Compositions and methods for ameliorating adverse reactions in therapy

Abstract

The present application provides a method of treating cancer in a subject involving administering to the subject a bone marrow cell activator or therapy (e.g., a TLR agonist or STING agonist) and a TNF [alpha] inhibitor. In some cases, the methods further involve administering to the subject an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, optionally further administering a lymphocyte activator (e.g., a cytokine (e.g., IL-2)) and / or an immune checkpoint inhibitor (e.g., anti-PD-1).

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 490,995, filed March 17, 2023, and U.S. Provisional Application No. 63 / 581,184, filed September 7, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to compositions and methods for treating diseases (e.g., cancer), involving the administration of TNFα inhibitors and bone marrow cell activators or therapies, and optionally SHP-1 inhibitors and / or tyrosine kinase inhibitors. Background of the Invention In cancers (e.g., solid tumors), intratumoral bone marrow leukocytes (including macrophages (i.e., tumor-associated macrophages or TAMs) and myeloid-derived suppressive cells (MDSCs)) play a crucial role in controlling immunosuppression within the tumor microenvironment (TME), which supports tumor growth and also confers resistance to immunotherapeutic treatments. An important mechanism by which bone marrow leukocytes adapt to an immunosuppressive phenotype or enhance their immunosuppressive capacity after cancer therapy is through their cell surface inhibitory receptors (iRs), which, upon activation, are also driven by their extracellular ligand binding. This extracellular ligand binding triggers a negatively regulated multi-pathway by activating SHP-1 (a central signaling regulator) to dephosphorylate and thus inactivate multiple signal transduction molecules, specifically the cytoplasmic domain-based tyrosine-based inhibitory motif (ITIM). This reduces the pro-inflammatory anticancer response induced by therapies. In solid tumors, essential cell surface receptors such as SIRPα, Siglec, LilRB, PirB, LAIR1, lectin receptors, SLAM family receptors, etc. (see, for example, Kang, XL et al., Cell Cycle 2016;15:25-40; and Zarrin, AA et al., Front Immunol. 2020;11, each of which is hereby incorporated by reference) (which also show increased expression in the TME as the tumor progresses to an advanced stage) are regulated by activation of SHP-1, which then mediates downstream inhibition.

[0005] In light of these inhibitory mechanisms elucidated over the past few years, therapeutic lines aimed at blocking iRs (e.g., anti-LilRB1 / 2 and anti-SIRPa) and their ligands (e.g., anti-CD47) are being developed (see, e.g., Carosella, E.D., et al., Trends Cancer 2021; 7: 389-392; Yanagita, T.Y., et al., JCI Insight 2017; 2; and Zhang, W., et al., Front Immunol. 2020; 11: 18, each of which is hereby incorporated by reference). However, these efforts that single-target each iR or its ligand, rather than simultaneously targeting all inhibitory pathways, reach weak to partial efficacy in controlling solid tumors.

[0006] Furthermore, the pro-inflammatory response of anti-cancer therapeutics can result in cytokine release syndrome (CRS) in patients, where clinical manifestations include elevated circulating cytokine levels (e.g., INF-g, CCL2, IL-10, or IL-6), acute systemic inflammatory symptoms, and secondary organ dysfunction (e.g., nephritis, hepatitis, and / or pneumonitis). CRS has been defined as a systemic inflammatory state that occurs due to robust systemic immune activation induced by cell-mediated immune responses. Currently, there are several treatments for CRS. Low-grade CRS is treated symptomatically with antihistamines, antipyretics, and fluids. More severe CRS can be treated, for example, with corticosteroids or anti-IL-6 therapy (e.g., tocilizumab), however these treatments can negatively impact the efficacy of the anti-cancer therapy. Engaging the immune system to eliminate cancer comes with the risk of developing CRS as a serious adverse event that can prove fatal or require the patient to terminate the anti-cancer treatment. Thus, there is a need for novel anti-cancer therapeutics that are safe and effective.

[0007] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated in their entirety by reference. SUMMARY

[0008] In one aspect, the present application provides a method of treating cancer in an individual, the method comprising administering to the individual a) a bone marrow cell activating agent or therapy and b) a TNFa inhibitor. In some embodiments, the method further comprises administering to the individual a SHP-1 pathway inhibitor.

[0009] In another aspect, a method of treating cancer in an individual is provided, the method comprising administering to the individual a TNFa inhibitor and a SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering a lymphocyte activating agent.

[0010] In some embodiments according to any of the above methods, the individual is under an inflammatory response. In some embodiments, the inflammatory response is characterized by: a) acute inflammation, b) cytokine release syndrome (e.g., CRS above Grade 1, above Grade 2, or above Grade 3), c) elevated levels of: 1) at least two or three of TNFa, IL-6, IFN-g, and IFN-a, and / or 2) at least two or three of CCL2, CCL5, CXCL1, and CXCL10, further optionally wherein the inflammatory response is characterized by elevated levels of IL-2, IL-12, IL1b, and / or IL-10.

[0011] In some embodiments according to any of the above methods, the SHP-1 pathway inhibitor comprises a SHP-1 inhibitor. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., siRNA, shRNA, antisense RNA, microRNA), a nucleic acid base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting SHP-1), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate (ADC), and any combination thereof. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), a-tocopherol acetate (aTA), a-tocopherol succinate (aTOS), phomoxanthone A (PXA), and PKC theta activator. In some embodiments, the SHP-1 inhibitor is TPI-1 or an analog or derivative thereof.

[0012] In some embodiments according to any of the above methods, the SHP-1 pathway inhibitor comprises a tyrosine kinase inhibitor. 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 base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting a tyrosine kinase or an activated tyrosine kinase), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate (ADC), and any combination thereof. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, Dasatinib, R406, Entospletinib, Fostamatinib, Cerdulatinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, Masitinib, Ponatinib, and NVP-BEP800.

[0013] In some embodiments according to any of the above methods, the tyrosine kinase inhibitor inhibits any one of Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation. In some embodiments, the one or more kinases involved in T cell activation comprises any one or more of Lck, Fyn, Zap70, Syk, and Csk. In some embodiments, the tyrosine kinase inhibitor is a Src family tyrosine kinase inhibitor.

[0014] In some embodiments according to any of the above methods, the SHP-1 pathway inhibitor is an antibody that blocks a cell surface inhibitory receptor. In some embodiments, the antibody that blocks a cell surface inhibitory receptor is selected from any one of the following: LILRB1, LILRB2, LILRB3, LILRB4, LILRB5, SIRPa, PirB, gp49B1, Siglec-1, Siglec-2, Siglec-3, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, Siglec-10, Siglec-11, Siglec-12, Siglec-14, Siglec-15, Siglec-E, Siglec-F, Siglec-G, Siglec-H, DCIR4, CD371, CD200R, SLAMF1, SLAMF3, SLAMF5, SLAMF6, SLAMF7, SLAMF8, and SLAMF9.

[0015] In some embodiments according to any of the above methods, the pro-inflammatory agent capable of activating myeloid cells (i.e., myeloid cell activating agent or therapy) activates cells selected from any one of the following: macrophages with M1 phenotype, intratumoral dendritic cells, intratumoral B cells, antigen presenting cells, and any combination thereof. In some embodiments, the myeloid cell activating agent or therapy is selected from the group consisting of: STING activators, Toll-like receptor (TLR) agonists, PAMP / DAMP activators, chemotherapy, pro-inflammatory cytokines, cancer vaccines, bacteria or components thereof, viruses or components thereof, fungi or components thereof, immune cells, sonic wave therapy, magnetic therapy, electric therapy, cryotherapy, surgery, thermal therapy, radiation therapy, radiopharmaceutical therapy, electrostatic therapy, antibody drug conjugates, and any combination thereof.

[0016] In some embodiments according to any of the above methods, the myeloid cell activating agent or therapy comprises a TLR agonist. In some embodiments, the TLR agonist activates TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, and / or zymosan. In some embodiments, the TLR agonist comprises CpG, poly I:C, and / or R848.

[0017] In some embodiments according to any of the above methods, the myeloid cell activator or therapy comprises a STING activator. In some embodiments, the STING activator is selected from the group consisting of 2'3'-cGAMP, ADU-s100, G10, SR-717, Vadimezan (DMXAA; ASA-404), Sting Agonist-20, MSA-2, diABZI Sting Agonist-1, cGAMP (cyclic GMP-AMPP), Sting Agonist-3, and c-di-AMP (Cyclic Diadenylate) Sodium.

[0018] In some embodiments according to any of the above methods, the myeloid cell activator comprises immune cells. In some embodiments, the immune cells comprise T cells. In some embodiments, the T cells express an antigen receptor (CAR) or an antigen-specific TCR. In some embodiments, the immune cells comprise at least about 10 6 , 2 x 10 6 , 5 x 10 6 , 10 7 , 2 x 10 7 , 5 x 10 7 , 10 8 , 2 x 10 8 , 5 x 10 8 T cells. In some embodiments, the method comprises administering at least two or three doses of immune cells (i.e., two to three administrations of immune cells). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) the administration of immune cells (e.g., per dose of immune cells).

[0019] In some embodiments according to any of the above methods, the TNFa inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNFa receptor blocking antibody, a soluble TNFa receptor, a short interfering RNA (siRNA) targeting TNFa, a chemical inhibitor of TNFa mRNA stability, an inhibitor of TNFa converting enzyme (TACE), and derivatives thereof. In some embodiments, the TNFa inhibitor is a TNFa neutralizing antibody. In some embodiments, the antibody is selected from the group consisting of infliximab, adalimumab, etanercept, golimumab, and certolizumab.

[0020] In some embodiments according to any of the above methods, the method further comprises administering to the individual an effective amount of a lymphocyte activating agent. In some embodiments, the lymphocyte is a T cell. In some embodiments, the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolic modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacterium or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, and any combination thereof.

[0021] In some embodiments according to any of the above methods, the TNFa inhibitor is administered prior to administration of the myeloid cell activating agent or therapy. In some embodiments, the TNFa inhibitor is administered after administration of the myeloid cell activating agent or therapy. In some embodiments, the TNFa inhibitor is administered within 5, 4, 3, 2, or 1 day of administration of the myeloid cell activating agent or therapy, or wherein the TNFa inhibitor is administered no more than four days after administration of the myeloid cell activating agent or therapy.

[0022] In some embodiments according to any of the above methods, the TNFa inhibitor is administered within two weeks, concurrently, or within 3 hours after administration of a) the myeloid cell activating agent or therapy and / or b) the SHP-1 pathway inhibitor.

[0023] In some embodiments according to any of the above methods, the TNFa inhibitor is administered within two weeks, concurrently, or within 3 hours after administration of a) the lymphocyte activating agent and / or b) the SHP-1 pathway inhibitor.

[0024] In some embodiments according to any of the above methods, the myeloid cell activating agent or therapy is administered systemically or locally. In some embodiments, the TNFa inhibitor is administered systemically or locally. In some embodiments, the SHP-1 signaling pathway inhibitor is administered systemically or locally. In some embodiments, the systemic administration comprises oral administration, intravenous administration, subcutaneous administration, or intraperitoneal administration. In some embodiments, the local administration comprises intratumoral administration.

[0025] In some embodiments according to any of the above methods, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently.

[0026] In some embodiments according to any of the above methods, the SHP-1 signaling pathway inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 signaling pathway inhibitor is administered intermittently.

[0027] In some embodiments according to any of the above methods, the SHP-1 signaling pathway inhibitor and the myeloid cell activating agent or therapy or the lymphocyte activating agent are administered within 24 hours of each other. In some embodiments, the SHP-1 signaling pathway inhibitor and the myeloid cell activating agent or therapy or the lymphocyte activating agent are administered simultaneously or concurrently to the individual.

[0028] In some embodiments according to any of the above methods, the TNFα inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered no more than about once every two weeks, no more than once a week, or no more than once every five days. In some embodiments, the TNFα inhibitor is administered to the individual for at least two cycles, wherein each cycle has from about three days to about seven days.

[0029] In some embodiments according to any of the above methods, the method further comprises assessing the level of TNFα levels (e.g., serum or blood TNFα levels) in the individual.

[0030] In some embodiments according to any of the above methods, the method further comprises administering an IL-6 inhibitor.

[0031] In some embodiments according to any of the above methods, the method comprises administering at least two doses of the TNFα inhibitor, optionally wherein the two doses of the TNFα inhibitor are separated by a) at least 2, 3, 4, 5, 6, or 7 days, or b) at most 4, 3, 2, or 1 week, 6 days, or 5 days.

[0032] In some embodiments according to any of the above methods, the SHP-1 pathway inhibitor comprises a tyrosine kinase inhibitor and a SHP-1 inhibitor.

[0033] In some embodiments according to any of the above methods, the method comprises administering a) a SHP-1 inhibitor, optionally the SHP-1 inhibitor is TPI-1 or an analog or derivative thereof, b) a TLR agonist, optionally wherein the TLR agonist activates TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, and / or zymosan, and c) a TNFα inhibitor, optionally wherein the TNFα inhibitor is an anti-TNFα antibody.

[0034] In some embodiments according to any of the above methods, the method comprises administering a) a SHP-1 inhibitor, optionally the SHP-1 inhibitor is TPI-1 or an analog or derivative thereof, b) a STING activator, and c) a TNFα inhibitor, optionally wherein the TNFα inhibitor is an anti-TNFα antibody.

[0035] In some embodiments according to any of the above methods, the method comprises administering a) a SHP-1 inhibitor, optionally the SHP-1 inhibitor is TPI-1 or an analog or derivative thereof, b) radiation therapy, and c) a TNFα inhibitor, optionally wherein the TNFα inhibitor is an anti-TNFα antibody.

[0036] In some embodiments according to any of the above methods, the SHP-1 pathway inhibitor is administered to the individual concurrently with the myeloid cell activator or therapy. In some embodiments, the SHP-1 pathway inhibitor and the myeloid cell activator or therapy are administered sequentially. In some embodiments, the SHP-1 pathway inhibitor and the myeloid cell activator or therapy are administered to the individual until the individual experiences tumor clearance.

[0037] In some embodiments according to any of the above methods, the SHP-1 pathway inhibitor, the myeloid cell activator or therapy, and / or the TNFα inhibitor are further administered intermittently to the individual after tumor clearance, wherein prior to tumor clearance, the myeloid cell activator or therapy, the SHP-1 pathway inhibitor, and / or the TNFα inhibitor are administered to the individual according to any of the methods described herein.

[0038] In some embodiments according to any of the above methods, the lymphocyte activator is a cytokine, wherein the cytokine comprises IL-2, IL-4, IL-7, IL-9, IL-21, or IL-15, or a biologically active derivative thereof. In some embodiments, the cytokine comprises IL-2, or a biologically active derivative thereof.

[0039] In some embodiments according to any of the above methods, the myeloid cell activator or the lymphocyte activator is an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody.

[0040] In some embodiments according to any of the above methods, the IL-2 or biologically active derivative thereof and / or the anti-PD-1 antibody is administered to the individual daily (e.g., for at least 2, 3, 4, 5, 6, or 7 days). In some embodiments, the IL-2 or biologically active derivative thereof and / or the anti-PD-1 antibody is administered intermittently to the individual. In some embodiments, the IL-2 or biologically active derivative thereof and / or the anti-PD-1 antibody is administered to the individual for at least two cycles, wherein each cycle has about three days to about 20 days.

[0041] In some embodiments according to any of the above methods, the individual does not develop grade 2-4 cytokine release syndrome or proinflammatory organ damage. In some embodiments, administration of the TNFa inhibitor does not impair or weakly impairs tumor clearance.

[0042] In some embodiments according to any of the above methods, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is resistant or refractory to radiotherapy, a chemotherapeutic agent, and / or a checkpoint inhibitor. In some embodiments, the individual is a human. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 A schematic overview of the experimental design of the LLC mouse model is provided. Mice with LLC transplants were treated daily with each of: a) s.c. TPI-1, 1 mg / kg; b) s.c. PolyI:C + R848, 20 µg each; and c) s.c. dasatinib, 2 mg / kg (hereinafter KX147.AB&C) and IL-2 and anti-PD1 mAb to promote T cell immunity. One group of mice was also given a dose of anti-TNFa mAb prior to the initiation of KX147.AB&C treatment (-1 d), followed by a second dose on d5. LLC, lewis lung carcinoma; s.c., subcutaneous injection; i.p., intraperitoneal injection; d, day; tox, toxicity; mAb, monoclonal antibody.

[0044] Figure 2 Luminescence images showing KX147.AB&C induced rapid regression of LLC tumors with or without anti-TNFa mAb. LLC, lewis lung carcinoma; ctl, control; CR, complete response; OS, overall survival; mAb, monoclonal antibody.

[0045] Figure 3ARecorded tumor volume changes over time following treatment with vehicle (n = 5 mice), KX147.AB&C (n = 5 mice), or KX147.AB&C and anti-TNFa mAb combination treatment (n = 7 mice). V, volume; d, days; ctl, control; CR, complete response; mAb, monoclonal antibody.

[0046] Figure 3B Recorded overall survival of animals over time following treatment with vehicle (n = 5 mice), KX147.AB&C (n = 5 mice), or KX147.AB&C and anti-TNFa mAb combination treatment (n = 7 mice). Ctl, control; d, days; mAb, monoclonal antibody.

[0047] Figures 4A-4B Reduction of key cytokines and chemokines in mice treated with anti-TNFa mAb and KX147.AB&C combination therapy. Figure 4A Cytokine levels of TNFa, IL-6, IL-10, IFNa, IFB, IFNy, IL-1b, IL-12, and GM-CSF in serum from mice treated with anti-TNFa mAb and without anti-TNFa mAb, including key inflammatory cytokines indicative of CRS. Figure 4B Chemokine levels of CCL2, CCL5, CXCL1, and CXCL10 in serum from mice treated with anti-TNFa mAb and without anti-TNFa mAb. H, hours; mAb, monoclonal antibody. ***, p < 0.0001.

[0048] Figure 5 Clinical scores and body weight loss of mice administered KX147.AB&C therapy and co-treated with anti-TNFa mAb and without anti-TNFa mAb. D, days; mAb, monoclonal antibody.

[0049] Figures 6A-6B Organ assessment of mice treated with KX147.AB&C with and without anti-TNFa mAb administration following euthanasia. Figure 6A Organ weights of spleen, liver, kidney, and colon. Figure 6B Photographs of murine colon and spleen with ruler for size comparison. D, days; g, grams; mAb, monoclonal antibody. ***, p < 0.0001.

[0050] Figure 7PMN infiltration in organs based on tissue MPO assays using tissue from spleen, liver, lung, kidney, and colon harvested from mice treated with KX147.AB&C following euthanasia with and without anti-TNFa mAb administration. PMN, polymorphonuclear leukocyte or neutrophil; MPO, myeloperoxidase activity assay; mAb, monoclonal antibody. ***, p < 0.0001.

[0051] Figure 8 Tissue section staining to assess PMN infiltration in lungs of mice treated with KX147.AB&C following euthanasia with and without anti-TNFa mAb administration. PMN, polymorphonuclear leukocyte or neutrophil; d, day; mAb, monoclonal antibody.

[0052] Figure 9 A schematic overview of the MC38 mouse model experimental design is provided. Mice with single or dual MC 38 colorectal cancer transplants were treated for three days with each of the following: a) s.c. TPI-1, 1 mg / kg; b) s.c. PolyI:C + R848, 20 pg each; and c) s.c. dasatinib, 2 mg / kg (hereinafter referred to as KX147.AB&C) along with IL-2 and anti-PD1 mAb to promote T cell immunity. On d4, mice were switched to KX147.AB treatment (i.e., a) s.c. TPI-1, 1 mg / kg; and b) s.c. PolyI:C + R848, 20 pg each). One group of mice was also given a dose of anti-TNFa mAb prior to the start of KX147.AB&C treatment (-1 d), followed by a second dose on d5. MC38, C57B1 / 6 murine colon adenocarcinoma cell line; s.c., subcutaneous injection; i.p., intraperitoneal injection; d, day; tox, toxicity; mAb, monoclonal antibody.

[0053] Figures 10A-10B Recorded tumor volume changes over time following treatment with a) vehicle ( Figure 10A ; n = 3 mice / group), or b) KX147.AB&C, daily for three days, followed by KX147.AB in combination with anti-TNFa mAb, IL-2, and anti-PD-1 mAb on d4 ( Figure 10B ; n = 4 mice). Control mice tested as indicated in Figure 10A include the following groups: vehicle, IL-2 alone, anti-PD-1 mAb alone, and IL-2 / anti-PD-1 mAb combination treatment. Control mice tested as indicated in Figure 10BThe mice tested in the middle include the following: Mouse No. 1, MC38 implanted in both flanks; Mouse No. 2, MC38 implanted in one flank; Mouse No. 3, MC38 implanted in one flank; Mouse No. 4, MC38 implanted in both flanks. V, volume; d, days; ctl, control; CR, complete response; OS, overall survival; mAb, monoclonal antibody.

[0054] Figure 11 A schematic overview of the experimental design is provided, in which mice with established MC38 colorectal cancer (200-400 mm 3 ) were treated with aTLR, TPI-1 and dasatinib (s.c.) with or without additional treatment with anti-TNFa mAb or anti-IL-6 mAb (150 pg, i.p.). Treatments were repeated once (d1 and d2). In this model, KX147.AB&C treatment involved administration of a) s.c. TPI-1, 3 mg / kg; b) s.c. PolyI:C + R848, 20 pg each; and c) s.c. dasatinib, 5 mg / kg. Mice were euthanized for analysis on d6 after start of treatment. aTLR, TLR agonist; s.c., subcutaneous injection; i.p., intraperitoneal injection; d, days; mAb, monoclonal antibody.

[0055] Figure 12 The tumor volume change over six days after various treatments within two days of treatment administration is shown. KX147.AB&C alone effectively controlled tumor growth and induced regression. Neither anti-TNFa mAb nor anti-IL-6 mAb treatment affected KX147.AB&C efficacy. V, volume; d, days; NT, no treatment; aTLR, TLR agonist; mAb, monoclonal antibody.

[0056] Figures 13A-13D FACS plot analysis showing immune cell infiltration into the TME of various immune lineages (i.e. CD8 T cells, CD4 T H cells, NK cells, PMNs, macrophages and MDSCs). Figure 13A FACS plot showing the no treatment group. Figure 13B FACS plot showing the aTLR / TPI-1 / dasatinib therapy (KX147.AB&C). Figure 13C FACS plot showing the aTLR / TPI-1 / dasatinib therapy (KX147.AB&C) in combination with anti-TNFa mAb. Figure 13D FACS plot showing the aTLR / TPI-1 / dasatinib therapy (KX147.AB&C) in combination with anti-IL-6 mAb. SSC, side scatter; FSC, forward scatter; T HT helper cells; NK, natural killer; PMN, polymorphonuclear leukocytes or neutrophils; MDSC, myeloid-derived suppressor cells; αTLR, TLR agonist; mAb, monoclonal antibody; NT, no treatment; d, day.

[0057] Figure 14 The above is displayed in bar chart format. Figures 13A-13D The quantitative FACS results of the TME analysis described. c Cytotoxic T cells; T cells H T helper cells; NK cells, natural killer cells; PMN cells, polymorphonuclear leukocytes or neutrophils; Mac cells, macrophages; MDSC cells, myeloid-derived suppressor cells; αTLR cells, TLR agonists; mAb cells, monoclonal antibodies; ns cells, not significant; ctl cells, control. **, p<0.001. ***, p<0.0001.

[0058] Figure 15 This figure shows serum cytokine levels of TNFα, IL-6, IL-1β, IL-10, IFNα, and IFNγ, and chemokine levels of CCL2, CCL5, CXCL1, and CXCL10 from mice treated with αTLR / TPI-1 / dasatinib or in combination with either anti-TNFα mAb or anti-IL-6 mAb. αTLR, TLR agonist; mAb, monoclonal antibody; Mo, monocyte; Mac, macrophage; PMN, polymorphonuclear leukocyte or neutrophil. *, p<0.05. ***, p<0.0001.

[0059] Figure 16 Photographs of mouse colons and spleens with rulers for size comparison from mice treated with αTLR / TPI-1 / dasatinib therapy or in combination with either anti-TNFα mAb or anti-IL-6 mAb. αTLR, TLR agonist; mAb, monoclonal antibody.

[0060] Figure 17 This provides a schematic overview of the experimental design in which KPC pancreatic duct adenocarcinoma subcutaneously (sc) was implanted into the left and right ventral regions of mice. Mice were treated with KX147.AB&C for 4 days and then switched to KX147.AB therapy until tumor clearance. IL-2 and anti-PD-1 mAb were combined to enhance T-cell immunity. Anti-TNFα mAb was administered one day before the start of KX147.AB&C treatment and again on day 5. D, day; sc, subcutaneous injection; ip, intraperitoneal injection; mAb, monoclonal antibody.

[0061] Figure 18Fluorescent images showing KX147.AB&C induced rapid regression of KPC tumors with or without anti-TNFa mAb. Four treatment groups were tested: (1) no treatment (control), (2) IL-2 and anti-PD-1 mAb combination therapy, (3) KX147.AB&C in combination with IL-2 and anti-PD-1 mAb, and (4) KX147.AB&C in combination with IL-2, anti-PD-1 mAb, and anti-TNFa mAb. KPC, KPC pancreatic ductal adenocarcinoma; d, days; ctl, control; CR, complete response; OS, overall survival; mAb, monoclonal antibody.

[0062] Figure 19 A schematic overview of the experimental design is provided, where mice were i.p. orthotopically implanted with KPC pancreatic ductal adenocarcinoma. Mice were treated with KX147.AB&C for 2 days and then switched to KX147.AB therapy until tumor clearance. IL-2 and anti-PD-1 mAb were combined to enhance T cell immunity. Anti-TNFa mAb was administered one day prior to the start of KX147.AB&C treatment and again on d5. D, days; s.c., subcutaneous injection; i.p., intraperitoneal injection; mAb, monoclonal antibody.

[0063] Figure 20 Fluorescent images showing KX147.AB&C induced rapid regression of KPC tumors with or without anti-TNFa mAb. Three treatment groups were tested: (1) IL-2 and anti-PD-1 mAb combination therapy, (2) KX147.AB&C in combination with IL-2 and anti-PD-1 mAb, and (3) KX147.AB&C in combination with IL-2, anti-PD-1 mAb, and anti-TNFa mAb. KPC, KPC pancreatic ductal adenocarcinoma; d, days; ctl, control; CR, complete response; OS, overall survival; mAb, monoclonal antibody.

[0064] Figure 21 Tumor volume changes in mice bearing s.c. KPC tumors from two days prior to treatment until nine days post-treatment are shown. KX147.AB&C effectively controlled tumor growth and induced regression in combination with IL-2 and anti-PD-1 mAb alone. Anti-TNFa mAb did not affect KX147.AB&C efficacy. V, volume; d, days; s.c., subcutaneous injection; ctl, control; CR, complete response; mAb, monoclonal antibody.

[0065] Figure 22Tumor volume changes in mice bearing i.p. orthotopic KPC tumors are shown from two days before treatment until seven days after treatment. KX147.AB&C with IL-2 and anti-PD-1 mAb effectively controlled tumor growth and induced regression. Anti-TNFa mAb did not affect KX147.AB&C efficacy. V, volume; d, days; i.p., intraperitoneal injection; ctl, control; CR, complete response; mAb, monoclonal antibody.

[0066] Figure 23 Survival curves of mice treated with one of the following treatments are shown: (1) no treatment (control; n = 10 mice), (2) IL-2 and anti-PD-1 mAb (n = 6 mice), (3) KX147.AB&C with IL-2 and anti-PD-1 mAb (n = 6 mice), and (4) KX147.AB&C with IL-2, anti-PD-1 mAb, and anti-TNFa mAb combination (n = 8 mice). Although the anti-TNFa mAb did not promote tumor elimination induced by KX147.AB&C, its presence improved adverse effects and achieved 100% survival. KPC, KPC pancreatic ductal adenocarcinoma; d, days; mAb, monoclonal antibody.

[0067] Figure 24 Two steps of cytokine release events associated with CAR-T therapy against cancer are shown. In Step 1, activated CAR-T cells release cytokines (e.g., IFNy, TNFa, and IL-2) while performing effector functions, including killing cancer cells. In Step 2, the cytokines released by CAR-T cells induce extensive activation of macrophages and other immune and body cells, which together produce high levels of pro-inflammatory cytokines (e.g., IL-6) and chemokines. Activation in Step 2 causes acute reactions, leukocyte infiltration, and immune-related adverse effects (irAEs).

[0068] Figures 25A-25C Neutralization of TNFa produced by CAR-T leads to inhibited macrophage activation and reduced pro-inflammatory cytokine production in vitro is shown. Figure 25A A dual-plate method for testing the effects of cytokines produced by activated CAR-T cells on macrophages in vitro is outlined. Plate 1 contains a co-culture of CD19 CAR-T cells and B-ALL leukemia cells, while Plate 2 contains a culture of human macrophages. Plate 2 is incubated with supernatant from Plate 1 with or without neutralization of TNFa, IFNy, or IL-2 mediated by monoclonal antibodies (mAbs). Figure 25BQuantification of CAR-T cell effector function against B-ALL cells and cytokine production from the activated CAR-T cells over 24 hours of co-culture in culture dish 1. Figure 25C Results showing cytokine and chemokine release from macrophages in culture dish 2 after 16 hours of culture with supernatant from culture dish 1 with or without mAb-mediated neutralization of target cytokines.

[0069] Figures 26A-26C Results showing that neutralization of CAR-T produced TNFa prevents peripheral macrophages from producing high levels of IL-6 and inflammatory chemokines in vitro. Figure 26A An in vitro co-culture system is outlined. CD19 CAR-T and B-ALL are co-cultured with human monocyte-derived macrophages in a single culture dish at a ratio of CAR-T:B-ALL:hMac = 1:10:3 (1 x 10 6 cells / ml) with or without mAb-mediated cytokine neutralization for 24 hours. After culture, cytokine and chemokine concentrations in the media are determined by ELISA. Figure 26B Results showing that CD19 CAR-T mediated killing of B-ALL cells is not affected by mAb treatment neutralization. Figure 26C Results showing resulting changes in cytokine and chemokine levels after 24 hours of co-culture with or without mAb-mediated cytokine neutralization.

[0070] Figures 27A-27E Results showing that prophylactic anti-TNFa neutralization prevents severe cytokine release syndrome (CRS) without compromising CAR-T anti-tumor efficacy in a patient-derived xenograft (PDX) mouse model. Figure 27A Experimental design is outlined. F3 B-ALL PDX mouse model is established by i.v. injection of B-ALL harvested from F2 PDX (1 x 10 6 cells / mouse). Once B-ALL cells are detectable in the peripheral blood of B-ALL xenograft mice (>10% in PBMCs), 1-2 x 10 6 CD19 CAR-T cells are i.v. infused with or without prophylactic anti-TNFa mAb administration (i.p., 100 pg, 3 h prior to CAR-T infusion). The same dose of anti-TNFa mAb is then given once a week until mice reach complete response (CR). Figure 27BRepresentative flow cytometry analysis of B-ALL cells in peripheral blood mononuclear cells (PBMCs) of F3 B-ALL PDX model mice with or without prophylactic anti-TNFa mAb treatment is shown. Figure 27C CAR-T proliferation and B-ALL cell killing in the F3 B-ALL PDX model was determined not to be hindered by prophylactic anti-TNFa mAb administration. Figure 27D Overall survival (OS) of PDX mice receiving CAR-T therapy with or without prophylactic anti-TNFa mAb administration is shown. Figure 27E Levels of cytokines and chemokines in serum of PDX model mice following CAR-T therapy are shown.

[0071] Figures 28A-28B Prophylactic anti-TNFa mAb administration is shown to protect mice from CD3 / CD28 TCR ligation-induced CRS. Figure 28A Experimental design is outlined. Mice with and without prophylactic administration of anti-TNFa mAb (100 pg, i.p., 3 h prior to CD3 / CD28 Ab treatment) were given a mixture of CD3 and CD28 ligation mAbs (50 pg each, i.p.) to stimulate endogenous and systemic T cell activation. Levels of cytokines and chemokines in serum from treated mice were analyzed by multiplex ELISA at 0 h, 3 h, and 16 h post-CD3 / CD28 mAb treatment. Figure 28B Levels of cytokines and chemokines in serum of mice following CD3 / CD28 mAb ligation treatment are shown.

[0072] Figures 29A-29D Prophylactic anti-TNFa mAb administration is shown to ameliorate CRS induced by adoptive infusion of activated T cells. Figure 29A Experimental design is outlined. Mice with and without prophylactic administration of anti-TNFa mAb (100 pg, i.p., 3 h prior to treatment) were i.v. infused with 2 x 10 7 activated T cells by anti-CD3 / CD28 mAb ligation. Levels of cytokines and chemokines in serum from treated mice were analyzed by multiplex ELISA at 0 h, 3 h, and 16 h post-infusion. Figure 29B Levels of cytokines and chemokines in serum of mice following single infusion of activated splenocyte T cells are shown. Figure 29C Body weight measurements and clinical scores of mice receiving repeated infusion of activated splenocyte T cells (3 x i.v. on days 0, 2, and 4; 2 x 10 7 cells per infusion) with or without prophylactic anti-TNFa mAb administration are shown.Figure 29D Show the effect of repeated infusion of activated splenocyte T cells on the spleen weight and splenomegaly condition of recipient mice with or without prophylactic anti-TNFa mAb administration.

[0073] Figures 30A-30D Show local therapy for skin / subcutaneous 4T1 breast cancer. Figure 30A Show the overall experimental design. BalbC mice are implanted with 4T1 breast cancer cells in the skin / subcutaneous and allowed to develop tumors for 10-15 days. After the tumor growth phase, mice receive prophylactic anti-TNFa intraperitoneal (i.p.) injection followed by treatment with control or experimental conditions. Control conditions include treatment with a local non-drug lotion (Johnson's lotion alone); while experimental conditions include a local lotion containing aTLR (polyI:C and R848) alone (condition A), dTPI-1 alone (condition B), or aTLR and dTPI-1 (condition A+B). All lotion treatments are administered twice daily for nine days after prophylactic TNFa treatment, and all mice receive systemic anti-PD-1 (aPD-1) therapy on the first, fourth, and seventh days of treatment. Efficacy analysis is performed on day 10 after prophylactic TNFa treatment. Figure 30B Show quantification of 4T1 breast cancer tumor volume change over the course of treatment. Figure 30C Show bioluminescence images of 4T1 breast cancer tumors of mice treated with condition A (aTLR) and condition B (dTPI-1) (A+B) plus systemic anti-PD-1 (aPD-1) therapy treatment. Figure 30D Show survival rates of mice receiving each treatment.

[0074] Figures 31A-31B Show local therapy for skin / subcutaneous lung cancer (LLC). Figure 31A Show bioluminescence images of mice implanted with lung cancer tumors (LLC) over a seven-day course of treatment with control local lotion only, anti-PD-1 (aPD-1) systemic treatment only, anti-PD-1 (aPD-1) systemic treatment with local aTLR + dTPI-1 treatment, or anti-PD-1 (aPD-1) systemic treatment with local aSTING + dTPI-1 treatment. All local treatments are provided twice daily, while anti-PD-1 (aPD-1) systemic treatment is provided once every three days. Figure 31B Show quantification of tumor volume change over the course of treatment.

[0075] Figures 32A-32DTherapeutic anti-cancer efficacy of the combination of SHP-1 inhibition and T cell activation was shown. MC38 colorectal carcinoma was established in C57B1 / 6 mice. After tumor formation, tumors were treated by intratumoral (i.t.) injection of each of: (i) anti-PD-1 Ab alone (aPD-1, 50 μg every 3 days), or aPD-1 in combination with SHP-1 inhibitor, TPI-1 (1 mg / kg every 2 days) Figure 32A ); (ii) a single dose of anti-CD3 and anti-CD28 antibodies (50 μg each) or anti-CD3 / anti-CD28 antibodies in combination with TPI-1 Figure 32B ); or (iii) IL-2 alone (30,000 IU every 3 days) or in combination with TPI-1, or IL-2 in combination with TPI-1 with anti-TNFa and anti-IL-6 antibodies (50 μg each) Figure 32C ). The addition of neutralizing anti-TNFa and anti-IL-6 antibodies did not affect treatment efficacy. Figure 32D ) shows that treatment of mice with TPI-1 alone did not halt tumor progression. iSHP-1, SHP-1 inhibitor; V, volume.

[0076] Figures 33A-33C It was shown that prophylactic anti-TNFa monoclonal antibody (mAb) treatment did not affect TLR agonist R848, TPI-1, or their combination in tumor treatment. Figure 33A Experimental design is outlined. Murine pancreatic ductal adenocarcinoma cells (KPC) were implanted (5 x 10 5 , s.c.) into the right flank of C57BL6 mice. After tumor formation (about 200 mm 3 in tumor volume), mice were treated daily with R848 (20 μg or 60 μg, s.c.) or TPI-1 (1 or 3 mg / kg, s.c.), or R848 plus TPI-1. All treatment conditions were tested with or without prophylactic anti-TNFa mAb (i.p., 100 μg). Figure 33B Changes in tumor burden over the 8-day treatment window following each treatment are shown. Figure 33C Immune cell infiltration within the tumor microenvironment (TME) on day 8 of treatment is shown.

[0077] Figures 34A-34CPreventive anti-TNFa monoclonal antibody (mAb) treatment ameliorates cytokine release syndrome (CRS) induced by TLR agonist R848 therapy, TPI-1 therapy, and R848 and TPI-1 combination therapy is shown. Mice were treated daily with R848 (20 or 60 pg, s.c.), TPI-1 (1 or 3 mg / kg, s.c.), or combinations thereof, with and without preventive anti-TNFa (100 pg mAb, i.p., 3 h prior to first treatment). Cytokine and chemokine release in serum of mice receiving each treatment regimen was determined by multiplex ELISA Figure 34A ) at days 2, 4, and 6 post-treatment. Figure 34B Body weight and clinical score changes in mice treated over an 8-day treatment window are shown. Figure 34C Analysis of colitis and splenomegaly (symptoms of CRS) 8 days after treatment initiation is shown.

[0078] Figures 35A-35C Preventive anti-TNFa monoclonal antibody (mAb) treatment does not affect STING agonist (ADU-S100) and its combination with TPI-1 in tumor therapy is shown. Figure 35A Experimental design is shown. C57BL6 mice were implanted with murine pancreatic ductal adenocarcinoma (KPC; 5 x 10 5 , s.c.). Once tumors formed >150 mm 3 , mice were treated prophylactically with anti-TNFa mAb (i.p., 100 pg) followed by ADU-S100 (100 pg / mouse, s.c.) daily with or without TPI-1 (1 mg / kg, s.c.). Figure 35B KPC tumor burden changes over a 19-day time course after treatment initiation is shown. Figure 35C Immune cell infiltration within the tumor microenvironment (TME) on day 8 of treatment is shown.

[0079] Figures 36A-36C Preventive anti-TNFa monoclonal antibody (mAb) treatment ameliorates cytokine release syndrome (CRS) associated with STING agonist therapy is shown. Mice were treated daily with STING agonist ADU-S100 (100 pg / mouse, s.c.) with and without preventive administration of anti-TNFa (100 pg mAb, i.p., 3 h prior to first STING agonist treatment). Cytokine and chemokine release in serum of mice receiving each treatment regimen was determined by multiplex ELISA Figure 36A ) at days 2, 4, and 6 post-treatment. Figure 36B Body weight and clinical score changes in mice treated over an 8-day treatment window are shown. Figure 36CAnalysis of colitis and splenomegaly (symptoms of CRS) shown 8 days after the start of treatment. DETAILED DESCRIPTION

[0080] In one aspect, the present application provides a method of treating cancer in an individual, the method comprising administering to the individual a) a bone marrow cell activator or therapy and b) a TNFa inhibitor. In some embodiments, the present application provides a method of treating cancer in an individual, the method further comprising administering to the individual a SHP-1 pathway inhibitor. In another aspect, a method of treating cancer in an individual is provided, the method comprising administering to the individual a TNFa inhibitor and a SHP-1 pathway inhibitor, wherein the individual is under an inflammatory response or has a persistent infection. In some embodiments, the SHP-1 pathway inhibitor is a SHP-1 inhibitor, such as TPI-1 or an analog or derivative thereof. In some embodiments, the SHP-1 pathway inhibitor is a tyrosine kinase inhibitor, such as dasatinib. In some embodiments, the SHP-1 signaling pathway inhibitor is administered systemically. In some embodiments, the method comprises administering the SHP-1 signaling pathway inhibitor daily for at least 2, 3, 4, 5, 6, or 7 days or intermittently. In some embodiments, the bone marrow cell activator or therapy comprises an agent selected from the group consisting of a STING activator, a Toll-like receptor (TLR) agonist, a PAMP / DAMP activator, a chemotherapy, a proinflammatory cytokine, a cancer vaccine, a bacterium or component thereof, a virus (e.g., an oncolytic virus) or component thereof, a fungus or component thereof, a sonic wave therapy, a magnetic therapy, an electric therapy, a radiation therapy, a radiopharmaceutical therapy, an electrostatic therapy, an antibody drug conjugate, and any combination thereof. In some embodiments, the TNFa inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNFa receptor blocking antibody, a soluble TNFa receptor, a short interfering RNA (siRNA) targeting TNFa, a chemical inhibitor of TNFa mRNA stability, an inhibitor of TNFa converting enzyme (TACE), and a derivative thereof. In some embodiments, the bone marrow cell activator or therapy is administered systemically. In some embodiments, the TNFa inhibitor is administered systemically. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within about any of one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior to) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor.In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. Other combination treatment methods are provided.

[0081] The present application is based, at least in part, on the surprising discovery that the combination of a TNFa inhibitor with a pro-inflammatory treatment that activates bone marrow cells (e.g., tumor infiltrating macrophages) and one or more SHP-1 signaling pathway inhibitors that potentially inhibit the activation of the "master" suppressor SHP-1, results in a dramatic reprogramming of the tumor microenvironment (TME) and enhances activation of innate and adaptive immune cells to promote anti-cancer immunity with little or no systemic toxicity or CRS. In particular, it was discovered that administration of an anti-TNFa neutralizing antibody during the course of an aggressive anti-cancer therapy significantly improved the extent of systemic toxicity and pro-inflammatory organ damage associated with the anti-cancer therapy without compromising treatment efficacy in preclinical models. This discovery is particularly surprising because the same effect was not seen after administration of an anti-IL-6 neutralizing antibody, where CRS and organ damage still occurred. See Figures 4A-8 、 Figures 12-16 and Figure 23 This discovery highlights the potential to utilize TNFa inhibition to improve or eliminate adverse events (e.g., CRS or pro-inflammatory organ damage) resulting from the combination of SHP-1 pathway inhibiting therapy with bone marrow cell (e.g., macrophage or dendritic cell) activating agents. By improving or eliminating these adverse events, the potential to directly or via upstream tyrosine kinases inhibit SHP-1 (which potentially depletes ITIM phosphorylation and SHP-1 activation as a combination in tumor immunotherapy) can be unlocked in order to achieve safe efficacy in cancer treatment. These discoveries are further validated in treatments involving T cell therapies (e.g., cell-based immunotherapies (e.g., CAR-T cells)). It has been discovered that prophalactic, concurrent, or shortly after (e.g., within 3 hours after) cell therapy combination treatment with a TNFa inhibitor and a cell-based immunotherapy prevents CRS formation and has no effect on anti-tumor activity of the therapeutic intervention. See, e.g., Figures 34A-34C 、 Figures 35A-35B and Figures 36A-36C .

[0082] Accordingly, the present application provides novel methods that can effectively re-engage immune suppression imposed by tumor conditions and permit both innate and adaptive immunity against cancer while significantly preventing therapeutic agent-induced toxicity, resulting in significant and safe anti-tumor efficacy. The present application further provides novel methods that can preserve efficacy of T cell therapy (e.g., CAR-T therapy) against cancer while significantly preventing therapeutic agent-induced toxicity, resulting in significant and safe anti-tumor efficacy.

[0083] I. DEFINITIONS In general, the terms used in the claims and this specification are intended to have their ordinary meaning in the art unless otherwise indicated. To the extent that common meaning is inconsistent with the provided definitions, the provided definitions prevail.

[0084] The terms“individual,”“subject,” or“patient” are used synonymously herein to describe an animal, such as a reptile, a bird, a fish, or a mammal (e.g., a human). An individual includes, but is not limited to, a fish, a reptile, a bird, a human, a bovine, a horse, a cat, a dog, a rodent, or a primate. In some embodiments, the individual is a human. In some embodiments, the individual has a disease, such as cancer. In some embodiments, the individual is in need of treatment.

[0085] As used herein,“reference” refers to any sample, standard, or level used for purposes of comparison. A reference can be obtained from a healthy and / or disease-free sample. In some examples, a reference can be obtained from an untreated sample. In some examples, the reference is obtained from a disease-free or untreated sample of the individual. In some examples, the reference is obtained from one or more healthy individuals who are not the individual undergoing one or more ongoing treatments.

[0086] As used herein, the term“intermittent” or“intermittently” in the context of dosing refers to non-continuous dosing. For example, in some cases,“intermittent” dosing refers to dosing in which treatment is administered at least twice, and the two administrations are separated by at least one day (i.e., on day 1 and day 3).

[0087] As used herein, the term "cycle" in the context of dosing refers to a period during which there is at least one therapeutic administration. Day 1 of a cycle is defined as the day when the first therapeutic administration occurs during the period. When there are several daily consecutive administrations of a therapy, then Day 1 of a cycle is defined as the day when the first administration occurs in the several daily consecutive administrations. The last day of a cycle is defined as the day preceding the next non-consecutive administration of therapy. Cycles need not be of the same length. For example, a first cycle can have five days and a second cycle can have seven days. Each cycle can have a different number of therapeutic administrations. For example, a first cycle, which can have five days, can have one therapeutic administration and a second cycle, which can have seven days, can have two therapeutic administrations. Where therapy involves administration of more than one compound, then each compound can follow the same or different cycles described above. In some examples, each compound can have a cycle that is a combination of the same and different cycles of any other compound.

[0088] As used herein, the term "immunogenicity" is the ability to elicit an immune response, e.g., via T cells, B cells, or both.

[0089] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviation of one or more symptoms resulting from the disease, diminishment of extent of disease, stabilized (e.g., not worsening) state of disease, preventing or delaying spread (e.g., metastasis) of disease, preventing or delaying onset or recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, remission (whether partial or total), decreasing the dose of one or more other medications required to treat the disease, delay of disease progression, improving quality of life, and / or prolonging survival. "Treatment" also encompasses alleviating a pathological consequence of a cancer. The methods of the application encompass any one or more of these treatment aspects.

[0090] As used herein, "delaying development of cancer" means postponing, hindering, slowing, retarding, stabilizing, and / or postponing the development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention such that the individual does not develop the disease. A method that "delays development of cancer" is one that reduces the probability of development of the disease within a given timeframe and / or reduces the extent of the disease within a given timeframe as compared to not using the method. Such comparisons are typically based on clinical studies using a statistically significant number of individuals. Development of cancer can be detected using standard methods, including, but not limited to, computed axial tomography (CAT scan), magnetic resonance imaging (MRI), abdominal ultrasound, coagulation testing, arteriography, or biopsy. Development can also refer to progression of cancer that can not be initially detectable and includes onset, recurrence, and attack.

[0091] As used herein, the term "simultaneous administration" means that the first therapy and the second therapy in a combination therapy are administered with a time interval of no more than about 15 minutes, e.g., no more than any of about 10 minutes, 5 minutes, or 1 minute. When the first therapy and the second therapy are administered simultaneously, the first therapy and the second therapy can be contained in the same composition (e.g., a composition comprising both the first therapy and the second therapy) or in separate compositions (e.g., the first therapy in one composition and the second therapy contained in another composition).

[0092] As used herein, the term "sequential administration" means that the first therapy and the second therapy in a combination therapy are administered with a time interval of more than about 15 minutes, e.g., more than any of about 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, or longer. Either the first therapy or the second therapy can be administered first. The first therapy and the second therapy are contained in separate compositions, which can be contained in the same or different packaging or kits.

[0093] As used herein, the term "concurrent administration" means that the administration of the first therapy and the administration of the second therapy in a combination therapy overlap each other.

[0094] As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" means that the material is biologically or otherwise, pharmaceutically, acceptable in that the material is not biologically or otherwise undesirable, e.g., the material can be incorporated into a pharmaceutical composition administered to a subject without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients are preferably nontoxic to the subject to whom the composition is administered at dosages and in amounts necessary to achieve its intended purpose.

[0095] It should be understood that the embodiments of the present application described herein include "consisting" embodiments and / or "consisting essentially of embodiments.

[0096] Herein, reference to "about" a value or parameter is meant to encompass variations that would normally occur in that value or parameter when it is, for example, measured or determined by a person of ordinary skill in the art.

[0097] As used herein, reference to "not (non)" a value or parameter generally means and describes "except" a value or parameter. For example, a method is not used to treat a cancer of type X means that the method is used to treat cancer types other than X.

[0098] The term "about X-Y" as used herein has the same meaning as "about X to about Y."

[0099] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0100] Any terms not directly defined herein are to be understood to have meanings that are conventionally associated with them in the technical field of the present application. Certain terms are discussed herein to provide additional guidance to the practitioner in describing compositions, devices, methods, etc., and how to make or use them, in connection with the aspects of the present application. It will be appreciated that the same thing can be expressed in more than one way. Consequently, alternative language and synonyms can be used for any one or more of the terms discussed herein. No significance is to be

[0101] II. Methods of Treatment In one aspect, the application provides a method of treating cancer in an individual, the method comprising administering to the individual a) a bone marrow cell activator or therapy and b) a TNFa inhibitor. In some embodiments, the individual being treated has received, is receiving, or will receive one or more SHP-1 pathway inhibitors, such as any of those described herein. In another aspect, a method of treating cancer in an individual is provided, the method comprising administering to the individual a TNFa inhibitor and a SHP-1 pathway inhibitor, wherein the individual is under an inflammatory response or has a persistent infection. In some embodiments, the individual is further administered an immune checkpoint inhibitor and / or a cytokine.

[0102] In some embodiments, the method comprises administering to the individual both a TNFa inhibitor and a bone marrow cell activator or therapy. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activator or therapy and / or SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately following (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, following) the administration of the bone marrow cell activator or therapy and / or SHP-1 pathway inhibitor. In some embodiments, the method comprises administering to the individual a TNFa inhibitor, wherein the individual is under an inflammatory response or has a persistent infection. In some embodiments, the inflammatory response or persistent infection promotes a proinflammatory immune response in the individual. In some embodiments, the method further comprises administering a SHP-1 inhibitor and / or a tyrosine kinase inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered daily. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor systemically.

[0103] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a bone marrow cell activator or therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., a radiation therapy), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and optionally wherein the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered systemically (e.g., intravenously or subcutaneously). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered at an interval of no more than once every two days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered no less than two times and no more than 5 times within a consecutive ten days (e.g., two times within ten days, three times within ten days, four times within ten days, or five times within ten days). In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered concurrently. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered concurrently. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered concurrently with the bone marrow cell activator or therapy and / or the TNFa inhibitor. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered concurrently with the bone marrow cell activator or therapy and / or the TNFa inhibitor. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered sequentially and 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) of the bone marrow cell activator or therapy and / or the TNFa inhibitor.In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the tyrosine kinase inhibitor is effective to inhibit more than 50% of tyrosine kinase activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor is effective to inhibit more than 50% of SHP-1 activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor and / or 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 base inhibitor (e.g., a circular RNA inhibitor; see, e.g., Holdt, L.M., et al., Front Physiol 2018; 9: 1262), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting SHP-1 or a tyrosine kinase or an activated tyrosine kinase), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate (ADC), and any combination thereof. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinylpyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin Xanthene A (PXA), and PKC theta activator. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800.In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering to the individual an effective amount of a bone marrow cell activating agent or therapy locally (e.g., intra-tumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within about any of one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2).

[0104] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a bone marrow cell activating agent or therapy (e.g., a TLR agonist, e.g., a STING activating agent, e.g., a radiation therapy), wherein the individual a) has received, is receiving, or will receive an administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and wherein the method optionally comprises oral, intravenous, or subcutaneous administration of the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual at an interval of no more than once every three days for at least two times. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered twice (e.g., two execution days) every seven to twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered three times (e.g., three execution days) every ten to twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at an interval of no more than once every two days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered no less than two times and no more than 5 times within a consecutive ten days (e.g., two times within ten days, three times within ten days, four times within ten days, or five times within ten days). In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered concurrently with the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered sequentially with the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof.In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, and / or cytokine or biologically active fragment thereof is administered concurrently with the myeloid cell activator or therapy and / or TNFa inhibitor. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, and / or cytokine or biologically active fragment thereof is administered concurrently with the myeloid cell activator or therapy and / or TNFa inhibitor. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, and / or cytokine or biologically active fragment thereof and the myeloid cell activator or therapy and / or TNFa inhibitor are administered sequentially and within 2 weeks of each other (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor and / or 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 base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting SHP-1 or a tyrosine kinase or an activated tyrosine kinase), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate (ADC), and any combination thereof. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinylpyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, semdustib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering to the individual an effective amount of a bone marrow cell activator or therapy locally (e.g., intra-tumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within about any of 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior to) administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0105] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a myeloid cell activating agent or therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., a radiation therapy), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and wherein the method comprises oral, intravenous, or subcutaneous administration of the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently.In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy and / or TNFa inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered in parallel with the myeloid cell activator or therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered in parallel with the myeloid cell activator or therapy and / or TNFa inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the myeloid cell activator or therapy are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, and myeloid cell activator or therapy are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, tyrosine kinase inhibitor, myeloid cell activator or therapy, and / or TNFa inhibitor are administered intermittently to the individual. In some embodiments, the SHP-1 inhibitor and / or 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 base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting SHP-1 or a tyrosine kinase or an activated tyrosine kinase), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate (ADC), and any combination thereof. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinylpyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators.In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of: Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of: RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, secaitinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method further comprises locally (e.g., intratumorally) administering to the individual a bone marrow cell activating agent or therapy. In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or subsequent to) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately following (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, following) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib).In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0106] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematologic cancer, e.g., an advanced cancer) in an individual is provided, the method comprising orally, intravenously, subcutaneously, intraperitoneally, and / or intratumorally administering to the individual a SHP-1 inhibitor, a tyrosine kinase inhibitor, and a myeloid cell activator or therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., a radiation therapy), optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is effective to inhibit more than 50% of SHP-1 and / or tyrosine kinase activity for no more than about 5 days, and optionally wherein the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual every day, wherein the individual is further administered a TNFα inhibitor, and wherein the individual does not develop cytokine release syndrome or a proinflammatory organ injury. In some embodiments, the TNFα inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematologic cancer, e.g., an advanced cancer) in an individual is provided, the method comprising orally, intravenously, subcutaneously, intraperitoneally, and / or intratumorally administering to the individual a SHP-1 inhibitor, a tyrosine kinase inhibitor, and a myeloid cell activator or therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., a radiation therapy), optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is effective to inhibit more than 50% of SHP-1 and / or tyrosine kinase activity for no more than about 5 days, and optionally wherein the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual at least two times (e.g., at least 3, 4, 5, or 6 times) at an interval of no more than once every three days, wherein the individual is further administered a TNFα inhibitor, and wherein the individual does not develop cytokine release syndrome or a proinflammatory organ injury. In some embodiments, the myeloid cell activator or therapy and / or the TNFα inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activator or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activator or therapy is administered intermittently. In some embodiments, the TNFα inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered to the individual for at least two cycles, wherein each cycle has from about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days.In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at an interval of no more than twice per seven to twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at an interval of no more than three times per seven to twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at an interval of about 1-3 times per seven to twenty days for a period of at least fourteen to twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least about 2, 3, 4, 5, or 6 times over a period of about fourteen to about forty days (e.g., about fourteen to about twenty days). In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy and / or TNFα inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy and / or TNFα inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the myeloid cell activator or therapy are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is effective to inhibit more than 50% of SHP-1 and / or tyrosine kinase activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the individual is administered the SHP-1 inhibitor, tyrosine kinase inhibitor, and myeloid cell activator or therapy until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is administered the SHP-1 inhibitor, tyrosine kinase inhibitor, myeloid cell activator or therapy, and / or TNFα inhibitor intermittently.In some embodiments, the SHP-1 inhibitor and / or 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 base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting SHP-1 or a tyrosine kinase or activated tyrosine kinase), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate (ADC), and any combination thereof. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivative, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin A (PXA), and PKC theta activator. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, plinabulin, secaitinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, plinabulin, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method further comprises administering to the individual a bone marrow cell activating agent or therapy locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior to) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor.In some embodiments, the TNFa inhibitor is administered simultaneously with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., before or after) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the bone marrow cell activating agent or therapy is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered both systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0107] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a bone marrow cell activating agent or therapy (e.g., a TLR agonist, e.g., a STING activating agent, e.g., a radiation therapy), wherein the individual a) has received, is receiving, or will receive an administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and wherein the method comprises oral, intravenous, subcutaneous, and / or intratumoral administration of the SHP-1 inhibitor, the tyrosine kinase inhibitor, the immune checkpoint inhibitor, and / or the cytokine or biologically active fragment thereof and the bone marrow cell activating agent or therapy, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is effective to inhibit more than 50% of SHP-1 and / or tyrosine kinase activity for no more than about 5 days (e.g., no more than 5, 4, or 3 days). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the bone marrow cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the bone marrow cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the bone marrow cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle.In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy and / or TNFa inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with the myeloid cell activator or therapy and / or TNFa inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the myeloid cell activator or therapy are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, and myeloid cell activator or therapy are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, tyrosine kinase inhibitor, myeloid cell activator or therapy, and / or TNFa inhibitor are administered intermittently to the individual. In some embodiments, the SHP-1 inhibitor and / or 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 base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting SHP-1 or a tyrosine kinase or an activated tyrosine kinase), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate (ADC), and any combination thereof.In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or subsequent to) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor.In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours after) administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a bone marrow cell activator or therapy locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the bone marrow cell activator or therapy is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered both systemically and intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0108] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering (e.g., orally, intravenously, subcutaneously, and / or intratumorally) to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a myeloid cell activating agent or therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., a radiation therapy), wherein the individual a) has received, is receiving, or will receive an administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and wherein the method further comprises administering an immune cell (e.g., any of the immune cells described herein). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the individual has received, is receiving, or will receive a myeloid cell activating agent or therapy (e.g., a TLR agonist, e.g., a radiation therapy). In some embodiments, the individual is under an inflammatory response or has a persistent infection. In some embodiments, the immune cell is derived from the same individual. In some embodiments, the immune cell comprises a monocyte or a macrophage. In some embodiments, the immune cell comprises a T cell (e.g., a CAR-T cell). In some embodiments, the immune cell comprises an NK cell (e.g., a CAR-NK cell). In some embodiments, the immune cell comprises a neutrophil (e.g., a CAR-expressing neutrophil cell). In some embodiments, the immune cell comprises an antigen presenting cell (APC). In some embodiments, the immune cell is engineered to express a chimeric receptor that specifically binds to a tumor antigen. In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has from about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently.In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, cytokine or biologically active fragment thereof, immune cell, and / or bone marrow cell activating agent or therapy is administered within 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and immune cell are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, cytokine or biologically active fragment thereof, immune cell, and / or bone marrow cell activating agent or therapy are administered simultaneously. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, cytokine or biologically active fragment thereof, immune cell, and / or bone marrow cell activating agent or therapy are administered concurrently. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, cytokine or biologically active fragment thereof, immune cell, and / or bone marrow cell activating agent or therapy are administered sequentially. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, and bone marrow cell activating agent or therapy are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, tyrosine kinase inhibitor, bone marrow cell activating agent or therapy, and / or TNFa inhibitor are administered intermittently to the individual. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinylpyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, semdustib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or less) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a bone marrow cell activating agent or therapy locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the bone marrow cell activating agent or therapy is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0109] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa neutralizing antibody and a TLR agonist, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least 3, 4, or 5 times). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa neutralizing antibody and a TLR agonist, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the TLR agonist are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor daily (e.g., daily for at least 7 days). In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual at least twice at an interval of no more than every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual for at least two cycles, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once (e.g., at least twice or three times) in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously or subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the TLR agonist and / or the TNFa neutralizing antibody is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the TLR agonist is administered daily for at least 2, 3, 4, 5, 6, or 7 days.In some embodiments, the TLR agonist is administered intermittently. In some embodiments, the TNFα neutralizing antibody is administered at least once a week, every five days, every three days, or daily. In some embodiments, the TNFα neutralizing antibody is administered intermittently. In some embodiments, the TNFα neutralizing antibody is administered to the individual for at least two cycles, wherein each cycle is from about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the TLR agonist are administered simultaneously, concurrently, or sequentially. In some embodiments, the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises triacylated lipoprotein, peptidoglycan, zymosan, and / or Pam3CSK4. In some embodiments, the TLR agonist activates any of TLR2, TLR3, TLR4, TLR5, and TLR6, optionally wherein the TLR agonist comprises diacylated lipopeptide, heat shock protein, HMGB1, uric acid, fibronectin, and / or ECM protein. In some embodiments, the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and / or CBLB612. In some embodiments, the TLR agonist activates TLR3, optionally wherein the TLR agonist comprises dsRNA, Poly I:C, PolyICIC, Poly-IC12U, IPH302, ARNAX, and / or MPLA. In some embodiments, the TLR agonist activates TLR4, optionally wherein the TLR agonist comprises LPS, lipophosphosaccharide beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, and / or GLA-SE. In some embodiments, the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and / or M-VM3. In some embodiments, the TLR agonist activates TLR6. In some embodiments, the TLR agonist activates TLR7 or TLR8, optionally wherein the TLR agonist comprises ssRNA, CpG-A, Poly G10, and / or Poly G3. In some embodiments, the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and / or R848. In some embodiments, the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463 and / or R848. In some embodiments, the TLR agonist activates TLR9, optionally wherein the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and / or ODN M362.In some embodiments, the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam3CSK4. In some embodiments, the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises Toxoplasma gondii. Toxoplasma gondii) profilin. In some embodiments, the TLR agonist activates TLR12. In some embodiments, the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV. In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and / or TLR9. In some embodiments, the TLR agonist activates TLR9, TLR4, and TLR7 / 8. In some embodiments, the TLR agonist comprises CpG, poly I:C, and / or R848. In some embodiments, the TLR agonist comprises CpG, poly I:C, and R848, e.g., in a 1:1:1 ratio. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the TLR agonist are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the TLR agonist, and / or the TNFα neutralizing antibody are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa neutralizing antibody. In some embodiments, the TNFa neutralizing antibody is administered prior to (e.g., within about any of 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a TLR agonist locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the TLR agonist is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0110] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa neutralizing antibody and a TLR agonist, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7, and TLR8. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the TLR agonist and / or the TNFa neutralizing antibody is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the TLR agonist is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the TLR agonist is administered intermittently. In some embodiments, the TNFa neutralizing antibody is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa neutralizing antibody is administered intermittently. In some embodiments, the TNFa neutralizing antibody is administered to the individual for at least two cycles, wherein each cycle has from about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the TLR agonist are administered on the same day. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and / or the TLR agonist is administered at least two times (e.g., at least three times, four times, five times, or six times). In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the TLR agonist are administered for at least two cycles (e.g., at least three cycles), optionally wherein in each cycle the SHP-1 inhibitor and / or 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). In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the TLR agonist are administered simultaneously, concurrently, or sequentially. In some embodiments, each cycle has from about seven to about twenty days. In some embodiments, the TLR agonist activates a TLR on a macrophage, optionally wherein the TLR comprises TLR9.In some embodiments, the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9). In some embodiments, the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4, and TLR7 / 8). In some embodiments, the TLR agonist comprises CpG, poly I:C, and / or R848. In some embodiments, the TLR agonist comprises CpG, poly I:C, and R848, e.g., in a 1:1:1 ratio. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, and TLR agonist are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, tyrosine kinase inhibitor, TLR agonist, and / or TNFα neutralizing antibody are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, semdustib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa neutralizing antibody. In some embodiments, the TNFa neutralizing antibody is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or less, before) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered sequentially (e.g., before or after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a TLR agonist locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the TLR agonist is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0111] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor and a STING activator (e.g., cGAMP), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the STING activator are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual at an interval of no more than once every three days for at least two times. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual for at least two cycles, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once (e.g., at least two or three times) in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously or subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the STING activator are administered sequentially, simultaneously, or concurrently.In some embodiments, the STING activator is cyclic-guanosine monophosphate- adenosine monophosphate (cGAMP, e.g., 3'3' cGAMP, e.g., 2'3' cGAMP), a bacterial vector (e.g., SYNB1891, STACT-TREX-1), a CDN compound (e.g., ADU-S100, BI-STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3'3'-cyclic AIMP), a non-CDN small molecule (e.g., ALG-031048, E7755, JNJ-'6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI-10001), a nanovaccine (e.g., PC7A NP, cCAMP-NP, ONM-500), or an antibody-drug conjugate (e.g., XMT-2056, CRD-5500). In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the STING activator are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the STING activator, and / or the TNFα neutralizing antibody are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa neutralizing antibody. In some embodiments, the TNFa neutralizing antibody is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or less, before) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered sequentially (e.g., before or after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a STING activating agent locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the STING activating agent is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0112] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a radiation therapy, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and optionally wherein the method comprises administering to the individual a SHP-1 inhibitor and / or a tyrosine kinase inhibitor for at least two cycles, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the radiation therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the radiation therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three days to about seven days. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual at least twice at intervals of no more than once every three days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the radiation therapy are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the radiation therapy comprises irradiation at a site of a cancer to be treated. In some embodiments, the radiation therapy comprises irradiation at a site different from a site of a cancer to be treated. In some embodiments, the dose of the radiation therapy 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), whole-body radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectors.In some embodiments, the radiation therapy is external beam radiation therapy, which optionally includes 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, which optionally includes interstitial brachytherapy, intracavitary brachytherapy, intraluminal radiotherapy, and intravenously administered radiolabeled molecules. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the individual is administered the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the radiation therapy until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is administered the SHP-1 inhibitor, the tyrosine kinase inhibitor, the radiation therapy, and / or the TNFα inhibitor intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibgluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, semdustib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0113] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa neutralizing antibody and a radiation therapy, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the radiation therapy comprises irradiating a site different from the site of the cancer to be treated. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the radiation therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the radiation therapy is administered intermittently. In some embodiments, the TNFa neutralizing antibody is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa neutralizing antibody is administered intermittently. In some embodiments, the TNFa neutralizing antibody is administered to the individual for at least two cycles, wherein each cycle has from about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least two (at least three, four, five, or six) times. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual at least two times at an interval of no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual for at least two cycles, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the radiation therapy are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the radiation therapy comprises irradiating at the site of the cancer to be treated. In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer to be treated. In some embodiments, the dose of the radiation therapy 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 radioprotectors. In some embodiments, the radiation therapy is external beam radiation therapy, which optionally includes 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, which optionally includes interstitial brachytherapy, intracavitary brachytherapy, intraluminal radiation therapy, and intravenously administered radiolabeled molecules. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the radiation therapy are administered to the individual until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the radiation therapy, and / or the TNFα neutralizing antibody are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, semdustib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa neutralizing antibody. In some embodiments, the TNFa neutralizing antibody is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa neutralizing antibody is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0114] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering a TNFa neutralizing antibody and a radiation therapy, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the radiation therapy are administered on the same day. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and / or the radiation therapy is administered at least two times (e.g., at least three times, four times, five times, or six times). In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the radiation therapy is administered for at least two cycles (e.g., at least three cycles), optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the radiation therapy are administered on the same day for at least two consecutive days (e.g., at least three consecutive days) in each cycle. In some embodiments, each cycle has from about seven to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the radiation therapy are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the radiation therapy comprises irradiation at a site of the cancer to be treated. In some embodiments, the radiation therapy comprises irradiation at a site different from the site of the cancer to be treated. In some embodiments, the dose of the radiation therapy is insufficient to kill tumor cells. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the individual is administered the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the radiation therapy until the individual experiences tumor clearance.In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the radiation therapy, and / or the TNFα neutralizing antibody are administered intermittently to the individual after tumor clearance. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvoputranexone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emodin, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFα neutralizing antibody. In some embodiments, the TNFα neutralizing antibody is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor.In some embodiments, the TNFα neutralizing antibody is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0115] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a PAMP / DAMP activator, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the PAMP / DAMP activator are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the PAMP / DAMP activator and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the PAMP / DAMP activator is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has from about three days to about seven days. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual at least twice at an interval of no more than once every three days.In some embodiments, the method comprises administering to the individual a SHP-1 inhibitor and / or a tyrosine kinase inhibitor for at least two cycles, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the myeloid cell activator or therapy is a PAMP activator. In some embodiments, the PAMP activator is a triacyl lipopeptide, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosome phospholipid, Pam3Cys porin, lipoarabinomannan, double stranded RNA, poly(I:C), trypanosome lipid, paclitaxel, Pseudomonas exotoxin S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptide, single stranded RNA, imiquimod, single stranded RNA, resquimod, bacterial / viral DNA, CpG DNA, ureobacteria, or toxoplasma LPS. In some embodiments, the myeloid cell activator or therapy is a DAMP activator. In some embodiments, the DAMP activator is a defensin, HSP60, HSP70, messenger RNA, low molecular weight hyaluronan, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, or unmethylated CpG DNA. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the individual is administered the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the PAMP / DAMP activator until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is administered the SHP-1 inhibitor, the tyrosine kinase inhibitor, the PAMP / DAMP activator, and / or the TNFα inhibitor intermittently.In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or subsequent to) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor.In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a PAMP / DAMP activating agent locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the PAMP / DAMP activating agent is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered both systemically and intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0116] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a myeloid cell activating agent or therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., a radiation therapy), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least two (at least three, four, five, or six) times. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a myeloid cell activating agent or therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., a radiation therapy), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the immune checkpoint inhibitor are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently.In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle. In some embodiments, the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG / PVRL2, CEACAM1, CEACAM 5 / 6, FAK, CCL2 / CCR2, LIF, CD47 / SIRPalpha, CSF-1 (M-CSF) / CSF-1R, IL-1 / IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine.In some embodiments, the checkpoint inhibitor comprises or is lipilimumab, Cemiplimab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO-201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, Lanotuzumab (MCS110), LY3022855, SNDX-6352, Emactuzumab (RG7155), Pexidartinib (PLX3397), CAN04, Canakinumab (ACZ885), BMS-986253, Pepinemab (VX15 / 2503), Trebananib, FP-1305, Enapotamab vedotin (EnaV), or Bavituximab. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, and myeloid cell activator or therapy, and / or TNFa inhibitor is administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, tyrosine kinase inhibitor, myeloid cell activator or therapy, and / or TNFa inhibitor is administered to the individual intermittently.In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or subsequent to) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor.In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours after) administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a bone marrow cell activator or therapy locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the bone marrow cell activator or therapy is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered both systemically and intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0117] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a proinflammatory cytokine (e.g., IL-1 beta, IL-18, and / or IL-6), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least two (at least three, four, five, or six) times. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., a neutralizing antibody) and a proinflammatory cytokine (e.g., IL-1 beta, IL-18, and / or IL-6), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the proinflammatory cytokine are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently.In some embodiments, the method comprises administering to the individual a SHP-1 inhibitor and / or a tyrosine kinase inhibitor for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle. In some embodiments, the proinflammatory cytokine promotes Ml macrophages, dendritic cells (e.g., intratumorally), B cells (e.g., intratumorally), antigen presenting cells, and the like. In some embodiments, the proinflammatory cytokine comprises or is a TNF family member, IFNy, and / or GM-CSF. In some embodiments, the proinflammatory cytokine comprises IFNy. In some embodiments, the proinflammatory cytokine comprises IL-1. In some embodiments, the proinflammatory cytokine comprises any member of the TNF family other than TNFa. In some embodiments, the proinflammatory cytokine comprises IL-6. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the proinflammatory cytokine are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the proinflammatory cytokine, and / or the TNFa inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Syk inhibitor.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, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, secaitinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, before) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., before or after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a proinflammatory cytokine locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the proinflammatory cytokine is administered intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0118] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a chemotherapeutic agent (e.g., azathioprine), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least two (at least three, four, five, or six) times. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a chemotherapeutic agent (e.g., azathioprine), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the chemotherapy are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently.In some embodiments, the method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle. 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), alkyl sulfonates (e.g., busulfan), and ethylenimines (e.g., thiotepa). In some embodiments, the chemotherapeutic agent is an antimetabolite. In some embodiments, the antimetabolite is selected from the group consisting of cytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (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), 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 immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the chemotherapeutic agent are administered to the individual until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the chemotherapeutic agent, and / or the TNFa inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopoxvirus-derived xanthene-like compound A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Syk inhibitor.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, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emodin, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, secaitinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, before) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., before or after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a chemotherapeutic agent locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual (e.g., locally or systemically) an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the chemotherapeutic agent is administered intratumorally. In some embodiments, the method further comprises administering to the individual (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0119] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a cancer vaccine, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a cancer vaccine, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the cancer vaccine are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has from about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or the tyrosine kinase inhibitor to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days.In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least three consecutive days) in each cycle. In some embodiments, the cancer vaccine comprises a cell-based vaccine, a peptide-based vaccine, a viral-based vaccine, and / or a nucleic acid-based vaccine. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has from about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the cancer vaccine are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the cancer vaccine, and / or the TNFα inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin Xanthene A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800.In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within about any of 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within about any of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a cancer vaccine locally (e.g., intratumorally). In some embodiments, the method comprises administering to the individual an effective amount (e.g., locally or systemically) of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the cancer vaccine is administered intratumorally. In some embodiments, the method further comprises administering to the individual an effective amount (e.g., locally or systemically) of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0120] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and an oncolytic virus, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and an oncolytic virus, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the oncolytic virus are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days.In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least three consecutive days) in each cycle. In some embodiments, the oncolytic virus comprises or is an adenovirus (e.g., ONYX- 15, LOAd703 virus), a parvovirus, a picornavirus (e.g., H-1PV), a vaccinia virus (VACV), a reovirus (e.g., Reolysin), 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), a marabá virus or its MG1 variant, DNX2440 adenovirus, fowlpox virus, or Sendai virus. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the oncolytic virus are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the oncolytic virus, and / or the TNFα inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, stibophen, phenylhydrazinopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvusaxanthone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) the administration of the bone marrow cell activating agent or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method further comprises administering to the individual a local (e.g., intratumoral) oncolytic virus. In some embodiments, the method comprises administering to the individual an effective amount (e.g., locally or systemically) of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the oncolytic virus is administered intratumorally. In some embodiments, the method further comprises administering to the individual an effective amount (e.g., locally or systemically) of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2).In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0121] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a sonic wave therapy (e.g., high intensity focused ultrasound (HIFU), e.g., low intensity focused ultrasound (LIPUS)), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least two (at least three, four, five, or six) times. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a sonic wave therapy (e.g., high intensity focused ultrasound (HIFU), e.g., low intensity focused ultrasound (LIPUS)), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the sonic wave therapy are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently.In some embodiments, the method comprises administering to the individual the SHP-1 inhibitor and / or the tyrosine kinase inhibitor for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the sonic wave therapy are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the sonic wave therapy, and / or the TNFa inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activator. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method comprises administering sonic wave therapy at the site of the cancer to be treated. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0122] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a magnetotherapy (e.g., a pulsed magnetic field, e.g., a static magnetic field), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least two (at least three, four, five, or six) times. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and a magnetotherapy (e.g., a pulsed magnetic field, e.g., a static magnetic field), wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the magnetotherapy are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently.In some embodiments, the method comprises administering to the individual the SHP-1 inhibitor and / or the tyrosine kinase inhibitor for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the magnetotherapy are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the magnetotherapy, and / or the TNFa inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, semdustib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or subsequent to) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method comprises administering a magnetotherapy at the site of the cancer to be treated. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0123] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and an electrotherapy or electrochemical therapy, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and an electrotherapy or electrochemical therapy, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the electrotherapy or electrochemical therapy are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the bone marrow cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the bone marrow cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the bone marrow cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three days to about seven days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered intermittently.In some embodiments, the method comprises administering to the individual the SHP-1 inhibitor and / or the tyrosine kinase inhibitor for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the electrotherapy or electrochemotherapy is administered to the individual until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the electrotherapy or electrochemotherapy, and / or the TNFa inhibitor is administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, semdustib, TAK-659, bosutinib, ponatinib, serabutib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or subsequent to) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method comprises administering an electrotherapy or electrochemical therapy at the site of the cancer to be treated. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0124] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and an electrostatic therapy, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least two times (at least three, four, five, or six times). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and an electrostatic therapy, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the electrostatic therapy are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days.In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least three consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the electrostatic therapy are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the electrostatic therapy, and / or the TNFa inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopontin Xanthene A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of: Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800.In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method comprises administering electrostatic therapy at the site of the cancer to be treated. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0125] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and an antibody drug conjugate, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least two times (at least three, four, five, or six times). In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody) and an antibody drug conjugate, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof, and wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and the antibody drug conjugate are administered within 24 hours of each other (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days.In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least three consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the antibody drug conjugate are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the antibody drug conjugate, and / or the TNFa inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazono pyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvopoxvirus A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, semdustib, TAK-659, bosutinib, ponatinib, serabutib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or subsequent to) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method comprises administering an antibody drug conjugate at the site of the cancer to be treated. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0126] In some embodiments, a lymphocyte activating agent described herein is administered to an individual. For example, in some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody), a TLR agonist, and a myeloid cell activating agent or therapy, wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. 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 myeloid cell activating agent or therapy and / or the TNFa inhibitor are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the TNFa inhibitor is administered to the individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle.In some embodiments, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is administered at least three times (e.g., at least three consecutive days) in each cycle. In some embodiments, the TLR agonist activates a TLR on a macrophage, optionally wherein the TLR comprises TLR9. In some embodiments, the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9). In some embodiments, the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4, and TLR7 / 8). In some embodiments, the TLR agonist comprises CpG, poly I:C, and / or R848. In some embodiments, the TLR agonist comprises CpG, poly I:C, and R848, e.g., in a 1:1:1 ratio. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or the cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the TLR agonist are administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, the tyrosine kinase inhibitor, the TLR agonist, and / or the TNFa inhibitor are administered to the individual intermittently. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTP-I, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinylpyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), alpha-tocopherol acetate (aTA), alpha-tocopherol succinate (aTOS), parvone A (PXA), and PKC theta activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the 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 of: Src, Syk, Hck, Lck, Lyn, JAK, and Yes.In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, emibetuzumab, foratinib, sedutinib, TAK-659, bosutinib, ponatinib, serabutinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of a TNFa inhibitor. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, prior thereto) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered concurrently with the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered sequentially (e.g., prior to or after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFa inhibitor is administered immediately after (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours, after) the administration of the bone marrow cell activator or therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of both a SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the TLR agonist is administered intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered both systemically and intratumorally. In some embodiments, the method further comprises administering (e.g., locally or systemically) to the individual an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0127] In some embodiments, a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., an advanced cancer) in an individual is provided, the method comprising administering to the individual a TNFa inhibitor (e.g., an anti-TNFa neutralizing antibody), wherein the individual is selected for treatment based on having a persistent inflammatory response, and wherein the individual a) has received, is receiving, or will receive administration of a SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or biologically active fragment thereof. In some embodiments, the TNFa inhibitor is administered prior to (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes) administration of the other agent(s) described above. In some embodiments, the individual has an acute inflammatory response. In some embodiments, the inflammatory response is located in the tumor. In some embodiments, the inflammatory response is located at a site different from the tumor. In some embodiments, the individual has an inflammatory response when there are at least two (e.g., two, three, four, or five) events selected from the group consisting of: a) an increase in one or more (e.g., at least one, two, three, four, five) inflammatory cytokines (e.g., IFNy, IL-12p, TNFa, IL-6, IL-1p, IFN-a1, IFN-a2, IFN-b1), b) a decrease in one or more (e.g., at least one, two, or three) anti-inflammatory cytokines (e.g., TGFp1, TGFp2, TGFp3), c) an increase in infiltrating immune cells (e.g., T cells, NK cells, macrophages, neutrophils), d) a decrease in suppressive immune cells (e.g., MDSCs), and / or e) 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) in a tissue (e.g., tumor tissue) or immune cells (e.g., macrophages). In some embodiments, the myeloid cell activating agent or therapy and / or the TNFa inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activating agent or therapy is administered intermittently. In some embodiments, the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFa inhibitor is administered intermittently. In some embodiments, the individual is administered the TNFa inhibitor for at least two cycles, wherein each cycle has from about three days to about seven days.In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor and / or 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 base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting SHP-1 or a tyrosine kinase or an activated tyrosine kinase), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate (ADC), and any combination thereof. In some embodiments, the method comprises administering to the individual the SHP-1 inhibitor and / or tyrosine kinase inhibitor for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (e.g., at least for two consecutive days) in each cycle. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least three times (e.g., at least for three consecutive days) in each cycle. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered to the individual for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or cytokine or biologically active fragment thereof is administered at least once in each cycle, and wherein each cycle has about three days to about twenty days. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, and myeloid cell activating agent or therapy, and / or TNFα inhibitor is administered to the individual until the individual experiences tumor clearance. In some embodiments, following tumor clearance, the SHP-1 inhibitor, tyrosine kinase inhibitor, myeloid cell activating agent or therapy, and / or TNFα inhibitor is administered to the individual intermittently.In some embodiments, the SHP-1 inhibitor is selected from the group consisting of: TPI-1 and its analogues or derivatives, PTP-I, NSC-87877, NSC-87877 disodium, sodium antimony gluconate, phenylhydrazine pyrazolone (PHPS1) sulfonate, hydroxyindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotanshinone, vitamin E derivatives, tococelenol (TPGS), α-tocopherol acetate (αTA), α-tocopherol succinate (αTOS), pyroxanthone A (PXA), and PKCθ activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of: RK-20449, dasatinib, R406, entotinib, fantatinib, cedutinib, TAK-659, besutinib, ponatinib, cicatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masatitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method includes administering (e.g., locally or systemically) an effective amount of TNFα inhibitor to an individual. In some embodiments, the TNFα inhibitor is administered before (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor.In some embodiments, a TNFα inhibitor is administered immediately after the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor (e.g., within any of approximately 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours thereafter). In some embodiments, the method further includes the local (e.g., intratumoral) administration of a bone marrow cell activator or therapy to the individual. In some embodiments, the method includes administering (e.g., locally or systemically) an effective amount of both an SHP-1 inhibitor (e.g., TPI-1 or an analogue or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) to the individual. In some embodiments, both the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the bone marrow cell activator or therapy is administered intratumorally. In some embodiments, the method further includes administering (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or its biologically active fragment (e.g., IL-2) to the individual. In some embodiments, the method further includes administering to an individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascades or cytokine storms (e.g., anti-IL-6 antibody or anti-IL-1 antibody).

[0128] In some embodiments, a method is provided for treating cancer (e.g., solid tumors, such as hematologic malignancies, such as advanced cancers) in an individual, the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) to the individual, wherein the individual a) has received, is receiving, or will receive administration of an SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and wherein the individual is selected for treatment based on having persistent immunogenic cell death (ICD). In some embodiments, an individual has ICD when a sample from cancer has a higher level of one or more (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) DAMP than a reference sample (e.g., a corresponding sample in a healthy control, such as a sample from cancer prior to administration of a therapy that induces ICD). In some embodiments, a TNFα inhibitor is administered before (e.g., 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day) the administration of one or more of the other agents described above, concurrently with, or shortly thereafter (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, a bone marrow activator or therapy and / or a TNFα inhibitor are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, a bone marrow activator or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, a bone marrow activator or therapy is administered intermittently. In some embodiments, a TNFα inhibitor is administered at least once a week, every five days, every three days, or daily. In some embodiments, a TNFα inhibitor is administered intermittently. In some embodiments, a TNFα inhibitor is administered to an individual for at least two cycles, each cycle consisting of approximately three to approximately seven days. In some embodiments, an SHP-1 inhibitor and / or a tyrosine kinase inhibitor are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered intermittently. In some embodiments, DAMP is selected from the group consisting of: endoplasmic reticulum (ER) chaperone proteins (e.g., calreticulin (CALR), heat shock protein (HSP)), non-histone chromatin-binding protein high mobility cassette 1 (HMGB1), cytoplasmic protein annexin A1 (ANXA1), and small metabolites ATP and type I interferon (IFN).In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is selected from the group consisting of: small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid base inhibitors (e.g., circular RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptides, protein agents (e.g., antibodies targeting SHP-1 or tyrosine kinase or activated tyrosine kinase), protein degraders or destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof. In some embodiments, the method includes administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual for at least two cycles, further optionally wherein the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least once in each cycle, and wherein each cycle has approximately three days to approximately twenty days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., at least for two consecutive days). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least three times in each cycle (e.g., at least for three consecutive days). In some embodiments, an immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered daily. In some embodiments, an immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered intermittently. In some embodiments, an individual is administered an immune checkpoint inhibitor and / or cytokine or its bioactive fragment for at least two cycles, further optionally wherein an immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered at least once in each cycle, and wherein each cycle has approximately three days to approximately twenty days. In some embodiments, an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a bone marrow cell activator or therapy are administered to the individual until the individual experiences tumor clearance. In some embodiments, after tumor clearance, an SHP-1 inhibitor, a tyrosine kinase inhibitor, a bone marrow cell activator or therapy, and / or a TNFα inhibitor are administered intermittently to the individual. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of: TPI-1 and its analogues or derivatives, PTP-I, NSC-87877, NSC-87877 disodium, sodium antimony gluconate, phenylhydrazine pyrazolone (PHPS1) sulfonate, hydroxyindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotanshinone, vitamin E derivatives, tococelenol (TPGS), α-tocopherol acetate (αTA), α-tocopherol succinate (αTOS), Pseudomonas xanthone A (PXA), and PKCθ activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor.In some embodiments, the tyrosine kinase inhibitor is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of: RK-20449, dasatinib, R406, entotinib, fantatinib, cedutinib, TAK-659, besutinib, ponatinib, cicatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masatitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method includes administering (e.g., locally or systemically) an effective amount of TNFα inhibitor to an individual. In some embodiments, the TNFα inhibitor is administered before (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, a TNFα inhibitor is administered immediately after the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor (e.g., within any of approximately 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours thereafter). In some embodiments, the method further includes the local (e.g., intratumoral) administration of a bone marrow cell activator or therapy to the individual. In some embodiments, the method includes administering (e.g., locally or systemically) an effective amount of both an SHP-1 inhibitor (e.g., TPI-1 or an analogue or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) to the individual. In some embodiments, both the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the bone marrow cell activator or therapy is administered intratumorally.In some embodiments, the method further includes administering (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or its biologically active fragment (e.g., IL-2) to the individual. In some embodiments, the method further includes administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascades or cytokine storms (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0129] In some embodiments, this application provides a method of treating cancer (e.g., solid tumors, such as hematologic malignancies, such as advanced cancers) in an individual, the method comprising administering to the individual a) a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody), b) tyrosine kinase expression or activation of defective monocytes or macrophages, and c) a bone marrow cell activator or therapy (e.g., a TLR agonist, such as a STING activator, such as radiotherapy), wherein the individual a) has received, is receiving, or will receive administration of an SHP-1 inhibitor and / or a tyrosine kinase inhibitor; and / or b) has received, is receiving, or will receive an immune checkpoint inhibitor and / or cytokines or biologically active fragments thereof. In some embodiments, the TNFα inhibitor is administered before (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day), concurrently with, or shortly thereafter (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes) the administration of one or more of the other agents described above. In some embodiments, the monocytes or macrophages are derived from the same individual. In some embodiments, monocytes or macrophages are engineered to express chimeric receptors targeting tumor antigens. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors, monocytes or macrophages, and bone marrow cell activators or therapies are administered at 24-hour intervals (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes). In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors, monocytes or macrophages, and bone marrow cell activators or therapies are administered simultaneously, in parallel, or sequentially. In some embodiments, monocytes or macrophages are administered before bone marrow cell activators or therapies. In some embodiments, monocytes or macrophages are administered after bone marrow cell activators or therapies. In some embodiments, monocytes or macrophages are administered before SHP-1 inhibitors and / or tyrosine kinase inhibitors. In some embodiments, monocytes or macrophages are administered after SHP-1 inhibitors and / or tyrosine kinase inhibitors. In some embodiments, immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered daily. In some embodiments, immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered intermittently. In some embodiments, the individual is administered immune checkpoint inhibitors and / or cytokines or their bioactive fragments for at least two cycles, further optionally wherein the immune checkpoint inhibitor and / or cytokines or their bioactive fragments are administered at least once in each cycle, and wherein each cycle has approximately three days to approximately twenty days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a bone marrow cell activator or therapy until the individual experiences tumor clearance.In some embodiments, after tumor clearance, an SHP-1 inhibitor, a tyrosine kinase inhibitor, a bone marrow cell activator or therapy, and / or a TNFα inhibitor are administered intermittently to the individual. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of: TPI-1 and its analogs or derivatives, PTP-I, NSC-87877, NSC-87877 disodium, sodium antimony gluconate, phenylhydrazine pyrazolone (PHPS1) sulfonate, hydroxyindole, NSC-117199, salicylic acid, diterpenoid quinones, cryptotanshinone, vitamin E derivatives, tococelenol (TPGS), α-tocopherol acetate (αTA), α-tocopherol succinate (αTOS), pyroxanthone A (PXA), and PKCθ activators. In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling. In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more of the following: Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of: RK-20449, dasatinib, R406, entotinib, fantatinib, cedutinib, TAK-659, besutinib, ponatinib, cicatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK-20466, masatitinib, ponatinib, and NVP-BEP800. In some embodiments, the tyrosine kinase inhibitor does not inhibit or weakly inhibits one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method includes administering (e.g., locally or systemically) an effective amount of TNFα inhibitor to an individual. In some embodiments, the TNFα inhibitor is administered before (e.g., within any of about one week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor.In some embodiments, a TNFα inhibitor is administered immediately after the administration of a bone marrow cell activator or therapy and / or an SHP-1 pathway inhibitor (e.g., within any of about 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 1 hour, 2 hours, or 3 hours thereafter). In some embodiments, the method further includes the local (e.g., intratumoral) administration of a bone marrow cell activator or therapy to the individual. In some embodiments, the method includes administering (e.g., locally or systemically) an effective amount of both an SHP-1 inhibitor (e.g., TPI-1 or an analogue or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) to the individual. In some embodiments, both the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the bone marrow cell activator or therapy is administered intratumorally. In some embodiments, the method further includes administering (e.g., locally or systemically) an effective amount of both an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or its biologically active fragment (e.g., IL-2) to the individual. In some embodiments, the method further includes administering to an individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascades or cytokine storms (e.g., anti-IL-6 antibody or anti-IL-1 antibody).

[0130] In some embodiments, a method of treating cancer (e.g., solid tumors, such as hematologic malignancies, such as advanced cancers) in an individual is provided, the method comprising administering (e.g., orally, intravenously, subcutaneously, and / or intratumorally) a TNFα inhibitor (e.g., a neutralizing antibody) and immune cells (e.g., T cells, such as CAR-T cells, such as antigen-specific T cells) to the individual. In some embodiments, the immune cells comprise T cells. In some embodiments, the immune cells are derived from the same individual. In some embodiments, the immune cells are derived from a donor different from the individual. In some embodiments, the T cells are engineered to express a chimeric receptor (e.g., CAR) that specifically binds to a tumor antigen. In some embodiments, the CAR specifically binds to an antigen selected from the group consisting of: CD19, CD20, CD22, HER2, IL13Ra2, MUC1, PSMA, EGFR, MSLN, CEA, and BMCA. In some embodiments, the CAR specifically binds to CD19. In some embodiments, the CAR specifically binds to CD22. In some embodiments, the CAR-T cells are administered to the individual at a dose effective in treating cancer. In some implementations, the immune cells contain at least about 0.1 x 10⁻⁶ cells. 6 0.5 x 10 6 1 x 10 6 2 x 10 6 2.5 x 10 6 3x10 64 x 10 6 5 x 10 6 5.5 x 10 6 6 x 10 6 6.5 x 10 6 7 x 10 6 7.5 x 10 6 8 x 10 6 8.5 x 10 6 9x10 6 9.5 x 10 6 10 7 One T cell (e.g., CAR T cells or antigen-specific T cells) per kg individual (e.g., human individual). In some embodiments, the immune cells comprise at least about 10 6 2x10 6 5x10 6 10 7 2x10 7 5x10 7 10 8 2x10 8 2.5x10 8 3 x 10 8 4 x 10 8 5x10 8 6 x 10 8 7 x 10 8 7.5 x 10 8 8 x 10 8 9 x 10 8 Or 1x10 9Individual T cells (e.g., CAR T cells or antigen-specific T cells). In some embodiments, CAR-T cells are administered systemically (e.g., intravenously, subcutaneously, or intraperitoneally) or locally (e.g., within a tumor). In some embodiments, T cells (e.g., CAR-T cells) are administered to an individual in a single dose. In some embodiments, T cells (e.g., CAR-T cells) are administered to an individual until the individual experiences tumor clearance. In some embodiments, a TNFα inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., within a tumor). In some embodiments, a TNFα inhibitor is administered to an individual at least once a week, once every five days, once every three days, or daily. In some embodiments, the individual is administered a TNFα inhibitor for at least two cycles, each cycle having approximately three to approximately seven days. In some embodiments, the TNFα inhibitor is administered before (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day) the administration of immune cells (e.g., each dose of immune cells), concurrently with, or shortly after (e.g., within 6 hours, 5 hours, 4 hours, 3 hour...

Claims

1. A method of treating cancer in an individual, the method comprising administering to the individual a) a myeloid cell activator or therapy and b) a TNFa inhibitor.

2. The method of claim 1, wherein the method further comprises administering to the individual a SHP-1 pathway inhibitor.

3. A method of treating cancer in an individual, the method comprising administering to the individual a TNFa inhibitor and a SHP-1 pathway inhibitor, optionally wherein the individual is under an inflammatory response, optionally wherein the inflammatory response is characterized by: a) acute inflammation, b) cytokine release syndrome, or c) an increase in the level of each of: 1) at least two or three of TNFa, IL-6, IFN-g, and IFN-a, and / or 2) at least two or three of CCL2, CCL5, CXCL1, and CXCL10, further optionally wherein the inflammatory response is characterized by an increase in the level of IL-2, IL-12, IL1b, and / or IL-10.

4. The method of claim 2 or 3, wherein the SHP-1 pathway inhibitor comprises a SHP-1 inhibitor, optionally wherein the SHP-1 inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., siRNA, shRNA, antisense RNA, microRNA), a nucleic acid base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., a CRISPR, ZFN, or TALENS system), a peptide agent, a protein agent (e.g., an antibody agent targeting SHP-1), a protein degradation or destabilization agent, a protein modified with a non-natural amino acid, an antibody-directed therapy, an antibody drug conjugate, and any combination thereof.

5. The method of claim 4, wherein the SHP-1 inhibitor is selected from the group consisting of TPI-1 and analogs or derivatives thereof, PTPI, NSC-87877, NSC-87877 disodium, sodium stibogluconate, phenylhydrazinylpyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpene quinone, cryptotanshinone, vitamin E derivatives, tocophersolan (TPGS), a-tocopherol acetate (aTA), a-tocopherol succinate (aTOS), parvone A (PXA), and a PKC theta activator.

6. The method of claim 4 or claim 5, wherein the SHP-1 inhibitor is TPI-1 or an analog or derivative thereof.

7. The method of any one of claims 1-6, wherein the myeloid cell activator or therapy activates cells selected from any of the following: macrophages with an Ml phenotype, intratumoral dendritic cells, intratumoral B cells, antigen presenting cells, and any combination thereof.

8. The method of any one of claims 1-7, wherein the myeloid cell activator or therapy is selected from the group consisting of: a STING activator, a Toll-like receptor (TLR) agonist, a PAMP / DAMP activator, a chemotherapy, a proinflammatory cytokine, a vaccine (e.g., a cancer vaccine), a bacterium or component thereof, a virus or component thereof, a fungus or component thereof, an immune cell, a sonic wave therapy, a magnet therapy, an electric therapy, a cryotherapy, a surgery, a heat therapy, a radiation therapy, a radiopharmaceutical therapy, a static electric therapy, an antibody drug conjugate, and any combination thereof.

9. The method of claim 8, wherein the myeloid cell activator or therapy is a STING activator or a Toll-like receptor (TLR) agonist.

10. The method of claim 8 or claim 9, wherein the myeloid cell activator or therapy comprises a TLR agonist, optionally wherein the TLR agonist activates TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, and / or zymosan, further optionally wherein the TLR agonist comprises CpG, poly I:C, and / or R848.

11. The method of claim 8, wherein the myeloid cell activator or therapy comprises a STING activator, optionally wherein the STING activator is selected from the group consisting of: 2'3'-cGAMP, ADU-s100, G10, SR-717, Vadimezan (DMXAA; ASA-404), Sting agonist-20, MSA-2, diABZI STING agonist-1, cGAMP (cyclic GMP-AMPP), STING agonist-3, and c-di-AMP (Cyclic Diadenylate) Sodium.

12. The method of claim 8, wherein the myeloid cell activator or therapy comprises an immune cell.

13. The method of claim 12, wherein the immune cells comprise T cells, optionally wherein the T cells express a chimeric antigen receptor (CAR) or an antigen-specific TCR, optionally the immune cells comprise at least about 10 6 , 2 x 10 6 , 5 x 10 6 , 10 7 , 2 x 10 7 , 5 x 10 7 , 10 8 , 2 x 10 8 , 5 x 10 8 T cells, further optionally wherein the method comprises administering at least two or three doses of the immune cells.

14. The method of any one of claims 1-13, wherein the TNFa inhibitor is selected from the group consisting of: a small molecule inhibitor, a neutralizing antibody, a TNFa receptor blocking antibody, a soluble TNFa receptor, a short interfering RNA (siRNA) targeting TNFa, a chemical inhibitor of TNFa mRNA stability, an inhibitor of TNFa converting enzyme (TACE), and a derivative thereof.

15. The method of claim 14, wherein the TNFa inhibitor is a TNFa neutralizing antibody, further optionally wherein the antibody is selected from the group consisting of: infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol.

16. The method of any one of claims 1-15, wherein the method further comprises administering to the individual an effective amount of a lymphocyte activator.

17. The method of claim 16, wherein the lymphocyte is a T cell.

18. The method of claim 16 or claim 17, wherein the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolic modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacterium or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T-cell engager (BiTE), an antibody-drug conjugate, and any combination thereof.

19. The method of any one of claims 1-18, wherein the TNFa inhibitor is administered within two weeks prior to, concurrently with, or within 3 hours after administration of a) the myeloid cell activating agent or therapy and / or b) the SHP-1 pathway inhibitor.

20. The method of any one of claims 2-19, wherein the TNFa inhibitor is administered within two weeks prior to, concurrently with, or within 3 hours after administration of the SHP-1 pathway inhibitor.

21. The method of any one of claims 2-20, wherein the SHP-1 signaling pathway inhibitor is administered systemically, optionally wherein the SHP-1 signaling pathway inhibitor is administered orally, intravenously, subcutaneously, or intraperitoneally.

22. The method of any one of claims 2-20, wherein the SHP-1 signaling pathway inhibitor is administered locally, optionally wherein the SHP-1 signaling pathway inhibitor is administered intratumorally or locally.

23. The method of any one of claims 1-22, wherein the myeloid cell activating agent or therapy is administered systemically, optionally wherein the myeloid cell activating agent or therapy is administered orally, intravenously, subcutaneously, or intraperitoneally.

24. The method of any one of claims 1-22, wherein the myeloid cell activating agent or therapy is administered locally, optionally wherein the inhibitor of the myeloid cell activating agent or therapy is administered intratumorally or locally.

25. The method of any one of claims 1-24, wherein the myeloid cell activating agent or therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days.

26. The method of any one of claims 2-25, wherein the SHP-1 signaling pathway inhibitor is administered daily for at least 2, 3, 4, 5, 6, or 7 days.

27. The method of any one of claims 2-26, wherein the SHP-1 pathway inhibitor and the myeloid cell activating agent or therapy are administered within 24 hours of each other, optionally wherein the SHP-1 pathway inhibitor and the myeloid cell activating agent or therapy are administered simultaneously or concurrently to the individual.

28. The method of any one of claims 1-27, wherein the TNFa inhibitor is administered at least once a week, once every five days, once every three days, or daily.

29. The method of any one of claims 1-27, wherein the TNFa inhibitor is administered no more than about once a week.

30. The method of any one of claims 1-29, wherein the method further comprises assessing TNFa levels (e.g., serum or blood TNFa levels) in the individual.

31. The method of any one of claims 1-30, wherein the method further comprises administering an IL-6 inhibitor.

32. The method of any one of claims 1-31, wherein the method comprises administering at least two doses of the TNFa inhibitor, optionally wherein the two doses of the TNFa inhibitor are separated by a) at least 2, 3, 4, 5, 6, or 7 days, or b) at most 4, 3, 2, or 1 week, 6 days, or 5 days.

33. The method of any one of claims 1-32, wherein the TNFa inhibitor is administered to the individual for at least two cycles, wherein each cycle has from about three days to about seven days.

34. The method of any one of claims 2-33, wherein the method comprises administering both a tyrosine kinase inhibitor and a SHP-1 inhibitor.

35. The method of any one of claims 1-34, wherein the method comprises administering a) a SHP-1 inhibitor, optionally the SHP-1 inhibitor is TPI-1 or an analog or derivative thereof; b) a TLR agonist, optionally wherein the TLR agonist activates TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, and / or zymosan; and c) a TNFa inhibitor, optionally wherein the TNFa inhibitor is an anti-TNFa antibody.

36. The method of any one of claims 1-35, wherein the method comprises administering a) a SHP-1 inhibitor, optionally the SHP-1 inhibitor is TPI-1 or an analog or derivative thereof; b) a STING activator; and c) a TNFa inhibitor, optionally wherein the TNFa inhibitor is an anti-TNFa antibody.

37. The method of any one of claims 1-36, wherein the method comprises administering a) a SHP-1 inhibitor, optionally the SHP-1 inhibitor is TPI-1 or an analog or derivative thereof; b) radiation therapy; and c) a TNFa inhibitor, optionally wherein the TNFa inhibitor is an anti-TNFa antibody.

38. The method of any one of claims 2-37, wherein the SHP-1 pathway inhibitor and the myeloid cell activating agent or therapy are administered to the individual until the individual experiences tumor clearance.

39. The method of any one of claims 16-38, wherein the lymphocyte activating agent is a cytokine, wherein the cytokine comprises IL-2, IL-4, IL-7, IL-9, IL-21, or IL-15, or a biologically active derivative thereof, optionally the cytokine comprises IL-2 or a biologically active derivative thereof.

40. The method of any one of claims 16-39, wherein the lymphocyte activating agent is an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody.

41. The method of claim 39 or claim 40, wherein the cytokine and / or the anti-PD-1 antibody is administered to the individual every day for at least 2, 3, 4, 5, 6, or 7 days, optionally wherein the cytokine and / or the anti-PD-1 antibody is administered to the individual for at least two cycles, wherein each cycle has about three days to about 20 days.

42. The method of any one of claims 1-41, wherein the individual does not experience grade 2-4 cytokine release syndrome or proinflammatory organ damage.

43. The method of any one of claims 1-42, wherein administration of the TNFa inhibitor does not impair or weakly impairs tumor clearance.

44. The method of any one of claims 1-43, wherein the cancer is a) a solid tumor or a hematological cancer, b) an advanced cancer, and / or c) resistant or refractory to radiotherapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

45. The method of any one of claims 1-44, wherein the individual is a human. ​ ​ ​

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