison to PBMC control or PEM treatment condition (up to 200-fold, P ⁇ 0.008, FIG. 3C).
  • CD34 + cells from AML patients at diagnosis, with relatively high expression of AXL were treated with SLC-391 or PEM, alone or combination, in the presence or absence activated PBMCs (at the effector: target ratio 5:1).
  • SLC-391 or PEM treatment in the presence of activated PBMCs showed significantly reduced cell viability in AML patient cells, compared to the same cells without co-culturing with PBMC (50% or 60% reduction vs. 25% or 10%, P ⁇ 0.014, FIG. 4A).
  • Increased PD-L1 was also observed under the combination treatment conditions when co-cultured with PBMC (up to 3-fold, P ⁇ 0.0002, FIG. 4D).
  • intracellular staining or cytokine array assays demonstrated increased IFN-y in T-cells or in co-culture media after the combination treatment, compared to control or single agents (P ⁇ 0.0002, FIG. 4E), which correlated well with increased PD-L1 expression since IFN-y can induce upregulation of PD-L1.
  • cytokines involved in activation of innate and adaptive immune responses such as TNF-a and sFasL, were detected at elevated levels in co-cultured media obtained from the combination treatment of AML stem/progenitor cells co-cultured with PBMCs as compared to controls or single agents, as assessed by a LEGENDplex multiplex assay (P ⁇ 0.02, FIGS. 4F and 4G).
  • TIM3, an immune checkpoint receptor that is associated with regulation of T-cell and NK cell exhaustion were reduced by the combination treatment, suggesting that its inhibition may boost innate and adaptive immune responses (up to 3-fold, P ⁇ 0.03, FIG. 4G).
  • a humanized PDX model was recently developed using an immunodeficient NSG mouse strain (NOD-scid IL2Rgnull), which allows mice to be humanized by engraftment of human healthy CD34 + cells (FIG. 5A).
  • NOD-scid IL2Rgnull an immunodeficient NSG mouse strain
  • FIG. 5A In vivo conditions for immune reconstitution were determined by transplanting CD34 + human cord blood (CB) cells into mice at 4 weeks old. Efficient engraftment of multiple-lineage circulating human CD45 + cells (-50%), T cells, NK cells and dendritic cells (DCs), etc.
  • mice with the combination treatment were still alive after 62 days compared to vehicle, PEM- treated mice and SLC-391 -treated mice (median survival 47, 47, and 56 days, respectively, FIG. 5F).
  • an increase in immune cells was also observed in the combination treated-mice, particularly CD3 + T cells, NK cells and pDC cells detected in peripheral blood or BM (up to 3-fold, FIG. 6A-B).
  • Immunohistological staining was performed to evaluate the number of leukemic cells, CD3+ cells, and CD8+ cells for mice receiving combination treatment of SLC-391 and PEM. Spleens of treated mice were harvested and fixed in 10% formalin. The fixed tissues were further individually processed for Haemotoxylin and Eosin staining and IHC staining of antihuman CD3, CD8, and PDL1 antibodies. The representative 40X imaging of each treated mouse is shown in FIG. 5G. The percentage of CD3-positive, CD8-positive, and PDL1- positive cells from each treatment condition are shown in the bar graph (FIG. 5G) wherein the cell numbers were manually counted and calculated based on the total 4000 cells in each field.
  • Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia. Journal for immunotherapy of cancer 10.

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Abstract

L'invention concerne des polythérapies pour traiter le cancer du sang, en particulier, la leucémie aiguë myéloïde, en ciblant simultanément AXL et PD-1.
PCT/US2025/014420 2024-02-05 2025-02-04 Combinaison de l'inhibiteur d'axl slc-391 et d'un inhibiteur de pd-1 destinée à être utilisée dans le traitement du cancer du sang Pending WO2025170888A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100266617A1 (en) 2007-06-18 2010-10-21 N.V. Organon Antibodies to human programmed death receptor pd-1
US10233176B2 (en) 2013-11-27 2019-03-19 Signalchem Lifesciences Corporation Aminopyridine derivatives as TAM family kinase inhibitors
WO2020061216A1 (fr) * 2018-09-18 2020-03-26 Signalchem Lifesciences Corporation Polythérapie pour traiter le cancer du sang
WO2021214492A1 (fr) * 2020-04-24 2021-10-28 Bergenbio Asa Procédé de sélection de patients pour un traitement avec une combinaison d'un inhibiteur axl et d'un modulateur de point de contrôle immunitaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100266617A1 (en) 2007-06-18 2010-10-21 N.V. Organon Antibodies to human programmed death receptor pd-1
US10233176B2 (en) 2013-11-27 2019-03-19 Signalchem Lifesciences Corporation Aminopyridine derivatives as TAM family kinase inhibitors
WO2020061216A1 (fr) * 2018-09-18 2020-03-26 Signalchem Lifesciences Corporation Polythérapie pour traiter le cancer du sang
WO2021214492A1 (fr) * 2020-04-24 2021-10-28 Bergenbio Asa Procédé de sélection de patients pour un traitement avec une combinaison d'un inhibiteur axl et d'un modulateur de point de contrôle immunitaire

Non-Patent Citations (39)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2000, PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
"Safety, activity, and immune correlates of anti-PD-1 antibody in cancer", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 366, 2012, pages 2443 - 2454
"UniProt", Database accession no. Q15116
BEN-BATALLA, I.SCHULTZE, A.WROBLEWSKI, M.ERDMANN, R.HEUSER, M.WAIZENEGGER, J. S.RIECKEN, K.BINDER, M.SCHEWE, D.SAWALL, S. ET AL.: "Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma", BLOOD, vol. 122, 2013, pages 2443 - 2452, XP055242664, DOI: 10.1182/blood-2013-03-491431
BEYER, A. I.MUENCH, M. O.: "Comparison of Human Hematopoietic Reconstitution in Different Strains of Immunodeficient Mice", STEM CELLS AND DEVELOPMENT, vol. 26, 2017, pages 102 - 112
BIOINFORMATICS, vol. 15, 2016, pages 298 - 300
CHOTHIALESK, J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
DAVER, N.GARCIA-MANERO, G.BASU, S.BODDU, P. C.ALFAYEZ, M.CORTES, J. E.KONOPLEVA, M.RAVANDI-KASHANI, F.JABBOUR, E.KADIA, T. ET AL.: "Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study", CANCER DISCOVERY, vol. 9, 2019, pages 370 - 383
DELBRIDGE, A. R.GRABOW, S.STRASSER, A.VAUX, D. L.: "Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies", NATURE REVIEWS CANCER, vol. 16, 2016, pages 99 - 109
DINARDO, C. D.PRATZ, K.PULLARKAT, V.JONAS, B. A.ARELLANO, M.BECKER, P. S.FRANKFURT, O.KONOPLEVA, M.WEI, A. H.KANTARJIAN, H. M. ET : "Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia", BLOOD, vol. 133, 2019, pages 7 - 17, XP055706803, DOI: 10.1182/blood-2018-08-868752
DOHNER, H.ESTEY, E. H.AMADORI, S.APPELBAUM, F. R.BUCHNER, T.BURNETT, A. K.DOMBRET, H.FENAUX, P.GRIMWADE, D.LARSON, R. A. ET AL.: "Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet", BLOOD, vol. 115, 2010, pages 453 - 474
DOHNER, H.WEISDORF, D. J.BLOOMFIELD, C. D.: "Acute Myeloid Leukemia", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 373, 2015, pages 1136 - 1152, XP009509723, DOI: 10.1056/NEJMra1406184
GARON, E. B.RIZVI, N. A.HUI, R.LEIGHL, N.BALMANOUKIAN, A. S.EDER, J. P.PATNAIK, A.AGGARWAL, C.GUBENS, M.HORN, L. ET AL.: "Pembrolizumab for the treatment of non-small-cell lung cancer", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 372, 2015, pages 2018 - 2028, XP055306209, DOI: 10.1056/NEJMoa1501824
GARRIS, C. S.ARLAUCKAS, S. P.KOHLER, R. H.TREFNY, M. P.GARREN, S.PIOT, C.ENGBLOM, C.PFIRSCHKE, C.SIWICKI, M.GUNGABEESOON, J. ET AL: "Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-gamma and IL-12", IMMUNITY, vol. 49, 2018, pages 1148 - 1161, XP055727087
GAY, C. M.BALAJI, K.BYERS, L. A.: "Giving AXL the axe: targeting AXL in human malignancy", BRITISH JOURNAL OF CANCER, vol. 116, 2017, pages 415 - 423
GOMEZ-LLOBELL, M.PELETEIRO RAINDO, A.CLIMENT MEDINA, J.GOMEZ CENTURION, I.MOSQUERA ORGUEIRA, A.: "Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: A Meta-Analysis", FRONTIERS IN ONCOLOGY, vol. 12, 2022, pages 882531
GOSWAMI, M.GUI, G.DILLON, L. W.LINDBLAD, K. E.THOMPSON, J.VALDEZ, J.KIM, D. Y.GHANNAM, J. Y.OETJEN, K. A.DESTEFANO, C. B. ET AL.: "Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia", JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2022, pages 10
GRAHAM, D. K.DERYCKERE, D.DAVIES, K. D.EARP, H. S.: "The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer", NATURE REVIEWS CANCER, vol. 14, 2014, pages 769 - 785, XP002781598, DOI: 10.1038/nrc3847
GRASSO, C. S., TSOI, J., ONYSHCHENKO, M., ABRIL-RODRIGUEZ, G., ROSS-MACDONALD,P., WIND-ROTOLO, M., CHAMPHEKAR, A., MEDINA, E., TOR: "Conserved Interferon-gamma Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma", CANCER CELL, vol. 38, 2020, pages 500 - 515
GUAMERA LBRAVO-PEREZ CVISCONTE V.: "Immunotherapy in Acute Myeloid Leukemia: A Literature Review of Emerging Strategies", BIOENGINEERING, vol. 10, no. 10, 20 October 2023 (2023-10-20), pages 1228
HONEGGERPLÜCKTHUN, J. MOL. BIO., vol. 309, 2001, pages 657 - 670
HUGO, W.ZARETSKY, J. M.SUN, L.SONG, C.MORENO, B. H.HU-LIESKOVAN, S.BERENT-MAOZ, B.PANG, J.CHMIELOWSKI, B.CHERRY, G. ET AL.: "Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma", CELL, vol. 165, 2016, pages 35 - 44, XP093153037, DOI: 10.1016/j.cell.2016.02.065
KABAT ET AL.: "Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services, Public Health Service National Institutes of Health", 1991
KHWAJA, A.BJORKHOLM, M.GALE, R. E.LEVINE, R. L.JORDAN, C. T.EHNINGER, G.BLOOMFIELD, C. D.ESTEY, E.BURNETT, A.CORNELISSEN, J. J. ET: "Acute myeloid leukaemia", NAT REV DIS PRIMERS, vol. 2, 2016, pages 16010
KRUPKA, C.KUFER, P.KISCHEL, R.ZUGMAIER, G.LICHTENEGGER, F. S.KOHNKE, T.VICK, B.JEREMIAS, I.METZELER, K. H.ALTMANN, T. ET AL.: "Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism", LEUKEMIA, vol. 30, 2016, pages 484 - 491, XP037784546, DOI: 10.1038/leu.2015.214
LEFRANC ET AL., DEV. COMP. IMMUNOL., vol. 27, 2003, pages 55
MILLER, P. H.CHEUNG, A. M.BEER, P. A.KNAPP, D. J.DHILLON, K.RABU, G.ROSTAMIRAD, S.HUMPHRIES, R. K.EAVES, C. J.: "Enhanced normal short-term human myelopoiesis in mice engineered to express human-specific myeloid growth factors", BLOOD, vol. 121, 2013, pages 4
NIU XIAOJIA ET AL: "Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia", BLOOD, vol. 137, no. 26, 30 March 2021 (2021-03-30), AMSTERDAM, NL, pages 3641 - 3655, XP093273700, ISSN: 0006-4971, Retrieved from the Internet <URL:https://watermark.silverchair.com/bloodbld2020007651.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAABGQwggRgBgkqhkiG9w0BBwagggRRMIIETQIBADCCBEYGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMTirMlTtwxZhF2FCXAgEQgIIEF8BMq_JKsdiSwee__I_TvOxcsfh943OL-03Kbisn00g7CWCQjIttCtj5IVLgG3pYId4Ov1Gwt5jrj6Yt1> [retrieved on 20250502], DOI: 10.1182/blood.2020007651 *
NIU, X.ROTHE, K.CHEN, M.GRASEDIECK, S.LI, R.NAM, S. E.ZHANG, X.NOVAKOVSKIY, G. E.AHN, Y. H.MAKSAKOVA, I. ET AL.: "Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia", BLOOD, vol. 137, 2021, pages 3641 - 3655
PARDOLL, D. M.: "The blockade of immune checkpoints in cancer immunotherapy", NATURE REVIEWS CANCER, vol. 12, 2012, pages 252 - 264, XP037114946, DOI: 10.1038/nrc3239
SCHOUMACHER, M.BURBRIDGE, M.: "Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies", CURRENT ONCOLOGY REPORTS, vol. 19, 2017, pages 19
SHARMA, P.ALLISON, J. P.: "Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential", CELL, vol. 161, 2015, pages 205 - 214, XP055427087, DOI: 10.1016/j.cell.2015.03.030
THOMAS, D.MAJETI, R.: "Biology and relevance of human acute myeloid leukemia stem cells", BLOOD, vol. 129, 2017, pages 1577 - 1585, XP086677269, DOI: 10.1182/blood-2016-10-696054
TIRADO-GONZALEZ IRENE ET AL: "AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Na�ve and Treatment-Resistant Leukemia", CANCER DISCOVERY, vol. 11, no. 11, 8 June 2021 (2021-06-08), US, pages 2924 - 2943, XP093274122, ISSN: 2159-8274, Retrieved from the Internet <URL:https://watermark.silverchair.com/2924.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA2AwggNcBgkqhkiG9w0BBwagggNNMIIDSQIBADCCA0IGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMlPqoyBtpeTYLC1v2AgEQgIIDEw0inrLp9CpECHz6CYXdDSZJKoa9xMbTz9Y_TuZt28Ig0uYyJdCrP88s9dmccp-Npbbxl6g6pb2BEcDpz_L1T3dpz2vhe57> [retrieved on 20250501], DOI: 10.1158/2159-8290.CD-20-1378 *
TIRADO-GONZALEZ, I.DESCOT, A.SOETOPO, D.NEVMERZHITSKAYA, A.SCHAFFER, A.KUR, I. M.CZLONKA, E.WACHTEL, C.TSOUKALA, I.MULLER, L. ET A: "AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naive and Treatment-Resistant Leukemia", CANCER DISCOVERY, vol. 11, 2021, pages 2924 - 2943
VADDEPALLY, R. K.KHAREL, P.PANDEY, R.GARJE, R.CHANDRA, A. B.: "Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence", CANCERS, 2020, pages 12
WILLIAMS, P.BASU, S.GARCIA-MANERO, G.HOURIGAN, C. S.OETJEN, K. A.CORTES, J. E.RAVANDI, F.JABBOUR, E. J.AL-HAMAL, Z.KONOPLEVA, M. E: "The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia", CANCER, vol. 125, 2019, pages 1470 - 1481, XP071178030, DOI: 10.1002/cncr.31896
ZEIDNER JFVINCENT BG ET AL.: "Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia", BLOOD CANCER DISCOV., vol. 2, no. 6, 10 September 2021 (2021-09-10), pages 616 - 629
ZHU, C.WEI, Y.WEI, X.: "AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications", MOLECULAR CANCER, vol. 18, 2019, pages 153, XP093013311, DOI: 10.1186/s12943-019-1090-3

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