Combining tyrosine kinase inhibitors with pro-inflammatory agents for cancer treatment

Abstract

The present application provides a method of treating cancer in an individual, the method comprising administering to the individual a tyrosine kinase inhibitor and an inflammatory agent (such as a TLR agonist, a STING activator, radiation therapy, or an immune checkpoint inhibitor). In some cases, the method involves administering the tyrosine kinase inhibitor when the individual is under inflammatory conditions. In one aspect, the present application provides a method of treating cancer in an individual, the method comprising administering to the individual a) a tyrosine kinase inhibitor and b) an inflammatory agent, optionally comprising intermittently administering the tyrosine kinase inhibitor to the individual.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 382,003, filed November 2, 2022, U.S. Provisional Patent Application No. 63 / 491,000, filed March 17, 2023, and U.S. Provisional Patent Application No. 63 / 581,197, filed September 7, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to compositions and methods for treating cancer comprising administering a tyrosine kinase inhibitor and, optionally, a pro-inflammatory agent. [Background technology]

[0003] In cancers, such as solid tumors, intratumoral myeloid leukocytes, including macrophages (i.e., tumor-associated macrophages or TAMs) and myeloid-derived suppressor cells (MDSCs), play a crucial role in regulating the immunosuppressive tumor microenvironment (TME) that supports tumor growth and may also contribute to tumor resistance to immunotherapy treatment. One key mechanism by which myeloid leukocytes adopt an immunosuppressive phenotype or enhance their immunosuppressive capabilities after tumor treatment is through cell surface inhibitory receptors (iRs). Upon activation, these receptors are regulated by extracellular ligand binding and trigger multiple pathways of negative regulation via cytoplasmic domain immunoreceptor tyrosine-based inhibitory motifs (ITIMs). This activates the central signal regulator SHP-1, which dephosphorylates and thus inactivates several signaling molecules, thereby reducing the anti-cancer pro-inflammatory response induced by therapeutic agents (Figure 1). In solid tumors, key cell surface iRs, such as SIRPα, Siglec family, LilRB family, and PirB, LAIR1, lectin receptor family, and SLAM receptor family, show increased expression in the TME as tumor progression progresses, and these receptors regulate SHP-1 activation, thereby suppressing downstream signaling.

[0004] Given these inhibitory mechanisms elucidated over the past few years, a pipeline of therapeutic developments is underway aimed at blocking iRs (e.g., anti-LilRB1 / 2 and anti-SIRPα) and their ligands (e.g., anti-CD47). (3-5) However, these efforts to specifically target each iR or its ligand, rather than all inhibitory pathways at once, have only minimal or partial effects on solid tumor control.

[0005] The disclosures of all publications, patents, patent applications and published patent applications mentioned herein are hereby incorporated by reference in their entirety. Summary of the Invention [Means for solving the problem]

[0006] In one aspect, the present application provides a method of treating cancer in an individual, comprising administering to the individual: a) a tyrosine kinase inhibitor; and b) an inflammatory agent, optionally comprising intermittently administering the tyrosine kinase inhibitor to the individual. In some embodiments, the method comprises administering the tyrosine kinase inhibitor systemically or locally (e.g., intratumorally). In some embodiments, the inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP molecule, a checkpoint inhibitor, a proinflammatory cytokine, a proinflammatory cell, a cell, a cancer vaccine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

[0007] In another aspect, the application provides a method of treating cancer in an individual, comprising administering to the individual: a) a tyrosine kinase inhibitor; and b) an inflammatory agent, wherein the method comprises systemically administering the tyrosine kinase inhibitor. In some embodiments, the method comprises intermittently administering the tyrosine kinase inhibitor to the individual. In some embodiments, the inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a proinflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

[0008] In another aspect, the present application provides methods of treating cancer in an individual, comprising administering to the individual: a) a tyrosine kinase inhibitor; and b) an inflammatory inducer, wherein the inflammatory inducer comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP / DAMP activator, chemotherapy, a proinflammatory cytokine, a cancer vaccine, a bacterial component, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy. In some embodiments, the method comprises intermittently administering the tyrosine kinase inhibitor to the individual. In some embodiments, the method comprises systemically administering the tyrosine kinase inhibitor.

[0009] In another aspect, the application provides methods of treating cancer in an individual, comprising administering a tyrosine kinase inhibitor to the individual, wherein the individual is exhibiting an inflammatory response or has a persistent infection. In some embodiments, the method comprises intermittently administering the tyrosine kinase inhibitor to the individual. In some embodiments, the method comprises systemically administering the tyrosine kinase inhibitor. In some embodiments, the method further comprises immune cells.

[0010] In some embodiments of any one of the aforementioned methods, the method comprises administering to the individual the tyrosine kinase inhibitor at least twice, not more than once every three days.

[0011] In some embodiments of any one of the aforementioned methods, the method comprises administering to the individual the tyrosine kinase inhibitor in at least two cycles, each cycle lasting from about 3 days to about 20 days.

[0012] In some embodiments of any of the aforementioned methods, the tyrosine kinase inhibitor has a half-life of about 5 days or less, and optionally, the tyrosine kinase inhibitor has a half-life of about 3 days or less.

[0013] In some embodiments of any of the above methods, the tyrosine kinase inhibitor is effective to inhibit greater than 50% of tyrosine kinase activation within about 5 days, and optionally, the tyrosine kinase inhibitor is effective to inhibit greater than 50% of tyrosine kinase activation within about 3 days.

[0014] In some embodiments of any of the above-described methods, the tyrosine kinase inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., siRNA, shRNA, antisense RNA, microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein formulation (e.g., an antibody formulation targeting a tyrosine kinase or an activated tyrosine kinase). In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits a Src family kinase (SFK). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406.

[0015] In some embodiments of any of the aforementioned methods, the tyrosine kinase inhibitor is administered at least three times. In some embodiments of any one of the aforementioned methods, the method comprises systemic and local administration of the tyrosine kinase inhibitor, and optionally, the method comprises intratumoral administration of the tyrosine kinase inhibitor.

[0016] In some embodiments of any of the methods described above, systemic administration of the tyrosine kinase comprises oral administration, intravenous administration, subcutaneous administration, and / or intraperitoneal administration.

[0017] In some embodiments of any of the above methods, the pro-inflammatory agent and the tyrosine kinase inhibitor are administered within about 24 hours (e.g., within about 16 hours, 8 hours, 4 hours, 2 hours, 1 hour, or 0.5 hours) of each other.

[0018] In some embodiments of any of the methods described above, the method comprises intratumorally administering an inducing inflammatory agent.

[0019] In some embodiments of any of the aforementioned methods, the method includes administering the pro-inflammatory agent to a site different from the site of the cancer being treated.

[0020] In some embodiments of any of the above-described methods, the pro-inflammatory agent comprises a TLR agonist. In some embodiments, the TLR agonist activates a TLR on macrophages. In some embodiments, the TLR comprises TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and / or TLR9. In some embodiments, the TLR agonist comprises CpG, PolyIC and / or R848, flagellin (TLR5), zymosan (TLR2 / 4), radiation therapy-generated DAMPs, e.g., HMGB1 (TLR2 / 4), DNA and RNA molecules (TLR3 / 7 / 8 / 9), etc. In some embodiments, the TLR agonist comprises CpG, PolyIC, and R848, e.g., in a 1:1:1 ratio.

[0021] In some embodiments of any of the aforementioned methods, the pro-inflammatory agent comprises a bacterial component, and optionally, the bacterial component comprises lipopolysaccharide (LPS).

[0022] In some embodiments of any of the aforementioned methods, the pro-inflammatory agent comprises a STING activator, hi some embodiments, the STING activator comprises 2'3'-cGAMP.

[0023] In some embodiments of any of the aforementioned methods, the pro-inflammatory agent comprises a chemotherapeutic agent. In some embodiments, the chemotherapy comprises azathioprine (AZA).

[0024] In some embodiments of any of the above methods, the inducing agent comprises a proinflammatory cytokine, hi some embodiments, the proinflammatory cytokine includes IL-1 family cytokines (e.g., IL-1b, IL-18), IL-6, IL-17, TNF family cytokines (e.g., TNFα), and combinations thereof with type I and type II interferons (IFNα, IFNβ, and IFNγ).

[0025] In some embodiments of any of the above-described methods, the pro-inflammatory agent comprises radiation therapy. In some embodiments, the radiation therapy comprises irradiating the site of the cancer being treated. In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated. In some embodiments, the radiation therapy is administered at a dose that does not cause epidermal necrosis and is insufficient to eliminate the tumor (kill all tumor cells).

[0026] In some embodiments of any of the aforementioned methods, the pro-inflammatory agent comprises a checkpoint inhibitor, hi some embodiments, the checkpoint inhibitor comprises an anti-PD-L1 antibody, an anti-PD-1 antibody, or an anti-CLTA4 antibody.

[0027] In some embodiments of any of the above methods, the pro-inflammatory agent is administered intermittently.

[0028] In some embodiments of any of the above methods, the pro-inflammatory agent and the tyrosine kinase inhibitor are administered simultaneously or concurrently.

[0029] In some embodiments of any of the above-described methods, the pro-inflammatory agent comprises immune cells. In some embodiments, the immune cells are derived from the same individual. In some embodiments, the immune cells comprise or are macrophages, optionally, the macrophages have a pro-inflammatory (M1) phenotype. In some embodiments, the immune cells are derived from monocytes. In some embodiments, the immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86. In some embodiments, the immune cells express one or more pro-inflammatory cytokines, optionally, the one or more pro-inflammatory cytokines include TNFα and / or IL-12. In some embodiments, the immune cells do not express significant levels of TGFβ and / or IL-10. In some embodiments, the immune cells comprise T cells. In some embodiments, the immune cells are engineered to express a chimeric antigen receptor, optionally, the chimeric antigen receptor specifically binds to a tumor antigen. In some embodiments, the macrophages are engineered to be defective in tyrosine kinase expression and / or activation. In some embodiments, the tyrosine kinase inhibitor and the immune cells are administered within about 24 hours of each other, and optionally, the tyrosine kinase inhibitor and the immune cells are administered within about 4 hours of each other, hi some embodiments, the immune cells are administered simultaneously or concurrently with the tyrosine kinase inhibitor.

[0030] In some embodiments of any of the above-described methods, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, SHP-1 is administered simultaneously with the tyrosine kinase inhibitor. In some embodiments, SHP-1 is administered sequentially with (e.g., before or after) the tyrosine kinase inhibitor. In some embodiments, administration of SHP-1 follows the same administration schedule as the tyrosine kinase inhibitor.

[0031] In some embodiments of any of the above-described methods, the method further includes administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm, including, but not limited to, an anti-TNFα antibody and an anti-IL6 antibody. In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to the tyrosine kinase inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly after (e.g., within about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after) the tyrosine kinase inhibitor. In some embodiments, administration of the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm follows the same administration schedule as the tyrosine kinase inhibitor.

[0032] In some embodiments of any of the aforementioned methods, the cancer is a solid tumor.

[0033] In some embodiments of any of the above methods, the cancer is a hematological cancer.

[0034] In some embodiments of any of the above methods, the cancer is a terminal cancer.

[0035] In some embodiments of any of the aforementioned methods, the cancer is resistant or refractory to radiation therapy, chemotherapy, and / or checkpoint inhibitors.

[0036] In some embodiments of any of the above methods, the individual is a human.

[0037] In another aspect, the application provides a composition comprising a tyrosine kinase inhibitor and an inducing agent, optionally wherein the inducing agent comprises an agent selected from the group consisting of an immune cell, a TLR agonist, a STING activator, an agent used in radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a proinflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, and an agent used in acoustic therapy, magnetic therapy, electrical therapy, or electrostatic therapy. [Brief explanation of the drawings]

[0038] [Figure 1] We demonstrate that SHP-1 functions as a "master" signaling mediator downstream of multiple inhibitory receptors on myeloid leukocytes in the tumor microenvironment (TME). Activation of SHP-1 attenuates proinflammatory pathways and the anticancer effects of RT and immunotherapy, maintaining the immunosuppressive phenotype of myeloid leukocytes. Tyrosine kinase inhibition approaches as anticancer strategies are circled. Examples include immunotherapy using SIRPα (SIRPα antagonists, anti-CD47 Gilead) and anti-SIRPα (Biosion) approaches, as well as companies and approaches aimed at depleting or blocking individual cell surface inhibitory receptors, such as Siglec (NextCure), LilRB (Next-IO), and SLAMF (BMS).

[0039] [Figure 2A] A to E show sample assays for in vitro studies of RK-20449 and dasatinib. A shows the in vitro assay system. [Figure 2B] These results show that RK20449 and dasatinib dose-dependently reduced macrophage SHP-1 activity induced by ligation of αTLR and cancer cells. [Figure 2C] These results show that RK20449 and dasatinib reduced αTLR and cancer cell ligation-induced iR phosphorylation and binding to SHP-1. [Figure 2D] Panels D and E show that treatment with RK-20449 or dasatinib enabled macrophages to overcome tumor cell inhibition and unleash the αTLR-induced proinflammatory phenotype, demonstrating a significant increase in the production of the proinflammatory cytokines TNFα, IL-6, and CXCL1 (Figure D) and the expression of cell surface antigen presentation machinery (Figure 2E). The SHI-1 inhibitor TPI-1 also demonstrated similar effects and was used in parallel experiments. [Figure 2E] Panels D and E show that treatment with RK-20449 or dasatinib enabled macrophages to overcome tumor cell inhibition and unleash the αTLR-induced proinflammatory phenotype, demonstrating a significant increase in the production of the proinflammatory cytokines TNFα, IL-6, and CXCL1 (Figure D) and the expression of cell surface antigen presentation machinery (Figure 2E). The SHI-1 inhibitor TPI-1 also demonstrated similar effects and was used in parallel experiments.

[0040] [Figure 3A] A-G show the effect of RK-20449 or dasatinib in combination with TLR agonists on solid tumors. The top panel of A shows the experimental design. [Figure 3B]We demonstrate the efficacy of tyrosine kinase inhibitor (TKi) treatment alone or in combination with TLR agonists against MC38 colorectal cancer. [Figure 3C] We demonstrate the efficacy of TKi treatment alone or in combination with TLR agonists for KPC pancreatic ductal adenocarcinoma. [Figure 3D] Figure 1 shows the dose-dependent effect of TKi on LLC lung cancer. [Figure 3E] We demonstrate the efficacy of the combination of dasatinib with various TLR agonists in the treatment of MC38 colorectal cancer. [Figure 3F] The top panel shows the experimental design. Efficacy of TKi treatment alone or in combination with a TLR agonist against KPC pancreatic ductal adenocarcinoma. [Figure 3G] Inhibition of TKs has been shown to reduce tumor angiogenesis. TKi such as dasatinib inhibit angiogenesis within tumors. This effect is mediated by inhibition of the receptor tyrosine kinase VEGR.

[0041] [Figure 4A-1] A-B show that the combination of dasatinib and αTLR induces antitumor T cell immunity. A shows flow cytometry analysis of the frequency of immune cells (CD45+) within the total cell population of tumor dissociates, as well as the frequency of individual immune cell types labeled by specific antibodies. [Figure 4A-2] A-B show that the combination of dasatinib and αTLR induces antitumor T cell immunity. A shows flow cytometry analysis of the frequency of immune cells (CD45+) within the total cell population of tumor dissociates, as well as the frequency of individual immune cell types labeled by specific antibodies. [Figure 4A-3] A-B show that the combination of dasatinib and αTLR induces antitumor T cell immunity. A shows flow cytometry analysis of the frequency of immune cells (CD45+) within the total cell population of tumor dissociates, as well as the frequency of individual immune cell types labeled by specific antibodies. [Figure 4B]The dynamics of each immune population are summarized. Dasatinib, when combined with αTLR, showed a dose-dependent effect of increasing CD8+ T cells and NK cells and decreasing macrophages and MDSCs in the TME.

[0042] [Figure 5A] A–C show the efficacy of combining RK-20449 or dasatinib with Sting activators ( Fig. 5A ), tumor-localized RT ( Fig. 5B ), or proinflammatory cytokines ( Fig. 5C ) in the treatment of MC38 colorectal cancer. [Figure 5B] A–C show the efficacy of combining RK-20449 or dasatinib with Sting activators ( Fig. 5A ), tumor-localized RT ( Fig. 5B ), or proinflammatory cytokines ( Fig. 5C ) in the treatment of MC38 colorectal cancer. [Figure 5C] A–C show the efficacy of combining RK-20449 or dasatinib with Sting activators ( Fig. 5A ), tumor-localized RT ( Fig. 5B ), or proinflammatory cytokines ( Fig. 5C ) in the treatment of MC38 colorectal cancer.

[0043] [Figure 6A] A–C show that PD-1 / PD-L1 immune checkpoint blockade enhances the efficacy of dasatinib and αTLR combination therapy. A shows the experimental design. [Figure 6B] luminescence images showing the location and size of the tumor are shown. [Figure 6C] Changes in tumor volume after treatment are shown.

[0044] [Figure 7A]Figures 7A-C show in vitro testing of UM-164, R406, piceatannol, bafetinib, and ibrutinib to attenuate the TK-iRS-SHP-1 axis in TAMs induced by αTLR and cancer cell ligation. Several TKs were tested for their ability to attenuate macrophage SHP-1 activity (Figure 7A), enhance antigen presentation (Figure 7B), and induce proinflammatory cytokines (Figure 7C) induced by αTLR and cancer cell ligation. [Figure 7B] Figures 7A-C show in vitro testing of UM-164, R406, piceatannol, bafetinib, and ibrutinib to attenuate the TK-iRS-SHP-1 axis in TAMs induced by αTLR and cancer cell ligation. Several TKs were tested for their ability to attenuate macrophage SHP-1 activity (Figure 7A), enhance antigen presentation (Figure 7B), and induce proinflammatory cytokines (Figure 7C) induced by αTLR and cancer cell ligation. [Figure 7C] Figures 7A-C show in vitro testing of UM-164, R406, piceatannol, bafetinib, and ibrutinib to attenuate the TK-iRS-SHP-1 axis in TAMs induced by αTLR and cancer cell ligation. Several TKs were tested for their ability to attenuate macrophage SHP-1 activity (Figure 7A), enhance antigen presentation (Figure 7B), and induce proinflammatory cytokines (Figure 7C) induced by αTLR and cancer cell ligation.

[0045] [Figure 8A-1] Figures A-C show in vivo antitumor testing of R406, UM-164, piceatannol, and the SHP inhibitor 3Ac in combination with αTLR. Figure A shows that R406, when combined with αTLR, effectively suppressed LLC tumors, unlike the other inhibitors. [Figure 8A-2]Figures A-C show in vivo antitumor testing of R406, UM-164, piceatannol, and the SHP inhibitor 3Ac in combination with αTLR. Figure A shows that R406, when combined with αTLR, effectively suppressed LLC tumors, unlike the other inhibitors. [Figure 8B-1] 1 shows TME analysis demonstrating that the combination of R406 and αTLR induced proliferation of intratumoral CD8+ T cells. [Figure 8B-2] 1 shows TME analysis demonstrating that the combination of R406 and αTLR induced proliferation of intratumoral CD8+ T cells. [Figure 8C] This indicates that the combination of R406 and αTLR induced intratumoral macrophages for antigen presentation.

[0046] [Figure 9A] Figures 9A-9C show the anticancer effects of the TK inhibitors ponatinib, bosutinib, saracatinib, and KX2-391. Four TK inhibitors, including ponatinib, bosutinib, saracatinib, and KX2-391, were tested for their ability to reduce macrophage SHP-1 activity induced by αTLR and cancer cell ligation (Figure 9A) and to enhance the expression of antigen-presenting molecules inhibited by cancer cell ligation (Figure 9B). [Figure 9B] Figures 9A-9C show the anticancer effects of the TK inhibitors ponatinib, bosutinib, saracatinib, and KX2-391. Four TK inhibitors, including ponatinib, bosutinib, saracatinib, and KX2-391, were tested for their ability to reduce macrophage SHP-1 activity induced by αTLR and cancer cell ligation (Figure 9A) and to enhance the expression of antigen-presenting molecules inhibited by cancer cell ligation (Figure 9B). [Figure 9C] The combination of αTLRs has demonstrated antitumor effects in vivo.

[0047] [Figure 10A]A-E show the synergistic effect of the SHP-1 inhibitor TPI-1 and the TK inhibitor dasatinib. A shows the experimental design for testing treatments for KPC. [Figure 10B] Changes in KPC tumor volume following treatment with αTLR+TPI-1, or αTLR+TPI-1 and dasatinib, compared with tumors that did not receive treatment (NT) and tumors that showed continued progression, are shown. [Figure 10C] Results of TME analysis are shown. Compared with treatment with αTLR+TPI-1, αTLR+TPI-1 and dasatinib further enhanced T cell immunity and reduced PMN infiltration, resulting in increased CD8 (Tc) and CD4 (Th) T cells and a moderate increase in NK cells, but reduced PMNs in the TME after treatment. [Figure 10D] 1 shows the experimental design for testing treatments against MC38. [Figure 10E] Shown is the change in MC38 tumor volume after treatment with αTLR+TPI-1, αTLR+dasatinib, or αTLR+TPI-1 and dasatinib compared with non-treated tumors (NT) and tumors that showed continued progression.

[0048] [Figure 11A] Figures A–G show that anti-TNFα mAb reduces systemic inflammation and adverse toxicity. Figure A shows the experimental design. Mice with established MC38 colorectal carcinoma (200–400 mm3) were treated with αTLR, TPI-1, and dasatinib (sc) and were either not treated or additionally treated with anti-TNFα mAb or anti-IL-6 mAb (150 μg, intraperitoneally). Treatment was repeated once (d1 and d2). Changes in tumor volume were recorded, and immune infiltration in the tumor TME was analyzed 6 days after treatment. [Figure 11B] The change in tumor volume after various treatments is shown. [Figure 11C-1] The results of the TME analysis are shown. [Figure 11C-2] The results of the TME analysis are shown. [Figure 11C-3] The results of the TME analysis are shown. [Figure 11C-4]The results of the TME analysis are shown. [Figure 11D] Results of TME analysis are shown. Treatment with anti-TNFα mAb or anti-IL-6 mAb did not affect the increase in CD8 T cells (Tc) and NK cells, or the decrease in macrophages and MDSCs in the TME induced by αTLR / TPI-1 / dasatinib therapy. [Figure 11E-1] We show that treatment of mice with anti-TNFα mAb, but not anti-IL-6 mAb, significantly reduces the induction of proinflammatory cytokines (TNFα, IL-6, IL-1β, IL-10, IFNα, and IFNγ) associated with αTLR / TPI-1 / dasatinib combination therapy. [Figure 11E-2] We show that treatment of mice with anti-TNFα mAb, but not anti-IL-6 mAb, significantly reduces the induction of proinflammatory cytokines (TNFα, IL-6, IL-1β, IL-10, IFNα, and IFNγ) associated with αTLR / TPI-1 / dasatinib combination therapy. [Figure 11F] We show that anti-TNFα treatment significantly reduced circulating monocyte and PMN chemokines CCL2, CCL5, and CXCL1, but not CXCL10, which is essential for T cell migration. [Figure 11G] We show that anti-TNFα treatment protected mice from developing splenomegaly and intestinal inflammation normally associated with αTLR / TPI-1 / dasatinib therapy.

[0049] [Figure 12] We show that proinflammatory stimuli (TLR agonists, proinflammatory cytokines IL-1β, IL-6, IL-12, IL-17, IL-18, TNFα, IFNγ, etc., and cancer treatments) induce phosphorylation of SIRPα ITIM and exclusive binding of SHP-1 (but not SHP-2). DETAILED DESCRIPTION OF THE INVENTION

[0050] In one aspect, the application provides a method of treating cancer in an individual, comprising administering to the individual a tyrosine kinase inhibitor, wherein the individual a) has previously received, is currently receiving, or will soon receive an inflammatory agent, or b) is experiencing an inflammatory response or a persistent infection. In another aspect, the application provides a method of treating cancer in an individual, comprising administering to the individual monocytes or macrophages having a defect in tyrosine kinase expression or activation, wherein the individual a) has previously received, is currently receiving, or will soon receive an inflammatory agent, or b) is experiencing an inflammatory response or a persistent infection. In some embodiments, the tyrosine kinase inhibitor is administered systemically. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the method includes administering to the individual a tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, radiation therapy, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy. Still other combination therapies are provided.

[0051] This application is based on the remarkable discovery that the combination of a tyrosine kinase inhibitor, potentially blocking the activation of the "master inhibitory effector" SHP-1, with a pro-inflammatory therapeutic agent unleashes pro-inflammatory signaling in the tumor environment, particularly in tumor-infiltrating macrophages, leading to a radical remodeling of the TME and promoting the activation of innate and adaptive immune cells, enhancing anti-cancer immunity. Specifically, we found that intratumoral iR and SHP-1-mediated inhibitory regulation is significantly enhanced under oncology therapy, as these treatments often induce ITIM hyperphosphorylation, thereby promoting SHP-1 "hyperactivation," which functions as a feedback loop protecting tumors from therapeutic damage and inflammatory responses and further inducing wound healing responses to promote tumor progression. This discovery highlights the potential of inhibiting upstream tyrosine kinases, potentially reducing ITIM phosphorylation and SHP-1 activation, as a promising combination for tumor immunotherapy. This approach, by abolishing TK activity, reduces ITIM phosphorylation and SHP-1 activation, thereby treating cancer.

[0052] Combining tyrosine kinase inhibitors with pro-inflammatory agents (e.g., TLR agonists and / or checkpoint inhibitors) has been shown to achieve the surprising effect of converting the immunosuppressive TME to an inflammatory TME, activating various types of immune cells (e.g., macrophages, T cells, and B cells), and completely eliminating tumors. See, for example, Figures 3B-3E, 4A-4B, and 5A-5C.

[0053] Furthermore, combining tyrosine kinase inhibitors and TLR agonists with immune checkpoint inhibitors (e.g., anti-PD-L1 inhibitors) further enhanced the therapeutic effect and promoted tumor regression (see Figures 6A-6C).

[0054] Furthermore, combining a tyrosine kinase inhibitor and a TLR agonist with an SHP-1 inhibitor shows synergistic effects in various tumor models (see Figures 10A-10E). Administering agents that reduce systemic inflammation (e.g., anti-TNFα mAb) further suppresses systemic inflammation and reduces adverse toxicity (see Figures 11A-11G).

[0055] Therefore, the present application provides a novel method for effectively reconstructing immunosuppression caused by the tumor microenvironment and activating innate and adaptive immunity against cancer, thereby achieving significant cancer-suppressing effects.

[0056] I. Definition In general, the terms used in the claims and the specification are intended to be interpreted as having their ordinary meanings as understood by those of ordinary skill in the art. However, certain terms are defined below for clarity. If there is a conflict between the ordinary meaning and a given definition, the given definition shall govern.

[0057] The terms "individual," "subject," or "patient" are used synonymously herein and refer to a mammal, including a human. An individual includes, but is not limited to, a human, a cow, a horse, a cat, a dog, a rodent, or a primate. In some embodiments, the individual is human. In some embodiments, the individual is suffering from a disease, such as cancer. In some embodiments, the individual is in need of treatment.

[0058] As used herein, a "reference value" refers to any sample, standard, or level used for comparison purposes. The reference can be obtained from a healthy sample and / or a non-diseased sample. In some examples, the reference value may be obtained from an untreated sample. In some examples, the reference value is obtained from a non-diseased or untreated sample from an individual. In some examples, the reference value is obtained from one or more healthy individuals who are not the individual or the individual.

[0059] As used herein, the terms "intermittent" or "intermittently" in the context of dosing refer to discontinuous dosing. In some cases, "intermittent" administration refers to a) administering the tyrosine kinase inhibitor for less than 12 consecutive days (e.g., less than 11, 10, 9, 8, 7, 6, 5, 4, and 3 days), and b) administering the tyrosine kinase inhibitor at least twice, with at least one day between the two doses (i.e., days 1 and 3).

[0060] As used herein, the term "cycle" in the context of administration refers to a period during which a tyrosine kinase inhibitor is administered at least once. Day 1 of a cycle is defined as the day on which the first administration of the tyrosine kinase inhibitor is administered during that period. When a tyrosine kinase inhibitor is administered continuously over several days, day 1 of the cycle is defined as the day on which the first of several consecutive administrations is administered. The last day of a cycle is defined as the day before the next non-consecutive administration of the tyrosine kinase inhibitor. See Figures 12A and 14A for exemplary cycles. The duration of each cycle does not have to be the same. For example, the first cycle is 5 days, and the second cycle is 7 days. Each cycle may differ in the number of administrations of the tyrosine kinase inhibitor. For example, in a first cycle, which may have a cycle duration of 5 days, the tyrosine kinase inhibitor may be administered once, and in a second cycle, which may have a cycle duration of 7 days, the tyrosine kinase inhibitor may be administered twice.

[0061] As used herein, the term immunogenic refers to the ability to elicit an immune response, for example, via T cells, B cells, or both.

[0062] As used herein, "treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing one or more symptoms attributable to the disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the progression of the disease), preventing or slowing the spread of the disease (e.g., metastasis), preventing or slowing the onset or recurrence of the disease, slowing or slowing the progression of the disease, ameliorating the condition of the disease, providing remission (whether partial or total) of the disease, reducing the dose of one or more other drugs required to treat the disease, slowing the progression of the disease, improving quality of life, and / or prolonging survival. "Treatment" also encompasses reducing the pathological consequences of cancer. The methods of the present invention contemplate any one or more of these treatment aspects.

[0063] As used herein, "delaying" the onset of cancer means extending, preventing, slowing, inhibiting, stabilizing, and / or postponing the onset of the disease. This delay can be of varying duration depending on the disease history and / or the individual being treated. As will be apparent to one skilled in the art, a sufficient or significant delay can essentially encompass prevention, in the sense that the individual does not develop the disease. A method that "delays" the onset of cancer is one that reduces the likelihood of disease onset in a given timeframe and / or reduces the extent of disease in a given timeframe compared to the absence of the method. Such comparisons are usually based on clinical studies using a statistically significant number of individuals. Cancer onset can be detected using standard methods, including, but not limited to, computed tomography (CAT scan), magnetic resonance imaging (MRI), abdominal ultrasound, coagulation studies, arteriography, or biopsy. Onset also refers to cancer progression, which may be undetectable initially, and includes onset, recurrence, and onset.

[0064] The term "co-administration," as used herein, means that the first and second therapies in a combination therapy are administered at a time interval of about 15 minutes or less, e.g., about 10 minutes or less, 5 minutes or less, or 1 minute or less. When the first and second therapeutic agents are administered at the same time, the first and second therapeutic agents may be contained in the same composition (e.g., a composition containing both the first and second therapeutic agents) or may be contained in separate compositions (e.g., one composition containing the first therapeutic agent and another composition containing the second therapeutic agent).

[0065] As used herein, the term "sequential administration" means that the first and second therapeutic agents in a combination therapy are administered at intervals of more than about 15 minutes, e.g., more than about 20 minutes, more than 30 minutes, more than 40 minutes, more than 50 minutes, more than 60 minutes, or more. Either the first or second therapeutic agent may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.

[0066] As used herein, "concurrent administration" means that the administration of a first therapeutic agent and the administration of a second therapeutic agent in a combination therapy overlap with each other.

[0067] As used herein, "pharmaceutically acceptable" or "pharmaceutically compatible" means a material that is biologically or otherwise undesirable; e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. A pharmaceutically acceptable carrier or excipient preferably has met the required standards of toxicology and manufacturing testing and / or is listed in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0068] It is understood that the embodiments of the present application described herein include embodiments that include "consisting of" and / or "consisting essentially of."

[0069] Reference herein to "about" a value or parameter includes (and describes) a variation about that value or parameter itself. For example, a reference to "about X" includes a reference to "X."

[0070] As used herein, reference to "not being" a value or parameter generally means and describes "other than" a value or parameter. For example, a method is not used to treat cancer type X means that the method is used to treat cancer types other than X.

[0071] As used herein, the term "about X to Y" has the same meaning as "about X to about Y."

[0072] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0073] Any term not directly defined herein will be understood to have the general meaning understood in the art of the present invention. Certain terms are explained herein to provide additional guidance to practitioners in describing the compositions, devices, methods, etc. of the present invention, as well as methods for making or using them. It will be understood that the same meaning may be expressed differently. Accordingly, alternative and synonymous terms may be used for any one or more of the terms discussed herein. No importance should be placed on whether a term is detailed or discussed herein. Some synonyms or alternative methods, materials, etc. are provided. The description of one or more synonyms or equivalents allows for the use of other synonyms or equivalents unless expressly stated otherwise. Various examples, including examples of terms, are used for illustrative purposes only and do not limit the scope and meaning of the inventive embodiments described herein.

[0074] II. Treatment method In one aspect, the present application provides methods for treating cancer by administering a tyrosine kinase inhibitor. In some embodiments, the individual to be treated has previously received, is currently receiving, or will receive, e.g., any of the pro-inflammatory agents described herein. In some embodiments, the individual is exhibiting an inflammatory response or has a persistent infection.

[0075] In some embodiments, the method comprises administering both a tyrosine kinase inhibitor and an inducing agent to the individual. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering the tyrosine kinase inhibitor systemically.

[0076] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering a tyrosine kinase inhibitor to the individual, wherein the individual a) has previously received, is currently receiving, or will receive an inflammatory agent (e.g., a TLR agonist, e.g., radiation therapy), or b) is exhibiting an inflammatory response or has an ongoing infection, and optionally the tyrosine kinase inhibitor is administered systemically (e.g., intravenously or subcutaneously). In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the tyrosine kinase inhibitor is administered no more than once every two days. In some embodiments, the tyrosine kinase inhibitor is administered two to five times within 10 consecutive days (e.g., twice every 10 days, three times every 10 days, four times every 10 days, or five times every 10 days). In some embodiments, the tyrosine kinase inhibitor is administered simultaneously with the inflammatory agent. In some embodiments, the tyrosine kinase inhibitor is administered concurrently with the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered sequentially within 2 weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the tyrosine kinase inhibitor has a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less). In some embodiments, the tyrosine kinase inhibitor is effective to inhibit more than 50% of tyrosine kinase activation in no more than about 7 days (e.g., about 5, 4, or 3 days). In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein formulations (e.g., antibody formulations targeting tyrosine kinases or activated tyrosine kinases). In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits a Src family kinase (SFK).In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises locally (e.g., intratumorally) administering to the individual an inflammatory agent. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) to the tyrosine kinase inhibitor.In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor. In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0077] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and an inflammatory agent (e.g., a TLR agonist, e.g., radiation therapy), optionally comprising administering the tyrosine kinase inhibitor orally, intravenously, or subcutaneously, and optionally, wherein the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual the tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the tyrosine kinase inhibitor is administered twice (e.g., on two consecutive days) every 7 to 20 days. In some embodiments, the tyrosine kinase inhibitor is administered three times (e.g., on three consecutive days) every 10 to 20 days. In some embodiments, the tyrosine kinase inhibitor is administered no more than once every two days. In some embodiments, the tyrosine kinase inhibitor is administered two or more times but not more than five times within 10 consecutive days (e.g., twice 10 days, three times 10 days, four times 10 days, or five times 10 days). In some embodiments, the tyrosine kinase inhibitor is administered simultaneously with the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor is administered concurrently with the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered sequentially within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or on the same day). In some embodiments, the tyrosine kinase inhibitor has a half-life of about 10 days or less (e.g., about 7 days, 5 days, 4 days, or 3 days or less). In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., siRNA, shRNA, antisense RNA, microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein formulation (e.g., an antibody formulation targeting a tyrosine kinase or an activated tyrosine kinase). In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling.In some embodiments, the tyrosine kinase inhibitor inhibits a Src family kinase (SFK). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises locally (e.g., intratumorally) administering to the individual an inflammation-inducing agent. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or the pro-inflammatory agent.In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine (e.g., IFN-gamma). In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0078] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and an inflammation-inducing agent (e.g., a TLR agonist, e.g., radiation therapy), wherein the method comprises administering the tyrosine kinase inhibitor orally, intravenously, or subcutaneously, and optionally, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual the tyrosine kinase inhibitor in at least two cycles, further optionally, the tyrosine kinase inhibitor is administered at least once in each cycle, each cycle lasting from about 3 to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., on at least two consecutive days). In some embodiments, the tyrosine kinase inhibitor is administered at least three times in each cycle (e.g., on at least three consecutive days). In some embodiments, the tyrosine kinase inhibitor is administered simultaneously with the inflammation-inducing agent. In some embodiments, the tyrosine kinase inhibitor is administered concurrently with the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered sequentially within 2 weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the tyrosine kinase inhibitor has a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less). In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein formulations (e.g., antibody formulations targeting tyrosine kinases or activated tyrosine kinases). In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor.In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises locally (e.g., intratumorally) administering an inducing agent to the individual. In some embodiments, the method further comprises administering (e.g., locally or systemically) an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) to the individual. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or the pro-inflammatory agent.In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine (e.g., IFN-gamma). In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0079] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising orally, intravenously, subcutaneously, and / or intratumorally administering to the individual a tyrosine kinase inhibitor and an inflammatory agent (e.g., a TLR agonist, e.g., radiation therapy), optionally wherein the tyrosine kinase inhibitor is effective to inhibit greater than 50% of tyrosine kinase activation within about 5 days, and optionally wherein the method comprises administering the tyrosine kinase inhibitor to the individual at least twice (e.g., at least 3, 4, 5, or 6 times) at intervals of no more than once every 3 days. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the tyrosine kinase inhibitor is administered no more than twice every 7-20 days. In some embodiments, the tyrosine kinase inhibitor is administered no more than three times every 7-20 days. In some embodiments, the tyrosine kinase inhibitor is administered about 1 to 3 times every 7 to 20 days for at least 14 to 20 days. In some embodiments, the tyrosine kinase inhibitor is administered at least about 2, 3, 4, 5, or 6 times within a period of about 14 to about 40 days (e.g., about 14 to about 20 days). In some embodiments, the tyrosine kinase inhibitor is administered simultaneously with the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor is administered concurrently with the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered sequentially within 2 weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the tyrosine kinase inhibitor has a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less). In some embodiments, the tyrosine kinase inhibitor is effective to inhibit greater than 50% of tyrosine kinase activation for no more than about 7 days (eg, about 5 days, 4 days, or 3 days).In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein formulations (e.g., antibody formulations targeting tyrosine kinases or activated tyrosine kinases). In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises locally (e.g., intratumorally) administering to the individual an inducing agent. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the inducing agent is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the tyrosine kinase inhibitor and / or the pro-inflammatory agent.In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with a tyrosine kinase inhibitor and / or a pro-inflammatory agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or a pro-inflammatory agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor and / or a pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine (e.g., IFN-gamma). In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0080] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising orally, intravenously, subcutaneously, and / or intratumorally administering to the individual a tyrosine kinase inhibitor and an inflammatory agent (e.g., a TLR agonist, e.g., radiation therapy), wherein the tyrosine kinase inhibitor is effective to inhibit greater than 50% of tyrosine kinase activation within about 5 days (e.g., within 5 days, 4 days, 3 days), and wherein the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual the tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., on at least two consecutive days). In some embodiments, the tyrosine kinase inhibitor is administered at least three times in each cycle (e.g., on at least three consecutive days). In some embodiments, the tyrosine kinase inhibitor is administered simultaneously with the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor is administered concurrently with the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered sequentially within 2 weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the tyrosine kinase inhibitor has a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less). In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein formulations (e.g., antibody formulations targeting tyrosine kinases or activated tyrosine kinases). In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor.In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering to the individual an inflammatory agent locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor is administered systemically and the inflammatory agent is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or the pro-inflammatory agent.In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine (e.g., IFN-gamma). In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0081] In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering (e.g., orally, intravenously, subcutaneously, and / or intratumorally) to the individual a tyrosine kinase inhibitor and immune cells (e.g., any immune cells described herein). In some embodiments, the individual has previously received, is currently receiving, or will receive an inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy). In some embodiments, the individual is exhibiting an inflammatory response or has a persistent infection. In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering (e.g., intravenously, subcutaneously, and / or intratumorally) to the individual a tyrosine kinase inhibitor and an inflammatory agent (e.g., a TLR agonist, e.g., radiation therapy), and immune cells. In some embodiments, the immune cells are derived from the individual. In some embodiments, the immune cells comprise monocytes or macrophages. In some embodiments, the immune cells comprise T cells (e.g., CAR-T cells). In some embodiments, the immune cells comprise NK cells (e.g., CAR-NK cells). In some embodiments, the immune cells comprise neutrophils (e.g., CAR-expressing neutrophil cells). In some embodiments, the immune cells comprise antigen-presenting cells (APCs). In some embodiments, the immune cells are engineered to express a chimeric receptor that specifically binds to a tumor antigen. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the tyrosine kinase inhibitor, the immune cells, and / or the pro-inflammatory agent are administered within about 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the tyrosine kinase inhibitor and the immune cells are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of each other. In some embodiments, the tyrosine kinase inhibitor, the immune cells, and / or the pro-inflammatory agent are administered simultaneously.In some embodiments, the tyrosine kinase inhibitor, immune cells, and / or pro-inflammatory agent are administered concurrently. In some embodiments, the tyrosine kinase inhibitor, immune cells, and / or pro-inflammatory agent are administered sequentially. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the pro-inflammatory agent is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or the pro-inflammatory agent.In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or an inducing agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or an inducing agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or an inducing agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine (e.g., IFN-gamma). In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0082] In some embodiments, a method is provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual a tyrosine kinase inhibitor and a TLR agonist (e.g., R848), wherein the tyrosine kinase inhibitor is administered at least twice (e.g., at least three, four, or five times). In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, a method is provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual a tyrosine kinase inhibitor and a TLR agonist, wherein the tyrosine kinase inhibitor and the TLR agonist are administered within 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, not more than once every three days. In some embodiments, the method includes administering to the individual a tyrosine kinase inhibitor for at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once (e.g., at least two or three times) in each cycle, and each cycle is for about 3 to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously or subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor and the TLR agonist are administered simultaneously, concurrently, or sequentially. In some embodiments, the TLR agonist activates TLR1 or TLR2, and optionally, the TLR agonist comprises triacylated lipoprotein, peptidoglycan, zymosan, and / or Pam3CSK4. In some embodiments, the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, and optionally, the TLR agonist comprises a diacylated lipopeptide, a heat shock protein, HMGB1, uric acid, fibronectin, and / or an ECM protein.In some embodiments, the TLR agonist activates TLR2, and optionally, the TLR agonist comprises Pam3Cys, SMP-105, and / or CBLB612. In some embodiments, the TLR agonist activates TLR3, and optionally, the TLR agonist comprises dsRNA, polyIC, polyICIC, poly-IC12U, IPH302, ARNAX, and / or MPLA. In some embodiments, the TLR agonist activates TLR4, and optionally, the TLR agonist comprises LPS, lipoteichoic acid beta-defensin-2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, and / or GLA-SE. In some embodiments, the TLR agonist activates TLR5, and optionally, the TLR agonist comprises flagellin, CBLB502, and / or M-VM3. In some embodiments, the TLR agonist activates TLR6. In some embodiments, the TLR agonist activates TLR7 or TLR8, and optionally, the TLR agonist comprises ssRNA, CpG-A, polyG10, and / or polyG3. In some embodiments, the TLR agonist activates TLR7, and optionally, the TLR agonist comprises bistriazolyl and / or R848. In some embodiments, the TLR agonist activates TLR8, and optionally, the TLR agonist comprises VTX1463 and / or R848. In some embodiments, the TLR agonist activates TLR9, and optionally, the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and / or ODN M362. In some embodiments, the TLR agonist activates TLR10, and optionally, the TLR agonist comprises Pam3CSK4. In some embodiments, the TLR agonist activates TLR11, and optionally, the TLR agonist comprises Toxoplasma gondiiprofilin. In some embodiments, the TLR agonist activates TLR12.In some embodiments, the TLR agonist activates TLR13, and optionally, the TLR agonist comprises VSV. In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and / or TLR9. In some embodiments, the TLR agonist activates TLR9, TLR4, and TLR7 / 8. In some embodiments, the TLR agonist comprises CpG, PolyIC, and / or R848. In some embodiments, the TLR agonist comprises CpG, PolyIC, and R848, for example, in a 1:1:1 ratio. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the TLR agonist is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits a Src family kinase (SFK). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the tyrosine kinase inhibitor and / or TLR agonist.In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with a tyrosine kinase inhibitor and / or a TLR agonist. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered in parallel with a tyrosine kinase inhibitor and / or a TLR agonist. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor and / or a TLR agonist. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or TLR agonist. In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0083] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering a tyrosine kinase inhibitor and a TLR agonist (e.g., R848), where optionally, the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7, and TLR8. In some embodiments, the tyrosine kinase inhibitor and the TLR agonist are administered on the same day. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the tyrosine kinase inhibitor and / or the TLR agonist are administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the tyrosine kinase inhibitor and the TLR agonist are administered for at least two cycles (e.g., at least three cycles), and optionally, the tyrosine kinase inhibitor and the TLR agonist are administered on the same day for at least two consecutive days (e.g., at least three consecutive days) per cycle. In some embodiments, each cycle lasts from about 7 to about 20 days. In some embodiments, the TLR agonist activates TLRs on macrophages, optionally including TLR9. In some embodiments, the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9). In some embodiments, the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4, and TLR7 / 8). In some embodiments, the TLR agonist comprises CpG, PolyIC, and / or R848. In some embodiments, the TLR agonist comprises CpG, PolyIC, and R848, e.g., in a 1:1:1 ratio. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the TLR agonist is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs).In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or TLR agonist. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or TLR agonist. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered in parallel with the tyrosine kinase inhibitor and / or TLR agonist. In some embodiments, an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or TLR agonist.In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or TLR agonist. In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0084] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and a STING activator (e.g., MSA-2, ADU-S100, or cGAMP), optionally wherein the tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and a STING activator (e.g., MSA-2, ADU-S100, or cGAMP), optionally wherein the tyrosine kinase inhibitor and STING activator are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one administration of the other. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor and the STING activator are administered sequentially, simultaneously, or concurrently.In some embodiments, the STING activator is a cyclic guanosine monophosphate-cyclic adenosine monophosphate (cGAMP, e.g., 3'3'cGAMP, e.g., 2'3'cGAMP), a bacterial vector (e.g., SYNB1891, STACT-TREX-1), a CDN compound (e.g., ADU-S100, BI-STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3'3'-cyclic AIMP), a non-CDN small molecule (e.g., ALG-031048, E7755, JNJ-'6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI-10001), a nanovaccine (e.g., PC7A NP, cCAMP-NP, ONM-500), or antibody-drug conjugates (e.g., XMT-2056, CRD-5500). In some embodiments, the tyrosine kinase inhibitor is administered systemically and the STING activator is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody).In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or STING activator. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or STING activator. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered in parallel with the tyrosine kinase inhibitor and / or STING activator. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or STING activator. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or STING activator.

[0085] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and radiation therapy; optionally, the method comprises administering to the individual at least two cycles of the tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is administered at least once per cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the method comprises administering to the individual the tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the tyrosine kinase inhibitor is administered at least three times over multiple days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor and radiation therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the radiation therapy comprises irradiating the site of the cancer being treated. In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated. In some embodiments, the radiation therapy dose is insufficient to kill tumor cells. In some embodiments, the radiation therapy is selected from the group consisting of external beam radiation therapy, internal radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectants. In some embodiments, the radiation therapy is external beam radiation therapy, optionally including three-dimensional conformal radiation therapy (3D-RT), intensity-modulated radiation therapy (IMRT), photon beam therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT). In some embodiments, the radiation therapy is brachytherapy, optionally including interstitial brachytherapy, intracavitary brachytherapy, intraluminal radiation therapy, and intravenously administered radiolabeled molecules. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling.In some embodiments, the tyrosine kinase inhibitor inhibits a Src family kinase (SFK). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered prior to (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or radiation therapy.In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or radiation therapy.

[0086] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and radiation therapy, wherein the radiation therapy comprises irradiation of a site different from the site of the cancer being treated. In some embodiments, the tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual the tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the method comprises administering to the individual the tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, each cycle lasting from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor and radiation therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the radiation therapy comprises irradiating the site of the cancer being treated. In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated. In some embodiments, the radiation therapy dose is insufficient to kill tumor cells. In some embodiments, the radiation therapy is selected from the group consisting of external beam radiation therapy, internal radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectants. In some embodiments, the radiation therapy is external beam radiation therapy, optionally including three-dimensional conformal radiation therapy (3D-RT), intensity-modulated radiation therapy (IMRT), photon beam therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT). In some embodiments, the radiation therapy is brachytherapy, optionally including interstitial brachytherapy, intracavitary brachytherapy, intracavitary radiation therapy, and intravenously administered radiolabeled molecules.In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered prior to (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or radiation therapy.In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or radiation therapy.

[0087] In some embodiments, provided are methods of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering a tyrosine kinase inhibitor and radiation therapy. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the tyrosine kinase inhibitor and radiation therapy are administered on the same day. In some embodiments, the tyrosine kinase inhibitor and / or radiation therapy are administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the tyrosine kinase inhibitor and radiation therapy are administered in at least two cycles (e.g., at least three cycles), optionally, the tyrosine kinase inhibitor and radiation therapy are administered on the same day for at least two consecutive days (e.g., at least three consecutive days) per cycle. In some embodiments, each cycle lasts from about 7 to about 20 days. In some embodiments, the tyrosine kinase inhibitor and radiation therapy are administered within 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of each other. In some embodiments, the radiation therapy comprises irradiating the site of the cancer being treated. In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated. In some embodiments, the radiation therapy dose is insufficient to kill tumor cells. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406.In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered prior to (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or radiation therapy.

[0088] In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual a tyrosine kinase inhibitor and a PAMP / DAMP activator, optionally administering the tyrosine kinase inhibitor at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual a tyrosine kinase inhibitor and a PAMP / DAMP activator, optionally administering the tyrosine kinase inhibitor and the PAMP / DAMP activator within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one administration of the other. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the method includes administering to the individual a tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the pro-inflammatory agent is a PAMP activator. In some embodiments, the PAMP activator is triacyl lipopeptide, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipid, Pam3Cys porin, lipoarabinomannan, double-stranded RNA, poly(IC), trepanosome lipid, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptide, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial / viral DNA, CpG DNA, urea bacteria, or Toxoplasma LPS. In some embodiments, the pro-inflammatory agent is a DAMP activator.In some embodiments, the DAMP activator is a defensin, HSP60, HSP70, messenger RNA, small hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, or unmethylated CpG DNA. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the PAMP / DAMP activator is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storms (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascades or cytokine storms (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or PAMP / DAMP activator. In some embodiments, an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with a tyrosine kinase inhibitor and / or a PAMP / DAMP activator.In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or a PAMP / DAMP activator. In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or PAMP / DAMP activator. In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or PAMP / DAMP activator.

[0089] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and a checkpoint inhibitor (e.g., an anti-PD-1 agent, an anti-PD-L1 agent, an anti-CTLA-4 agent), optionally administering the tyrosine kinase inhibitor at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and a checkpoint inhibitor (e.g., an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent), wherein one of the tyrosine kinase inhibitor and the checkpoint inhibitor is administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of the other. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG / PVRL2, CEACAM1, CEACAM5 / 6, FAK, CCL2 / CCR2, LIF, CD47 / SIRPα, CSF-1 (M-CSF) / CSF-1R, IL-1 / IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVA-1, Axl, or phosphatidylserine.In some embodiments, the checkpoint inhibitor is ipilimumab, cemiplimab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftiragimod alfa (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, monalizumab, COM701, CM24, NEO-201, defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI- The tyrosine kinase inhibitor may include or be 662, RRx-001, lanotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), pexidartinib (PLX3397), CAN04, canakinumab (ACZ885), BMS-986253, pepinemab (VX15 / 2503), trebananib, FP-1305, enapotamab vedotin (EnaV), or bavituximab. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the checkpoint inhibitor is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or checkpoint inhibitor. In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or checkpoint inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or a checkpoint inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor and / or a checkpoint inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after a tyrosine kinase inhibitor and / or a checkpoint inhibitor.

[0090] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and a pro-inflammatory cytokine (e.g., IL-1b, IL-18, IL-6, TNFα), optionally wherein the tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and a pro-inflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and / or TNFα), wherein one of the tyrosine kinase inhibitor and the pro-inflammatory cytokine is administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of the other. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the proinflammatory cytokine promotes M1 macrophages. In some embodiments, the proinflammatory cytokine includes or is TNF, IFNγ, and / or GM-CSF. In some embodiments, the proinflammatory cytokine includes IFNγ. In some embodiments, the proinflammatory cytokine includes IL-1. In some embodiments, the proinflammatory cytokine includes TNF-α. In some embodiments, the proinflammatory cytokine includes IL-6. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the pro-inflammatory cytokine is administered intratumorally.In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or pro-inflammatory cytokine. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or the inflammatory cytokine. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered in parallel with the tyrosine kinase inhibitor and / or the inflammatory cytokine.In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or the inflammatory cytokine. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or the inflammatory cytokine.

[0091] In some embodiments, a method of treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) is provided, comprising administering to the individual a tyrosine kinase inhibitor and a chemotherapeutic agent (e.g., azathioprine), optionally administering the tyrosine kinase inhibitor at least twice (at least three, four, five, or six times). In some embodiments, a method of treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) is provided, comprising administering to the individual a tyrosine kinase inhibitor and a chemotherapeutic agent (e.g., azathioprine), wherein the tyrosine kinase inhibitor and the chemotherapeutic agent are administered within 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the chemotherapeutic agent is an alkylating agent. In some embodiments, the alkylating agent is selected from the group consisting of nitrogen mustards (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkylsulfonates (e.g., busulfan), and ethyleneimines (e.g., thiotepa). In some embodiments, the chemotherapeutic agent is an antimetabolite.In some embodiments, the antimetabolite is selected from the group consisting of a cytidine analog (e.g., azacitidine, decitabine, cytarabine, gemcitabine), a folate antagonist (e.g., methotrexate, pemetrexed), a purine analog (e.g., cladribine, clofarabine, nelarabine), a pyrimidine analog (e.g., fluorouracil (5-FU), capecitabine (a prodrug of 5-FU)). In some embodiments, the chemotherapeutic agent is an anti-microtubule agent. In some embodiments, the anti-microtubule agent is selected from the group consisting of topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), and antibiotics (e.g., actinomycin D, bleomycin, daunomycin). In some embodiments, the chemotherapeutic agent is hydroxyurea, tretinoin, arsenic trioxide, or a proteasome inhibitor (e.g., bortezomib). In some embodiments, the tyrosine kinase inhibitor is administered systemically and the chemotherapeutic agent is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits a Src family kinase (SFK). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or chemotherapeutic agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or chemotherapeutic agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or chemotherapeutic agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or chemotherapeutic agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or chemotherapeutic agent.

[0092] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual a tyrosine kinase inhibitor and a cancer vaccine, optionally administering the tyrosine kinase inhibitor at least twice. In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual a tyrosine kinase inhibitor and a cancer vaccine, wherein the tyrosine kinase inhibitor and the cancer vaccine are administered within 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one administration. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, not more than once every three days. In some embodiments, the method comprises administering a tyrosine kinase inhibitor to the individual in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the cancer vaccine comprises a cell-based vaccine, a peptide-based vaccine, a virus-based vaccine, and / or a nucleic acid-based vaccine. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the cancer vaccine is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered prior to (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or cancer vaccine. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with a tyrosine kinase inhibitor and / or a cancer vaccine. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or a cancer vaccine. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor and / or a cancer vaccine. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly after the tyrosine kinase inhibitor and / or cancer vaccine, e.g., within about any of 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours).

[0093] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual a tyrosine kinase inhibitor and an oncolytic virus, optionally administering the tyrosine kinase inhibitor at least twice (at least three, four, five, or six times). In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual a tyrosine kinase inhibitor and an oncolytic virus, wherein the tyrosine kinase inhibitor and the oncolytic virus are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one administration. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the method includes administering to the individual a tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the oncolytic virus includes or is an adenovirus (e.g., ONYX-15, LOAd703 virus), a protoparvovirus, a parvovirus (e.g., H-1PV), a vaccinia virus (VACV), a reovirus (e.g., leolysin), or a herpes simplex virus (HSV, e.g., HSV-1, HSV-2, G207, L1BR1, HF10, T-VEC, Orien X010). In some embodiments, the oncolytic virus comprises JX-593, Coxsackievirus A21 (CVA21), Maraba virus or its MG1 variant, DNX2440 adenovirus, fowlpox virus, or Sendai virus. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the oncolytic virus is administered intratumorally.In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or oncolytic virus. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or oncolytic virus. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered in parallel with the tyrosine kinase inhibitor and / or oncolytic virus.In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or oncolytic virus. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or oncolytic virus.

[0094] In some embodiments, there are provided methods of treating cancer (e.g., a solid tumor, e.g., a blood cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and acoustic therapy (e.g., high-intensity focused ultrasound (HIFU), e.g., low-intensity focused ultrasound (LIPUS)), optionally wherein the tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, there are provided methods of treating cancer (e.g., a solid tumor, e.g., a blood cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor and acoustic therapy (e.g., high-intensity focused ultrasound (HIFU), e.g., low-intensity focused ultrasound (LIPUS)), wherein the tyrosine kinase inhibitor and acoustic therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual in at least two cycles, the tyrosine kinase inhibitor being administered at least once in each cycle, each cycle lasting from about 3 to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor is administered systemically and the method comprises administering acoustic therapy to the site of the cancer being treated. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storms (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascades or cytokine storms (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered prior to (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the tyrosine kinase inhibitor and / or acoustic therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with a tyrosine kinase inhibitor and / or acoustic therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or acoustic therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor and / or acoustic therapy. In some embodiments, an agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or acoustic treatment.

[0095] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a blood cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual a tyrosine kinase inhibitor and magnetic therapy (e.g., a pulsed magnetic field, e.g., a static magnetic field), optionally administering the tyrosine kinase inhibitor at least twice (at least three, four, five, or six times). In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a blood cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual a tyrosine kinase inhibitor and magnetic therapy (e.g., a pulsed magnetic field, e.g., a static magnetic field), wherein the tyrosine kinase inhibitor and magnetic therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor is administered systemically and the method comprises administering magnetic therapy to the site of the cancer being treated. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storms (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascades or cytokine storms (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered prior to (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or magnetic therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with a tyrosine kinase inhibitor and / or radiation therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or magnetic therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor and / or magnetic therapy. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or magnetic therapy.

[0096] In some embodiments, a method of treating cancer in an individual (e.g., a solid tumor, e.g., a blood cancer, e.g., a terminal cancer) is provided, comprising administering to the individual a tyrosine kinase inhibitor and electrical or electrochemical therapy, optionally administering the tyrosine kinase inhibitor at least twice (at least three, four, five, or six times). In some embodiments, a method of treating cancer in an individual (e.g., a solid tumor, e.g., a blood cancer, e.g., a terminal cancer) is provided, comprising administering to the individual a tyrosine kinase inhibitor and electrical or electrochemical therapy, wherein the tyrosine kinase inhibitor and electrical or electrochemical therapy are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of one administration. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the method comprises administering a tyrosine kinase inhibitor to the individual in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor is administered systemically, and the method comprises administering electrical or electrochemical therapy to the site of the cancer being treated. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storms (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascades or cytokine storms (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered prior to (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the tyrosine kinase inhibitor and / or the electrical or electrochemical treatment. In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with a tyrosine kinase inhibitor and / or electrical or electrochemical therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or acoustic therapy. In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) a tyrosine kinase inhibitor and / or electrical or electrochemical therapy.In some embodiments, an agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or electrical or electrochemical treatment.

[0097] In some embodiments, a method of treating cancer in an individual (e.g., a solid tumor, e.g., a blood cancer, e.g., a terminal cancer) is provided, comprising administering to the individual a tyrosine kinase inhibitor and electrostatic therapy, optionally administering the tyrosine kinase inhibitor at least twice (at least three, four, five, or six times). In some embodiments, a method of treating cancer in an individual (e.g., a solid tumor, e.g., a blood cancer, e.g., a terminal cancer) is provided, comprising administering to the individual a tyrosine kinase inhibitor and electrostatic therapy, wherein the tyrosine kinase inhibitor and electrostatic therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one administration. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor at least twice, no more than once every three days. In some embodiments, the method comprises administering a tyrosine kinase inhibitor to the individual in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor is administered systemically, and the method comprises administering electrostatic therapy to the site of the cancer being treated. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406.In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered prior to (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or electrostatic treatment. In some embodiments, the agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or electrostatic treatment. In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor and / or electrostatic treatment. In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor and / or electrostatic treatment. In some embodiments, an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after a tyrosine kinase inhibitor and / or electrostatic treatment.

[0098] In some embodiments, two or more pro-inflammatory agents described herein are administered to an individual. For example, in some embodiments, a method for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering a tyrosine kinase inhibitor, a TLR agonist or STING activator (e.g., MSA-2, ADU-S100, or cGAMP), and an immune checkpoint inhibitor. In some embodiments, the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7, and TLR8. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 agent (e.g., an anti-PD-1 antibody), an anti-PD-L1 agent (e.g., an anti-PD-L1 antibody), or an anti-CTLA-4 agent (e.g., an anti-CTLA-4 antibody). In some embodiments, the tyrosine kinase inhibitor, the TLR agonist, and the immune checkpoint inhibitor are administered on the same day. In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the tyrosine kinase inhibitor, TLR agonist, and / or immune checkpoint inhibitor are administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the tyrosine kinase inhibitor, TLR agonist, and immune checkpoint inhibitor are administered in at least two cycles (e.g., at least three cycles), optionally administered on the same day for at least two consecutive days (e.g., at least three consecutive days) per cycle. In some embodiments, each cycle lasts from about 7 to about 20 days. In some embodiments, the TLR agonist activates TLRs on macrophages, optionally including TLR9. In some embodiments, the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9). In some embodiments, the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4, and TLR7 / 8). In some embodiments, the TLR agonist comprises CpG, polyIC, and / or R848.In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine. In some embodiments, the TLR agonist comprises CpG, PolyIC, and R848, for example, in a 1:1:1 ratio. In some embodiments, the tyrosine kinase inhibitor is administered systemically and the TLR agonist is administered intratumorally. In some embodiments, the tyrosine kinase inhibitor is administered systemically and intratumorally. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or TLR agonist and / or immune checkpoint inhibitor.In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with a tyrosine kinase inhibitor and / or a TLR agonist and / or an immune checkpoint inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered in parallel with a tyrosine kinase inhibitor and / or a TLR agonist and / or an immune checkpoint inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor and / or a TLR agonist and / or an immune checkpoint inhibitor. In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or TLR agonist and / or immune checkpoint inhibitor. In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, PolyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0099] In some embodiments, provided are methods of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a cancer resistant or refractory to checkpoint inhibitors, e.g., a terminal cancer) in an individual, the method comprising administering to the individual a tyrosine kinase inhibitor (e.g., a Src family kinase inhibitor such as any of those exemplified in Table 2), a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof), and a TLR agonist or STING activator described herein. In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, polyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody).

[0100] In some embodiments, provided are methods of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual a tyrosine kinase inhibitor, wherein the individual is selected for treatment based on the individual experiencing an inflammatory response. In some embodiments, the individual exhibits an acute inflammatory response. In some embodiments, the inflammatory response occurs within the tumor. In some embodiments, the inflammatory response occurs at a site separate from the tumor. In some embodiments, an individual exhibits an inflammatory response as defined by: a) an increase in one or more (e.g., at least 1, 2, 3, 4, 5) pro-inflammatory cytokines (e.g., IFNγ, IL-12b, TNFα, IL-6, IL-1β, IFN-α1, IFN-α2, IFN-β1, etc.); b) a decrease in one or more (e.g., at least 1, 2, or 3) anti-inflammatory cytokines (e.g., TGFβ1, TGFβ2, TGFβ3, etc.); c) a decrease in infiltrating immune cells (e.g., T cells, NK cells, macrophages, etc.); In some embodiments, the tumor exhibits an inflammatory response accompanied by at least two (e.g., two, three, four, or five) events selected from the group consisting of: a) an increase in lymphocytes (e.g., lymphocytes, neutrophils, etc.); b) a decrease in inhibitory immune cells (e.g., MDSCs); and / or c) an increase in one or more (e.g., at least one, two, three, four, or five) immunogenic costimulatory molecules (e.g., CD80, CD86, OX40L, CD40, ICOS-L, PD-L1, GITRL, etc.) in tissue (e.g., tumor tissue) or immune cells (e.g., macrophages). In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., siRNA, shRNA, antisense RNA, microRNA), a nucleic acid editing system (e.g., CRISPR system), and a protein formulation (e.g., an antibody formulation targeting a tyrosine kinase or activated tyrosine kinase). In some embodiments, the tyrosine kinase inhibitor is administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the method comprises administering the tyrosine kinase inhibitor to the individual at least twice, no more than once every three days.In some embodiments, the method comprises administering a tyrosine kinase inhibitor to the individual in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor.In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with a tyrosine kinase inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to a tyrosine kinase inhibitor. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly after (e.g., within about any of 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours) the tyrosine kinase inhibitor.

[0101] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering a tyrosine kinase inhibitor to the individual, wherein the individual is selected for treatment based on the individual experiencing ongoing immune cell death (ICD). In some embodiments, the individual is determined to be experiencing ICD if a sample obtained from the cancer contains a higher level (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) of one or more DAMPs than a reference sample (e.g., a corresponding sample from a healthy control, e.g., a sample from the cancer prior to administration of an ICD-inducing therapy). In some embodiments, the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the DAMP is selected from the group consisting of endoplasmic reticulum (ER) chaperones (e.g., calreticulin (CALR), e.g., heat shock proteins (HSPs)), non-histone chromatin-binding protein high mobility group box 1 (HMGB1), cytoplasmic protein annexin A1 (ANXA1), and small molecule metabolites ATP and type I interferon (IFN). In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein formulations (e.g., antibody formulations targeting tyrosine kinases or activated tyrosine kinases). In some embodiments, the tyrosine kinase inhibitor is administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the method comprises administering the tyrosine kinase inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally).In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor inhibits Src family kinases (SFKs). In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or the pro-inflammatory agent.In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or the pro-inflammatory agent.

[0102] In some embodiments, the present application provides methods of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, the method comprising administering to the individual: a) monocytes or macrophages having a defect in tyrosine kinase expression or activation, and b) a pro-inflammatory agent (e.g., a TLR agonist, e.g., radiation therapy). In some embodiments, the monocytes or macrophages are derived from the same individual. In some embodiments, the monocytes or macrophages are engineered to express a chimeric receptor that targets a tumor antigen. In some embodiments, the monocytes or macrophages and the pro-inflammatory agent are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the monocytes or macrophages and the pro-inflammatory agent are administered simultaneously, concurrently, or sequentially. In some embodiments, the monocytes or macrophages are administered before the administration of the pro-inflammatory agent. In some embodiments, the monocytes or macrophages are administered after the administration of the pro-inflammatory agent. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the administration of monocytes or macrophages and / or a pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the administration of monocytes or macrophages and / or a pro-inflammatory agent.In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered in parallel with monocytes or macrophages and / or a pro-inflammatory agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) with respect to monocytes or macrophages and / or a pro-inflammatory agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after monocytes or macrophages and / or a pro-inflammatory agent. In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, polyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0103] The present application also provides a method for modulating monocytes or macrophages from an individual with cancer, the method comprising contacting the monocytes or macrophages with a tyrosine kinase inhibitor and an inflammation-inducing agent. In some embodiments, the monocytes or macrophages are from the same individual. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody). In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or the pro-inflammatory agent.In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about any of 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or the pro-inflammatory agent.

[0104] The present application also provides a method for activating phagocytosis of tumor cells in an individual bearing a tumor, comprising administering a tyrosine kinase inhibitor to the individual, wherein the individual a) has previously received, is currently receiving, or will soon receive an inflammatory agent, or b) is exhibiting an inflammatory response or has a persistent infection. In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., intravenously or subcutaneously). The present application also provides a method for activating tumor-infiltrating T cells in an individual bearing a tumor, comprising administering a tyrosine kinase inhibitor to the individual, wherein the individual a) has previously received, is currently receiving, or will soon receive an inflammatory agent, or b) is exhibiting an inflammatory response or has a persistent infection. In some embodiments, the method comprises administering a tyrosine kinase inhibitor to the individual at least twice, not more than once every three days. In some embodiments, the method comprises administering to the individual a tyrosine kinase inhibitor in at least two cycles, wherein the tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the pro-inflammatory agent and the tyrosine kinase inhibitor are administered within 24 hours of each other. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, and an oncolytic virus. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL-6 antibody).In some embodiments, the agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about one week, seven days, six days, five days, four days, three days, two days, one day, or less) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered shortly (e.g., within about 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours) after the tyrosine kinase inhibitor and / or the pro-inflammatory agent. In some embodiments, the TLR agonist is selected from the group consisting of LTA, CpG, polyIC, LPS, MPLA, flagellin, R848, vesatolimod, bropirimine, motolimod, and loxoribine.

[0105] The above-described cancer treatment methods may also be useful for 1) activating the SHP-1 signaling pathway in an individual, 2) depleting the immunosuppression of the tyrosine kinase-iR-SHP-1 axis in an individual, 3) activating intratumoral anti-cancer innate and / or adaptive immunity in an individual, 4) activating TLR-induced proinflammatory responses, and 5) increasing antigen presentation by tumor-associated macrophages (TAMs). Accordingly, the present application also provides methods for achieving any one or more of these objectives. Tumor microenvironment (TME) immunosuppression and SHP-1 signaling

[0106] Src homology region 2 (SH-2) domain-containing phosphatase 1 (SHP-1) is a non-receptor tyrosine phosphatase encoded by the PTPN6 gene, located on human chromosome 12p13 and containing two promoter regions (in exons 1 and 2). Two forms of SHP-1 are produced, differing in their N-terminal amino acid sequences but possessing similar phosphatase activity. Promoter I is activated in non-hematopoietic cells, whereas promoter II is activated in hematopoietic-derived cells. In some epithelial cancer cells, both promoters are functional, generating various alternative SHP-1 transcripts. The two SHP-1 isoforms exhibit distinct subcellular localizations: type I is primarily located in the nucleus, while type II is present in the cytoplasm, suggesting that they have distinct targets.

[0107] SHP-1 is a 595-amino acid protein consisting of two N-terminal SH2 domains (N-SH2 and C-SH2) arranged in succession, a classical catalytic protein tyrosine phosphatase (PTP) domain, and a C-terminal tail containing multiple phosphorylation sites. Its crystal structure revealed a structure in which the N-SH2 domain binds to the catalytic site of the protein via charge-charge interactions. In this autoinhibited, inactive state, substrate access to the activation site is blocked. However, binding of a phosphotyrosine residue to the SH2 domain induces a conformational change that impairs the interaction between the N-SH2 domain and the catalytic domain. This opens the conformation, allowing substrate access, which is further stabilized by new interactions between the SH2 domain and the catalytic domain. These molecular rearrangements determine the sophisticated regulatory mechanisms controlled by substrate recruitment.

[0108] An additional activation mechanism is mediated by phosphorylation of amino acids within the C-terminal tail. Three phosphorylation sites have been identified: two tyrosines (Tyr536 and Tyr564) and a serine (Ser591) residue. Tyr536 and Tyr564 ​​are phosphorylated upon various stimuli (i.e., insulin stimulation or apoptosis-inducing agents), resulting in increased SHP-1 activation. Although the molecular mechanism is unclear, it has been proposed that Tyr phosphorylation induces interaction with the N-SH2 domain, thereby relieving the inhibitory effect of this domain on PTPase activation. SHP-1 activation can also be negatively regulated by protein kinase C (PKC) or mitogen-activated protein kinase (MAPK) via phosphorylation of Ser591, although the inhibitory mechanism is not fully understood.

[0109] Protein tyrosine phosphorylation is a reversible post-translational modification that is tightly regulated by both kinases and phosphatases. Any deviation in the phosphorylation / dephosphorylation balance can promote the intracellular accumulation of tyrosine-phosphorylated proteins, resulting in altered regulation of cellular processes, including cell proliferation, migration, invasion, differentiation, survival, and cell trafficking. In this scenario, SHP-1 acts as a classic tumor suppressor, primarily involved in the homeostatic maintenance of all of these processes. Indeed, SHP-1 function is altered in both human solid and hematologic cancers via somatic mutations or epigenetic mechanisms. In addition to its well-documented role in regulating hematopoietic cell biology, SHP-1 has now been shown to correlate with several signaling pathways associated with cancer initiation and progression.

[0110] However, inhibition of SHP-1 is associated with severe side effects. SHP-1 gene-deficient mice, mothaten mice (me / me or me v / me v ) revealed significant immunological abnormalities and immune cell hyperactivation associated with the total loss of tyrosine kinases. Motheaten mice typically suffer from life-threatening autoimmune inflammatory diseases during infancy. Even partial depletion of SHP-1 in WT mice after they reached adulthood resulted in inflammatory disease characteristics, including widespread lung inflammation and splenomegaly. Although SHP-1 inhibition may enhance anti-cancer immunity, it is a double-edged sword that inevitably endangers the host by enhancing inflammatory responses, cytokine storms, and autoimmunity.

[0111] Development of inhibitors targeting tyrosine kinase phosphatase activation has been ongoing, with several currently in preclinical studies, including NSC-87877, sodium stibogluconate (SSG), tyrosine phosphatase inhibitor 1 (TPI-1 or its analogs or derivatives), and suramin. However, only a few of these have demonstrated activity in experimental tumor models. SSG has undergone Phase I trials for both malignant melanoma (NCT00498979) and advanced malignancies (NCT00629200). This drug has been administered in combination with interferon, with or without chemotherapy. Unfortunately, no effect on tumor development has been observed, and the most common toxic side effects are thrombocytopenia, elevated serum lipase, fatigue, fever, chills, anemia, hypokalemia, pancreatitis, and skin rash (observed in up to 68% of patients). Currently, no SHP-1 inhibitors are in Phase II trials.

[0112] The SHP-1 inhibitors described herein can be administered together with a tyrosine kinase inhibitor. In some embodiments, the method includes administering (e.g., locally or systemically) to an individual an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof). In some embodiments, SHP-1 is administered simultaneously with the tyrosine kinase inhibitor. In some embodiments, SHP-1 is administered sequentially with (e.g., before or after) the tyrosine kinase inhibitor. In some embodiments, administration of SHP-1 follows the same administration schedule as the tyrosine kinase inhibitor.

[0113] Drugs that reduce systemic inflammation In some cases, individuals develop systemic inflammation, i.e., cytokine release syndrome (CRS), after receiving (for example) immunotherapy treatment, a not fully understood inflammatory disease. CRS can be induced by direct target cell lysis and the sequential release of cytokines such as TNFα or IFNγ, or by therapeutic stimulation-induced T cell activation and subsequent cytokine release. These cytokines trigger a chain reaction by activating innate immune cells such as macrophages and endothelial cells, which then induces the release of additional cytokines. In particular, IL-6, IL-10, and IFNγ are most commonly found elevated in CRS patients.

[0114] The methods described herein may further include administering an agent that reduces systemic inflammation (e.g., an agent that suppresses the inflammatory cascade or cytokine storm, including, for example, a TNFα inhibitor such as an anti-TNFα antibody) to suppress systemic inflammation and reduce adverse toxicity. These agents include, but are not limited to, inhibitors of TNFα, IL-6, IL-10, and IFNγ. In some embodiments, the agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered before (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered simultaneously with the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered concurrently with the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered sequentially (e.g., before or after) the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered immediately after the tyrosine kinase inhibitor (e.g., within about 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours). In some embodiments, the agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) follows the same administration schedule as the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) is administered at a subtherapeutic dose, i.e., a dose lower than the amount effective to treat the disease when administered alone. In some embodiments, administration of an agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody) allows for more frequent administration of the tyrosine kinase inhibitor and / or pro-inflammatory agent (e.g., daily, once every two days, once every three days, etc.).

[0115] The agent can include any anti-inflammatory agent known in the art, including an inhibitor of an inflammatory agent or an antagonist to an inflammatory agent. For example, the agent can be an inhibitor or antagonist, including, but not limited to, a small molecule inhibitor, a neutralizing antibody, a receptor-blocking antibody, a soluble receptor, a targeting short interfering RNA (siRNA), a chemical inhibitor of mRNA stability and its analogs or derivatives, and any combination thereof, such as a combination of agents targeting one or more molecules (e.g., by targeting TNFα inhibition alone, IL-6 inhibition alone, or TNFα and IL-6 inhibition combined).

[0116] Anti-TNFα antagonists TNFα, a major pro-inflammatory cytokine, is secreted by activated macrophages, monocytes, and lymphocytes. The present inventors have surprisingly found that administering an anti-TNFα antibody to an individual treated with a tyrosine kinase inhibitor and an inflammatory agent mitigates the toxicity caused by systemic inflammation without compromising the efficacy of the therapeutic agent.

[0117] Thus, in some embodiments, the methods of the present application comprise administering a TNFα inhibitor, e.g., an anti-TNFα antagonist (e.g., when the pro-inflammatory agent is not TNFα). In some embodiments, the TNFα inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNFα receptor-blocking antibody, a soluble TNFα receptor, a TNFα-targeting short interfering RNA (siRNA), a chemical inhibitor of TNFα mRNA stability, a TNFα-converting enzyme (TACE) inhibitor, and analogs or derivatives thereof. In some embodiments, the TNFα inhibitor is an anti-TNFα neutralizing antibody. In some embodiments, the TNFα inhibitor is an anti-TNFα receptor-blocking antibody. In some embodiments, the anti-TNFα antibody is a monoclonal antibody. In some embodiments, the anti-TNFα antibody is a chimeric antibody, a humanized antibody, and / or a fully human antibody.

[0118] Suitable antibodies for use in the methods provided herein include, but are not limited to, Remicade® (infliximab (Centocor)) and antibodies described in, for example, U.S. Pat. Nos. 6,835,823, 6,790,444, 6,284,471, 6,277,969, 5,919,452, 5,698,195, 5,656,272, and 5,223,395, and European Patent No. 0610201, the contents of each of which are incorporated herein by reference in their entirety, or antibodies that bind to the same epitope as Remicade®. Other suitable anti-TNFα antibodies for use in the methods provided herein include, by way of non-limiting example, Humira (adalimumab (Abbott Laboratories, Esai)), described in U.S. Pat. Nos. 6,090,382, 6,258,562, or 6,509,015, and related patents and applications, the contents of which are incorporated herein by reference in their entireties; Simponi™ (golimumab, CNTO148 (Centocor)), described in PCT Publication No. WO 02 / 12502, and related patents and applications, the contents of which are incorporated herein by reference in their entireties; ART621 (Arana Therapeutics); SSS 07 (Epitopmics and 3SBio); or an antibody that binds to the same epitope as Humira, Simponi, ART621, or SSS 07.

[0119] In some embodiments, the TNFα inhibitor, e.g., an anti-TNFα antagonist, is a fusion protein. Suitable fusion proteins for use in the methods provided herein include, but are not limited to, Enbrel (etanercept (Amgen)) and other fusion proteins or fragments thereof described in U.S. Patent No. 5,712,155, PCT Publication No. WO 91 / 03553, and related patents and applications, the contents of which are incorporated herein by reference in their entireties.

[0120] In some embodiments, the TNFα inhibitor, e.g., anti-TNFα antagonist, is a modified antibody antagonist or a non-antibody-based antagonist. Such antagonists include Cimzia™ (certolizumab pegol, CDP870 (Enzon)), bispecific antibodies, Nanobodies® such as ABX 0402 (Ablinx), immunotoxins, and radiolabeled therapeutics; peptide therapeutics; gene therapy, particularly intrabodies; oligonucleotide therapeutics such as aptamer therapy, antisense therapy, and interfering RNA therapy; and advanced antibody therapeutics such as antibody fragments, including but not limited to small molecules such as LMP-420 (LeukoMed), as described in EP 0767793 and related patents and applications (the contents of which are incorporated herein by reference in their entirety).

[0121] In some embodiments, the TNFα inhibitor is administered systemically. In some embodiments, the TNFα inhibitor is administered at least once weekly, once every 5 days, once every 3 days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered to the individual in at least two cycles, each cycle lasting from about 3 to about 7 days. In some embodiments, the individual does not develop cytokine release syndrome or inflammation-induced organ damage. In some embodiments, administration of the TNFα inhibitor does not impair or only slightly impairs tumor clearance.

[0122] In some embodiments, the TNFα inhibitor is administered before the tyrosine kinase inhibitor and / or pro-inflammatory agent (e.g., within about 2 weeks, about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). Exemplary TNFα inhibitors, such as anti-TNFα antibodies, are typically stable for at least 1 or 2 weeks. In some embodiments, the TNFα inhibitor is administered simultaneously with the tyrosine kinase inhibitor and / or pro-inflammatory agent. In some embodiments, the TNFα inhibitor is administered in parallel with the tyrosine kinase inhibitor and / or pro-inflammatory agent. In some embodiments, the TNFα inhibitor is administered sequentially with (e.g., before or after) the tyrosine kinase inhibitor and / or pro-inflammatory agent. In some embodiments, the TNFα inhibitor is administered shortly after (e.g., within about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours) the tyrosine kinase inhibitor and / or pro-inflammatory agent.

[0123] Anti-IL6 antagonist An "anti-IL6 antagonist" or "IL6 inhibitor" refers to an agent that inhibits or blocks the biological activation of IL6 through binding to IL6 or the IL6 receptor. In some embodiments, the anti-IL6 antagonist is an antibody. In one embodiment, the anti-IL6 antagonist is an antibody that binds to the IL6 receptor. Antibodies that bind to the IL-6 receptor include tocilizumab (including their intravenous, i.v., and subcutaneous, sc, formulations) (Chugai, Roche, Genentech), satralizumab (Chugai, Roche, Genentech), sarilumab (Sanofi, Regeneron), NI-1201 (Novimmune and Tiziana), and bovalilizumab (Ablinx). In one embodiment, the anti-IL6 antagonist is a monoclonal antibody that binds to IL6. Antibodies that bind to IL-6 include sirukumab (Centecor, Janssen), olokizumab (UCB), clazakizumab (BMS and Alder), siltuximab (Janssen), and EBI-031 (Eleven Biotherapeutics and Roche). In one embodiment, the IL6 antagonist is olamuxcept.

[0124] In some embodiments, the IL6 inhibitor is administered systemically. In some embodiments, the IL6 inhibitor is administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, the IL6 inhibitor is administered intermittently. In some embodiments, the IL6 inhibitor is administered to an individual in at least two cycles, each cycle lasting from about 3 to about 7 days.

[0125] tyrosine kinase inhibitors A tyrosine kinase inhibitor as referred to herein is any type of agent that inhibits the expression or activation of tyrosine kinases.

[0126] In some embodiments, the tyrosine kinase inhibitor is capable of inhibiting tyrosine kinase activation by at least about 20% (e.g., at least 20%, 30%, 40%, or 50%). In some embodiments, the tyrosine kinase inhibitor is capable of inhibiting tyrosine kinase expression by at least about 20% (e.g., at least 20%, 30%, 40%, or 50%).

[0127] In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling.

[0128] In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein agents (e.g., antibody agents targeting tyrosine kinases or activated tyrosine kinases, such as dominant-negative tyrosine kinases or constitutively active tyrosine kinase mutants).

[0129] In some embodiments, the tyrosine kinase inhibitor has a half-life of about 10 days, 9 days, 8 days, or 7 days or less (e.g., a half-life of about 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day or less).

[0130] In some embodiments, the tyrosine kinase inhibitor is effective to inhibit greater than 50% of tyrosine kinase activation within about 10, 9, 8, 7, 6, or 5 days, hi some embodiments, the tyrosine kinase inhibitor is effective to inhibit greater than 50% of tyrosine kinase activation within about 4, 3, 2, or 1 day.

[0131] In some embodiments, the tyrosine kinase inhibitor is a covalent inhibitor. In some embodiments, the tyrosine kinase inhibitor is a non-covalent inhibitor.

[0132] In some embodiments, the tyrosine kinase inhibitor is a competitive inhibitor.

[0133] In some embodiments, the tyrosine kinase inhibitor is a nucleic acid editing method (such as a CRISPR system). In some embodiments, CRISPR components are introduced into cells (e.g., monocytes and macrophages), but the DNA encoding guide RNA or Cas9 is not integrated into the genome of the cell. Under this approach, the CRISPR method cuts the genomic DNA of the cell for a limited period of time. See, for example, Fister et al., Front Plant Sci. 2018 Mar 2; 9: 268.

[0134] In some embodiments, the tyrosine kinase inhibitor is administered at least twice (such as at least three, four, five, or six times).

[0135] In some embodiments, the method comprises administering the tyrosine kinase inhibitor at least twice (eg, at least three, four, five, or six times) no more than every other day.

[0136] In some embodiments, the method comprises administering the tyrosine kinase inhibitor at least twice (eg, at least three, four, five, or six times) no more than once every three days.

[0137] In some embodiments, the method includes administering a tyrosine kinase inhibitor for at least two cycles. In some embodiments, the tyrosine kinase inhibitor is administered at least once (e.g., two, three, or four times) in each cycle. In some embodiments, each cycle lasts for about 3 to about 50 days (e.g., about 3 to 40 days, about 3 to 30 days, about 3 to 20 days, about 3 to 15 days, about 3 to 10 days, or about 2 to 10 days).

[0138] In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, intraperitoneally). In some embodiments, the tyrosine kinase inhibitor is administered locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor is administered both systemically and locally (e.g., intratumorally).

[0139] In some embodiments, the tyrosine kinase inhibitor is complexed with a delivery vehicle prior to administration to the individual. In some embodiments, the delivery vehicle facilitates delivery into the tumor.

[0140] In some embodiments, the tyrosine kinase inhibitor modulates monocytes or macrophages in vitro (eg, monocytes or macrophages derived from the individual being treated).

[0141] In some embodiments, the tyrosine kinase inhibitor and pro-inflammatory agent listed below are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of each other. In some embodiments, the tyrosine kinase inhibitor and pro-inflammatory agent are administered simultaneously, concurrently, or sequentially. In some embodiments, the tyrosine kinase inhibitor is administered before the pro-inflammatory agent. In some embodiments, the tyrosine kinase inhibitor is administered after the pro-inflammatory agent.

[0142] Src family tyrosine kinases (SFKs) and ITIM phosphorylation in TAMs

[0143] In some embodiments, the tyrosine kinase is a Src family tyrosine kinase. Kinases in the Src family have a similar structure, consisting of an N-terminal Src homology ("SH") 4 ("SH4") domain, a "unique" domain, an SH3 domain, an SH2 domain, a catalytic domain (also called an SH1 domain or kinase domain), and a short C-terminal tail. Activity is regulated by tyrosine phosphorylation at two sites. Phosphorylation of the tyrosine in the C-terminal tail (Tyr-505, Src numbering) promotes intramolecular interaction between the tail and the SH2 domain, resulting in downregulation. The eight known mammalian members of the Src family are classified into two subfamilies. Lck is most similar to Hck, Lyn, and Blk (identity between any two members is 65% or greater). Other subfamilies consist of Src, Yes, Fyn, and Fgr (identity between any two members is 70% or greater). Residues important for the activity and / or substrate specificity of Src family kinases have been identified by X-ray crystallography and structural modeling studies and are highly conserved among family members.

[0144] The Src family of non-receptor tyrosine kinases (SFKs) consists of SRC, LCK, LYN, BLK, HCK, FYN, FGR, and YES (8 / 9 members expressed in humans) and is divided into two groups based on their expression patterns: SRC, YES, and FYN are ubiquitously expressed, whereas LCK, FGR, BLK, LYN, YRK, and HCK show specific expression in certain cell types and tissues.

[0145] In the immune system, SFKs play important regulatory roles in both myeloid and lymphoid immune cells, controlling cell activation, proliferation, differentiation, apoptosis, cytokine production, migration, metabolism, and more.

[0146] LCK is specifically expressed in T cells and is critically involved in T cell activation via the TCR. LCK deficiency abolishes TCR signaling, thereby reducing antigen-specific T cell activation, proliferation, and T cell immunity. LCK is not expressed in macrophages or other myeloid leukocytes.

[0147] LYN is highly expressed in B cells and myeloid leukocytes. Our study found that LYN maintains constitutive activity in macrophages and mediates low-level tyrosine phosphorylation of the cytoplasmic ITIM of inhibitory receptors (iRs). However, LYN does not appear to be involved in the potent ITIM-mediated tyrosine phosphorylation of iRs. Notably, under tumor treatment conditions, we found that HCK or its related complementary SFKs (e.g., FGR and YES; see Lowell CA, Soriano P, Varmus HE. Functional overlap in the src gene family: inactivation of hck and fgr impairs natural immunity. Genes and Development. 1994;8:387-398) phosphorylates the ITIM of iRs, leading to docking and activation of SHP-1 and mediating downstream inhibitory regulation.

[0148] Figure 12 shows an example where SIRPα, an iR abundantly expressed on tumor-associated macrophages (TAMs), was studied. As shown, pro-inflammatory stimuli (TLR agonists, pro-inflammatory cytokines IL-1β, IL-6, IL-12, IL-17, IL-18, TNFα, IFNγ, etc., and cancer treatments) induce phosphorylation of SIRPα ITIMs and exclusive binding of SHP-1 (but not SHP-2). Anti-inflammatory cytokine stimulation also induces phosphorylation of SIRPα ITIMs, but in association with SHP-2.

[0149] When macrophages were activated by proinflammatory stimuli or cancer treatment, inhibition of the Src family tyrosine kinases (SFKs) PP1 and PP2 (both SFK inhibitors) reduced SIRPα cytoplasmic ITIM phosphorylation and SIRPa association with SHP-1, but not inhibitors targeting other TKs, such as JAK (JAK inhibitor), Btk (LFMA-13), or Syk (piceatannol). In comparison, the specific inhibitor of LYN, bafetinib (also known as INNO-406), had only a minor effect. Test macrophages with Lyn deficiency confirmed that Lyn deficiency significantly affected the low level of SIRPa ITIM phosphorylation induced by CD47 ligation in the absence of proinflammatory stimuli, but Lyn did not affect proinflammatory factor-induced SIRPa ITIM phosphorylation or SIRPa association with SHP-1.

[0150] Notably, in the absence of treatment, the immunosuppressive tumor TME is regulated by IL-10, TGFβ, and IL-4 / 13, which activates Bruton's tyrosine kinase (Btk) in tumor-associated macrophages (TAMs), leading to phosphorylation of the cytoplasmic ITIMs of iRs (e.g., SIRPα) and docking of SHP-2, but not SHP-1. This series of events, in which immunosuppressive cytokines activate Btk and promote SIRPα-SHP-2 binding, further enhances immunosuppressive signaling within TAMs. A further consequence of this pathway is increased iR expression on TAMs, thereby functioning as a feed-forward mechanism to regulate TAMs and, therefore, TME immunosuppression.

[0151] In some embodiments, the TKi inhibits a Src family kinase (SFK), optionally the SFK is selected from SRC, LCK, LYN, BLK, HCK, FYN, FGR, and YES. In some embodiments, the TKi inhibits an SFK that is not LYN. In some embodiments, the TKi inhibits an SFK that is not HCK. In some embodiments, the SFK is selected from the group consisting of SRC, BLK, HCK, FYN, FGR, and YES. In some embodiments, the SFK is HCK or a related complementary SFK (e.g., FGR and YES). In some embodiments, the SFK is selected from the group consisting of HCK, FGR, and YES.

[0152] In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the multi-targeted tyrosine kinase inhibitor is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more (e.g., any two, three, four, five, or six) of Src, Syk, Hck, Lck, Lyn, and Yes. In some embodiments, the tyrosine kinase inhibitor inhibits Bcr-Abl. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of ponatinib, bosutinib, saracatinib, and KX2-391. These tyrosine kinase inhibitors are described in more detail below.

[0153] Src inhibitors Src is a member of the non-receptor protein tyrosine kinase family and has the activity of phosphorylating specific tyrosine residues in target proteins. Src may be derived from any animal species (e.g., mammals), and may be at least one selected from the group consisting of primate Src, including human Src (e.g., Accession No. NP_005408), monkey Src (e.g., Accession No. XP_002830325), and rodent Src, including, but not limited to, mouse Src (e.g., Accession No. NP_001020566), rat Src (e.g., Accession No. NP_114183), etc.

[0154] In some embodiments, the Src inhibitor (SRCi) may be an inhibitor of Src gene or Src protein expression or an inhibitor of Src protein activity. The inhibitor of Src gene or Src protein expression may be, but is not limited to, one or more selected from the group consisting of antisense nucleotides that bind complementary to the mRNA of the gene, short interfering RNA (siRNA), short hairpin RNA (shRNA), and ribozymes. The inhibitor of Src protein activity may be, but is not limited to, one or more selected from the group consisting of compounds that specifically bind to the protein, peptides, peptidomimetics, aptamers, antibodies, and natural products. Examples of antibodies include monoclonal, polyclonal, or recombinant antibodies that can specifically bind to Src protein, and can be prepared by methods known to those skilled in the art or purchased commercially. According to the present invention, the compound may be one or more selected from the group consisting of dasatinib, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105.

[0155] In one embodiment, the Src inhibitor can be at least one selected from the group consisting of dasatinib, saracatinib, and bosutinib, or any combination thereof.

[0156] KX2-391 (tirbanibulin), also known as N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, has the following structure: [ka]

[0157] Dasatinib, also known as N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide monohydrate, has the following structure: [ka]

[0158] Saracatinib, also known as AZD0530 (4-quinazolinamine, N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methyl-1-piperazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]-4-quinazolinamine), has the following structure: [ka]

[0159] Bosutinib, also known as 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, has the following structure: [ka]

[0160] Syk inhibitors Spleen tyrosine kinase (SYK) is a cytoplasmic non-receptor protein tyrosine kinase (PTK). The human SYK gene is located in the chromosome 9q22 region. Syk, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor tyrosine kinases share a characteristic dual SH2 domain separated by a linker domain.

[0161] In some embodiments, the Syk inhibitor may be an inhibitor of Syk gene or Syk protein expression, or an inhibitor of Syk protein activity. The inhibitor of Syk gene or Syk protein expression may be, but is not limited to, one or more selected from the group consisting of antisense nucleotides that bind complementary to the mRNA of the gene, short interfering RNA (siRNA), short hairpin RNA (shRNA), and ribozymes. The inhibitor of Syk protein activity may be, but is not limited to, one or more selected from the group consisting of compounds that specifically bind to the protein, peptides, peptidomimetics, aptamers, antibodies, and natural products. Examples of antibodies include monoclonal antibodies, polyclonal antibodies, and recombinant antibodies that can specifically bind to Syk protein. These antibodies may be prepared by methods known to those skilled in the art or purchased commercially.

[0162] In some embodiments, the Syk inhibitor is a small molecule inhibitor, ie, selected from the group consisting of entospletinib (GS-9973), fostamatinib (R788), R406, celdulatinib (PRT0626070), and TAK-659.

[0163] In some embodiments, the Syk inhibitor is R406, which has the formula: [ka]

[0164] Hck inhibitors Hck is a member of the Src family of non-receptor tyrosine kinases and plays many roles in signaling pathways involved in regulating cellular processes. Hck is expressed in cells of hematopoietic origin, specifically myelomonocytic cells and B lymphocytes. It is involved in phagocytosis, adhesion, migration, regulation of plasma membrane protrusions, lysosomal exocytosis, podosome formation, and actin polymerization. Hck levels are elevated in chronic myeloid leukemia and other hematologic malignancies. Hck may also be involved in the development of acute myeloid leukemia.

[0165] In some embodiments, the Hck inhibitor may be an inhibitor of Hck gene or Hck protein expression, or an inhibitor of Hck protein activity. The Hck gene or Hck protein expression inhibitor may be, but is not limited to, one or more selected from the group consisting of antisense nucleotides that bind complementary to the mRNA of the gene, short interfering RNA (siRNA), short hairpin RNA (shRNA), and ribozymes. The Hck protein activity inhibitor may be, but is not limited to, one or more selected from the group consisting of compounds that specifically bind to the protein, peptides, peptidomimetics, aptamers, antibodies, and natural products. Examples of antibodies include monoclonal antibodies, polyclonal antibodies, or recombinant antibodies that can specifically bind to Hck protein. These antibodies can be prepared by methods known to those skilled in the art or purchased commercially.

[0166] In some embodiments, the Hck inhibitor is a small molecule inhibitor, hi some embodiments, the Hck inhibitor is selected from the group consisting of RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, and RK-20466. In other embodiments, the HCK inhibitor is selected from RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, RK-20730, RK-20690, RK-20781, RK-20786, RK-20888, RK-20658, RK-20686, RK-20696, RK-20709, RK-20721, RK-20694, RK-20703, RK-20718, RK-20744, and compounds having Hck inhibitory activity disclosed in WO 2014 / 017659, which is incorporated herein by reference. Hck inhibitors are also disclosed in WO 2018 / 052120, which is incorporated herein by reference.

[0167] RK-20449 (alias A 419259): The structure of 7-((1R,4R)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is as follows: [ka]

[0168] Lck inhibitors Lck (or lymphocyte-specific protein tyrosine kinase) is a member of the Src kinase family that is important for activating T cell receptor signaling in both naive and effector T cells. The N-terminal tail of Lck is myristoylated and palmitoylated, which anchors the protein to the plasma membrane of cells. Furthermore, the protein contains an SH3 domain, an SH2 domain, and a tyrosine kinase domain in the C-terminal portion.

[0169] In some embodiments, the Lck inhibitor may be an inhibitor of Lck gene or Lck protein expression, or an inhibitor of Lck protein activity. The Lck gene or Lck protein expression inhibitor may be, but is not limited to, one or more selected from the group consisting of antisense nucleotides that complementarily bind to the mRNA of the gene, short interfering RNA (siRNA), short hairpin RNA (shRNA), and ribozymes. The Lck protein activity inhibitor may be, but is not limited to, one or more selected from the group consisting of compounds that specifically bind to the protein, peptides, peptidomimetics, aptamers, antibodies, and natural products. Examples of antibodies include monoclonal antibodies, polyclonal antibodies, or recombinant antibodies that can specifically bind to Lck protein. These antibodies can be prepared by methods known to those skilled in the art or purchased commercially.

[0170] In some embodiments, the Lck inhibitor is a small molecule inhibitor. In some embodiments, the Lck inhibitor is selected from the group consisting of salatinib, masitinib, and NVP-BEP800.

[0171] Bcr-Abl inhibitors Bcr-Abl is a fusion gene resulting from a reciprocal translocation between chromosomes 9 and 12 on the long arms. It encodes the BCR-ABL protein, a constitutively active cytoplasmic tyrosine kinase present in over 90% of patients with chronic myeloid leukemia (CML) and 15-30% of adult patients with acute lymphoblastic leukemia (ALL). Exemplary Bcr-Abl inhibitors include, but are not limited to, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, revastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole analogs or derivatives. Additional Bcr-Abl inhibitors can be found, for example, in WO 2006 / 052810, which is incorporated herein by reference.

[0172] Ponatinib (AP24534) is a dual Src / Abl inhibitor with the following structure: [ka]

[0173] Inflammatory agents Infection and tissue injury are two classic triggers of inflammation. See, e.g., Medzhitov, Nature. 2008 Jul 24;454(7203):428-35. Proinflammatory agents, as described herein, include at least two overlapping categories: 1) any agent or therapy that can promote inflammation (e.g., by promoting one or more proinflammatory cytokines or chemokines, inhibiting one or more anti-inflammatory cytokines or chemokines, recruiting macrophages, NK cells, neutrophils, effector T cells, or B cells to tissues, activating any of these cells, or suppressing regulatory / suppressive immune cells, such as regulatory T cells or MDSCs), and 2) any agent or therapy that can cause cancer cell damage (e.g., cancer cell necrosis).

[0174] In some embodiments, the proinflammatory agent induces proinflammatory signals on macrophages. See, e.g., FIG. 5A. In some embodiments, the proinflammatory agent activates TLR, TNFR, or ITAM-R. See, Lionel et al., Eur J Immunol. 2011 Sep;41(9):2477-2481. The proinflammatory agent can activate proinflammatory signals on macrophages via direct or indirect methods. For example, TLR agonists, which directly activate TLRs on macrophages, and radiation therapy, which indirectly activates proinflammatory signals on macrophages, both showed significant antitumor effects when used with tyrosine kinase inhibitors. See the Examples.

[0175] Exemplary pro-inflammatory agents include TLR agonists, STING activators, radiation therapy, PAMP / DAMP activators, checkpoint inhibitors, pro-inflammatory cytokines or chemokines, chemotherapeutic drugs, bacterial components, cancer vaccines, and oncolytic viruses. Other exemplary pro-inflammatory agents include acoustic therapy (e.g., high-intensity focused ultrasound), magnetic therapy, electrical therapy, and electrostatic therapy, which can kill cancer cells. See, for example, Naud et al., Nanoscale Adv., 2020, 2, 3632-3655; Rominiyi et al., Br J Cancer. 2021 Feb;124(4):697-709; Zandi et al., Cancer Med. 2021 Nov;10(21):7475-7491.

[0176] In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine or chemokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy (e.g., high intensity focused ultrasound), magnetic therapy, electrical therapy, and electrostatic therapy.

[0177] In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP / DAMP activator, a pro-inflammatory cytokine or chemokine, a bacterial component, a cancer vaccine, acoustic therapy (e.g., high intensity focused ultrasound), magnetic therapy, electrical therapy, and electrostatic therapy.

[0178] In some embodiments, the pro-inflammatory agent is acoustic therapy (e.g., high-intensity focused ultrasound (HIFU), e.g., low-intensity focused ultrasound (LIPUS)). See, e.g., Wood et al., Ultrasound Med Biol. 2015 Apr;41(4): 905-928; Sengupta et al., J Adv Res. 2018 Nov;14: 97-111.

[0179] In some embodiments, the pro-inflammatory agent is magnetic therapy (e.g., a pulsed magnetic field, e.g., a static magnetic field). See, e.g., Tatarov et al., Comp Med. 2011 Aug;61(4): 339-345; Sengupta et al., J Adv Res. 2018 Nov;14: 97-111.

[0180] In some embodiments, the pro-inflammatory agent is an electrical or electrochemical therapy. See, e.g., Ciria et al., Chin J Cancer Res. 2013 Apr;25(2): 223-234; Das et al., Front Bioeng Biotechnol. 2021;9: 795300.

[0181] In some embodiments, the pro-inflammatory agent is electrostatic therapy. See, e.g., Zandi et al., Cancer Med. 2021 Nov;10(21): 7475-7491.

[0182] In some embodiments, the pro-inflammatory agent is thermoacoustic therapy. See, e.g., Wen et al., Theranostics. 2017;7(7): 1976-1989.

[0183] In some embodiments, the pro-inflammatory agent comprises a microorganism (e.g., a fragment or lysate of a microorganism). Examples of microorganisms include bacteria, fungi, and viruses.

[0184] TLR agonists In some embodiments, the pro-inflammatory agent comprises or is a TLR agonist.

[0185] TLRs play an important role in activating the immune response. They recognize not only pathogen-associated molecular patterns (PAMPs) expressed by various microorganisms but also endogenous DAMPs released by stressed or dying cells. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are expressed on the cell surface, while TLR3, TLR7, TLR8, and TLR9 are located intracellularly in the endosomal membrane. TLR1 and TLR2 heterodimerize to recognize various bacterial lipid structures and cell wall components, such as triacylated lipoproteins, lipoteichoic acid, and β-glucan. TLR2 also heterodimerizes with TLR6 to bind diacylated lipopeptides. Furthermore, TLR2 can bind to various endogenous DAMPs, such as HSPs, HMGB1, uric acid, fibronectin, and other extracellular matrix proteins. It has also been shown that TLR1 and TLR6 can form heterodimers with TLR10, but the TLR agonist recognized by this dimer has not yet been identified. TLR3 recognizes viral dsRNA as well as synthetic analogs of dsRNA, such as the ligand polyIC. TLR4 binds to LPS in complex with lipid A-binding protein, CD14, and myeloid differentiation protein 2 (MD2), as well as recognizes various DAMPs. Reported endogenous TLR4 ligands include β-defensin 2, fibronectin extra domain A (EDA), HMGB1, snapin, and tenascin-C. TLR5 recognizes bacterial flagellin, while TLR7 and TLR8 bind viral ssRNA. Meanwhile, TLR9 interacts with unmethylated CpG DNA from bacteria and some viruses. More recently, additional TLRs have been identified in mice based on highly conserved sequence homology of their TIR domains. TLR10 is a surface receptor whose natural ligand remains unknown. TLR11, TLR12, and TLR13 are present in mice but not in humans. TLR11 has been shown to bind to T. gondii profilin and uropathogenic E. coli. The ligand for TLR12 has yet to be identified. Meanwhile, TLR13 is an endosomal receptor that recognizes VSV.See, e.g., Kaczanowska et al., J Leukoc Biol. 2013 Jun;93(6):847-63.

[0186] TLR signaling can act as a double-edged sword in cancer. It has become clear that stimulation of TLRs in cancer cells can contribute to either tumor progression or tumor suppression. For example, stimulation of TLR2, TLR4, and TLR7 / 8 has been shown to promote tumor progression through the production of immunosuppressive cytokines, increase cell proliferation, and increase resistance to apoptosis. R848 stimulation of TLR7 / 8-overexpressing pancreatic cancer cell lines increased cell proliferation and reduced chemosensitivity. Meanwhile, stimulation of TLR2, TLR3, TLR4, TLR5, TLR7 / 8, and TLR9, often in combination with chemotherapy or immunotherapy, can result in tumor inhibition through various pathways. See, for example, Grimmig et al., Int J Oncol. (2015) 47:857-66; Urban-Wojciuk et al., Front Immunol. 2019;10:2388.

[0187] In some embodiments, the TLR agonist activates any of the TLRs.

[0188] In some embodiments, the TLR agonist activates TLR1 or TLR2, and optionally, the TLR agonist comprises triacylated lipoprotein, peptidoglycan, zymosan, and / or Pam3CSK4.

[0189] In some embodiments, the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, and optionally, the TLR agonist comprises a diacylated lipopeptide, a heat shock protein, HMGB1, uric acid, fibronectin, and / or an ECM protein.

[0190] In some embodiments, the TLR agonist activates TLR2, and optionally, the TLR agonist comprises Pam3Cys, SMP-105, and / or CBLB612.

[0191] In some embodiments, the TLR agonist activates TLR3, and optionally, the TLR agonist comprises dsRNA, polyIC, polyICIC, poly-IC12U, IPH302, ARNAX, and / or MPLA.

[0192] In some embodiments, the TLR agonist activates TLR4, and optionally, the TLR agonist comprises LPS, lipoteichoic acid beta-defensin-2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, and / or GLA-SE.

[0193] In some embodiments, the TLR agonist activates TLR5, and optionally, the TLR agonist comprises flagellin, CBLB502, and / or M-VM3.

[0194] In some embodiments, the TLR agonist activates TLR6.

[0195] In some embodiments, the TLR agonist activates TLR7 or TLR8, and optionally, the TLR agonist comprises ssRNA, CpG-A, polyG10, and / or polyG3.

[0196] In some embodiments, the TLR agonist activates TLR7, and optionally, the TLR agonist comprises bistriazolyl and / or R848.

[0197] In some embodiments, the TLR agonist activates TLR8, and optionally, the TLR agonist comprises VTX1463 and / or R848.

[0198] In some embodiments, the TLR agonist activates TLR9, and optionally, the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and / or ODN M362.

[0199] In some embodiments, the TLR agonist activates TLR10, and optionally, the TLR agonist comprises Pam3CSK4.

[0200] In some embodiments, the TLR agonist activates TLR11, and optionally, the TLR agonist comprises Toxoplasma gondiiprofilin.

[0201] In some embodiments, the TLR agonist activates TLR12.

[0202] In some embodiments, the TLR agonist activates TLR13, and optionally, the TLR agonist comprises VSV.

[0203] In some embodiments, the TLR agonist activates a TLR on a macrophage.

[0204] In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and / or TLR9.

[0205] In some embodiments, the TLR comprises TLR1, TLR4, and / or TLR9. In some embodiments, the TLR comprises TLR9.

[0206] In some embodiments, the TLRs include TLR2, TLR4, TLR7, and / or TLR8.

[0207] In some embodiments, the TLR agonist comprises CpG. In some embodiments, the TLR agonist comprises PolyIC. In some embodiments, the TLR agonist comprises CpG and / or PolyIC. In some embodiments, the TLR agonist comprises CpG, PolyIC, and / or R848. In some embodiments, the TLR agonist comprises CpG, PolyIC, and R848, for example, in a 1:1:1 ratio.

[0208] In some embodiments, the methods described herein further comprise assessing whether the individual is persistently infected. In some embodiments, if the individual is persistently infected, the dosage of the TLR agonist is reduced. In some embodiments, if the individual is persistently infected, administration of the TLR agonist is avoided.

[0209] Radiation therapy In some embodiments, the pro-inflammatory agent includes or is radiation therapy. Radiation activates an interconnected network of cytokines, adhesion molecules, ROS / RNS, and DAMPs, triggering a self-amplifying cascade that creates a pro-inflammatory, pro-oxidant tumor microenvironment and ultimately kills tumor cells. See, e.g., McKelvey et al., Mamm Genome. 2018;29(11):843-865.

[0210] In some embodiments, radiation therapy involves irradiating the site of the cancer being treated.

[0211] In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated.

[0212] In some embodiments, the radiation therapy is intraoperative radiation therapy ("IORT"). In certain embodiments, radiation is administered locally to the tumor site. The patient may receive intraoperative radiation therapy before or after tumor resection. The tumor site may contain various types of cells, including cancerous and benign cells. In certain embodiments, the radiation therapy is stereotactic body radiation therapy ("SBRT") or stereotactic radiosurgery ("SRS").

[0213] In some embodiments, the radiation is ionizing radiation, such as particle radiation. The particle radiation can be selected from electrons, protons, neutrons, heavy ions such as carbon ions, or ions. The ionizing radiation can be selected from X-rays, UV light, gamma rays, or microwaves. In some embodiments, radiation therapy can include treating the patient with one or more types of radiation therapy.

[0214] In some embodiments, radiosensitizers are used to increase the radiosensitivity of tumor cells. The use of such pharmaceuticals, called radiosensitizers, provides a method for increasing the radiosensitivity of tumors to radiation therapy, avoiding the need to increase the radiation dose to levels harmful to surrounding organs and tissues. See, e.g., US9656098B2.

[0215] In some embodiments, the radiation therapy dose is insufficient to eliminate the tumor (kill all tumor cells) without causing epidermal necrosis, hi some embodiments, the radiation therapy is selected from the group consisting of external beam radiation therapy, internal radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectants.

[0216] In some embodiments, the radiation therapy is external beam radiation therapy, optionally including three-dimensional conformal radiation therapy (3D-RT), intensity-modulated radiation therapy (IMRT), photon beam therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT).

[0217] In some embodiments, radiation therapy comprises administering a radiopharmaceutical. The radiopharmaceutical may be delivered via any vehicle, such as a cell, protein, or small molecule complex. In some embodiments, the radiopharmaceutical is administered to tumor tissue. For example, see Sgouros et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19, 589-608 (2020).

[0218] In some embodiments, the radiation therapy is brachytherapy, optionally including interstitial brachytherapy, intracavitary brachytherapy, intraluminal radiation therapy, and intravenously administered radiolabeled molecules.

[0219] STING activator In some embodiments, the pro-inflammatory agent comprises or is a STING activator.

[0220] Stimulator of IFN genes (STING, also known as TMEM173, MITA, MPYS, or ERIS) is a pattern recognition receptor (PRR) that recognizes cytoplasmic DNA in the form of cyclic dinucleotides (CDNs), such as the bacterial product cyclic guanosine monophosphate-adenosine monophosphate (3'3'cGAMP). Other DNA that enters the cytoplasm, including bacterial components as well as viruses and host cells, is recognized by the enzyme c-GMP-AMP (cGAMP) synthase (cGAS). Upon binding to cytoplasmic DNA, cGAS converts ATP and GTP to the metazoan-specific CDN 2'3'-cGAMP, triggering STING recognition and activation. STING is a transmembrane protein that exists as a dimer anchored within the endoplasmic reticulum membrane, forming a V-shaped pocket that allows cytoplasmic CDN binding. Ligand binding induces a conformational change in the C-terminal domain of STING, which mediates its transport to the Golgi compartment. In the Golgi, STING recruits Tank-binding kinase 1 (TBK1), which promotes IRF3 phosphorylation, nuclear translocation, and potent induction of type I IFN (e.g., IFN-β) transcription. STING also triggers potent proinflammatory cytokine responses [e.g., tumor necrosis factor (TNF)] by activating nuclear factor kappa B (NF-κB), and part of this pathway is independent of TBK1 and can be mediated through the closely related homolog protein, IKK epsilon. See, e.g., Peng et al., Front Immunol. 2022 Feb 25;13:794776; Amougezar et al., Cancers (Basel). 2021 May 30;13(11):2695.

[0221] In some embodiments, the STING activator is cyclic guanosine monophosphate-adenosine monophosphate (cGAMP, e.g., 3'3'cGAMP, e.g., 2'3'cGAMP).

[0222] In some embodiments, the STING activator is a bacterial vector (e.g., SYNB1891, STACT-TREX-1).

[0223] In some embodiments, the STING activator is a CDN compound (e.g., ADU-S100, BI-STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3'3'-cyclic AIMP).

[0224] In some embodiments, the STING activator is a non-CDN small molecule (e.g., ALG-031048, E7755, JNJ-'6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI-10001).

[0225] In some embodiments, the STING activator is a nanovaccine (e.g., PC7A NP, cCAMP-NP, ONM-500).

[0226] In some embodiments, the STING activator is an antibody-drug conjugate (e.g., XMT-2056, CRD-5500).

[0227] Other exemplary STING activators include those described in Amougezar et al., Cancers (Basel). 2021 May 30;13(11):2695, which is incorporated herein by reference in its entirety.

[0228] PAMP / DAMP activator In some embodiments, the pro-inflammatory agent comprises or is a PAMP / DAMP activator.

[0229] Organisms sense microbial infections through genome-encoded innate immune receptors called pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), nucleotide-binding and oligomerization domain-like receptors (NOD-like receptors), and retinoic acid-inducible gene I (RIG-I)-like receptors. These receptors recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, fungi, and viruses, but also bind damage-associated molecular patterns (DAMPs), molecules released upon sterile injury. Thus, PAMPs and DAMPs that bind to the same receptor initiate the same intracellular pathways and culminate in the same effector functions. See, for example, Alisi et al., Hepatology. 2011 Nov;54(5):1500-2.

[0230] In some embodiments, the pro-inflammatory agent is a PAMP activator. Examples of PAMP activators include triacyl lipopeptides, LPS, lipoproteins, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porin, lipoarabinomannan, double-stranded RNA, poly(I:C), trepanosome lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial / viral DNA, CpG DNA, urea bacteria, and Toxoplasma LPS.

[0231] In some embodiments, the pro-inflammatory agent is a DAMP activator, examples of which include defensins, HSP60, HSP70, messenger RNA, small molecular weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, and unmethylated CpG DNA.

[0232] chemotherapy drugs In some embodiments, the pro-inflammatory agent comprises or is a chemotherapeutic agent.

[0233] In some embodiments, the chemotherapeutic agent is an alkylating agent. Examples of alkylating agents include nitrogen mustards (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkylsulfonates (e.g., busulfan), and ethylenimines (e.g., thiotepa).

[0234] In some embodiments, the chemotherapeutic agent is an antimetabolite. Examples of antimetabolites include cytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), and pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (a prodrug of 5-FU)).

[0235] In some embodiments, the chemotherapeutic agent is an anti-microtubule agent. Examples of anti-microtubule agents include topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin).

[0236] Other exemplary chemotherapeutic agents include hydroxyurea, tretinoin, arsenic trioxide, and proteasome inhibitors (eg, bortezomib).

[0237] Proinflammatory cytokines In some embodiments, the pro-inflammatory agent is a pro-inflammatory cytokine.

[0238] In some embodiments, the proinflammatory cytokine promotes M1 macrophages. See, e.g., Duque et al., Front Immunol. 2014;5:491. In some embodiments, the proinflammatory cytokine includes or is TNF, IFNγ, and / or GM-CSF.

[0239] In some embodiments, the proinflammatory cytokines include IL-6, TNFα, cytokines from the IL-1 family (e.g., IL-1α, IL-1β, IL-18, IL-33, and IL-36), and / or IFNγ.

[0240] In some embodiments, the proinflammatory cytokine comprises a cytokine from the IL-1 family. In some embodiments, the proinflammatory cytokine comprises any one or more of IL-1α, IL-1β, IL-18, IL-33, and IL-36. See, e.g., Sims, J., Smith, D. The IL-1 family: regulators of immunity. Nat Rev Immunol 10, 89-102 (2010).

[0241] Immune checkpoint inhibitors In some embodiments, the pro-inflammatory agent is a checkpoint inhibitor. Immune checkpoints are pathways with inhibitory or stimulatory characteristics that maintain self-tolerance and support immune responses. Most well-known immune checkpoints are inhibitory in nature, and examples include cytotoxic T-lymphocyte-associated molecule 4 (CTLA-4), programmed death receptor 1 (PD-1), and programmed death ligand 1 (PD-L1). See, e.g., Marin-Acevedo et al., J Hematol Oncol 14, 45 (2021).

[0242] In some embodiments, the checkpoint inhibitor targets CTLA-4, PD-1, or PD-L1 (e.g., an antibody that targets CTLA-4, PD-1, or PD-L1).

[0243] In some embodiments, the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG / PVRL2, CEACAM1, CEACAM5 / 6, FAK, CCL2 / CCR2, LIF, CD47 / SIRPα, CSF-1 (M-CSF) / CSF-1R, IL-1 / IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVA-1, Axl, or phosphatidylserine.

[0244] In some embodiments, the checkpoint inhibitor is ipilimumab, cemiplimab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftiragimod alfa (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, monalizumab, COM701, CM24, NEO-201, defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI- 662, RRx-001, lanotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), pexidartinib (PLX3397), CAN04, canakinumab (ACZ885), BMS-986253, pepinemab (VX15 / 2503), trebananib, FP-1305, enapotamab vedotin (EnaV), or bavituximab.

[0245] Cancer vaccines In some embodiments, the pro-inflammatory agent includes or is a cancer vaccine. Cancer vaccines stimulate anti-tumor immunity using tumor antigens that can be delivered in the form of whole cells, peptides, nucleic acids, etc. An ideal cancer vaccine would overcome immunosuppression in tumors and induce both humoral and cellular immunity.

[0246] In some embodiments, the cancer vaccine comprises a cell-based vaccine, a peptide-based vaccine, a virus-based vaccine, and / or a nucleic acid-based vaccine. See, e.g., Liu et al., J Hematol Oncol 15, 28 (2022).

[0247] Cell-based vaccines are an early form of cancer vaccine. They are often prepared from whole cells or cell fragments and almost always contain tumor antigens, inducing a broader antigen-specific immune response. DC vaccines are an important branch of cell-based vaccines. DC-based personalized neoantigen cancer vaccines have shown promising antitumor efficacy in clinical trials. Viruses are inherently immunogenic, and their genetic material can be engineered to contain sequences encoding tumor antigens. Some recombinant viruses, such as adenoviruses, can infect immune cells as vectors. Engineered viral vaccines can present large amounts of tumor antigens to the immune system and generate antitumor immunity. In addition, oncolytic viruses can also be used as vectors. In addition to delivering tumor antigens, viruses themselves can lyse tumors, releasing tumor antigens, further enhancing vaccine efficacy and generating long-term immune memory.

[0248] Peptide-based subunit vaccines, which contain chemical and biosynthetic formulations of predicted or known tumor-specific antigens, induce potent immune responses against specific tumor antigen sites. Peptide-based subunit vaccines combined with adjuvants can efficiently induce humoral immune responses suitable for the prevention and treatment of viral infectious diseases.

[0249] HBV and HPV vaccines for liver cancer and cervical cancer have mainly been peptide-based subunit vaccines. In particular, virus-like particle (VLP)-based subunit vaccines, which can activate cellular immune responses, have shown good antitumor activity in recent years.

[0250] Nucleic acid vaccines are a desirable cancer vaccine platform because they induce strong MHC I-mediated CD8+ T cell responses. They can simultaneously deliver multiple antigens to induce humoral and cellular immunity. Furthermore, nucleic acid vaccines can encode full-length tumor antigens, allowing APCs to cross-present various epitopes or present several antigens simultaneously. Finally, nucleic acid vaccine preparation is simple and rapid, making them suitable for the development of personalized neoantigen cancer vaccines.

[0251] Oncolytic viruses In some embodiments, the pro-inflammatory agent is an oncolytic virus (OV). Oncolytic viruses (OV) are microorganisms that can identify, infect, and lyse various cells present in the tumor environment, aiming to inhibit and stabilize tumor progression. They may exhibit natural tropism for cancer cells or may be genetically engineered to identify specific targets. See, for example, Apolonio et al., World J Virol. 2021 Sep 25;10(5): 229-255.

[0252] Oncolytic viruses represent an exciting new field in cancer therapy. Such viruses have the remarkable ability to track and destroy cancer cells without harming normal cells, and they also enhance the immune system's ability to recognize and destroy cancer cells. See, e.g., Cancer Cell. 2022 Aug 15;S1535-6108(22)00357-9.

[0253] In some embodiments, the oncolytic virus comprises or is an adenovirus (e.g., ONYX-15, LOAd703 virus), a protoparvovirus, a parvovirus (e.g., H-1PV), a vaccinia virus (VACV), a reovirus (e.g., leolysin), or a herpes simplex virus (HSV, e.g., HSV-1, HSV-2, G207, L1BR1, HF10, T-VEC, Orien X010).

[0254] Other exemplary oncolytic viruses include JX-593, Coxsackievirus A21 (CVA21), Maraba virus or its MG1 variant, DNX2440 adenovirus, fowlpox virus, and Sendai virus.

[0255] cell In some embodiments, the pro-inflammatory agent comprises a cell that causes an inflammatory factor. In some embodiments, the cell is a tumor-infiltrating lymphocyte. In some embodiments, the cell specifically recognizes a tumor antigen (e.g., is engineered to express a CAR that recognizes a tumor antigen). In some embodiments, the cell is a T cell. In some embodiments, the cell is a CAR-T cell. In some embodiments, the cell is an NK cell (e.g., a CAR-NK cell). In some embodiments, the cell is a neutrophil (e.g., a CAR-expressing neutrophil cell). In some embodiments, the cell is a TCR-T cell. In some embodiments, the cell is an APC (e.g., a macrophage or dendritic cell). In some embodiments, the cell is a CAR macrophage or CAR monocyte. In some embodiments, the cell is a SIRPant macrophage. In some embodiments, the cell is a stem cell. In some embodiments, the cell is an allogeneic cell. In some embodiments, the cell is an autologous cell.

[0256] immune cells, monocytes, or macrophages The immune cells described herein encompass various types of immune cells.

[0257] In some embodiments, the immune cells comprise monocytes or macrophages as described herein. In some embodiments, the macrophages are identified by expression of F4 / 80. In some embodiments, the macrophages exhibit an M1 phenotype. In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% of the macrophages of the immune cells exhibit an M1 phenotype.

[0258] In some embodiments, macrophages are engineered to be defective in the expression and / or activation of tyrosine kinase inhibitors. In some embodiments, the monocytes or macrophages express reduced levels of tyrosine kinase inhibitors or are resistant to activation for at least a period of time (e.g., at least 1, 2, 3, 4, or 5 days). In some embodiments, the period of time is less than about 10, 9, 8, 7, 6, 5, 4, or 3 days.

[0259] In some embodiments, the monocytes or macrophages remain in a state of reduced tyrosine kinase activation for up to about 5 consecutive days (e.g., 5, 4, or 3 days) until tyrosine kinase activation levels return to normal.

[0260] Methods for manipulating monocytes or macrophages to temporarily reduce the expression level of tyrosine kinase are well known in the art. Exemplary methods include contacting monocytes or macrophages with the tyrosine kinase inhibitors described herein (small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein preparations (e.g., antibody preparations targeting tyrosine kinase or activated tyrosine kinase)) in vivo or in vitro.

[0261] In some embodiments, the immune cells comprise T cells (e.g., CAR-T cells).

[0262] In some embodiments, the immune cells comprise NK cells (e.g., CAR-NK cells).

[0263] In some embodiments, the immune cells comprise neutrophils (e.g., CAR-expressing neutrophil cells).

[0264] In some embodiments, the immune cells comprise antigen-presenting cells (APCs, eg, dendritic cells).

[0265] In some embodiments, the immune cells are derived from the same individual (i.e., autologous). In some embodiments, the immune cells are allogeneic.

[0266] In some embodiments, immune cells are engineered to express a chimeric antigen receptor, optionally, the chimeric antigen receptor specifically binds to a tumor antigen.

[0267] In some embodiments, immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86. In some embodiments, immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86 when the expression levels of MHC-I, MHC-II, CD80, and / or CD86 on the immune cells are comparable (e.g., at least 50% greater) than the expression levels on activated antigen-presenting cells (APCs).

[0268] In some embodiments, the immune cells express one or more pro-inflammatory cytokines, optionally, the one or more pro-inflammatory cytokines include TNFα and / or IL-12.

[0269] In some embodiments, the immune cells do not express significant levels of TGFβ and / or IL-10.

[0270] In some embodiments, the tyrosine kinase inhibitor and the immune cells are administered within about 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, 1 hour, or 0.5 hours) of one another, and optionally, the tyrosine kinase inhibitor and the immune cells are administered within about 4 hours of one another.

[0271] In some embodiments, the tyrosine kinase inhibitor, immune cells, and pro-inflammatory agent are administered within about 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, 1 hour, or 0.5 hours) of one another. In some embodiments, the immune cells are administered simultaneously or concurrently with the tyrosine kinase inhibitor and / or pro-inflammatory agent.

[0272] Inflammatory response or persistent infection There is mounting evidence that both acute and chronic inflammation are involved in the development and progression of cancer. As research on inflammation advances, the association between inflammatory processes and the development of neoplastic transformation, tumor progression, metastasis, and recurrence has become clear. Furthermore, invasive procedures (both surgery and biopsy) affect residual tumor cells by increasing their survival, proliferation, and migration. One concept explaining this phenomenon is the induction of a wound healing response. While the induction of adaptive and innate immune responses associated with wound healing is necessary for tissue repair in normal tissues, in tumor tissues, it promotes tumor cell survival, angiogenesis, and extravasation of circulating tumor cells. See, for example, Singh et al., Ann Afr Med. 2019 Jul-Sep;18(3):121-126; Piotrowski et al., Rep Pract Oncol Radiother. 2020 May-Jun;25(3):422-427.

[0273] However, as demonstrated in the present application, the combination of a tyrosine kinase inhibitor with an inflammatory agent triggers a proinflammatory response, converting the immunosuppressive tumor environment into one with an inflammatory signature. See, e.g., Figure 7F. A significant antitumor effect was achieved. These results support the use of the methods described herein to treat individuals experiencing an inflammatory response.

[0274] In some embodiments, the individual is exhibiting an inflammatory response or has a persistent infection when treated with the methods described herein. The inflammatory response described herein can be understood by, for example, a) an increase in one or more (e.g., at least 1, 2, 3, 4, or 5) pro-inflammatory cytokines (e.g., IFNγ, IL-12b, TNFα, IL-6, IL-1b, IFN-α1, IFN-α2, IFN-β, etc.); b) a decrease in one or more (e.g., at least 1, 2, or 3) pro-anti-inflammatory cytokines (e.g., TGFβ1, TGFβ2, TGFβ3, etc.); c) an increase in infiltrating immune cells (e.g., T cells, NK cells, macrophages, neutrophils, etc.); d) a decrease in inhibitory immune cells (e.g., MDSCs), and / or e) an increase in one or more (e.g., at least 1, 2, 3, 4, or 5) immunogenic costimulatory molecules (e.g., CD80, CD86, OX40L, CD40, ICOS-L, PD-L1, GITRL, etc.) in tissue (e.g., tumor tissue) or immune cells (e.g., macrophages).

[0275] In some embodiments, the inflammatory response is an acute inflammatory response.

[0276] In some embodiments, the inflammatory response occurs within a tumor. In some embodiments, the inflammatory response occurs at a site separate from the tumor.

[0277] In some embodiments, the presence of an inflammatory response refers to a) an increase in one or more (e.g., at least 1, 2, 3, 4, 5) pro-inflammatory cytokines (e.g., IFNγ, IL-12b, TNFα, IL-6, IL-1b, IFN-a1, IFN-a2, IFN-b1, etc.), b) a decrease in one or more (e.g., at least 1, 2, or 3) anti-inflammatory cytokines (e.g., TGFb1, TGFb2, TGFb3, etc.), c) an increase in infiltrating immune cells (e.g., T cells, NK cells, macrophages, etc.), d) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), e) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), f) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), g) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), h) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), i) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), i) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), ii) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), iii) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), iv) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), iv) an increase in the expression of immune cells (e.g a) an increase in immune cells (e.g., phages, neutrophils, etc.), b) a decrease in inhibitory immune cells (e.g., MDSCs), and / or c) an increase in one or more (e.g., at least 1, 2, 3, 4, or 5) immunogenic costimulatory molecules (e.g., CD80, CD86, OX40L, CD40, ICOS-L, PD-L1, GITRL, etc.) in tissue (e.g., tumor tissue) or immune cells (e.g., macrophages).

[0278] In some embodiments, an increase as described herein refers to an increase in the amount of at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or 200% or more compared to a baseline state, optionally where the baseline state is a state in which the individual is not treated with a method described herein and is not infected with a pathogen. In some embodiments, an increase as described herein refers to an increase in the amount of at least about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 500-fold, or 1000-fold or more compared to a baseline state, optionally where the baseline state is a state in which the individual is not treated with a method described herein and is not infected with a pathogen. In some embodiments, the baseline state is a state in which a healthy individual is not infected with a pathogen.

[0279] In some embodiments, a reduction as described herein refers to a reduction of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 99.9% or less compared to a baseline state, optionally a state in which the individual is not treated with a method described herein and is not infected with a pathogen. In some embodiments, the baseline state is a state in which a healthy individual is not infected with a pathogen.

[0280] In some embodiments, the individual exhibits an inflammatory response (e.g., within a tumor, e.g., at a site different from the tumor) about 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before and / or after administration of the tyrosine kinase inhibitor.

[0281] In some embodiments, the individual has an ongoing inflammatory response (eg, within a tumor, eg, at a site different from the tumor) at the time the tyrosine kinase inhibitor is administered.

[0282] In some embodiments, the individual has an ongoing infection at the time the tyrosine kinase inhibitor is administered, hi some embodiments, the method further comprises assessing the presence or absence of an infection in the individual, e.g., an infection associated with a virus, a fungus, and / or a bacteria.

[0283] immunogenic cell death In some embodiments, immunogenic cell death occurs in individuals when treated with the methods described herein.

[0284] Immunogenic cell death (ICD) is a type of cancer cell death induced by various stressors, including, but not limited to, (1) intracellular pathogens, (2) conventional chemotherapy such as anthracyclines, DNA-damaging agents, and proteasome inhibitors, (3) targeted anticancer drugs such as the tyrosine kinase inhibitor crizotinib, the epidermal growth factor receptor-specific monoclonal antibody cetuximab, and poly (ADP-ribose) polymerase (PARP) inhibitors, and (4) various physical modalities, including photodynamic therapy with hypericin and redaporfin, extracorporeal photochemotherapy, various forms of ionizing radiation, high hydrostatic pressure, and severe heat shock. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD involves the release of damage-associated molecular patterns (DAMPs) from dying tumor cells, which leads to the activation of tumor-specific immune responses, thus combining direct cancer cell killing with antitumor immunity to enhance the long-term efficacy of anticancer drugs. DAMPs include cell surface exposure of calreticulin (CRT) and heat shock proteins (HSP70 and HSP90), extracellular release of adenosine triphosphate (ATP), high-mobility group box-1 (HMGB1), and members of the type I IFN and IL-1 cytokine families. See, e.g., Ahmed et al., Mol Oncol. 2020 Dec;14(12):2994-3006 and Fucikova et al., Cell Death Dis. 2020 Nov 26;11(11):1013.

[0285] Major DAMPs related to cell death recognized as immunogenic include calreticulin, high mobility group box 1 (HMGB1), ATP, annexin A1 (ANXA1), and type I IFN. The main characteristics of immunogenic cell death (ICD) can be assessed by a variety of different approaches, such as flow cytometry, (immuno)fluorescence microscopy, immunoblotting, or luminometry. See, for example, Cell Death Dis. 2020 Nov 26;11(11):1013.

[0286] In some embodiments, the individual exhibits ICD (e.g., within a tumor, e.g., at a site different from the tumor) about 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before and / or after administration of the tyrosine kinase inhibitor.

[0287] In some embodiments, the individual has persistent ICD (eg, intratumoral, eg, at a site different from the tumor) at the time the tyrosine kinase inhibitor is administered.

[0288] In some embodiments, an individual is determined to be experiencing ICD if a sample from the cancer contains a higher level (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) of one or more DAMPs than a reference sample (e.g., a corresponding sample from a healthy control, e.g., a sample from the cancer before administration of an ICD-inducing therapy). In some embodiments, the DAMPs are selected from the group consisting of endoplasmic reticulum (ER) chaperones (e.g., calreticulin (CALR), e.g., heat shock proteins (HSPs)), the non-histone chromatin-binding protein high mobility group box 1 (HMGB1), the cytoplasmic protein annexin A1 (ANXA1), and the small molecule metabolites ATP and type I interferon (IFN).

[0289] individual In some embodiments, the individual has a solid tumor, hi some embodiments, the individual has a hematological cancer.

[0290] In some embodiments, the individual has advanced cancer. In some embodiments, the individual has terminal cancer. In some embodiments, the individual has malignant cancer. In some embodiments, the individual has stage II, III, or IV cancer. In some embodiments, the individual has inoperable tumors and / or metastases. In some embodiments, the individual is in a terminal condition.

[0291] In some embodiments, the individual has previously received a therapy (e.g., radiation therapy) that induces an inflammatory response or immunogenic cell death (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., 1, 2, 3, 4, 5, 6, or 7 days, before administration of the tyrosine kinase inhibitor). In some embodiments, the individual will soon receive a therapy (e.g., radiation therapy) that induces an inflammatory response or immunogenic cell death (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., 1, 2, 3, 4, 5, 6, or 7 days after administration of the tyrosine kinase inhibitor).

[0292] In some embodiments, the individual has previously received an inflammatory agent (e.g., any of the inflammatory agents described herein) (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., 1, 2, 3, 4, 5, 6, or 7 days, before administration of the tyrosine kinase inhibitor). In some embodiments, the individual will soon receive an inflammatory agent (such as any of the inflammatory agents described herein) (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., 1, 2, 3, 4, 5, 6, or 7 days after administration of the tyrosine kinase inhibitor).

[0293] In some embodiments, the individual does not have an autoimmune disease.

[0294] In some embodiments, the individual is female. In some embodiments, the individual is male.

[0295] In some embodiments, the individual is a human. In some embodiments, the individual is at least about 50, 55, 60, 65, 70, or 75 years of age.

[0296] In some embodiments, an individual is selected for treatment based on a high expression level and / or high activation level of a tyrosine kinase in tumor tissue. In some embodiments, an individual has a high expression level and / or high activation level of a tyrosine kinase if the expression level and / or activation level is at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or 200% higher than the baseline expression level and / or baseline activation level of the tyrosine kinase. In some embodiments, an individual has a high expression level and / or activation level of a tyrosine kinase if the expression level and / or activation level is at least about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 500-fold, or 1000-fold higher than the baseline expression level and / or baseline activation level of the tyrosine kinase. In some embodiments, the baseline expression level or baseline activation level of the tyrosine kinase is the corresponding expression level or activation level of the tyrosine kinase in a baseline state, and the individual is not being treated with a pro-inflammatory agent (or any immunotherapy).

[0297] In some embodiments, the individual is at risk of developing systemic inflammation and / or CRS. In some embodiments, the individual has developed systemic inflammation and / or CRS before administration of an agent that reduces systemic inflammation (e.g., a TNFα inhibitor, e.g., an anti-TNFα antibody). Cytokine release syndrome can damage most organ systems or cause organ failure. For example, organs that may be damaged due to CRS can include, but are not limited to, the lungs, kidneys, liver, brain, heart, spleen, or any combination thereof, e.g., multiple organ failure.

[0298] In some embodiments, the individual is administered an agent that reduces systemic inflammation (e.g., a TNFα inhibitor, an anti-TNFα antibody, etc.). In some embodiments, administration occurs before the individual develops systemic inflammation. In some embodiments, the individual develops mild cytokine release syndrome. In some embodiments, the individual develops Grade 1 CRS. Symptoms of mild CRS may include fever, fatigue, headache, rash, joint pain, and muscle pain. Mild CRS may be treated by treating the symptoms or by administering anti-inflammatory medications such as corticosteroids. Mild CRS often resolves within 1-2 weeks and does not require or call for hospitalization.

[0299] In some embodiments, the individual does not develop severe cytokine release syndrome. In some embodiments, the individual does not develop Grade 2 CRS. In some embodiments, the individual does not develop Grade 3 CRS. In some embodiments, the individual does not develop Grade 4 CRS. More severe cases are characterized by hypotension and hyperthermia, and severe CRS can progress to circulatory shock requiring vasoconstrictors, vascular leakage, disseminated intravascular coagulation, and an uncontrolled systemic inflammatory response with multiple organ failure. More severe cases of CRS often require hospitalization for symptoms. Common laboratory abnormalities in CRS patients include cytopenias, elevated creatinine and liver enzyme levels, abnormal coagulation parameters, and elevated CRP levels. The GRADE system, which considers four factors, is currently used for cytokine release syndrome, as shown in Table 1 below. See, e.g., Liu, D. and Zhao, J., J Hematol Oncol. 2018 Sep 24;11(1):121; and Shimabukuro-Vornhagen, A. et al., J Immunother Cancer. 2018 Jun 15;6(1):56, which are incorporated by reference in their entireties.

[0300] In some embodiments, the individual develops CRS prior to administration of an agent that reduces systemic inflammation (e.g., a TNFα inhibitor, an anti-TNFα antibody, etc.). In some embodiments, the individual develops grade 1 CRS. In some embodiments, the individual develops grade 2 CRS. In some embodiments, the individual develops grade 3 CRS. In some embodiments, the individual develops grade 4 CRS. In some embodiments, an agent that reduces systemic inflammation (e.g., a TNFα inhibitor, an anti-TNFα antibody, etc.) is administered to the individual who has developed CRS. In some embodiments, the agent that reduces systemic inflammation (e.g., a TNFα inhibitor, an anti-TNFα antibody, etc.) ameliorates, eliminates, or reverses CRS, including organ damage, e.g., inflammation-induced organ damage (e.g., nephritis, hepatitis, pneumonia, myocarditis, appendicitis). [Table 1-1] [Table 1-2]

[0301] In some embodiments, the individual does not develop a cytokine storm. In some embodiments, the individual develops a mild cytokine storm. In some embodiments, the individual does not develop a severe or life-threatening cytokine storm. While cytokine storm appears to be primarily the result of non-specific T cell activation, CRS is more often the direct result of antigen-specific T cell activation. The clinical symptoms of cytokine storm and CRS can be similar (Liu, D. and Zhao, J., J Hematol Oncol. 2018 Sep 24;11(1):121).

[0302] cancer The cancers described herein can be of any type or variety. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer.

[0303] In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a terminal cancer. In some embodiments, the cancer is a terminal cancer. In some embodiments, the cancer is in stage II, III, or IV. In some embodiments, the cancer is an inoperable tumor and / or malignant.

[0304] In some embodiments, the tumor is at least 0.2 cm, 0.4 cm, 0.6 cm, 0.8 cm, 1 cm, 2 cm, 3 cm, 4 cm, or 5 cm in length.

[0305] Examples of cancers described herein include adrenocortical carcinoma, agnogenic myeloid metaplasia, metaplasia), AIDS-related cancer (e.g., AIDS-related lymphoma), anal cancer, appendiceal cancer, astrocytoma (e.g., cerebellar and cerebral), basal cell carcinoma, bile duct cancer (e.g., extrahepatic), bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain tumors (e.g., glioma, brain stem glioma, cerebellar or cerebral astrocytoma (e.g., pilocytic astrocytoma, diffuse astrocytoma, anaplastic (malignant) astrocytoma), malignant glioma, ependymoma, oligodendroglioma, meningioma, craniopharyngioma, hemangioblastoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, hypothalamic optic pathway glioma, and glioblastoma), breast cancer, bronchial adenoma / carcinoid, carcinoid tumor (e.g., gastrointestinal carcinoid tumor), cancer of unknown primaryprimary), central nervous system lymphoma, cervical cancer, colon cancer, colorectal cancer, chronic myeloproliferative disorders, uterine cancer (e.g., uterine cancer), ependymoma, esophageal cancer, Ewing's family of tumors, eye cancer (e.g., intraocular melanoma and retinoblastoma), gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor (e.g., extracranial, extragonadal, ovarian), gestational trophoblastic tumor, Head and neck cancer, hepatocellular (liver) cancer (e.g., hepatocarcinoma and heptoma), hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), laryngeal cancer, larynx cancer, leukemia, lip and oral cavity cancer, oral cancer, liver cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), lymphoid neoplasms (e.g., lymphoma), medulloblastoma, melanoma, mesothelioma, metastatic squamous cell neck cancer, oral cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndrome, myelodysplastic / Myeloproliferative disorders, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, oropharyngeal cancer, ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, parathyroid cancer, penile cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, pleuropulmonary blastoma, lymphoma, primary central nervous system lymphoma (microglioma), pulmonary lymphangioleiomyomatosis, rectal cancer, kidney cancer, renal pelvis and ureter cancer (transitional cell carcinoma), striated muscle These include, but are not limited to, sarcoma, salivary gland cancer, skin cancer (e.g., non-melanoma (e.g., squamous cell carcinoma), melanoma, and Merkel cell carcinoma), small intestine cancer, squamous cell carcinoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, urethral cancer, vaginal cancer, vulvar cancer, Wilms' tumor, and post-transplant lymphoproliferative disorder (PTLD), abnormal blood vessel growth associated with nevus syndrome, edema (e.g., edema associated with brain tumors), and Meigs' syndrome.

[0306] In some embodiments, the cancer is a viral infection-associated cancer. In some embodiments, the cancer is a human papillomavirus (HPV)-associated cancer (e.g., HPV-associated cervical cancer, e.g., HPV-associated head and neck cancer, e.g., HPV-associated squamous cell carcinoma). In some embodiments, the cancer is a human herpesvirus 8 (HHV8)-associated cancer (e.g., Kaposi's sarcoma). In some embodiments, the cancer is a human T-lymphotropic virus (HTLV-1)-associated cancer (e.g., adult T-cell leukemia or lymphoma). In some embodiments, the cancer is an Epstein-Barr virus (EBV)-associated cancer (e.g., Burkitt's lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, gastric cancer). In some embodiments, the cancer is a hepatitis B virus (HBV)-associated cancer (e.g., liver cancer). In some embodiments, the cancer is a hepatitis C virus-associated cancer (e.g., liver cancer, non-Hodgkin's lymphoma).

[0307] In some embodiments, the cancer is liver cancer, kidney cancer, endometrial cancer, thymic epithelial neoplasm, lung cancer, spindle cell sarcoma, chondrosarcoma, uterine smooth muscle, colon cancer, or pancreatic cancer.

[0308] In some embodiments, the cancer has previously undergone and / or failed one or more therapies, such as immune checkpoint blockade therapy (e.g., PD-1 antibodies), chemotherapy, surgery, or cell therapy (e.g., allogeneic NK cell infusion therapy).

[0309] In some embodiments, the cancer is a recurrent or refractory cancer.

[0310] In some embodiments, the cancer is resistant to one or more of radiation therapy, chemotherapy, or immunotherapy (eg, checkpoint blockade).

[0311] Dosage, Administration Method, and Delivery Vehicle The tyrosine kinase inhibitors, pro-inflammatory agents, and immune cells (e.g., monocytes / macrophages) described herein can be administered at any desired dosage. Exemplary dosing regimens are described, for example, in the "Tyrosine Kinase Inhibitors" section.

[0312] In some embodiments, the dosage of the pro-inflammatory agent, tyrosine kinase inhibitor, and / or immune cells (e.g., monocytes / macrophages) administered is determined based on one or more criteria, such as the disease burden in the subject (e.g., tumor burden, tumor mass, tumor size, or extent, extent, or type of metastasis, stage of disease, and / or the likelihood or frequency of a toxic reaction in the subject, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or a host immune response to the administered activated immune cells. For example, in some embodiments, the number of monocytes or macrophages to be included in the administered dose is determined based on the tumor burden present in the subject immediately prior to the initial administration of cells.

[0313] The pro-inflammatory agent, tyrosine kinase inhibitor, and / or immune cells (e.g., monocytes / macrophages) can be administered by any suitable means, e.g., bolus injection, injection, e.g., intravenous or subcutaneous injection. In some embodiments, the pro-inflammatory agent, tyrosine kinase inhibitor, and / or monocytes or macrophages are administered systemically (e.g., intravenously, subcutaneously, or intraperitoneally). In some embodiments, the pro-inflammatory agent, tyrosine kinase inhibitor, and / or monocytes or macrophages are administered locally (e.g., intratumorally).

[0314] In some embodiments, the pro-inflammatory agent, tyrosine kinase inhibitor, and / or immune cells (e.g., monocytes / macrophages) are administered parenterally, intrapulmonary, intranasally, or, if localized treatment is desired, intralesionally or intratumorally. Parenteral injections include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pro-inflammatory agent and / or the tyrosine kinase inhibitor are administered orally.

[0315] In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered simultaneously. In some embodiments, the monocytes or macrophages and the pro-inflammatory agent are administered in parallel. In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered sequentially. In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered within about 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered within about 24, 16, 12, 8, 4, 2, or 1 hour. In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered within 30 minutes.

[0316] In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered simultaneously. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered concurrently. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered sequentially. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered within about 7, 6, 5, 4, 3, 2, or 1 day of each other. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered within about 24, 16, 12, 8, 4, 2, or 1 hour of each other. In some embodiments, the tyrosine kinase inhibitor and the pro-inflammatory agent are administered within 30 minutes of each other.

[0317] It is also contemplated that the tyrosine kinase inhibitors and / or pro-inflammatory agents described herein can be delivered via any suitable vehicle or method. In some embodiments, the tyrosine kinase inhibitors and / or pro-inflammatory agents are delivered directly to tumor tissue. Various carrier systems may be utilized for this purpose. See, for example, Manzari et al. Targeted drug delivery strategies for precision medicines. Nat Rev Mater 6, 351-370 (2021); Tewabe et al., J Multidiscip Healthc. 2021;14: 1711-1724. In some embodiments, the tyrosine kinase inhibitors and / or pro-inflammatory agents are delivered via nanoparticles. In some embodiments, the tyrosine kinase inhibitors and / or pro-inflammatory agents are delivered via a controlled release system. In some embodiments, the tyrosine kinase inhibitors and / or pro-inflammatory agents are delivered via a biomaterial implant scaffold. In some embodiments, the tyrosine kinase inhibitors and / or pro-inflammatory agents are delivered via an injectable biomaterial scaffold. In some embodiments, the tyrosine kinase inhibitor and / or pro-inflammatory agent is delivered via a transdermal delivery system. See, e.g., Riley et al., Nat Rev Drug Discov. 2019 Mar;18(3): 175-196.

[0318] In some embodiments, the tyrosine kinase inhibitor and / or pro-inflammatory agent is delivered by cells. See, e.g., Millian et al., Ther Deliv. 2012 Jan;3(1):25-41. In some embodiments, the cells comprise macrophages. See, e.g., Visser et al., Front Pharmacol. 2019 Jan 25;10:22. In some embodiments, the cells comprise polymer-encapsulated human retinal pigment epithelial (aRPE) cells. See, e.g., Nash et al., Clin Cancer Res. 2022 Aug 22;CCR-22-1493. In some embodiments, the cells are encapsulated in a biocompatible material (e.g., the biocompatible alginate capsules discussed in Nash et al.).

[0319] In some embodiments, the tyrosine kinase inhibitor and / or pro-inflammatory agent is associated with the antibody construct. In some embodiments, the tyrosine kinase inhibitor and / or pro-inflammatory agent is attached to the antibody construct via a linker (e.g., a cleavable linker). In some embodiments, the antibody construct specifically recognizes a tumor-associated antigen. In some embodiments, the antibody construct comprises an antibody that recognizes a tumor antigen. In some embodiments, the antibody construct is an antibody-drug conjugate (ADC).

[0320] In some embodiments, the tyrosine kinase inhibitor and / or pro-inflammatory agent is delivered via a method or device that facilitates delivery to a specific organ (e.g., a tumor-bearing organ). Examples of these methods or devices include those described in, for example, Alsaggar et al., J Drug Target. 2018 Jun-Jul;26(5-6):385-397; Zhao et al., Cell. 2020 Apr 2;181(1):151-167, which are incorporated by reference in their entireties.

[0321] In embodiments, the tyrosine kinase inhibitor is delivered via a controlled drug delivery system (e.g., a sustained release system or vehicle, e.g., a sustained release system or vehicle). Examples of such systems include those described in, for example, Adepu et al., Molecules. 2021 Oct;26(19): 5905; Oh et al., Chem. Asian J. 2022, 17, e202200333, which are incorporated by reference in their entirety.

[0322] VI. Compositions Comprising Tyrosine Kinase Inhibitors The present application also provides compositions (eg, pharmaceutical compositions) comprising a tyrosine kinase inhibitor, an inflammatory agent, and / or an immune cell for the above treatment.

[0323] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and an inflammatory agent (e.g., any inflammatory agent described herein). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0324] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and a TLR agonist (e.g., CpG, PolyIC, and / or R848). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0325] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising a tyrosine kinase inhibitor and a STING activator (e.g., cGAMP, e.g., 2'3'-cGAMP, e.g., 3'3'-cGAMP). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0326] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and a chemotherapeutic agent (e.g., azathioprine (AZA), e.g., gemcitabine). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0327] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising a tyrosine kinase inhibitor and a proinflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and / or TNFα). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0328] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and a checkpoint inhibitor (e.g., an anti-PD-L1 antibody, an anti-PD-1 antibody, or an anti-CLTA4 antibody). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0329] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and a bacterial component (e.g., LPS). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0330] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and an agent that promotes immunogenic cell death (ICD). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0331] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and an agent used in radiation therapy (e.g., any radiation therapy described herein). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0332] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and a PAMP / DAMP activator (e.g., any PAMP / DAMP activator described herein). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0333] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and a cancer vaccine (e.g., any cancer vaccine described herein). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0334] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and an oncolytic virus (e.g., any oncolytic virus described herein). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0335] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and an agent used in acoustic therapy (e.g., any of the acoustic therapy methods described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0336] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and an agent for use in magnetic therapy (e.g., any of the magnetic therapies described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0337] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and an agent used in an electrical or electrochemical treatment (e.g., any electrical or electrochemical treatment described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof).

[0338] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising a tyrosine kinase inhibitor and an agent used in electrostatic treatment (e.g., any of the electrostatic treatments described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises an SHP-1 inhibitor (e.g., TPI-1). Illustrative Embodiments 1. A method of treating cancer in an individual, comprising administering to said individual: a) a tyrosine kinase inhibitor; and b) an inflammation-inducing agent. 2. The method of embodiment 1, comprising administering said tyrosine kinase inhibitor systemically. 3. The method of embodiment 1 or 2, wherein the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP / DAMP activator, a chemotherapeutic drug, a pro-inflammatory cytokine, a cancer vaccine, a bacterial component, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy. 4. A method of treating cancer in an individual, comprising administering to said individual a tyrosine kinase inhibitor, said individual exhibiting an inflammatory response. 5. The method of any one of embodiments 1-4, comprising administering said tyrosine kinase inhibitor to said individual intermittently. 6. The method of embodiment 5, wherein said method comprises administering said tyrosine kinase inhibitor at least three times. 7. The method of embodiment 5 or embodiment 6, wherein the method comprises administering the tyrosine kinase inhibitor at least twice, not more than once every three days. 8. The method of any one of embodiments 5-7, wherein the method comprises administering to the individual the tyrosine kinase inhibitor in at least two cycles, each cycle lasting from about 3 days to about 20 days. 9. The method of any one of embodiments 1 to 8, wherein the tyrosine kinase inhibitor inhibits SHP-1 signaling. 10. The method of any one of embodiments 1-9, wherein the tyrosine kinase inhibitor has a half-life of about 5 days or less, and optionally, the tyrosine kinase inhibitor has a half-life of about 3 days or less. 11. The method of any one of embodiments 1-10, wherein the tyrosine kinase inhibitor is effective to inhibit greater than 50% of the tyrosine kinase activation within about 5 days, and optionally, the tyrosine kinase inhibitor is effective to inhibit greater than 50% of the tyrosine kinase activation within about 3 days. 12. The method of any one of embodiments 1 to 11, wherein the tyrosine kinase inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein preparations (e.g., antibody preparations targeting tyrosine kinases or activated tyrosine kinases). 13. The method of embodiment 12, wherein the tyrosine kinase inhibitor inhibits any one or more of Src, Syk, Hck, Lck, Lyn, and Yes. 14. The method of embodiment 13, wherein said tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, and R406. 15. The method of any one of embodiments 1 to 14, wherein said tyrosine kinase inhibitor is an inhibitor of the Src family of tyrosine kinases. 16. The method of any one of embodiments 1 to 15, wherein the method comprises systemic and local administration of the tyrosine kinase inhibitor, and optionally, the method comprises intratumoral administration of the tyrosine kinase inhibitor. 17. The method of any one of embodiments 2 to 16, wherein said systemic administration of the tyrosine kinase comprises oral administration, intravenous administration, subcutaneous administration, and / or intraperitoneal administration. 18. The method of any one of embodiments 1-3 and 5-17, wherein one of the pro-inflammatory agent and the tyrosine kinase inhibitor is administered within about 24 hours of the other, and optionally, one of the pro-inflammatory agent and the tyrosine kinase inhibitor is administered within about 4 hours of the other. 19. The method of any one of embodiments 1-3 and 5-18, wherein the method comprises administering the pro-inflammatory agent intratumorally. 20. The method of any one of embodiments 1-3 and 5-19, wherein the method comprises administering an inducing agent to a site different from the site of the cancer being treated. 21. The method of any one of embodiments 1-2 and 5-18, wherein the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy. 22. The method of any one of embodiments 1-3 and 5-21, wherein the pro-inflammatory agent comprises a TLR agonist. 23. The method of embodiment 22, wherein the TLR agonist activates TLRs on macrophages, and optionally, the TLRs include TLR2, TLR3, TLR7, TLR8, and / or TLR9. 24. The method of embodiment 23, wherein the TLR agonist comprises CpG, polyIC, and / or R848. 25. The method of any one of embodiments 1-3 and 5-24, wherein the pro-inflammatory agent comprises a bacterial component, and optionally, the bacterial component comprises lipopolysaccharide (LPS). 26. The method of any one of embodiments 1-3 and 5-25, wherein the pro-inflammatory agent comprises a STING activator. 27. The method of embodiment 26, wherein the STING activator comprises 2'3'-cGAMP. 28. The method of any one of embodiments 1-3 and 5-27, wherein the pro-inflammatory agent comprises a chemotherapeutic agent. 29. The method of embodiment 28, wherein the chemotherapy comprises azathioprine (AZA). 30. The method of any one of embodiments 1-3 and 5-29, wherein the pro-inflammatory agent comprises a pro-inflammatory cytokine. 31. The method of embodiment 30, wherein the proinflammatory cytokines comprise IL-1b, IL-18, IL-6, and / or TNFα. 32. The method of any one of embodiments 1-3 and 5-31, wherein the pro-inflammatory agent comprises radiation therapy. 33. The method of embodiment 32, wherein the radiation therapy comprises irradiating the site of the cancer being treated. 34. The method of embodiment 32 or embodiment 33, wherein the radiation therapy comprises irradiating a site different from the site of the cancer being treated. 35. The method of any one of embodiments 32-34, wherein the dose of radiation therapy is insufficient to kill tumor cells. 36. The method of any one of embodiments 1-3 and 5-35, wherein the pro-inflammatory agent comprises a checkpoint inhibitor. 37. The method of embodiment 36, wherein the checkpoint inhibitor comprises an anti-PD-L1 antibody, an anti-PD-1 antibody, or an anti-CLTA4 antibody. 38. The method of any one of embodiments 1-3 and 5-37, wherein the pro-inflammatory agent is administered intermittently. 39. The method of any one of embodiments 1-3 and 5-38, wherein the pro-inflammatory agent and the tyrosine kinase inhibitor are administered simultaneously or concurrently. 40. The method of any one of embodiments 1-3 and 5-39, wherein the pro-inflammatory agent comprises an immune cell. 41. The method of any one of embodiments 4 to 39, wherein the method further comprises administering immune cells. 42. The method of embodiment 40 or 41, wherein the immune cells are derived from the same individual. 43. The method of any one of embodiments 40 to 42, wherein the immune cells comprise or are macrophages, and optionally, the macrophages have an M1 phenotype. 44. The method of any one of embodiments 40 to 43, wherein the immune cells are derived from monocytes. 45. The method of any one of embodiments 40 to 44, wherein the immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86. 46. ​​The method of any one of embodiments 40 to 45, wherein the immune cells express one or more proinflammatory cytokines, and optionally, the one or more proinflammatory cytokines include TNFα and / or IL-12. 47. The method of any one of embodiments 40 to 46, wherein the immune cells do not express significant levels of TGFβ and / or IL-10. 48. The method of any one of embodiments 40 to 47, wherein the immune cells comprise T cells. 49. The method of any one of embodiments 40 to 48, wherein the immune cells are engineered to express a chimeric antigen receptor, and optionally, the chimeric antigen receptor specifically binds to a tumor antigen. 50. The method of any one of embodiments 43 to 49, wherein the macrophages are engineered to be defective in the expression and / or activation of a tyrosine kinase. 51. The method of any one of embodiments 40-50, wherein one of the tyrosine kinase inhibitor and the immune cells is administered within about 24 hours after the other, and optionally, one of the tyrosine kinase inhibitor and the immune cells is administered within about 4 hours after the other. 52. The method of any one of embodiments 40 to 51, wherein the immune cells are administered simultaneously or in parallel with the tyrosine kinase inhibitor. 53. The method of any one of embodiments 1-52, further comprising administering to said individual an effective amount of an SHP-1 inhibitor. 54. The method of any one of embodiments 1-53, further comprising administering to the individual an effective amount of an anti-TNFα antibody. 55. The method of any one of embodiments 1 to 54, wherein the cancer is a solid tumor. 56. The method of any one of embodiments 1 to 54, wherein the cancer is a blood cancer. 57. The method of any one of embodiments 1-56, wherein the cancer is a terminal cancer. 58. The method of any one of embodiments 1 to 57, wherein the cancer is resistant or refractory to radiation therapy, chemotherapy, and / or checkpoint inhibitors. 59. The method according to any one of the preceding embodiments, wherein the individual is a human. 60. A composition comprising a tyrosine kinase inhibitor and an inflammatory inducer, optionally wherein the inflammatory inducer comprises an agent selected from the group consisting of immune cells, TLR agonists, STING activators, agents used in radiation therapy, PAMP / DAMP activators, checkpoint inhibitors, proinflammatory cytokines, chemotherapeutic agents, bacterial components, cancer vaccines, oncolytic viruses, and agents used in acoustic therapy, magnetic therapy, electrical therapy, or electrostatic therapy. 61. The composition of embodiment 60, further comprising an SHP-1 inhibitor. [Example]

[0339] The following examples are intended to be purely illustrative of the present invention and therefore should not be construed as limiting the present invention in any way. The following examples and detailed description are offered by way of illustration and not by way of limitation. Example 1. RK-20449 and dasatinib are effective in treating tumors in tumor-associated macrophage (TAM) activation models and syngeneic mouse tumor models

[0340] In vitro assays. Experiments tested the effects of RK-20449 and dasatinib on human and mouse macrophages in response to TLR stimulation in the presence of cancer cells.

[0341] Human monocyte-derived macrophages (M) were pretreated with RK-20449 and dastinib for 15 min before adding human SW620 colon cancer cells (at a 2:1 ratio to M) and a mixture of TLR agonists (αTLR:CpG, PolyIC, and R848, each at 20 μg / ml). After 15 min of incubation at 37°C, the cells were gently washed to remove most of the SW620, and the macrophages were then lysed using Hank's buffer (pH 7.2) containing 1% Triton and 1 mM PMSF. Protein tyrosine phosphatase (PTP) activity was measured at 10 mM in Hank's buffer at 37°C.

[0342] As shown in Figure 2B, RK-20449 and dasatinib dose-dependently reduced macrophage SHP-1 activity induced by the ligation of TLR agonists and cancer cells. The presence of cancer cell ligation promotes TLR agonist-induced tyrosine kinase-mediated phosphorylation of iRs within the cytoplasmic ITIM. Figure 2C shows that RK20449 and dasatinib reduced TLR agonist- and cancer ligation-induced iR phosphorylation and binding to SHP-1. We examined the phosphorylation and binding to SHP-1 of two iRs, SIRPα and PirB, in mouse bone marrow-derived macrophages. Figures 2D and 2E further demonstrate that treatment with RK20449 and dasatinib enabled macrophages to overcome tumor cell inhibition and unleash the pro-inflammatory phenotype induced by TLR agonists, significantly increasing the production of pro-inflammatory cytokines TNFα, IL-6, and ad-CXCL1 (Figure 2D) and the expression of cell surface antigen-presenting machinery (Figure 2E). The SHP-1 inhibitor TPI-1, which showed similar effects, was also used in parallel experiments.

[0343] These experiments demonstrate that both RK-20449 and dasatinib are capable of deple...

Claims

1. 1. A method of treating cancer in an individual, comprising administering to the individual: a) a tyrosine kinase inhibitor; and b) an inflammation-inducing agent.

2. 10. The method of claim 1, comprising administering the tyrosine kinase inhibitor systemically.

3. 3. The method of claim 1 or 2, wherein the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP / DAMP activator, a chemotherapeutic drug, a pro-inflammatory cytokine, a cancer vaccine, a bacterial component, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

4. 1. A method of treating cancer in an individual, comprising administering to the individual a tyrosine kinase inhibitor, wherein the individual is exhibiting an inflammatory response.

5. 5. The method of any one of claims 1-4, wherein the method further comprises intermittently administering the tyrosine kinase inhibitor to the individual, and optionally wherein a) the tyrosine kinase inhibitor is administered at least three times, wherein the tyrosine kinase inhibitor is administered at least twice, with intervals of no more than once every three days, and / or the tyrosine kinase inhibitor is administered to the individual for at least two cycles, each cycle lasting from about 3 days to about 20 days.

6. The method according to any one of claims 1 to 5, wherein the tyrosine kinase inhibitor is an inhibitor of the Src family of tyrosine kinases.

7. The method of any one of claims 1 to 6, wherein the tyrosine kinase inhibitor inhibits any one or more of SRC, BLK, HCK, FYN, FGR and YES.

8. The method of any one of claims 1 to 7, wherein the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, polatinib, bosutinib, saracatinib, KX2-391, and R406.

9. The method according to any one of claims 1 to 8, wherein the tyrosine kinase inhibitor inhibits signal transduction of SHP-1.

10. The method of any one of claims 1 to 9, wherein the tyrosine kinase inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing systems (e.g., CRISPR systems), and protein pharmaceuticals (e.g., antibody pharmaceuticals targeting tyrosine kinases or activated tyrosine kinases).

11. 11. The method of any one of claims 1 to 10, wherein the method comprises systemic and local administration of the tyrosine kinase inhibitor, and optionally, the method comprises intratumoral administration of the tyrosine kinase inhibitor.

12. 12. The method of any one of claims 1-3 and 5-11, wherein the pro-inflammatory agent and the tyrosine kinase inhibitor are administered within 24 hours of each other, optionally wherein the pro-inflammatory agent and the tyrosine kinase inhibitor are administered within 4 hours of each other, optionally wherein the method comprises administering the pro-inflammatory agent intratumorally, and optionally wherein the method comprises administering the pro-inflammatory agent to a site different from the site of the cancer being treated.

13. The method of any one of claims 1 to 2 and 5 to 12, wherein the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic drug, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

14. 14. The method of any one of claims 1-3 and 5-13, wherein the pro-inflammatory agent comprises a TLR agonist, optionally wherein the TLR agonist activates a TLR on macrophages, optionally wherein the TLR comprises TLR2, TLR3, TLR7, TLR8, and / or TLR9, and optionally wherein the TLR agonist comprises CpG, Poly IC, and / or R848.

15. 15. The method of any one of claims 1 to 3 and 5 to 14, wherein the pro-inflammatory agent comprises a bacterial component, optionally wherein the bacterial component comprises lipopolysaccharide (LPS).

16. The method of any one of claims 1 to 3 and 5 to 15, wherein the pro-inflammatory agent comprises a STING activator, and optionally, the STING activator comprises 2'3'-cGAMP.

17. 17. The method of any one of claims 1-3 and 5-16, wherein the pro-inflammatory agent comprises a chemotherapeutic agent, and optionally, the chemotherapy comprises azathioprine (AZA).

18. 18. The method of any one of claims 1-3 and 5-17, wherein the pro-inflammatory agent comprises a pro-inflammatory cytokine, optionally wherein the pro-inflammatory cytokine comprises IL-1b, IL-18, IL-6, and / or TNFα.

19. 19. The method of any one of claims 1-3 and 5-18, wherein the pro-inflammatory agent comprises radiation therapy, optionally wherein the radiation therapy comprises irradiation to a site of the cancer being treated, optionally wherein the radiation therapy comprises irradiation to a site different from the site of the cancer being treated, and optionally wherein the dose of the radiation therapy is insufficient to kill tumor cells.

20. 20. The method of any one of claims 1-3 and 5-19, wherein the pro-inflammatory agent comprises a checkpoint inhibitor, optionally wherein the checkpoint inhibitor comprises an anti-PD-L1 antibody, an anti-PD-1 antibody, or an anti-CLTA4 antibody.

21. 21. The method of any one of claims 1 to 3 and 5 to 20, wherein the pro-inflammatory agent and the tyrosine kinase inhibitor are administered simultaneously or concurrently.

22. 22. The method of any one of claims 1 to 3 and 5 to 21, wherein the pro-inflammatory agent comprises immune cells, optionally wherein the immune cells are derived from the same individual.

23. The method further comprises administering immune cells, optionally wherein the immune cells are derived from the same individual, and optionally comprising: a) the immune cells comprise or are macrophages, optionally having an M1 phenotype, and optionally the macrophages are engineered to be defective in tyrosine kinase expression and / or activation; b) the immune cells are derived from monocytes; c) the immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86; d) the immune cells express one or more pro-inflammatory cytokines, optionally wherein the one or more pro-inflammatory cytokines include TNFα and / or IL-12; e) the immune cells do not express significant levels of TGFβ and / or IL-10; f) the immune cells include T cells; g) the immune cells are engineered to express a chimeric antigen receptor, optionally, the chimeric antigen receptor specifically binds to a tumor antigen, and / or h) the tyrosine kinase inhibitor and the immune cells are administered within 24 hours of each other, optionally the tyrosine kinase inhibitor and the immune cells are administered within 4 hours of each other, and / or the immune cells are administered simultaneously or in parallel with the tyrosine kinase inhibitor.

24. 24. The method of any one of claims 1 to 23, further comprising administering to the individual an effective amount of an SHP-1 inhibitor.

25. The method of any one of claims 1 to 24, further comprising administering to the individual an effective amount of an anti-TNFα antibody.

26. The method of any one of claims 1 to 25, wherein the cancer is a solid tumor.

27. The method of any one of claims 1 to 26, wherein the cancer is a blood cancer.

28. The method according to any one of claims 1 to 27, wherein the cancer is a terminal cancer.

29. 29. The method of any one of claims 1 to 28, wherein the cancer is resistant or refractory to radiation therapy, chemotherapy, and / or checkpoint inhibitors.

30. The method of any one of claims 1 to 29, wherein the individual is a human.

31. A composition comprising a tyrosine kinase inhibitor and an inflammatory inducer, optionally wherein the inflammatory inducer comprises an agent selected from the group consisting of immune cells, TLR agonists, STING activators, agents used in radiation therapy, PAMP / DAMP activators, checkpoint inhibitors, proinflammatory cytokines, chemotherapeutic drugs, bacterial components, cancer vaccines, oncolytic viruses, and agents used in acoustic therapy, magnetic therapy, electrical therapy, or electrostatic therapy.

32. 32. The composition of claim 31, further comprising an SHP-1 inhibitor.

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