Compositions and methods for mitigating adverse effects of therapy

Abstract

This application provides a method for treating cancer in an individual, the method comprising administering a myeloid cell activator or myeloid cell activation therapy (such as a TLR agonist or STING agonist) and a TNFα inhibitor to the individual. In some cases, the method further comprises administering an SHP-1 inhibitor and / or a tyrosine kinase inhibitor to the individual, and optionally further comprising administering a lymphocyte activator, such as a cytokine (such as IL-2) and / or an immune checkpoint inhibitor (such as anti-PD-1).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits and priority of U.S. Provisional Application No. 63 / 490,995, filed on 17 March 2023, and U.S. Provisional Application No. 63 / 581,184, filed on 7 September 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] Field of Invention The present invention relates to compositions and methods for treating diseases (e.g., cancer), comprising administering a TNFα inhibitor and a myeloid cell activator or performing myeloid cell activation therapy, and optionally administering a SHP-1 inhibitor and / or a tyrosine kinase inhibitor. [Background technology]

[0003] Background of the Invention In cancers such as solid tumors, intratumoral myeloid leukocytes, including macrophages (i.e., tumor-associated macrophages or TAMs) and myeloid-derived suppressor cells (MDSCs), play a crucial role in regulating immunosuppression of the tumor microenvironment (TME), which aids tumor growth and contributes to tumor resistance to immunotherapy. One key mechanism by which myeloid leukocytes adapt to an immunosuppressive phenotype or enhance their immunosuppressive capacity after tumor therapy is via cell surface inhibitory receptors (iRs), which, when activated, are facilitated by extracellular ligand binding and induce multiple pathways of negative regulation via cytoplasmic domain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that activate SHP-1, a central signaling modulator, leading to the dephosphorylation and thus inactivation of several signaling molecules. This reduces the pro-inflammatory anti-cancer response induced by therapy. In solid tumors, essential cell surface iRs, such as SIRPα, Siglec, LilRB, PirB, LAIR1, lectin receptors, and SLAM family receptors (see, e.g., Kang, XL et al., Cell Cycle 2016;15:25-40; and Zarrin, AA et al., Front Immunol. 2020;11, each incorporated herein by reference), which are regulated through the activation of SHP-1, thereby mediating subsequent downstream inhibition.

[0004] Taking into account these inhibitory mechanisms revealed in recent years, a pipeline of therapies aimed at blocking iRs (e.g., anti-LilRB1 / 2 and anti-SIRPα) and their ligands (e.g., anti-CD47) is currently underway (see, for example, Carosella, ED et al., Trends Cancer 2021;7:389-392; Yanagita, TY et al., JCI Insight 2017;2; and Zhang, W. et al., Front Immunol. 2020;11:18, the contents of each of these are incorporated herein by reference). However, these attempts, which target each iR or its ligand individually but do not target all inhibitory pathways at once, achieve only weak or partial efficacy in controlling solid tumors.

[0005] Furthermore, pro-inflammatory responses to anticancer therapy can cause cytokine release syndrome (CRS) in patients, in which case clinical symptoms include elevated circulating cytokine levels (e.g., INF-γ, CCL2, IL-10, or IL-6), acute systemic inflammatory symptoms, and secondary organ failure (e.g., nephritis, hepatitis, and / or pneumonia). CRS has been defined as a systemic inflammatory state resulting from potent systemic immune activation induced by cellular immune responses. Currently, there are several approaches to managing CRS. Low-grade CRS is symptomatically managed with antihistamines, antipyretics, and fluids. More severe CRS can be managed with, for example, corticosteroid treatment or anti-IL-6 treatment (e.g., tocilizumab), although these treatments may adversely affect the effectiveness of anticancer therapy. Eliminating cancer through immune system intervention carries the risk of developing CRS, a serious adverse event that can be fatal or require the patient to discontinue anticancer treatment. Therefore, there is a need for safe and effective novel anticancer therapies. All disclosures of publications, patents, patent applications, and patent application publications referenced herein are incorporated herein by reference in their entirety. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Kang,XLet al.,Cell Cycle 2016;15:25-40 [Non-Patent Document 2] Zarrin,AAet al.,Front Immunol.2020;11 [Non-Patent Document 3] Carosella,EDet al.,Trends Cancer 2021;7:389-392 [Non-Patent Document 4] Yanagita,TYet al.,JCI Insight 2017;2 [Non-Patent Document 5] Zhang,W.et al.,Front Immunol.2020;11:18 [Overview of the project]

[0007] Brief summary of the invention In one embodiment, this application provides a method for treating cancer in an individual, the method comprising administering to the individual a) a myeloid cell activator or myeloid cell activation therapy, and b) a TNFα inhibitor. In some embodiments, the method further comprises administering to the individual an inhibitor of the SHP-1 pathway.

[0008] In another embodiment, the provided method is a method for treating cancer in an individual, comprising administering to the individual a TNFα inhibitor and an inhibitor of the SHP-1 pathway. In some embodiments, the method further comprises administering a lymphocyte activator.

[0009] In some embodiments of any of the methods described above, the individual is in an inflammatory state. In some embodiments, the inflammatory state is characterized by a) acute inflammation, b) cytokine release syndrome (e.g., grade 1 or higher, grade 2 or higher, or grade 3 or higher CRS), c) 1) increased levels of at least two or three of TNFα, IL-6, IFN-g, and IFN-a, and / or 2) increased levels of at least two or three of CCL2, CCL5, CXCL1, and CXCL10, and further optionally, the inflammatory state is characterized by increased levels of IL-2, IL-12, IL-1b, and / or IL-10.

[0010] In some embodiments of any of the methods described above, the inhibitor of the SHP-1 pathway includes an SHP-1 inhibitor. In some embodiments, the SHP-1 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., cyclic RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptides, protein agents (e.g., antibodies targeting SHP-1), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone A (PXA), and PKCθ activators. In some embodiments, the SHP-1 inhibitor is TPI-1 or its analogs or derivatives.

[0011] In some embodiments of any of the methods described above, the SHP-1 pathway inhibitors include tyrosine kinase inhibitors. In some embodiments, the tyrosine kinase inhibitors are selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid base inhibitors (e.g., cyclic RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptide agents, protein agents (e.g., antibody agents targeting tyrosine kinase or activated tyrosine kinase), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK-20449, dasatinib, R406, entospretinib, hostamatinib, 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.

[0012] In some embodiments of any of the methods described above, the tyrosine kinase inhibitor inhibits one of Src, Syk, Hck, Lck, Lyn, JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation. In some embodiments, the one or more kinases involved in T cell activation include one or more of Lck, Fyn, Zap70, Syk, and Csk. In some embodiments, the tyrosine kinase inhibitor is an inhibitor of a tyrosine kinase of the Src family.

[0013] In some embodiments of any of the methods described above, the SHP-1 pathway inhibitor is an antibody that blocks a cell surface inhibitory receptor. In some embodiments, the antibody that blocks the cell surface inhibitory receptor is selected from one of LILRB1, LILRB2, LILRB3, LILRB4, LILRB5, SIRPα, 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.

[0014] In some embodiments of any of the methods described above, the pro-inflammatory agent capable of activating myeloid cells (i.e., myeloid cell activator or myeloid cell activation therapy) activates cells selected from any one of macrophages having the M1 phenotype, tumor dendritic cells, tumor B cells, antigen-presenting cells, and any combination thereof. In some embodiments, the myeloid cell activator or myeloid cell activation 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 their components, viruses or their components, fungi or their components, immune cells, sound therapy, magnetic therapy, electrotherapy, cryotherapy, surgery, hyperthermia, radiotherapy, radiopharmaceutical therapy, electrostatic therapy, antibody-drug conjugates, and any combination thereof.

[0015] In some embodiments according to any of the above methods, the myeloid cell activator or myeloid cell activation 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.

[0016] In some embodiments according to any of the above methods, the myeloid cell activator or myeloid cell activation 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 sodium c-di-AMP (cyclic diadenylate).

[0017] 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 a chimeric antigen receptor (CAR) or an antigen-specific TCR. In some embodiments, the immune cells are at least about 10 6 , 2×10 6 , 5×10 6 , 10 7 , 2×10 7 , 5×10 7 , 10 8 , 2×10 8 , 5×l0 8The method includes 1 T cell. In some embodiments, the method includes administering immune cells at least two or three times (i.e., two to three administrations of immune cells). 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., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes) thereafter.

[0018] In some embodiments of any of the methods described above, the TNFα inhibitor is selected from the group consisting of small molecule inhibitors, neutralizing antibodies, TNFα receptor blocking antibodies, soluble TNFα receptors, TNFα-targeting small interfering RNAs (siRNAs), chemical inhibitors of TNFα mRNA stability, inhibitors of TNFα-converting enzyme (TACE), and derivatives thereof. In some embodiments, the TNFα inhibitor is a TNFα neutralizing antibody. In some embodiments, the antibody is selected from the group consisting of infliximab, adalimumab, etanercept, golimumab, and certolizumab.

[0019] In some embodiments of any of the methods described above, the method further comprises administering an effective amount of a lymphocyte activator to an individual. In some embodiments, the lymphocytes are T cells. In some embodiments, the lymphocyte activator is selected from the group consisting of cytokines, chemokines, metabolic modifiers, metabolite antagonists, immune checkpoint inhibitors, immune cells, cancer vaccines, bacteria or their components, viruses or their components, fungi or their components, bispecific T cell engagers (BiTEs), antibody-drug conjugates, and any combination thereof.

[0020] In some embodiments of any of the methods described above, the TNFα inhibitor is administered before the administration of a myeloid cell activator or myeloid cell activation therapy. In some embodiments, the TNFα inhibitor is administered after the administration of a myeloid cell activator or myeloid cell activation therapy. In some embodiments, the TNFα inhibitor is administered within 5, 4, 3, 2, or 1 day prior to the administration of a myeloid cell activator or myeloid cell activation therapy, or within 4 days after the administration of a myeloid cell activator or myeloid cell activation therapy.

[0021] In some embodiments of any of the methods described above, the TNFα inhibitor is administered within two weeks prior to, concurrently with, or within three hours thereafter, the administration of a) myeloid cell activator or myeloid cell activation therapy and / or b) SHP-1 pathway inhibitor.

[0022] In some embodiments of any of the methods described above, the TNFα inhibitor is administered within two weeks prior to, concurrently with, or within three hours thereafter, the administration of a) a lymphocyte activator and / or b) an inhibitor of the SHP-1 pathway.

[0023] In some embodiments of any of the methods described above, myeloid cell activator administration or myeloid cell activation therapy is performed systemically or topically. In some embodiments, TNFα inhibitors are administered systemically or topically. In some embodiments, SHP-1 signaling pathway inhibitors are administered systemically or topically. In some embodiments, systemic administration includes oral administration, intravenous administration, subcutaneous administration, or intraperitoneal administration. In some embodiments, topical administration includes intratumoral administration.

[0024] In some embodiments of any of the methods described above, the administration of the myeloid cell activator or myeloid cell activation therapy is performed daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the administration of the myeloid cell activator or myeloid cell activation therapy is performed intermittently.

[0025] In some embodiments of any of the methods described above, 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.

[0026] In some embodiments of any of the methods described above, the administration of an SHP-1 pathway inhibitor and the administration of a myeloid cell activator or myeloid cell activation therapy or lymphocyte activator are each performed within 24 hours of each other's implementation. In some embodiments, the administration of an SHP-1 pathway inhibitor and the administration of a myeloid cell activator or myeloid cell activation therapy or lymphocyte activator are performed on the individual simultaneously or in parallel.

[0027] In some embodiments of any of the methods described above, the TNFα inhibitor is administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered about once every 2 weeks or less, once a week or less, or once every 5 days or less. In some embodiments, the TNFα inhibitor is administered to the individual over at least two cycles, each cycle lasting about 3 to about 7 days.

[0028] In some embodiments of any of the methods described above, the method further includes evaluating the level of TNFα in an individual (e.g., TNFα level in serum or blood).

[0029] In some embodiments of any of the methods described above, the method further includes administering an IL-6 inhibitor.

[0030] In some embodiments of any of the methods described above, the method comprises administering a TNFα inhibitor at least twice, optionally, the two administrations of the TNFα inhibitor being at intervals of a) at least 2, 3, 4, 5, 6, or 7 days, or b) at most 4, 3, 2, or 1 week, 6, or 5 days.

[0031] In some embodiments of any of the methods described above, the SHP-1 pathway inhibitor includes a tyrosine kinase inhibitor and an SHP-1 inhibitor.

[0032] In some embodiments of any of the methods described above, the method comprises administering: a) an SHP-1 inhibitor, optionally TPI-1 or an analog or derivative thereof; b) a TLR agonist, optionally activating TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, and / or zymosan; and c) a TNFα inhibitor, optionally an anti-TNFα antibody.

[0033] In some embodiments of any of the methods described above, the method comprises administering a) an SHP-1 inhibitor, which is optionally TPI-1 or an analog or derivative thereof; b) a STING activator; and c) a TNFα inhibitor, which is optionally an anti-TNFα antibody.

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

[0035] In some embodiments of any of the methods described above, the SHP-1 pathway inhibitor is administered to the individual simultaneously with a myeloid cell activator or myeloid cell activation therapy. In some embodiments, the administration of the SHP-1 pathway inhibitor and the administration of the myeloid cell activator or myeloid cell activation therapy are performed sequentially. In some embodiments, the administration of the SHP-1 pathway inhibitor and the administration of the myeloid cell activator or myeloid cell activation therapy are performed on the individual until the individual experiences tumor remission.

[0036] In some embodiments of any of the methods described above, the individual is further intermittently administered an SHP-1 pathway inhibitor, a myeloid cell activator or myeloid cell activation therapy, and / or a TNFα inhibitor after tumor disappearance, in which case the individual was administered a myeloid cell activator or myeloid cell activation therapy, an SHP-1 pathway inhibitor, and / or a TNFα inhibitor in accordance with any of the methods described herein before tumor disappearance.

[0037] In some embodiments of any of the methods described above, the lymphocyte activator is a cytokine, which includes IL-2, IL-4, IL-7, IL-9, IL-21, or IL-15, or a bioactive derivative thereof. In some embodiments, the cytokine includes IL-2 or a bioactive derivative thereof.

[0038] In some embodiments of any of the methods described above, the myeloid cell activator or lymphocyte activator is an immune checkpoint inhibitor, and the immune checkpoint inhibitor comprises an anti-PD-1 antibody.

[0039] In some embodiments of any of the methods described above, IL-2 or a bioactive derivative and / or 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, IL-2 or a bioactive derivative and / or anti-PD-1 antibody is administered to the individual intermittently. In some embodiments, IL-2 or a bioactive derivative and / or anti-PD-1 antibody is administered to the individual over at least two cycles, each cycle lasting approximately 3 to 20 days.

[0040] In some embodiments of any of the methods described above, individuals do not develop grade 2–4 cytokine release syndrome or pro-inflammatory organ injury. In some embodiments, administration of TNFα inhibitors does not impair or slightly impairs tumor disappearance.

[0041] In some embodiments of any of the methods described above, 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 unresponsive to radiotherapy, chemotherapy agents, and / or checkpoint inhibitors. In some embodiments, the individual is a human. [Brief explanation of the drawing]

[0042] [Figure 1] A schematic diagram of the experimental design for the LLC mouse model is shown. Mice that received multiple LLC transplants were treated daily with a) TPI-1 (1 mg / kg) sc, b) PolyI:C+R848 (20 μg each) sc, and c) dasatinib (2 mg / kg) (hereinafter referred to as KX147.AB&C) in combination with IL-2 and an anti-PD1 mAb sc to promote T cell immunity. The mouse groups received an anti-TNFα mAb before the start of KX147.AB&C treatment (-1d), followed by a second dose on d5. LLC = Lewis lung cancer, sc = subcutaneous injection, ip = intraperitoneal injection, d = day, tox = toxicity, mAb = monoclonal antibody.

[0043] [Figure 2] This image shows luminescence indicating that KX147.AB&C induces rapid regression of LLC tumors with or without anti-TNFα mAbs. LLC = Lewis lung cancer, ctl = control, CR = complete response, OS = overall survival, mAb = monoclonal antibody.

[0044] [Figure 3] A shows the time course of recorded tumor volume after treatment with vehicle (n=5 mice), KX147.AB&C (n=5 mice), or KX147.AB&C combined with anti-TNFα mAb (n=7 mice). V = volume, d = days, ctl = control, CR = complete response, mAb = monoclonal antibody.

[0045] B represents the time-course overall survival rate of recorded animals after treatment with vehicle (n=5 mice), KX147.AB&C (n=5 mice), or KX147.AB&C combined with anti-TNFα mAb (n=7 mice). ctl = control, d = day, mAb = monoclonal antibody.

[0046] [Figure 4A] This shows reductions in major cytokines and chemokines in mice treated with combination therapy of anti-TNFα mAb and KX147.AB&C. It also shows cytokine levels of TNFα, IL-6, IL-10, IFNα, IFNβ, IFNγ, IL-1β, IL-12, and GM-CSF in the serum of mice treated with / not treated with anti-TNFα mAb, including major inflammatory cytokines exhibiting CRS. [Figure 4B] This shows the reduction of major cytokines and chemokines in mice treated with combination therapy of anti-TNFα mAb and KX147.AB&C. It also shows chemokine levels of CCL2, CCL5, CXCL1, and CXCL10 in the serum of mice treated / not treated with anti-TNFα mAb. H = time(s), mAb = monoclonal antibody. *** = p<0.0001.

[0047] [Figure 5] This study shows the clinical scores and weight loss of mice that underwent KX147.AB&C therapy and were simultaneously treated with / not treated with an anti-TNFα mAb. d = day, mAb = monoclonal antibody.

[0048] [Figure 6] This shows organ evaluation after euthanasia in KX147.AB&C treated mice that were administered / not administered anti-TNFα mAb. A shows organ weights of the spleen, liver, kidney, and colon. B shows photographs of the mouse colon and spleen with a ruler for size comparison. D = days, g = grams, mAb = monoclonal antibody. *** = p < 0.0001.

[0049] [Figure 7] This shows PMN infiltration in organs based on a tissue MPO assay using tissues from the spleen, liver, lung, kidney, and colon collected after euthanasia from KX147.AB&C treated mice that were administered / not administered anti-TNFα mAbs. PMN = polymorphonuclear leukocytes or neutrophils, MPO = myeloperoxidase activity assay, mAb = monoclonal antibody. *** = p < 0.0001.

[0050] [Figure 8] This shows staining of post-euthanized tissue sections to evaluate PMN infiltration into the lungs of KX147.AB&C treated mice that were administered / not administered anti-TNFα mAb. PMN = polymorphonuclear leukocytes or neutrophils, d = day, mAb = monoclonal antibody.

[0051] [Figure 9]A schematic diagram of the experimental design for the MC38 mouse model is shown. Mice that had received one or two MC38 colorectal cancer transplants were treated daily for three days with a) TPI-1 (1 mg / kg) sc, b) polyI:C+R848 (20 μg each) sc, and c) dasatinib (2 mg / kg) (hereinafter referred to as KX147.AB&C) in combination with IL-2 and an anti-PD1 mAb sc to promote T cell immunity. On day 4, the mice were treated with KX147.AB treatment (i.e., a) TPI-1 (1 mg / kg) sc and b) polyI:C+R848 (20 μg each) sc). The mouse groups received an anti-TNFα mAb before the start of KX147.AB&C treatment (-1 day), followed by a second dose on day 5. MC38 = C57Bl / 6 mouse colon adenocarcinoma cell line, sc = subcutaneous injection, ip = intraperitoneal injection, d = day, tox = toxicity, mAb = monoclonal antibody.

[0052] [Figure 10] The following shows the time course of recorded tumor volume in two cases: a) when treated with a vehicle (A; n = 3 mice per group), or b) when treated daily with KX147.AB&C for 3 days, followed by combination treatment with KX147.AB, anti-TNFα mAb, IL-2, and anti-PD-1 mAb on day 4 (B; n = 4 mice). The control mice tested as shown in A included the following groups: vehicle, IL-2 alone, anti-PD-1 mAb alone, and IL-2 / anti-PD-1 mAb combination treatment. The mice tested as shown in B included: mouse #1 = MC38 implanted in both flanks; mouse #2 = MC38 implanted in one flank; mouse #3 = MC38 implanted in one flank; mouse #4 = MC38 implanted in both flanks. V = volume, d = day, ctl = control, CR = complete response, OS = overall survival, mAb = monoclonal antibody.

[0053] [Figure 11]A schematic diagram of the experimental design is shown. Mice with established MC38 colorectal cancer (200-400 mm3) were treated with αTLR, TPI-1, and dasatinib (sc), and either further treatment with anti-TNFα mAb or anti-IL-6 mAb (150 μg, ip) was performed or not. The treatment was repeated once (d1 and d2). In this model, KX147.AB&C treatment involved a) TPI-1 (3 mg / kg) sc, b) PolyI:C+R848 (20 μg each) sc, and c) dasatinib (5 mg / kg) sc. Mice were euthanized for analysis on d6 after the start of treatment. αTLR = TLR agonist, sc = subcutaneous injection, ip = intraperitoneal injection, d = day, mAb = monoclonal antibody.

[0054] [Figure 12] This shows tumor volume changes over 6 days following various treatments administered over 2 days. KX147.AB&C alone effectively controlled tumor growth and induced regression. Neither anti-TNFα mAb treatment nor anti-IL-6 mAb treatment affected the efficacy of KX147.AB&C. V=volume, d=days, NT=untreated, αTLR=TLR agonist, mAb=monoclonal antibody.

[0055] [Figure 13A] This shows FACS plot analysis of immune cell infiltration into the TME by multiple immune lineages (i.e., CD8 T cells, CD4 TH cells, NK cells, PMNs, macrophages, and MDSCs). The FACS plot for the untreated group is also shown. [Figure 13B] This shows FACS plot analysis of immune cell infiltration into the TME by multiple immune lineages (i.e., CD8 T cells, CD4 TH cells, NK cells, PMNs, macrophages, and MDSCs). The FACS plot for αTLR / TPI-1 / dasatinib therapy (KX147.AB&C) is also shown. [Figure 13C]This shows FACS plot analysis of immune cell infiltration into the TME by multiple immune lineages (i.e., CD8 T cells, CD4 TH cells, NK cells, PMNs, macrophages, and MDSCs). It also shows FACS plots of combination therapy with αTLR / TPI-1 / dasatinib (KX147.AB&C) and an anti-TNFα mAb. [Figure 13D] This shows FACS plot analysis of immune cell infiltration into the TME by multiple immune lineages (i.e., CD8 T cells, CD4 TH cells, NK cells, PMNs, macrophages, and MDSCs). It also shows FACS plots for combination therapy with αTLR / TPI-1 / dasatinib (KX147.AB&C) and an anti-IL-6 mAb. SSC = lateral scattering, FSC = forward scattering, TH = T helper cells, NK = natural killer cells, PMN = polymorphonuclear leukocytes or neutrophils, MDSC = myeloid-derived suppressor cells, αTLR = TLR agonist, mAb = monoclonal antibody, NT = untreated, d = day.

[0056] [Figure 14] Figures 13A-13D above show bar graphs of the quantified FACS results of TME analysis as described. Tc = cytotoxic T cells, TH = T helper cells, NK = natural killer cells, PMN = polymorphonuclear leukocytes or neutrophils, Mac = macrophages, MDSC = myeloid suppressor cells, αTLR = TLR agonists, mAb = monoclonal antibodies, ns = not significant, ctl = control. ** = p < 0.001. *** = p < 0.0001.

[0057] [Figure 15] This table shows the cytokine levels of TNFα, IL-6, IL-1β, IL-10, IFNα, and IFNγ, as well as the chemokine levels of CCL2, CCL5, CXCL1, and CXCL10, in the serum of mice treated with αTLR / TPI-1 / dasatinib therapy, or in combination with either an anti-TNFα mAb or an 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.

[0058] [Figure 16] Photographs of the colon and spleen of mice treated with αTLR / TPI-1 / dasatinib therapy, or in combination with either an anti-TNFα mAb or an anti-IL-6 mAb, are shown with a ruler for size comparison. αTLR = TLR agonist, mAb = monoclonal antibody.

[0059] [Figure 17] A schematic diagram of the experimental design is shown. KPC pancreatic ductal adenocarcinoma was sc-transplanted into the left and right flanks of mice. Mice were treated with KX147.AB&C for 4 days, and then the treatment was switched to KX147.AB therapy until tumor disappearance was observed. IL-2 and anti-PD-1 mAb were used in combination 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.

[0060] [Figure 18] The image shows luminescence indicating that KX147.AB&C induces rapid regression of KPC tumors, either with or without anti-TNFα mAbs. Four treatment groups were tested: (1) no treatment (control), (2) combination therapy with IL-2 and anti-PD-1 mAb, (3) combination therapy with KX147.AB&C and IL-2 and anti-PD-1 mAb, and (4) combination therapy with KX147.AB&C and IL-2, anti-PD-1 mAb, and anti-TNFα mAb. KPC = KPC pancreatic ductal adenocarcinoma, d = day, ctl = control, CR = complete response, OS = overall survival, mAb = monoclonal antibody.

[0061] [Figure 19]A schematic diagram of the experimental design is shown. Mice underwent orthotopic transplantation of KPC pancreatic ductal adenocarcinoma via ip (intracellular immunoglobulin). Mice were treated with KX147.AB&C for two days, and then the treatment was switched to KX147.AB therapy until tumor disappearance was observed. IL-2 and anti-PD-1 mAbs were used in combination to enhance T-cell immunity. Anti-TNFα mAbs were 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.

[0062] [Figure 20] The image shows luminescence indicating that KX147.AB&C induces rapid regression of KPC tumors, either with or without anti-TNFα mAbs. Three treatment groups were tested: (1) combination therapy with IL-2 and anti-PD-1 mAb, (2) combination therapy with KX147.AB&C and IL-2 and anti-PD-1 mAb, and (3) combination therapy with KX147.AB&C and IL-2, anti-PD-1 mAb, and anti-TNFα mAb. KPC = KPC pancreatic ductal adenocarcinoma, d = day, ctl = control, CR = complete response, OS = overall survival, mAb = monoclonal antibody.

[0063] [Figure 21] This shows the change in tumor volume from 2 days before treatment to 9 days after treatment in mice with scKPC tumors. Tumor growth was effectively controlled and regression was induced only when KX147.AB&C was used in combination with IL-2 and an anti-PD-1 mAb. Anti-TNFα mAbs did not affect the efficacy of KX147.AB&C. V=volume, sc=subcutaneous injection, d=days, ctl=control, CR=complete response, mAb=monoclonal antibody.

[0064] [Figure 22]This shows the change in tumor volume from 2 days before treatment to 7 days after treatment in mice with ip orthotopic KPC tumors. Tumor growth was effectively controlled and regression was induced only when KX147.AB&C was used in combination with IL-2 and an anti-PD-1 mAb. Anti-TNFα mAbs did not affect the efficacy of KX147.AB&C. V=volume, d=days, ip=intraperitoneal injection, ctl=control, CR=complete response, mAb=monoclonal antibody.

[0065] [Figure 23] The survival curves of mice treated with one of the following treatments are shown: (1) untreated (control; n=10 mice), (2) IL-2 and anti-PD-1 mAb (n=6 mice), (3) KX147.AB&C combined with IL-2 and anti-PD-1 mAb (n=6 mice), and (4) KX147.AB&C combined with IL-2, anti-PD-1 mAb, and anti-TNFα mAb (n=8 mice). Although anti-TNFα mAb did not contribute to KX147.AB&C-induced tumor clearance, its presence mitigated adverse effects, resulting in a 100% survival rate. KPC = KPC pancreatic ductal adenocarcinoma, d = day, mAb = monoclonal antibody.

[0066] [Figure 24] The following describes the two steps of the cytokine release event associated with CAR-T therapy for cancer. In Step 1, activated CAR-T cells perform effector functions, including killing cancer cells, while releasing cytokines (e.g., IFNγ, TNFα, and IL-2). In Step 2, the cytokines released by CAR-T cells induce widespread activation of macrophages and other immune and somatic cells, which together produce high levels of pro-inflammatory cytokines (e.g., IL-6) and chemokines. The activation in Step 2 results in acute reactions, leukocyte infiltration, and immune-related adverse events (irAEs).

[0067] [Figure 25A]This study demonstrates that neutralization of TNFα produced by CAR-T cells leads to suppression of macrophage activation and a reduction in pro-inflammatory cytokine production in vitro. A two-dish method for testing the in vitro effects of cytokines produced by activated CAR-T cells on macrophages is outlined. Dish 1 contains a co-culture of CD19 CAR-T cells and B-ALL leukemia cells, and dish 2 contains a human macrophage culture. Dish 2 is cultured with or without monoclonal antibody (mAb)-mediated neutralization of TNFα, IFNγ, or IL-2, along with the supernatant of dish 1. [Figure 25B] This study demonstrates that neutralization of TNFα produced by CAR-T cells suppresses macrophage activation and reduces pro-inflammatory cytokine production in vitro. It also quantifies the CAR-T cell effector function on B-ALL cells in a 24-hour co-culture in dish 1, and shows cytokine production from these activated CAR-T cells. [Figure 25C] This study demonstrates that neutralization of TNFα produced by CAR-T leads to suppression of macrophage activation and a reduction in pro-inflammatory cytokine production in vitro. The results of cytokine and chemokine release from macrophages in dish 2 after 16 hours of incubation with and without mAb-mediated neutralization of target cytokines are shown.

[0068] [Figure 26A] This study demonstrates that neutralization of TNFα produced by CAR-T cells prevents surrounding macrophages from producing high levels of IL-6 and inflammatory chemokines in vitro. The in vitro co-culture system is outlined. CD19 CAR-T cells and B-ALL cells were co-cultured with human monocyte-derived macrophages in a single dish for 24 hours at a ratio of CAR-T:B-ALL:hMac = 1:10:3 (1 × 10⁶ T cells / ml), with or without mAb-mediated cytokine neutralization. After culturing, cytokine and chemokine concentrations in the culture medium were measured by ELISA. [Figure 26B]This study demonstrates that neutralization of TNFα produced by CAR-T receptors prevents surrounding macrophages from producing high levels of IL-6 and inflammatory chemokines in vitro. It also shows that CD19 CAR-T-mediated killing of B-ALL cells was unaffected by neutralization by mAb treatment. [Figure 26C] This study demonstrates that neutralization of TNFα produced by CAR-T receptors prevents surrounding macrophages from producing high levels of IL-6 and inflammatory chemokines in vitro. Changes in cytokine and chemokine levels after 24 hours of co-culture with and without mAb-mediated cytokine neutralization are shown.

[0069] [Figure 27A] This study demonstrates that prophylactic anti-TNFα neutralization prevented severe cytokine release syndrome (CRS) in a patient-derived xenograft (PDX) mouse model without impairing CAR-T antitumor efficacy. The experimental design is outlined below. The F3 B-ALL PDX mouse model was established by IV injection of B-ALL cells (1 × 10⁶ cells per mouse) isolated from F2 PDX mice. Once B-ALL cells were detectable in the peripheral blood of B-ALL xenograft mice (>10% in PBMCs), 1–2 × 10⁶ CD19 CAR-T cells were IV-injected, with or without prophylactic anti-TNFα mAb administration (ip, 100 μg, 3 hours before CAR-T infusion). Subsequently, the same dose of anti-TNFα mAb was administered weekly until the mice achieved complete response (CR). [Figure 27B] This study demonstrates that prophylactic anti-TNFα neutralization prevented severe cytokine release syndrome (CRS) in a patient-derived xenograft (PDX) mouse model without impairing CAR-T antitumor efficacy. Representative flow cytometry analyses of B-ALL cells in peripheral blood mononuclear cells (PBMCs) from F3 B-ALL PDX model mice, with and without prophylactic anti-TNFα mAb treatment, are shown. [Figure 27C]This study demonstrates that prophylactic anti-TNFα neutralization prevented severe cytokine release syndrome (CRS) in a patient-derived xenograft (PDX) mouse model without impairing CAR-T antitumor efficacy. It also shows that CAR-T proliferation and killing in B-ALL cells in an F3 B-ALL PDX model were not inhibited by prophylactic anti-TNFα mAb administration. [Figure 27D] This study demonstrates that prophylactic anti-TNFα neutralization prevented severe cytokine release syndrome (CRS) in a patient-derived xenograft (PDX) mouse model without impairing CAR-T antitumor efficacy. Overall survival (OS) of PDX mice receiving CAR-T therapy with or without prophylactic anti-TNFα mAb administration is shown. [Figure 27E] This study demonstrates that prophylactic anti-TNFα neutralization prevented severe cytokine release syndrome (CRS) in a patient-derived xenograft (PDX) mouse model without impairing CAR-T antitumor efficacy. The levels of cytokines and chemokines in the serum of PDX model mice after CAR-T therapy are shown.

[0070] [Figure 28A] This study demonstrates that prophylactic administration of anti-TNFα mAbs protected mice from CD3 / CD28 TCR ligation-induced CRS. The experimental design is outlined below. Mice that received or did not receive prophylactic anti-TNFα mAb (100 μg, ip, 3 hours prior to CD3 / CD28 mAb treatment) were administered a mixture of CD3 and CD28 ligation mAbs (50 μg each, ip) to stimulate endogenous and systemic T cell activation. Serum from treated mice was analyzed for cytokine and chemokine levels by multiplex ELISA at 0, 3, and 16 hours after CD3 / CD28 mAb treatment. [Figure 28B] This shows that prophylactic anti-TNFα mAb administration protected mice from CD3 / CD28 TCR ligation-induced CRS. The levels of cytokines and chemokines in the serum of mice after CD3 / CD28 mAb ligation are shown.

[0071] [Figure 29A] This study demonstrates that prophylactic administration of anti-TNFα mAbs alleviated CRS induced by adoptive infusion of activated T cells. The experimental design is outlined below. Mice that received prophylactic anti-TNFα mAb administration (100 μg, ip, 3 hours prior to treatment) and untreated mice were intravenously infused with 2 × 10⁷ splenocyte T cells activated by anti-CD3 / CD28 mAb ligation. Serum from treated mice was analyzed for cytokine and chemokine levels by multiplex ELISA at 0, 3, and 16 hours after infusion. [Figure 29B] This shows that prophylactic administration of anti-TNFα mAbs alleviated CRS induced by adoptive infusion of activated T cells. It also shows the levels of cytokines and chemokines in the serum of mice after a single infusion of activated splenocyte T cells. [Figure 29C] This study demonstrates that prophylactic anti-TNFα mAb administration alleviated CRS induced by adoptive infusion of activated T cells. Body weight measurements and clinical scores are shown for mice that received repeated infusions of activated splenocyte T cells (3 × iv on days 0, 2, and 4; 2 × 10⁷ cells in each infusion) with or without prophylactic anti-TNFα mAb administration. [Figure 29D] This study demonstrates that prophylactic anti-TNFα mAb administration alleviated CRS induced by adoptive infusion of activated T cells. It also shows the effects of repeated infusion of activated splenocyte T cells on spleen weight and splenomegaly findings in recipient mice, with and without prophylactic anti-TNFα mAb administration.

[0072] [Figure 30A]This study describes a topical therapy for cutaneous / subcutaneous 4T1 breast cancer. The overall experimental design is as follows: 4T1 breast cancer cells were transplanted cutaneously / subcutaneously into BalbC mice and allowed to grow into tumors for 10–15 days. After the tumor growth phase, mice received prophylactic anti-TNFα intraperitoneal (ip) injections, followed by treatment under either control or experimental conditions. Control conditions included treatment with a topical non-drug lotion (Johnson lotion alone), while experimental conditions included treatment with a topical lotion containing aTLR (polyI:C and R848) alone (Condition A), dTPI-1 alone (Condition B), or aTLR and dTPI-1 (Conditions A+B). After prophylactic TNFα treatment, all lotion treatments were administered twice daily for 9 days, and systemic anti-PD-1 (αPD-1) therapy was given to all mice on days 1, 4, and 7 of treatment. Efficacy analysis was performed on day 10 after prophylactic TNFα treatment. [Figure 30B] This document describes local therapy for cutaneous / subcutaneous 4T1 breast cancer. It also shows the quantification of tumor volume changes in 4T1 breast cancer during treatment. [Figure 30C] This describes local therapies for cutaneous / subcutaneous 4T1 breast cancer. Bioluminescence images of 4T1 breast cancer tumors in mice treated with condition A (aTLR), condition B (dTPI-1) (A+B), and systemic treatment with anti-PD-1 (αPD-1) therapy are shown. [Figure 30D] This report describes local therapies for cutaneous / subcutaneous 4T1 breast cancer. The survival rates of mice treated with each therapy are shown.

[0073] [Figure 31A] This document describes local therapies for cutaneous / subcutaneous lung cancer (LLC). Bioluminescence images are shown of lung cancer tumor (LLC) transplanted mice treated for 7 days with either a control (topical lotion only), anti-PD-1 (αPD-1) systemic treatment only, anti-PD-1 (αPD-1) systemic treatment and local aTLR+dTPI-1 treatment, or anti-PD-1 (αPD-1) systemic treatment and local aSTING and dTPI-1 treatment. All local treatments were administered twice daily, while anti-PD-1 (αPD-1) systemic treatment was administered once every 3 days. [Figure 31B]This document describes local therapy for cutaneous / subcutaneous lung cancer (LLC). It also shows the quantification of tumor volume changes during treatment.

[0074] [Figure 32A] This study demonstrates therapeutic anticancer effects through a combination of SHP-1 inhibition and T cell activation. MC38 colorectal cancer was established in C57Bl / 6 mice. After tumor formation, tumors were treated by intratumoral (it) injection using the following: (i) anti-PD-1Ab alone (αPD-1, 50 μg, every 3 days) or αPD-1 in combination with the SHP-1 inhibitor TPI-1 (1 mg / kg, every 2 days) (A), (ii) single dose of anti-CD3 antibody and anti-CD28 antibody (50 μg each) or in combination with anti-CD3 / anti-CD28 antibody and TPI-1 (B), or (iii) IL-2 (30,000 IU, every 3 days) alone or in combination with TPI-1, or in combination with IL-2, TPI-1, anti-TNFα antibody, and anti-IL-6 antibody (50 μg each) (C). The addition of neutralizing anti-TNFα and anti-IL-6 antibodies did not affect the efficacy of the treatment. (D) This shows that tumor progression did not stop when mice were treated with TPI-1 alone. iSHP-1 = SHP-1 inhibitor, V = volume. [Figure 32B] This study demonstrates therapeutic anticancer effects through a combination of SHP-1 inhibition and T cell activation. MC38 colorectal cancer was established in C57Bl / 6 mice. After tumor formation, tumors were treated by intratumoral (it) injection using the following: (i) anti-PD-1Ab alone (αPD-1, 50 μg, every 3 days) or αPD-1 in combination with the SHP-1 inhibitor TPI-1 (1 mg / kg, every 2 days) (A), (ii) single dose of anti-CD3 antibody and anti-CD28 antibody (50 μg each) or in combination with anti-CD3 / anti-CD28 antibody and TPI-1 (B), or (iii) IL-2 (30,000 IU, every 3 days) alone or in combination with TPI-1, or in combination with IL-2, TPI-1, anti-TNFα antibody, and anti-IL-6 antibody (50 μg each) (C). The addition of neutralizing anti-TNFα and anti-IL-6 antibodies did not affect the efficacy of the treatment. (D) This shows that tumor progression did not stop when mice were treated with TPI-1 alone. iSHP-1 = SHP-1 inhibitor, V = volume. [Figure 32C]This study demonstrates therapeutic anticancer effects through a combination of SHP-1 inhibition and T cell activation. MC38 colorectal cancer was established in C57Bl / 6 mice. After tumor formation, tumors were treated by intratumoral (it) injection using the following: (i) anti-PD-1Ab alone (αPD-1, 50 μg, every 3 days) or αPD-1 in combination with the SHP-1 inhibitor TPI-1 (1 mg / kg, every 2 days) (A), (ii) single dose of anti-CD3 antibody and anti-CD28 antibody (50 μg each) or in combination with anti-CD3 / anti-CD28 antibody and TPI-1 (B), or (iii) IL-2 (30,000 IU, every 3 days) alone or in combination with TPI-1, or in combination with IL-2, TPI-1, anti-TNFα antibody, and anti-IL-6 antibody (50 μg each) (C). The addition of neutralizing anti-TNFα and anti-IL-6 antibodies did not affect the efficacy of the treatment. (D) This shows that tumor progression did not stop when mice were treated with TPI-1 alone. iSHP-1 = SHP-1 inhibitor, V = volume. [Figure 32D] This study demonstrates therapeutic anticancer effects through a combination of SHP-1 inhibition and T cell activation. MC38 colorectal cancer was established in C57Bl / 6 mice. After tumor formation, tumors were treated by intratumoral (it) injection using the following: (i) anti-PD-1Ab alone (αPD-1, 50 μg, every 3 days) or αPD-1 in combination with the SHP-1 inhibitor TPI-1 (1 mg / kg, every 2 days) (A), (ii) single dose of anti-CD3 antibody and anti-CD28 antibody (50 μg each) or in combination with anti-CD3 / anti-CD28 antibody and TPI-1 (B), or (iii) IL-2 (30,000 IU, every 3 days) alone or in combination with TPI-1, or in combination with IL-2, TPI-1, anti-TNFα antibody, and anti-IL-6 antibody (50 μg each) (C). The addition of neutralizing anti-TNFα and anti-IL-6 antibodies did not affect the efficacy of the treatment. (D) This shows that tumor progression did not stop when mice were treated with TPI-1 alone. iSHP-1 = SHP-1 inhibitor, V = volume.

[0075] [Figure 33A]This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment did not affect the TLR agonist R848, TPI-1, or combinations thereof in tumor treatment. The experimental design is outlined below. Mouse pancreatic ductal adenocarcinoma cells (KPCs) were transplanted into the right flank of C57BL6 mice (5 × 10⁵, sc). At tumor formation (tumor volume approximately 200 mm³), mice were treated daily with R848 (20 μg or 60 μg, sc), TPI-1 (1 or 3 mg / kg, sc), or both R848 and TPI-1. All treatment conditions were tested with or without prophylactic anti-TNFα mAb (ip, 100 μg). [Figure 33B] This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment did not affect the TLR agonists R848, TPI-1, or combinations thereof in tumor treatment. It shows the tumor volume changes after each treatment over an 8-day treatment period. [Figure 33C] This shows that prophylactic anti-TNFα monoclonal antibody (mAb) treatment did not affect the TLR agonists R848, TPI-1, or combinations thereof in tumor treatment. It also shows immune cell infiltration into the tumor microenvironment (TME) on day 8 of treatment.

[0076] [Figure 34A] This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment alleviates cytokine release syndrome (CRS) induced by TLR agonist R848, TPI-1, and combination therapy with R848 and TPI-1. Mice that received prophylactic anti-TNFα (100 μg mAb, ip, 3 hours prior to the first treatment) and those that did not were treated daily with R848 (20 μg or 60 μg, sc), TPI-1 (1 or 3 mg / kg, sc), or a combination thereof. Mice treated with each regimen were assayed by multiplex ELISA for cytokine and chemokine release in their serum. [Figure 34B]This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment alleviated cytokine release syndrome (CRS) induced by TLR agonists R848, TPI-1, and combination therapy with R848 and TPI-1. Changes in body weight and clinical scores in mice treated over an 8-day period are shown. [Figure 34C] This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment alleviated cytokine release syndrome (CRS) induced by TLR agonist R848, TPI-1, and combination therapy with R848 and TPI-1. Analysis of both colitis and splenomegaly, symptoms of CRS, is shown 8 days after the start of treatment.

[0077] [Figure 35A] This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment did not affect the STING agonist (ADU-S100) and its combination with TPI-1 in tumor treatment. The experimental design is as follows: C57BL6 mice were transplanted with mouse pancreatic ductal adenocarcinoma (KPC, 5 × 10⁵, sc). When tumors of >150 mm³ were formed, the mice were prophylactically treated with an anti-TNFα mAb (ip, 100 μg), followed by daily treatment with ADU-S100 (100 μg / mouse, sc) with or without TPI-1 (1 mg / kg, sc). [Figure 35B] This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment did not affect the STING agonist (ADU-S100) and its combination with TPI-1 in tumor treatment. It also shows changes in KPC tumor volume over 19 days following the start of treatment. [Figure 35C] This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment did not affect the STING agonist (ADU-S100) and its combination with TPI-1 in tumor treatment. It also shows immune cell infiltration into the tumor microenvironment (TME) on day 8 of treatment.

[0078] [Figure 36A]This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment mitigates cytokine release syndrome (CRS) associated with STING agonist therapy. Mice that received prophylactic anti-TNFα (100 μg mAb, ip, 3 hours before the first STING agonist treatment) and mice that did not receive the anti-TNFα treatment were treated daily with the STING agonist ADU-S100 (100 μg / mouse, sc). Mice undergoing each treatment regimen were assayed by multiplex ELISA for cytokine and chemokine release in their serum. [Figure 36B] This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment alleviated cytokine release syndrome (CRS) associated with STING agonist therapy. Changes in body weight and clinical scores in mice treated over an 8-day period are shown. [Figure 36C] This study demonstrates that prophylactic anti-TNFα monoclonal antibody (mAb) treatment alleviated cytokine release syndrome (CRS) associated with STING agonist therapy. Analysis of both colitis and splenomegaly, symptoms of CRS, is shown 8 days after the initiation of treatment. [Modes for carrying out the invention]

[0079] Detailed description of the invention In one embodiment, this application provides a method for treating cancer in an individual, the method comprising administering to the individual a) a myeloid cell activator or myeloid cell activation therapy and b) a TNFα inhibitor. In several embodiments, this application provides a method for treating cancer in an individual, the method further comprising administering to the individual an inhibitor of the SHP-1 pathway. In another embodiment, what is provided is a method for treating cancer in an individual, the method comprising administering to the individual a TNFα inhibitor and an inhibitor of the SHP-1 pathway, the individual being under an inflammatory response or having an ongoing infection. In some embodiments, the inhibitor of the SHP-1 pathway is an SHP-1 inhibitor, e.g., TPI-1 or an analog or derivative thereof. In some embodiments, the inhibitor of the SHP-1 pathway is a tyrosine kinase inhibitor, e.g., dasatinib. In some embodiments, the inhibitor of the SHP-1 signaling pathway is administered systemically. In some embodiments, the method involves administering an inhibitor of the SHP-1 signaling pathway daily or intermittently for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the myeloid cell activator or myeloid cell activation therapy includes agents selected from the group consisting of STING activators, Toll-like receptor (TLR) agonists, PAMP / DAMP activators, chemotherapy, pro-inflammatory cytokines, cancer vaccines, bacteria or their components, viruses (e.g., oncolytic viruses) or their components, fungi or their components, sound therapy, magnetic therapy, electrotherapy, radiotherapy, radiopharmaceutical therapy, electrostatic therapy, antibody-drug conjugates, and any combination thereof. In some embodiments, the TNFα inhibitor is selected from the group consisting of small molecule inhibitors, neutralizing antibodies, TNFα receptor blocking antibodies, soluble TNFα receptors, TNFα-targeting small interfering RNA (siRNA), chemoinhibitors of TNFα mRNA stability, TNFα-converting enzyme (TACE) inhibitors, and derivatives thereof. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is performed systemically. In some embodiments, TNFα inhibitors are administered systemically.In some embodiments, the TNFα inhibitor is administered before the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (for example, within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially to the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (for example, before or after). In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). Further combination therapy methods are provided. This application is based, at least in part, on the remarkable finding that the combination of a TNFα inhibitor with a pro-inflammatory treatment that activates myeloid cells (e.g., tumor-infiltrating macrophages) and an inhibitor of one or more SHP-1 signaling pathways (potentially inhibiting the activation of the “master” inhibitory factor SHP-1) leads to dramatic reprogramming of the tumor microenvironment (TME) and enhanced activation of innate and adaptive immune cells, promoting anti-cancer immunity with minimal or no systemic toxicity or CRS. Specifically, it was found that administration of anti-TNFα neutralizing antibodies during the course of intensive anti-cancer treatment in preclinical models dramatically improved the degree of systemic toxicity and pro-inflammatory organ damage associated with the anti-cancer treatment without impairing the efficacy of the treatment. This finding is particularly noteworthy because the same effect was not observed with the administration of anti-IL-6 neutralizing antibodies, and CRS and organ damage still occurred. See Figures 4A-8, 12-16, and 23. These findings highlight the potential of using TNFα inhibition to mitigate or eliminate adverse events (e.g., CRS or pro-inflammatory organ injury) arising from the combined use of SHP-1 pathway inhibitory treatments with myeloid cell (e.g., macrophage or dendritic cell) activators. To achieve safe efficacy in cancer treatment, the possibility of inhibiting SHP-1 directly or via upstream tyrosine kinases (potentially reducing ITIM phosphorylation and SHP-1 activation) as an adjunct treatment in tumor immunotherapy may be opened up by mitigating or eliminating these adverse events. These findings have been further demonstrated in treatments including T-cell therapies such as cell-based immunotherapies (e.g., CAR-T cells). Adjunct treatments of TNFα inhibitors with cell-based immunotherapies (administered prophylactically, in parallel with cell therapy, or within a short window immediately following it (e.g., within 3 hours thereafter)) have been found to prevent CRS formation without affecting the antitumor activity of the therapeutic intervention. See, for example, Figures 34A-34C, 35A-35B, and 36A-36C.

[0080] Therefore, this application provides a novel method that can effectively reconstruct the immunosuppression imposed by the tumor state to obtain innate and adaptive immunity against cancer, while significantly preventing treatment-induced toxicity, thereby achieving a remarkable and safe antitumor effect. This application further provides a novel method that can significantly prevent treatment-induced toxicity while maintaining the effectiveness of T-cell therapy (e.g., CAR-T therapy) for cancer, thereby achieving a remarkable and safe antitumor effect.

[0081] I. Definition In general, terms used in the claims and specification are intended to be interpreted as having the ordinary meaning that would be understood by a person skilled in the art. For further clarification, specific terms are defined below. In the event of any conflict between the ordinary meaning and a given definition, the given definition shall prevail.

[0082] The terms “individual,” “subject,” or “patient” are used synonymously herein to describe animals such as reptiles, birds, fish, or mammals (e.g., humans). Individuals include, but are not limited to, fish, reptiles, birds, humans, cattle, horses, cats, dogs, rodents, or primates. In some embodiments, the individual is human. In some embodiments, the individual suffers from a disease such as cancer. In some embodiments, the individual requires treatment.

[0083] As used herein, “reference” means any sample, standard, or level used for comparative purposes. References may be obtained from healthy and / or unaffected samples. In some cases, references may be obtained from untreated samples. In some cases, references may be obtained from unaffected or untreated samples of individuals. In some cases, references may be obtained from one or more healthy individuals, not one or more individuals under treatment.

[0084] As used herein, the terms “intermittent” or “intermittently” in the context of administration refer to non-continuous administration. For example, in some cases, “intermittent” administration refers to administration in which the treatment by administration is performed at least twice, with the two administrations being performed at least one day apart (i.e., on day 1 and day 3).

[0085] As used herein, the term “cycle” in the context of administration refers to a period during which the treatment is administered at least once. Day 1 of a cycle is defined as the day on which the first treatment is administered during that period. If the treatment is administered consecutively every day over several days, Day 1 of a cycle is defined as the day on which the treatment was administered first among the consecutive daily administrations over several days. The last day of a cycle is defined as the day before the next discontinuous treatment is administered. Each cycle does not have to be of the same length. For example, the first cycle may be 5 days long, and the second cycle may be 7 days long. Each cycle may have a different number of treatments administered. For example, the first cycle, which may be 5 days long, may have one treatment, while the second cycle, which may be 7 days long, may have two treatments. If the treatment involves administration of multiple compounds, each compound may follow the same or different cycles as described above. In some examples, each compound may have a cycle that is a combination of the same and different cycles as any other compound.

[0086] As used herein, the term “immunogenicity” refers to the ability to induce an immune response, for example, through T cells, B cells, or both.

[0087] As used herein, “treatment” or “to treat” refers to an approach to obtain beneficial or desired outcomes, including clinical outcomes. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reduction of one or more symptoms caused by the disease; reduction of disease spread; stabilization of the disease (e.g., prevention or delay of disease exacerbation); prevention or delay of disease spread (e.g., metastasis); prevention or delay of disease onset or recurrence; delay or slowing of disease progression; relief of symptoms; provision of disease remission (whether partial or total); reduction of the dose of one or more other drugs required to treat the disease; delay of disease progression; improvement of quality of life; and / or extension of survival. “Treatment” also includes reduction of the pathological outcomes of cancer. The methods of the present invention take into account one or more of these therapeutic aspects.

[0088] As used herein, “delaying” the onset of cancer means extending, interfering with, slowing, suppressing, stabilizing, and / or postponing the onset of the disease. This delay may be of varying durations depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, sufficient or significant delay may substantially encompass prevention in the sense that the individual does not develop the disease. A method of “delaying” the onset of cancer is a method that reduces the likelihood of developing the disease and / or the severity of the disease in a given timeframe compared to not using the method. Such comparisons are usually based on clinical studies using a statistically significant number of individuals. The onset of cancer can be detected using standard methods, including, but not limited to, computed tomography (CAT scan), magnetic resonance imaging (MRI), abdominal ultrasonography, coagulation tests, angiography, or biopsy. Onset also refers to cancer progression, which may be undetectable in its early stages, and includes development, recurrence, and onset.

[0089] When used herein, the term "simultaneous administration" means that the first and second therapies in combination therapy are administered within a time interval of about 15 minutes or less, for example, about 10 minutes or less, 5 minutes or less, or 1 minute or less. When the first and second therapeutic agents are administered simultaneously, they may be contained in the same composition (e.g., a composition containing both the first and second therapeutic agents) or in separate compositions (e.g., one composition containing the first therapeutic agent and another composition containing the second therapeutic agent).

[0090] As used herein, the term “sequential administration” means that the first and second therapeutic agents in combination therapy are administered at intervals of more than about 15 minutes, for example, more than about 20 minutes, more than 30 minutes, more than 40 minutes, more than 50 minutes, more than 60 minutes, or longer. Either the first or second therapeutic agent may be administered first. The first and second therapies may be contained in separate compositions, and these may be contained in the same or different packaging or kits.

[0091] As used herein, "parallel administration" means that the administration of the first therapeutic agent and the administration of the second therapeutic agent in combination therapy overlap with each other.

[0092] As used herein, “pharmaceutically acceptable” or “pharmacologically compatible” means a material that is biologically or otherwise undesirable, for example, a material that may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effect or without harmful interaction with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients preferably meet the requirements of toxicity and manufacturing testing and / or are listed in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0093] The embodiments of this application described herein are understood to include "consisting of" and / or "essentially consisting of" the embodiments.

[0094] References to values ​​or parameters in this specification that use the term "about" include (and should be described) variations in the value or parameter itself. For example, a statement referring to "about X" includes a statement of "X".

[0095] Where used herein, a reference to "not" a certain value or parameter generally means and describes "other than" a certain value or parameter. For example, "a method is not used to treat type X cancer" means "a method is used to treat type X cancer."

[0096] As used herein, the term "approximately X to Y" has the same meaning as "approximately X to approximately Y".

[0097] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context clearly indicates otherwise.

[0098] Any term not directly defined herein will be understood to have the general meaning understood in the art of the present invention. In this specification, certain terms are explained to provide additional guidance to practitioners when describing compositions, apparatus, methods, etc., of embodiments of the present invention, as well as methods for their manufacture or use. It will be understood that the same content may be expressed in different ways. Therefore, alternative and synonymous terms may be used for one or more of the terms discussed herein. In this specification, emphasis should not be placed on whether a term is detailed or discussed. Several synonyms or alternative methods, materials, etc., are provided. The mention of one or more synonyms or equivalents may, unless explicitly stated, be used in conjunction with other synonyms or equivalents. Various examples, including examples of terminology, are used for illustrative purposes only and do not limit the scope and meaning of the embodiments of the invention described herein.

[0099] II. Treatment Methods In one embodiment, this application provides a method for treating cancer in an individual, the method comprising administering to the individual a) a myeloid cell activator or myeloid cell activation therapy, and b) a TNFα inhibitor. In some embodiments, the individual being treated has already received, is currently receiving, or is about to receive treatment with one or more SHP-1 pathway inhibitors, such as any of those described herein. In another embodiment, what is provided is a method for treating cancer in an individual, the method comprising administering to the individual a TNFα inhibitor and an SHP-1 pathway inhibitor, the individual being under an inflammatory response or having an ongoing infection. In some embodiments, the individual is further administered an immune checkpoint inhibitor and / or cytokine.

[0100] In some embodiments, the method involves administering both a TNFα inhibitor and a myeloid cell activator or myeloid cell activation therapy to an individual. In some embodiments, the TNFα inhibitor is administered before the administration of the myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with the administration of the myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of the myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of the myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method comprises administering a TNFα inhibitor to an individual that is under an inflammatory response or has an ongoing infection. In some embodiments, the inflammatory response or ongoing infection promotes a pro-inflammatory immune response in the individual. In some embodiments, the method further comprises administering an SHP-1 inhibitor and / or a tyrosine kinase inhibitor. 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 daily. In some embodiments, the method comprises systemic administration of the SHP-1 inhibitor and / or the tyrosine kinase inhibitor.

[0101] In some embodiments, methods are provided for treating cancer in an individual (e.g., solid tumors, e.g., hematological malignancies, e.g., terminal cancers), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and administering a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy), wherein the individual has already received, is currently receiving or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving or is about to receive an immune checkpoint inhibitor and / or a cytokine or a bioactive fragment thereof, optionally, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, and / or cytokine or a bioactive fragment thereof are administered systemically (e.g., intravenously or subcutaneously). In some embodiments, TNFα inhibitors are administered before (e.g., within 2 weeks, 1 week, 5 days, 3 days, 2 days, or 1 day) or in parallel with, or immediately after (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 drugs mentioned above. In some embodiments, SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments are administered intermittently. In some embodiments, SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments are administered at intervals of no more than once every 2 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered two to five times within a continuous 10-day period (e.g., twice in 10 days, three times in 10 days, four times in 10 days, or five times in 10 days). In some embodiments, SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments are administered simultaneously. In some embodiments, SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments are administered in parallel.In some embodiments, SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments are administered concurrently with myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors. In some embodiments, SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments are administered in parallel with myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors. In some embodiments, the administration of SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments, myeloid cell activators or myeloid cell activation therapy, and / or TNFα inhibitors is carried out sequentially and within two weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor have a half-life of about 10 days or less (e.g., about 7 days, 5 days, 4 days, or 3 days or less). In some embodiments, the tyrosine kinase inhibitor is effective in inhibiting more than 50% of tyrosine kinase activity over a period of about 7 days or less (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor is effective in inhibiting more than 50% of SHP-1 activity over a period of about 7 days or less (e.g., about 5 days, 4 days, or 3 days).In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid base inhibitors (e.g., cyclic RNA inhibitors; see, e.g., Holdt, L M et al., Front Physiol 2018;9:1262), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptide agents, protein agents (e.g., antibody agents targeting SHP-1 or tyrosine kinase or activated tyrosine kinase), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly 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 an effective amount of myeloid cell activator or myeloid cell activation therapy to an individual locally (e.g., within a tumor). In some embodiments, the method includes administering an effective amount of TNFα inhibitor to an individual (e.g., locally or systemically). In some embodiments, the TNFα inhibitor is administered before administering the myeloid cell activator or myeloid cell activation therapy and / or the SHP-1 pathway inhibitor (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with administering the myeloid cell activator or myeloid cell activation therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with administering the myeloid cell activator or myeloid cell activation therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after the administration of the myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a biologically active fragment thereof (e.g., IL-2) (e.g., topically or systemically).

[0102] In some embodiments, methods are provided for treating cancer in an individual (e.g., solid tumors, e.g., hematological malignancies, e.g., terminal cancers), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and administering a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy), wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) an immune checkpoint inhibitor and / or a cytokine or a bioactive fragment thereof, the method optionally comprising administering the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, and / or cytokine or a bioactive fragment thereof orally, intravenously, or subcutaneously. 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 one or more of the other drugs described above, in parallel with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, and / or cytokine or a bioactive fragment thereof is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, and / or cytokine or a bioactive fragment thereof is administered intermittently. In some embodiments, the method includes administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to the individual at least twice at intervals of no more than 3 days apart. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered twice (e.g., 2 consecutive days) at intervals of 7 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered three times at intervals of 10 to 20 days (e.g., for three consecutive days).In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at intervals of no more than once every two days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least two but no more than five times within a continuous 10-day period (e.g., twice in 10 days, three times in 10 days, four times in 10 days, or five times in 10 days). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered daily. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered daily for at least two, three, four, five, six, or seven days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with an immune checkpoint inhibitor and / or cytokine or a biologically active fragment thereof. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered sequentially with an immune checkpoint inhibitor and / or cytokine or a biologically active fragment thereof. In some embodiments, SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments are administered concurrently with myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors. In some embodiments, SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments are administered in parallel with myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors. In some embodiments, the administration of SHP-1 inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and / or cytokines or their biologically active fragments, myeloid cell activators or myeloid cell activation therapy, and / or TNFα inhibitors is carried out sequentially and within two weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor has a half-life of about 10 days or less (e.g., about 7 days, 5 days, 4 days, or 3 days or less).In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid base inhibitors (e.g., cyclic RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptides, protein agents (e.g., antibody agents targeting SHP-1 or tyrosine kinase or activated tyrosine kinase), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly 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 an effective amount of myeloid cell activator or myeloid cell activation therapy to an individual locally (e.g., within a tumor). In some embodiments, the method includes administering an effective amount of TNFα inhibitor to an individual (e.g., locally or systemically). In some embodiments, the TNFα inhibitor is administered before administering the myeloid cell activator or myeloid cell activation therapy and / or the SHP-1 pathway inhibitor (e.g., within about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with administering the myeloid cell activator or myeloid cell activation therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with administering the myeloid cell activator or myeloid cell activation therapy and / or the SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after the administration of the myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway).In some embodiments, the method comprises administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the method further comprises administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a biologically active fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0103] In some embodiments, methods are provided for treating cancer in an individual (e.g., solid tumors, e.g., hematological malignancies, e.g., terminal cancers), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy), wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) an immune checkpoint inhibitor and / or a cytokine or a bioactive fragment thereof, the method comprising administering the SHP-1 inhibitor, tyrosine kinase inhibitor, immune checkpoint inhibitor, and / or cytokine or a bioactive fragment thereof orally, intravenously, or subcutaneously. 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 one or more of the other drugs described above, in parallel with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the administration of the myeloid cell activator or myeloid cell activation therapy and / or the administration of the TNFα inhibitor is performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumor). In some embodiments, the administration of the myeloid cell activator or myeloid cell activation therapy is performed daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the administration of the myeloid cell activator or myeloid cell activation therapy is performed intermittently. In some embodiments, the TNFα inhibitor is administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered to the individual for at least two cycles, each cycle lasting approximately 3 to 7 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 method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered intermittently. In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to an individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with a myeloid cell activator or myeloid cell activation therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with a myeloid cell activator or myeloid cell activation therapy and / or a TNFα inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered in parallel with a myeloid cell activator or myeloid cell activation therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered in parallel with a myeloid cell activator or myeloid cell activation therapy and / or a TNFα inhibitor.In some embodiments, SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration, as well as myeloid cell activator administration or myeloid cell activation therapy, are administered sequentially and within two weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor have a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less). In some embodiments, the individual is administered SHP-1 inhibitor, tyrosine kinase inhibitor, and myeloid cell activator administration or myeloid cell activation therapy until the individual experiences tumor disappearance. In some embodiments, after tumor disappearance, the individual is intermittently administered SHP-1 inhibitor, tyrosine kinase inhibitor, myeloid cell activator administration or myeloid cell activation therapy, and / or TNFα inhibitor. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid base inhibitors (e.g., cyclic RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptides, protein agents (e.g., antibody agents targeting SHP-1 or tyrosine kinase or activated tyrosine kinase), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method further includes administering a myeloid cell activator or myeloid cell activation therapy to an individual locally (e.g., within a tumor). In some embodiments, the method includes administering an effective amount of a TNFα inhibitor to an individual (e.g., locally or systemically). In some embodiments, the TNFα inhibitor is administered before administering a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of the periods approximately 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less prior to such administration). In some embodiments, the TNFα inhibitor is administered concurrently with administering a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered in parallel with administering a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway.In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway). In some embodiments, the method comprises administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the method further comprises administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody).

[0104] In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy) orally, intravenously, subcutaneously, intraperitoneally, and / or intratumorally, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is effective in inhibiting more than 50% of the activity of SHP-1 and / or tyrosine kinase for a period of about 5 days or less, and the method optionally comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to the individual daily, the individual further being administered a TNFα inhibitor, and the individual does not develop cytokine release syndrome or pro-inflammatory organ injury. 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy) orally, intravenously, subcutaneously, intraperitoneally, and / or intratumorally, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is effective in inhibiting more than 50% of the activity of SHP-1 and / or tyrosine kinase for a period of approximately 5 days or less, and the method optionally comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to the individual at least twice (e.g., at least 3, 4, 5, or 6 times) at intervals of no more than once every 3 days, the individual is further administered a TNFα inhibitor, and the individual does not develop cytokine release syndrome or pro-inflammatory organ injury.In some embodiments, myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to the individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at intervals of 2 or less, every 7 to 20 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at intervals of 3 or less, every 7 to 20 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at intervals of approximately 1 to 3 times, every 7 to 20 days, over a period of at least 14 to 20 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at least 2, 3, 4, 5, or 6 times over a period of approximately 14 to approximately 40 days (e.g., approximately 14 to approximately 20 days). In some embodiments, immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered daily. In some embodiments, immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to an individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with a myeloid cell activator or myeloid cell activation therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered concurrently with a myeloid cell activator or myeloid cell activation therapy and / or a TNFα inhibitor. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered in parallel with a myeloid cell activator or myeloid cell activation therapy. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered in parallel with a myeloid cell activator or myeloid cell activation therapy and / or a TNFα inhibitor. In some embodiments, SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration, as well as myeloid cell activator administration or myeloid cell activation therapy, are administered sequentially and within two weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor have a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor are effective in inhibiting more than 50% of the activity of SHP-1 and / or tyrosine kinase over a period of about 7 days or less (e.g., about 5, 4, or 3 days). In some embodiments, the individual is administered the SHP-1 inhibitor, the tyrosine kinase inhibitor, and the myeloid cell activator administration or myeloid cell activation therapy until the individual experiences tumor clearance. In some embodiments, after tumor disappearance, the individual is intermittently administered SHP-1 inhibitors, tyrosine kinase inhibitors, myeloid cell activators or myeloid cell activation therapy, and / or TNFα inhibitors.In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid base inhibitors (e.g., cyclic RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptides, protein agents (e.g., antibody agents targeting SHP-1 or tyrosine kinase or activated tyrosine kinase), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method further includes administering a myeloid cell activator or myeloid cell activation therapy to an individual locally (e.g., within a tumor). In some embodiments, the method includes administering an effective amount of a TNFα inhibitor to an individual (e.g., locally or systemically). In some embodiments, the TNFα inhibitor is administered before administering a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of the periods approximately 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less prior to such administration). In some embodiments, the TNFα inhibitor is administered concurrently with administering a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered in parallel with administering a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after the administration of the myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the myeloid cell activator administration or myeloid cell activation therapy is performed intratumorally. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, methods are provided for treating cancer in an individual (e.g., solid tumors, e.g., hematological malignancies, e.g., terminal cancers), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and administering a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy), wherein the individual has a) already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) an immune checkpoint inhibitor and / or cytokine or its biologically active The administration of a sexual fragment is already being received, is currently being received, or is to be received, and the method comprises administering an SHP-1 inhibitor, a tyrosine kinase inhibitor, an immune checkpoint inhibitor, and / or a cytokine or a bioactive fragment thereof, as well as a myeloid cell activator or myeloid cell activation therapy, orally, intravenously, subcutaneously, and / or intratumorally, wherein the SHP-1 inhibitor and / or the tyrosine kinase inhibitor is effective in inhibiting more than 50% of the activity of SHP-1 and / or tyrosine kinase for approximately 5 days or less (e.g., 5, 4, or 3 days or less). 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), in parallel with, or immediately after (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 drugs described above. In some embodiments, myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily.In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered to the individual over at least two cycles, each cycle lasting approximately 3 to 7 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 method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to the individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor being administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least two consecutive days). In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at least three times in each cycle (e.g., for at least three consecutive days). 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, immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered to an individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered concurrently with myeloid cell activators or myeloid cell activation therapy. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered concurrently with myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors.In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered in parallel with myeloid cell activators or myeloid cell activation therapy. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered in parallel with myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors. In some embodiments, the administration of SHP-1 inhibitors and / or tyrosine kinase inhibitors, as well as the administration of myeloid cell activators or myeloid cell activation therapy, is carried out sequentially and within two weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors have a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less). In some embodiments, the individual is administered SHP-1 inhibitors, tyrosine kinase inhibitors, and myeloid cell activators or myeloid cell activation therapy until the individual experiences tumor clearance. In some embodiments, after tumor remission, the individual is intermittently administered SHP-1 inhibitors, tyrosine kinase inhibitors, myeloid cell activators or myeloid cell activation therapy, and / or TNFα inhibitors. In some embodiments, the SHP-1 inhibitors and / or tyrosine kinase inhibitors are selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid base inhibitors (e.g., cyclic RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptides, protein agents (e.g., antibody agents targeting SHP-1 or tyrosine kinase or activated tyrosine kinase), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof.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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, tyrosine kinase inhibitors do not inhibit, or only slightly inhibit, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of the TNFα inhibitor to an individual (e.g., topically or systemically).In some embodiments, the TNFα inhibitor is administered before the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (for example, within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially to the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (for example, before or after). In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further includes administering the myeloid cell activator or myeloid cell activation therapy locally (e.g., intratumor) to the individual. In some embodiments, the method includes administering both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative) and a tyrosine kinase inhibitor (e.g., dasatinib) to the individual (e.g., locally or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the myeloid cell activator or myeloid cell activation therapy is administered intratumor. 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 an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a biologically active fragment thereof (e.g., IL-2) (e.g., topically or systemically).In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, methods are provided for treating cancer in an individual (e.g., solid tumors, e.g., hematological malignancies, e.g., terminal cancers), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and administering a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy) (e.g., orally, intravenously, subcutaneously, and / or intratumor), wherein the individual has already received, is currently receiving, or is about to receive an administration of a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) an immune checkpoint inhibitor and / or a cytokine or a bioactive fragment thereof, the method further comprising administering immune cells (e.g., any of the immune cells described herein). 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 one or more of the other drugs described above, in parallel with it, or immediately afterward (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the individual has already received, is currently receiving, or is about to receive a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., radiotherapy). In some embodiments, the individual is under an inflammatory response or has an ongoing infection. In some embodiments, the immune cells originate from the same individual. In some embodiments, the immune cells include monocytes or macrophages. In some embodiments, the immune cells include T cells (e.g., CAR-T cells). In some embodiments, the immune cells include NK cells (e.g., CAR-NK cells). In some embodiments, the immune cells include neutrophils (e.g., CAR-expressing neutrophils). In some embodiments, the immune cells include antigen-presenting cells (APCs). In some embodiments, immune cells are engineered to express chimeric receptors that specifically bind to tumor antigens.In some embodiments, myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to the individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, SHP-1 inhibitor administration, tyrosine kinase inhibitor administration, immune checkpoint inhibitor administration, cytokine or its biologically active fragment administration, immune cell administration, and / or myeloid cell activator administration or myeloid cell activation therapy are performed within 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration and immune cell administration are each performed within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of each other. In some embodiments, SHP-1 inhibitor administration, tyrosine kinase inhibitor administration, immune checkpoint inhibitor administration, cytokine or its biologically active fragment administration, immune cell administration, and / or myeloid cell activator administration or myeloid cell activation therapy are performed simultaneously.In some embodiments, SHP-1 inhibitor administration, tyrosine kinase inhibitor administration, immune checkpoint inhibitor administration, cytokine or its biologically active fragment administration, immune cell administration, and / or myeloid cell activator administration or myeloid cell activation therapy are performed in parallel. In some embodiments, SHP-1 inhibitor administration, tyrosine kinase inhibitor administration, immune checkpoint inhibitor administration, cytokine or its biologically active fragment administration, immune cell administration, and / or myeloid cell activator administration or myeloid cell activation therapy are performed sequentially. In some embodiments, the individual is administered SHP-1 inhibitor, tyrosine kinase inhibitor, and myeloid cell activator administration or myeloid cell activation therapy until the individual experiences tumor disappearance. In some embodiments, after tumor disappearance, the individual is intermittently administered SHP-1 inhibitor, tyrosine kinase inhibitor, myeloid cell activator administration or myeloid cell activation therapy, and / or TNFα inhibitor administration. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further includes administering the myeloid cell activator or myeloid cell activation therapy locally (e.g., within a tumor) to the individual.In some embodiments, the method comprises administering to an individual (e.g., topically or systemically) both an effective amount of an 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 myeloid cell activator administration or myeloid cell activation therapy is performed 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 an individual (e.g., topically or systemically) both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα neutralizing antibody and a TLR agonist, the individual having a) already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a bioactive fragment thereof, wherein the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (e.g., at least three, four, or five times). In some embodiments, the TNFα inhibitor is administered before (e.g., within two weeks, one week, five days, three days, two days, or one day), in parallel with, or immediately after (e.g., within six hours, five hours, four hours, three hours, two hours, one hour, or 30 minutes) the administration of one or more of the other agents described above. 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 provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα neutralizing antibody and a TLR agonist, the individual having already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the TLR agonist are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of the other, respectively.In some embodiments, the method includes administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor daily (e.g., daily for at least 7 days). In some embodiments, the method includes administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual at least twice, at intervals of no more than 3 days. In some embodiments, the method includes administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least 2 cycles, wherein the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least once in each cycle (e.g., at least 2 or 3 times), and each cycle is approximately 3 to approximately 20 days long. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered systemically (e.g., intravenously or subcutaneously) and / or topically (e.g., intratumorally). In some embodiments, the TLR agonist and / or TNFα neutralizing antibody is administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or topically (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, once every 5 days, once every 3 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 2 cycles, each cycle being approximately 3 to approximately 7 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the TLR agonist are administered simultaneously, in parallel, or sequentially. In some embodiments, the TLR agonist activates TLR1 or TLR2, and optionally, the TLR agonist comprises triacylated lipoprotein, peptidoglycan, zymosan, and / or Pam3CSK4.In some embodiments, the TLR agonist activates one of TLR2, TLR3, TLR4, TLR5, and TLR6, and optionally the TLR agonist comprises a diacylated lipopeptide, a heat shock protein, HMGB1, uric acid, fibronectin, and / or an ECM protein. In some embodiments, the TLR agonist activates TLR2, and optionally the TLR agonist comprises Pam3Cys, SMP-105, and / or CBLB612. In some embodiments, the TLR agonist activates TLR3, and optionally the TLR agonist comprises dsRNA, poly-I:C, poly-ICIC, poly-IC12U, IPH302, ARNAX, and / or MPLA. In some embodiments, the TLR agonist activates TLR4 and optionally comprises LPS, lipoteichoic acid beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, and / or GLA-SE. In some embodiments, the TLR agonist activates TLR5 and optionally comprises flagellin, CBLB502, and / or M-VM3. In some embodiments, the TLR agonist activates TLR6. In some embodiments, the TLR agonist activates TLR7 or TLR8 and optionally comprises ssRNA, CpG-A, polyG10, and / or polyG3. In some embodiments, the TLR agonist activates TLR7 and optionally comprises bistriazolyl and / or R848. In some embodiments, the TLR agonist activates TLR8 and optionally comprises VTX1463 and / or R848. In some embodiments, the TLR agonist activates TLR9 and optionally comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and / or ODN M362.In some embodiments, the TLR agonist activates TLR10, and optionally, the TLR agonist contains Pam3CSK4. In some embodiments, the TLR agonist activates TLR11, and optionally, the TLR agonist contains Toxoplasma prophyllin. In some embodiments, the TLR agonist activates TLR12. In some embodiments, the TLR agonist activates TLR13, and optionally, the TLR agonist contains 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 contains CpG, polyI:C, and / or R848. In some embodiments, the TLR agonist contains CpG, poly(I:C), and R848 in a ratio, for example, 1:1:1. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a TLR agonist until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a TLR agonist, and / or a TNFα neutralizing antibody.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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, tyrosine kinase inhibitors do not inhibit, or only slightly inhibit, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of TNFα neutralizing antibody to an individual (e.g., topically or systemically).In some embodiments, the TNFα neutralizing antibody is administered before the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor (for example, within a period of approximately 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα neutralizing antibody is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered sequentially to the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor (for example, before or after). In some embodiments, the TNFα neutralizing antibody is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further includes administering a TLR agonist to the individual topically (e.g., intratumor). In some embodiments, the method comprises administering to an individual (e.g., topically or systemically) both an effective amount of an 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 an individual (e.g., topically or systemically) both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα neutralizing antibody and a TLR agonist, the individual having a) already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a bioactive fragment thereof, and optionally, the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7, and TLR8. 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), in parallel with, or immediately after (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 drugs described above. In some embodiments, TLR agonists and / or TNFα neutralizing antibodies are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or topically (e.g., intratumorally). In some embodiments, TLR agonists are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, TLR agonists are administered intermittently. In some embodiments, TNFα neutralizing antibodies are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα neutralizing antibodies are administered intermittently. In some embodiments, TNFα neutralizing antibodies are administered to an individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors and TLR agonists are administered on the same day. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and / or TLR agonist are administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and TLR agonist are administered for at least two cycles (e.g., at least three cycles), and optionally, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor and TLR agonist 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, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and TLR agonist are administered simultaneously, in parallel, or sequentially. In some embodiments, each cycle is approximately 7 to approximately 20 days long. In some embodiments, the TLR agonist activates TLRs on macrophages, and optionally, the TLRs include 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 contains CpG, polyI:C, and / or R848. In some embodiments, the TLR agonist contains CpG, polyI:C, and R848 in a ratio, for example, 1:1:1. In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered intermittently. In some embodiments, an immune checkpoint inhibitor and / or cytokine or a biologically active fragment thereof is administered to an individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or a biologically active fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days.In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a TLR agonist until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a TLR agonist, and / or a TNFα neutralizing antibody. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, tyrosine kinase inhibitors do not inhibit, or only slightly inhibit, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk).In some embodiments, the method involves administering an effective amount of TNFα-neutralizing antibody to an individual (e.g., topically or systemically). In some embodiments, the TNFα-neutralizing antibody is administered before (e.g., within a period of approximately 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after administration). In some embodiments, the method further comprises administering a TLR agonist to the individual topically (e.g., intratumorally). In some embodiments, the method comprises administering both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative) and a tyrosine kinase inhibitor (e.g., dasatinib) to the individual (e.g., topically or systemically). 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 an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a biologically active fragment thereof (e.g., IL-2) (e.g., topically or systemically).In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor and a STING activator (e.g., cGAMP), wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor and a STING activator (e.g., cGAMP), wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the STING activator are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each of the other. 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 one or more of the other drugs described above, in parallel with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). 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 method includes administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual at least twice at intervals of no more than 3 days apart. In some embodiments, the method includes administering an individual the SHP-1 inhibitor and / or tyrosine kinase inhibitor over at least 2 cycles, wherein the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least once (e.g., at least 2 or 3 times) in each cycle, and each cycle lasts approximately 3 to approximately 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered systemically (e.g., intravenously or subcutaneously) and / or topically (e.g., intratumor). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the STING activator are administered sequentially, simultaneously, or in parallel. In some embodiments, the STING activator is a cyclic guanosine monophosphate-adenosine monophosphate (cGAMP, e.g., 3'3'cGAMP, e.g., 2'3'cGAMP), a bacterial vector (e.g., SYNB1891, STACT-TREX-1), a CDN compound (e.g., ADU-S100, BI-STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3'3'-cyclic AIMP), a non-CDN small molecule (e.g., ALG-031048, E7755, JNJ-'6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI-10001), or a nanovaccine (e.g., PC7A). These are NPs (cCAMP-NP, ONM-500) or antibody-drug conjugates (e.g., XMT-2056, CRD-5500). In some embodiments, the immune checkpoint inhibitor and / or cytokine or its biologically active fragment is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its biologically active fragment is administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a STING activator until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a STING activator, and / or a TNFα neutralizing antibody. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of TNFα-neutralizing antibody to an individual (e.g., topically or systemically). In some embodiments, the TNFα-neutralizing antibody is administered before (e.g., within a period of approximately 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further includes administering a STING activator to the individual topically (e.g., intratumorally).In some embodiments, the method comprises administering to an individual (e.g., topically or systemically) both an effective amount of an 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 activator 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 an individual (e.g., topically or systemically) both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a biologically active fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and radiotherapy to the individual, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and optionally, the method comprises administering the SHP-1 inhibitor and / or 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 each cycle is approximately 3 to approximately 20 days long. 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 one or more of the other drugs described above, in parallel with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, radiotherapy and / or TNFα inhibitor administration is performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumor). In some embodiments, radiotherapy is performed intermittently. In some embodiments, the TNFα inhibitor is administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered to the individual over at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, the method involves administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual at least twice, at intervals of no more than once every three days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least three times.In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumor). In some embodiments, SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration and radiotherapy are each performed within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or within 30 minutes) of each other. In some embodiments, radiotherapy includes irradiating the site of the cancer being treated. In some embodiments, radiotherapy includes irradiating a site different from the site of the cancer being treated. In some embodiments, the dose of radiotherapy is insufficient to kill tumor cells. In some embodiments, radiotherapy is selected from the group consisting of external beam radiation therapy, internal beam radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), whole-body radiotherapy, radioimmunotherapy, and administration of radiosensitizers and radioprotective agents. In some embodiments, radiotherapy is external beam radiation therapy and optionally includes three-dimensional conformal radiotherapy (3D-RT), intensity-modulated radiation therapy (IMRT), photon therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT). In some embodiments, radiotherapy is brachytherapy and optionally includes intratissue brachytherapy, intraluminal near-brightness radiation therapy, intraluminal radiation therapy, and radiolabeled molecules administered intravenously. 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, immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered to an individual over at least two cycles, and optionally, the immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered SHP-1 inhibitors, tyrosine kinase inhibitors, and radiotherapy until the individual experiences tumor disappearance.In some embodiments, after tumor remission, the individual is intermittently administered SHP-1 inhibitors, tyrosine kinase inhibitors, radiotherapy, and / or TNFα inhibitors. 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 stivogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly 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 an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically).In some embodiments, the TNFα inhibitor is administered before the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (for example, within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially to the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (for example, before or after). In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα neutralizing antibody and radiotherapy to the individual, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a bioactive fragment thereof, the radiotherapy comprising irradiation at a site different from the site of the cancer being treated. 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), in parallel with, or immediately after (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, radiotherapy and / or TNFα inhibitor administration is performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, radiotherapy is performed intermittently. In some embodiments, TNFα neutralizing antibodies are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα neutralizing antibodies are administered intermittently. In some embodiments, TNFα neutralizing antibodies are administered to the individual for at least two cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at least twice (at least 3, 4, 5, or 6 times). In some embodiments, the method includes administering an SHP-1 inhibitor and / or a tyrosine kinase inhibitor to an individual at least twice, at intervals of no more than once every three days.In some embodiments, the method comprises administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, wherein the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least once in each cycle, and each cycle lasts approximately 3 to approximately 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g. subcutaneously) and / or locally (e.g., intratumor). In some embodiments, the administration of the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the radiotherapy are each performed within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or within 30 minutes) of each other. In some embodiments, the radiotherapy includes irradiating the site of the cancer being treated. In some embodiments, the radiotherapy includes irradiating a site different from the site of the cancer being treated. In some embodiments, the dose of the radiotherapy is insufficient to kill the tumor cells. In some embodiments, radiotherapy is selected from the group consisting of external beam radiation therapy, internal beam radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), total body radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotective agents. In some embodiments, radiotherapy is external beam radiation therapy and optionally includes three-dimensional conformal radiation therapy (3D-RT), intensity-modulated radiation therapy (IMRT), photon therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT). In some embodiments, radiotherapy is brachytherapy and optionally includes intratissue brachytherapy, intraluminal near-brightness radiation therapy, intraluminal radiation therapy, and radiolabeled molecules administered intravenously. In some embodiments, immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered daily. In some embodiments, immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and radiotherapy until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, radiotherapy, and / or a TNFα neutralizing antibody. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of TNFα-neutralizing antibody to an individual (e.g., topically or systemically). In some embodiments, the TNFα-neutralizing antibody is administered before (e.g., within a period of approximately 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα-neutralizing antibody is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor (for example, within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα neutralizing antibody and radiotherapy, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment 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), in parallel with, or immediately after (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 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 administration of the SHP-1 inhibitor and / or tyrosine kinase inhibitor and radiotherapy are performed on the same day. In some embodiments, the administration of the SHP-1 inhibitor and / or tyrosine kinase inhibitor and / or radiotherapy is performed at least twice (e.g., at least three, four, five, or six times). In some embodiments, the administration of the SHP-1 inhibitor and / or tyrosine kinase inhibitor and radiotherapy is performed over at least two cycles (e.g., at least three cycles), and optionally, in each cycle, the administration of the SHP-1 inhibitor and / or tyrosine kinase inhibitor and radiotherapy are performed on the same day for at least two consecutive days (e.g., at least three consecutive days). In some embodiments, each cycle is approximately 7 to approximately 20 days long. In some embodiments, SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration and radiotherapy are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each other.In some embodiments, radiotherapy includes irradiating the site of the cancer being treated. In some embodiments, radiotherapy includes irradiating a site different from the site of the cancer being treated. In some embodiments, the dose of radiotherapy is insufficient to kill tumor cells. 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, immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered SHP-1 inhibitors, tyrosine kinase inhibitors, and radiotherapy until the individual experiences tumor disappearance. In some embodiments, after tumor remission, the individual is intermittently administered SHP-1 inhibitors, tyrosine kinase inhibitors, radiotherapy, and / or TNFα neutralizing antibodies. 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 stivogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Hck inhibitor.In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of TNFα neutralizing antibody to an individual (e.g., topically or systemically). In some embodiments, the TNFα neutralizing antibody is administered before administration of a myeloid cell activator or myeloid cell activation therapy and / or administration of an SHP-1 pathway inhibitor (e.g., within any of the periods of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα neutralizing antibody is administered concurrently with administration of a myeloid cell activator or myeloid cell activation therapy and / or administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered in parallel with administration of a myeloid cell activator or myeloid cell activation therapy and / or administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor. In some embodiments, the TNFα neutralizing antibody is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an SHP-1 pathway inhibitor (e.g., within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after the administration).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and a PAMP / DAMP activator, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and a PAMP / DAMP activator, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the PAMP / DAMP activator are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each of the other administrations. 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 one or more of the other drugs described above, in parallel with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). 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, PAMP / DAMP activators and / or TNFα inhibitors are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or topically (e.g., intratumorally). In some embodiments, PAMP / DAMP activators are administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to an individual over at least two cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, the method includes administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual at least twice at intervals of no more than once every 3 days. In some embodiments, the method includes administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, with the SHP-1 inhibitor and / or tyrosine kinase inhibitor administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered systemically (e.g., intravenously, e.g. subcutaneously) and / or topically (e.g., intratumorally). In some embodiments, the myeloid cell activator or myeloid cell activation therapy is a PAMP activator. In some embodiments, the PAMP activator is a triacyl lipopeptide, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal lipid, Pam3Cysporin, lipoarabinomannan, double-stranded RNA, poly(I:C), trypanosomal lipid, taxol, Pseudomonas extracellular enzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptide, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial / viral DNA, CpG DNA, urea bacteria (ureobacteria), or Toxoplasma LPS. In some embodiments, the myeloid cell activator or myeloid cell activation therapy is a DAMP activator.In some embodiments, the DAMP activator is defensin, HSP60, HSP70, messenger RNA, low molecular weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, or unmethylated CpG DNA. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a PAMP / DAMP activator until the individual experiences tumor remission. In some embodiments, after tumor remission, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a PAMP / DAMP activator, and / or a TNFα inhibitor. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 is a Syk inhibitor.In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of the TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (e.g., within any of the periods of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an inhibitor of the SHP-1 pathway.In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further comprises administering a PAMP / DAMP activator to the individual topically (e.g., intratumorally). In some embodiments, the method comprises administering both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative) and a tyrosine kinase inhibitor (e.g., dasatinib) to the individual (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the PAMP / DAMP activator 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 an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a biologically active fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy), wherein the individual has already received, is currently receiving or is about to receive, an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving or is about to receive, an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and a myeloid cell activator or myeloid cell activation therapy (e.g., a TLR agonist, e.g., a STING activator, e.g., radiotherapy), wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the immune checkpoint inhibitor, respectively, within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each of the other administrations. 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes).In some embodiments, myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to the individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are 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 method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days).In some embodiments, the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG / PVRL2, CEACAM1, CEACAM5 / 6, FAK, CCL2 / CCR2, LIF, CD47 / SIRPα, CSF-1(M-CSF) / CSF-1R, IL-1 / IL-1R3(IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine. In some embodiments, the checkpoint inhibitor targets ipilimumab, semiprimab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, LAG525(IMP701), REGN3767, BI 754,091, Teboterimab (MGD013), Eftiragimod alfa (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO-201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RR x-001, lanotuzumab (MCS110), LY3022855, SNDX-6352, emuctuzumab (RG7155), pexidartinib (PLX3397), CAN04, canakinumab (ACZ885), BMS-986253, pepinemab (VX15 / 2503), trevananib, FP-1305, enapotamab vedotin (EnaV), or bavituximab are included or are all of the above. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a myeloid cell activator or myeloid cell activation therapy until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a myeloid cell activator or myeloid cell activation therapy, and / or a TNFα inhibitor. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further includes administering the myeloid cell activator or myeloid cell activation therapy locally (e.g., within a tumor) to the individual.In some embodiments, the method comprises administering to an individual (e.g., topically or systemically) both an effective amount of an 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 myeloid cell activator administration or myeloid cell activation therapy is performed 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 an individual (e.g., topically or systemically) both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and a pro-inflammatory cytokine (e.g., IL-1β, IL-18, and / or IL-6), wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., a neutralizing antibody) and a pro-inflammatory cytokine (e.g., IL-1β, IL-18, and / or IL-6), wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the pro-inflammatory cytokine are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of each of the other administrations. 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes).In some embodiments, myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to the individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are 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 method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). In some embodiments, the pro-inflammatory cytokine promotes M1 macrophages, dendritic cells (e.g., intratumor), B cells (e.g., intratumor), antigen-presenting cells, etc. In some embodiments, the pro-inflammatory cytokine includes or is TNF family members, IFNγ, and / or GM-CSF. In some embodiments, the pro-inflammatory cytokine includes IFNγ.In some embodiments, the pro-inflammatory cytokine includes IL-1. In some embodiments, the pro-inflammatory cytokine includes any member of the TNF family other than TNFα. In some embodiments, the pro-inflammatory cytokine includes IL-6. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a pro-inflammatory cytokine until the individual experiences tumor clearance. In some embodiments, after tumor remission, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a pro-inflammatory cytokine, and / or a TNFα inhibitor. 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 stivogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Hck inhibitor.In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of the TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (e.g., within any of the periods of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after the administration of the myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway).In some embodiments, the method further comprises administering a pro-inflammatory cytokine to an individual topically (e.g., intratumorally). In some embodiments, the method comprises administering both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) to an individual (e.g., topically or systemically). In some embodiments, the SHP1 inhibitor and tyrosine kinase inhibitor are administered systemically, and the pro-inflammatory cytokine is administered intratumorally. In some embodiments, the method further comprises administering both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) to an individual (e.g., topically or systemically). In some embodiments, the method further comprises administering an agent that reduces systemic inflammation and / or an agent that reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody) to an individual.

[0116] In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and a chemotherapeutic agent (e.g., azathioprine), wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and a chemotherapeutic agent (e.g., azathioprine), wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, the SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration and the chemotherapeutic administration are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each other. 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 one or more of the other drugs described above, in parallel with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the administration of the myeloid cell activator or myeloid cell activation therapy and / or the TNFα inhibitor is performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally).In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to an individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, the method comprises administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). 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 ethyleneimines (e.g., thiotepa). In some embodiments, the chemotherapeutic agent is an antimetabolite.In some embodiments, the antimetabolite is selected from the group consisting of icitidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nerarabine), and pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (a prodrug of 5-FU)). In some embodiments, the chemotherapeutic agent is a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from the group consisting of topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), and antibiotics (e.g., actinomycin D, bleomycin, daunomycin). In some embodiments, the chemotherapeutic agent is hydroxyurea, tretinoin, arsenic trioxide, or a proteasome inhibitor (e.g., bortezomib). In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered intermittently. In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a chemotherapeutic agent until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a chemotherapeutic agent, and / or a TNFα inhibitor.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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, tyrosine kinase inhibitors do not inhibit, or only slightly inhibit, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of the TNFα inhibitor to an individual (e.g., topically or systemically).In some embodiments, the TNFα inhibitor is administered before the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (for example, within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially to the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (for example, before or after). In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5, 10, 15, 30, 45, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further includes administering the chemotherapeutic agent to the individual topically (e.g., intratumorally). In some embodiments, the method includes administering both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative) and a tyrosine kinase inhibitor (e.g., dasatinib) to the individual (e.g., topically or systemically). 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 includes administering both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) to the individual (e.g., topically or systemically). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and a cancer vaccine, wherein the individual has already received, is currently receiving, or is about to receive a SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice. In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and a cancer vaccine, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the cancer vaccine are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each of the other administrations. 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 one or more of the other drugs described above, in parallel with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the administration of the myeloid cell activator or myeloid cell activation therapy and / or the TNFα inhibitor is performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumor). In some embodiments, the administration of the myeloid cell activator or myeloid cell activation therapy is performed daily for at least 2, 3, 4, 5, 6, or 7 days.In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is performed intermittently. In some embodiments, the TNFα inhibitor is administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered to the individual for at least two cycles, each cycle being approximately 3 to approximately 7 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 method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to the individual for at least two cycles, further optionally, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor being administered at least once in each cycle, each cycle being approximately 3 to approximately 20 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at least twice in each cycle (e.g., for at least two consecutive days). In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at least three times in each cycle (e.g., for at least three consecutive days). In some embodiments, the cancer vaccine includes cell-based vaccines, peptide-based vaccines, virus-based vaccines, and / or nucleic acid-based vaccines. 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, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a cancer vaccine until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a cancer vaccine, and / or a TNFα inhibitor. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further includes administering a cancer vaccine to the individual topically (e.g., intratumorally).In some embodiments, the method comprises administering to an individual (e.g., topically or systemically) both an effective amount of an 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 SHP1 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 an individual (e.g., topically or systemically) both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and an oncolytic virus, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and an oncolytic virus, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the oncolytic virus are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each of the other administrations. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy and / or TNFα inhibitor administration are performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally).In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to an individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, the method comprises administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). In some embodiments, the oncolytic virus includes or is an adenovirus (e.g., ONYX-15, LOAd703 virus), protoparvovirus, parvovirus (e.g., H-1PV), vaccinia virus (VACV), reovirus (e.g., reolysin), or herpes simplex virus (HSV, e.g., HSV-1, HSV-2, G207, L1BR1, HF10, T-VEC, Orien X010).In some embodiments, the oncolytic virus includes JX-593, coxsackievirus A21 (CVA21), maraba virus or its MG1 variant, DNX2440 adenovirus, fowlpox virus, or Sendai virus. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered intermittently. In some embodiments, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or its bioactive fragment is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and the oncolytic virus until the individual experiences tumor clearance. In some embodiments, after tumor remission, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, an oncolytic virus, and / or a TNFα inhibitor. 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 stivogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Hck inhibitor.In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of the TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor (e.g., within any of the periods of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less). In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours after the administration of the myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway).In some embodiments, the method further comprises administering an oncolytic virus to an individual topically (e.g., intratumorally). In some embodiments, the method comprises administering both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) to an individual (e.g., topically or systemically). In some embodiments, the SHP1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the oncolytic virus is administered intratumorally. In some embodiments, the method further comprises administering both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) to an individual (e.g., topically or systemically). In some embodiments, the method further comprises administering an agent that reduces systemic inflammation and / or an agent that reduces an inflammatory cytokine cascade or cytokine storm (e.g., an anti-IL-6 antibody or an anti-IL-1 antibody) to an individual.

[0119] In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and acoustic therapy (e.g., high-intensity focused ultrasound (HIFU), e.g., low-intensity focused ultrasound (LIPUS)) to the individual, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and acoustic therapy (e.g., high-intensity focused ultrasound (HIFU), e.g., low-intensity focused ultrasound (LIPUS)) to the individual, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and the SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration and acoustic therapy are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each other.In some embodiments, myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to the individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are 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 method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g. subcutaneously) and / or topically (e.g., intratumor). In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered daily.In some embodiments, immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered intermittently. In some embodiments, immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered to the individual over at least two cycles, and optionally, the immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered SHP-1 inhibitors, tyrosine kinase inhibitors, and acoustic therapy until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is administered SHP-1 inhibitors, tyrosine kinase inhibitors, acoustic therapy, and / or TNFα inhibitors intermittently. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (for example, within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method involves performing sound therapy on the site of the cancer being 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 involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and magnetic therapy (e.g., a pulsed magnetic field, e.g., a static magnetic field) to the individual, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and magnetic therapy (e.g., a pulsed magnetic field, e.g., a static magnetic field) to the individual, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and the SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration and magnetic therapy are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each other. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy and / or TNFα inhibitor administration are performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally).In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to an individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, the method comprises administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g. subcutaneously) and / or locally (e.g., intratumor). In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and magnetic therapy until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, magnetic therapy, and / or a TNFα inhibitor. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (for example, within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method involves performing magnetic therapy on the site of the cancer being treated. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and performing electrotherapy or electrochemotherapy on the individual, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and performing electrotherapy or electrochemotherapy on the individual, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, the SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration and the electrotherapy or electrochemotherapy are each performed within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each other. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy and / or TNFα inhibitor administration are performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally).In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to an individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, the method comprises administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g. subcutaneously) and / or locally (e.g., intratumor). In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and electrotherapy or electrochemotherapy until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, electrotherapy or electrochemotherapy, and / or a TNFα inhibitor. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (for example, within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method involves performing electrotherapy or electrochemotherapy on the site of the cancer being treated. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and electrotherapy to the individual, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and electrotherapy to the individual, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, and the SHP-1 inhibitor administration and / or tyrosine kinase inhibitor administration and electrotherapy are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each other. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy and / or TNFα inhibitor administration are performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally).In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to an individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, the method comprises administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g. subcutaneously) and / or locally (e.g., intratumor). In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual over at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and electrotherapy until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, electrotherapy, and / or a TNFα inhibitor. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (for example, within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method involves performing electrotherapy on the site of the cancer being treated. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and an antibody-drug conjugate, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice (at least three, four, five, or six times). 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 one or more of the other drugs described above, concurrently with it, or immediately after (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes). In some embodiments, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering to the individual a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) and an antibody-drug conjugate, wherein the individual has already received, is currently receiving, or is about to receive a) an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment thereof, the SHP-1 inhibitor and / or tyrosine kinase inhibitor and the antibody-drug conjugate are each administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour or 30 minutes) of each of the other administrations. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy and / or TNFα inhibitor administration are performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally).In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activator administration or myeloid cell activation therapy is administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to an individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors 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, the method comprises administering an SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least 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., for at least three consecutive days). In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered systemically (e.g., intravenously, e.g. subcutaneously) and / or locally (e.g., intratumor). In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered daily. In some embodiments, the immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and an antibody-drug conjugate until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, an antibody-drug conjugate, and / or a TNFα inhibitor. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (for example, within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the method involves administering an antibody-drug conjugate to the site of the cancer being treated. In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically and intratumorally. In some embodiments, the method further involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the lymphocyte activators described herein are administered to an individual. For example, in some embodiments, a method is provided for treating cancer in an individual (e.g., solid tumors, e.g., hematological malignancies, e.g., terminal cancers), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody), administering a TLR agonist, and administering a myeloid cell activator or myeloid cell activation therapy, wherein the individual has already received, is currently receiving, or is about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or has already received, is currently receiving, or is about to receive an immune checkpoint inhibitor and / or a cytokine or a bioactive fragment 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), in parallel with, or immediately after (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 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, TLR agonist, and immune checkpoint inhibitor are administered on the same day. In some embodiments, the administration of myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors is performed systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, the administration of myeloid cell activators or myeloid cell activation therapy is performed daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, the administration of myeloid cell activators or myeloid cell activation therapy is performed 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 over at least two cycles, each cycle lasting approximately 3 to 7 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 method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to the individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or the tyrosine kinase inhibitor being administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the SHP-1 inhibitor and / or tyrosine kinase inhibitor is administered at least twice in each cycle (e.g., for at least two consecutive days). In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at least three times in each cycle (e.g., for at least three consecutive days). In some embodiments, the TLR agonist activates TLRs on macrophages, optionally including TLR9. In some embodiments, the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9). In some embodiments, the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4, and TLR7 / 8). In some embodiments, the TLR agonist includes CpG, polyI:C, and / or R848. In some embodiments, the TLR agonist includes CpG, polyI:C, and R848 in a ratio of, for example, 1:1:1. In some embodiments, immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered daily. In some embodiments, immune checkpoint inhibitors and / or cytokines or their biologically active fragments are administered intermittently.In some embodiments, an immune checkpoint inhibitor and / or cytokine or a bioactive fragment thereof is administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitor and / or cytokine or bioactive fragment thereof is administered at least once in each cycle, each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, and a TLR agonist until the individual experiences tumor clearance. In some embodiments, after tumor clearance, the individual is intermittently administered an SHP-1 inhibitor, a tyrosine kinase inhibitor, a TLR agonist, and / or a TNFα inhibitor. 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 a Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (for example, within approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later).In some embodiments, the method involves administering to an individual both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a tyrosine kinase inhibitor (e.g., dasatinib) (e.g., topically or systemically). 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 involves administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a bioactive fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further involves administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological malignancy, e.g., terminal cancer), the method comprising administering a TNFα inhibitor (e.g., an anti-TNFα neutralizing antibody) to the individual, the individual being selected for treatment based on an ongoing inflammatory response, the individual having a) already received, currently receiving, or about to receive an SHP-1 inhibitor and / or a tyrosine kinase inhibitor, and / or b) already received, currently receiving, or about to receive an immune checkpoint inhibitor and / or a cytokine or a biologically active fragment 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), in parallel with, or immediately after (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 drugs described above. In some embodiments, the individual has an acute inflammatory response. In some embodiments, the inflammatory response occurs within the tumor. In some embodiments, the inflammatory response occurs in a site different from the tumor. In some embodiments, the individual experiences a) an increase in one or more (e.g., at least 1, 2, 3, 4, or 5) inflammatory cytokines (e.g., IFNγ, IL-12β, TNFα, IL-6, IL-1β, IFN-α1, IFN-α2, IFN-β1) or a decrease in one or more (e.g., at least 1, 2, or 3) anti-inflammatory cytokines (e.g., TGFβ1, TGFβ2, TGFβ3) in tissues (e.g., tumor tissue) or immune cells (e.g., macrophages). An inflammatory response is observed if at least two (e.g., 2, 3, 4, or 5) events are selected from the group consisting of 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 1, 2, 3, 4, or 5) immunogenic costimulatory molecules (e.g., CD80, CD86, OX40L, CD40, ICOS-L, PD-L1, GITRL).In some embodiments, myeloid cell activators or myeloid cell activation therapy and / or TNFα inhibitors are administered systemically (e.g., orally, intravenously, subcutaneously, or intraperitoneally) or locally (e.g., intratumorally). In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered daily for at least 2, 3, 4, 5, 6, or 7 days. In some embodiments, myeloid cell activators or myeloid cell activation therapy are administered intermittently. In some embodiments, TNFα inhibitors are administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, TNFα inhibitors are administered intermittently. In some embodiments, TNFα inhibitors are administered to the individual for at least 2 cycles, each cycle lasting approximately 3 to 7 days. In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are 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 small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid base inhibitors (e.g., cyclic RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptides, protein agents (e.g., antibody agents targeting SHP-1 or tyrosine kinase or activated tyrosine kinase), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates (ADCs), and any combination thereof. In some embodiments, the method comprises administering the SHP-1 inhibitor and / or tyrosine kinase inhibitor to an individual over at least two cycles, further optionally, the SHP-1 inhibitor and / or tyrosine kinase inhibitor being administered at least once in each cycle, each cycle lasting approximately 3 to approximately 20 days.In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at least twice in each cycle (e.g., for at least two consecutive days). In some embodiments, SHP-1 inhibitors and / or tyrosine kinase inhibitors are administered at least three times in each cycle (e.g., for at least three consecutive days). 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, immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered to the individual for at least two cycles, and optionally, the immune checkpoint inhibitors and / or cytokines or their bioactive fragments are administered at least once in each cycle, with each cycle lasting approximately 3 to 20 days. In some embodiments, the individual is administered SHP-1 inhibitors, tyrosine kinase inhibitors, and myeloid cell activators or myeloid cell activation therapy until the individual experiences tumor clearance. In some embodiments, after tumor remission, the individual is intermittently administered SHP-1 inhibitors, tyrosine kinase inhibitors, myeloid cell activators or myeloid cell activation therapy, and / or TNFα inhibitors. 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 stivogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone 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 is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits 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, entospretinib, hostamatinib, 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. In some embodiments, the tyrosine kinase inhibitor does not inhibit, or slightly inhibits, one or more kinases involved in T cell activation (e.g., Lck, Fyn, Zap70, Syk, and Csk). In some embodiments, the method involves administering an effective amount of a TNFα inhibitor to an individual (e.g., topically or systemically). In some embodiments, the TNFα inhibitor is administered before (e.g., within a period of about 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered concurrently with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered in parallel with the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor. In some embodiments, the TNFα inhibitor is administered sequentially (e.g., before or after) the administration of a myeloid cell activator or myeloid cell activation therapy and / or the administration of an SHP-1 pathway inhibitor.In some embodiments, the TNFα inhibitor is administered immediately after the administration of a myeloid cell activator or myeloid cell activation therapy and / or an inhibitor of the SHP-1 pathway (e.g., within any of approximately 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1 hour, 2 hours, or 3 hours later). In some embodiments, the method further includes administering the myeloid cell activator or myeloid cell activation therapy locally (e.g., within a tumor) to the individual. In some embodiments, the method includes administering both an effective amount of an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative) and a tyrosine kinase inhibitor (e.g., dasatinib) to the individual (e.g., locally or systemically). In some embodiments, the SHP-1 inhibitor and the tyrosine kinase inhibitor are administered systemically, and the myeloid cell activator or myeloid cell activation therapy is administered within a tumor. In some embodiments, the method further comprises administering to an individual both an effective amount of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) and a cytokine or a biologically active fragment thereof (e.g., IL-2) (e.g., topically or systemically). In some embodiments, the method further comprises administering to an individual an agent that reduces systemic inflammation and / or an agent that 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, the provided method is for treating...

Claims

1. A method for treating cancer in an individual, comprising: a) administering a myeloid cell activator or performing myeloid cell activation therapy to the individual; and b) administering a TNFα inhibitor.

2. The method according to claim 1, further comprising administering an inhibitor of the SHP-1 pathway to the individual.

3. A method for treating cancer in an individual, comprising administering to the individual a TNFα inhibitor and an inhibitor of the SHP-1 pathway, optionally, the individual being under an inflammatory response, optionally, the inflammatory response a) acute inflammation; b) Cytokine release syndrome, or c) The method wherein the inflammatory response is characterized by an increase in the 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, and optionally further characterized by an increase in the levels of IL-2, IL-12, IL-1b, and / or IL-10.

4. The method according to claim 2 or 3, wherein the inhibitor of the SHP-1 pathway comprises an SHP-1 inhibitor, and optionally the SHP-1 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., cyclic RNA inhibitors), nucleic acid editing systems (e.g., CRISPR, ZFN, or TALENS systems), peptide agents, protein agents (e.g., antibody agents targeting SHP-1), proteolytic agents or protein destabilizers, proteins modified with non-natural amino acids, antibody-targeted therapies, antibody-drug conjugates, and any combination thereof.

5. The method according to claim 4, wherein 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 stibogluconate, phenylhydrazonopyrazolone (PHPS1) sulfonate, oxindole, NSC-117199, salicylic acid, diterpenoid quinone, cryptotancinone, vitamin E derivatives, tocopherolol (TPGS), α-tocopherol acetate (αTA), α-tocopheryl succinate (αTOS), homoxanthone A (PXA), and PKCθ activators.

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

7. The method according to any one of claims 1 to 6, wherein the myeloid cell activator or myeloid cell activation therapy activates cells selected from any one of macrophages having an M1 phenotype, tumor dendritic cells, tumor B cells, antigen-presenting cells, and any combination thereof.

8. The method according to any one of claims 1 to 7, wherein the myeloid cell activator or myeloid cell activation therapy is selected from the group consisting of STING activators, Toll-like receptor (TLR) agonists, PAMP / DAMP activators, chemotherapy, pro-inflammatory cytokines, vaccines (e.g., cancer vaccines), bacteria or components thereof, viruses or components thereof, fungi or components thereof, immune cells, sound therapy, magnetic therapy, electrotherapy, cryotherapy, surgery, hyperthermia, radiotherapy, radiopharmaceutical therapy, electrostatic therapy, antibody drug conjugates, and any combination thereof.

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

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

11. The method according to claim 8, wherein the myeloid cell activator or myeloid cell activation therapy comprises a STING activator, and optionally the STING activator is selected from the group consisting of 2'3'-cGAMP, ADU-s100, G10, SR-717, bazimesan (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 according to claim 8, wherein the myeloid cell activator or myeloid cell activation therapy includes immune cells.

13. The immune cells include T cells, optionally, the T cells express a chimeric antigen receptor (CAR) or an antigen-specific TCR, and optionally, the immune cells are at least about 10 ６ , 2×10 ６ , 5×10 ６ , 10 ７ , 2×10 ７ , 5×10 ７ , 10 ８ , 2×10 ８ , 5×10 ８ individual T cells, and further optionally, the method includes administering the immune cells at least 2 or 3 times. The method according to claim 12.

14. The method according to any one of claims 1 to 13, wherein the TNFα inhibitor is selected from the group consisting of small molecule inhibitors, neutralizing antibodies, TNFα receptor blocking antibodies, soluble TNFα receptors, TNFα-targeting small interfering RNA (siRNA), chemical inhibitors of TNFα mRNA stability, TNFα-converting enzyme (TACE) inhibitors, and derivatives thereof.

15. The method according to claim 14, wherein the TNFα inhibitor is a TNFα neutralizing antibody, and optionally the antibody is selected from the group consisting of infliximab, adalimumab, etanercept, golimumab, and certolizumab.

16. The method according to any one of claims 1 to 15, further comprising administering an effective amount of lymphocyte activator to the individual.

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

18. The method according to claim 16 or claim 17, wherein the lymphocyte activator is selected from the group consisting of cytokines, chemokines, metabolic regulators, metabolite antagonists, immune checkpoint inhibitors, immune cells, cancer vaccines, bacteria or components thereof, viruses or components thereof, fungi or components thereof, bispecific T cell engagers (BiTEs), antibody drug conjugates, and any combination thereof.

19. The method according to any one of claims 1 to 18, wherein the TNFα inhibitor is administered within two weeks prior to, in parallel with, or within three hours thereafter, the administration of the myeloid cell activator or myeloid cell activation therapy, and / or b) the administration of the SHP-1 pathway inhibitor.

20. The method according to any one of claims 2 to 19, wherein the TNFα inhibitor is administered within two weeks prior to the administration of the SHP-1 pathway inhibitor, concurrently therewith, or within three hours thereafter.

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

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

23. The method according to any one of claims 1 to 22, wherein the myeloid cell activator administration or myeloid cell activation therapy is performed systemically, and optionally, an inhibitor of the myeloid cell activator or myeloid cell activation therapy is administered orally, intravenously, subcutaneously, or intraperitoneally.

24. The method according to any one of claims 1 to 22, wherein the myeloid cell activator administration or myeloid cell activation therapy is performed locally, and optionally, an inhibitor of the myeloid cell activator or myeloid cell activation therapy is administered intratumor or locally.

25. The method according to any one of claims 1 to 24, wherein the administration of the myeloid cell activator or the myeloid cell activation therapy is performed daily for at least two, three, four, five, six, or seven days.

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

27. The method according to any one of claims 2 to 26, wherein the administration of the SHP-1 pathway inhibitor and the administration of the myeloid cell activator or myeloid cell activation therapy are each performed within 24 hours of each other, and optionally, the administration of the SHP-1 pathway inhibitor and the administration of the myeloid cell activator or myeloid cell activation therapy are performed simultaneously or in parallel on the individual.

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

29. The method according to any one of claims 1 to 27, wherein the TNFα inhibitor is administered approximately once a week or less.

30. The method according to any one of claims 1 to 29, further comprising evaluating the level of TNFα in the individual (e.g., TNFα level in serum or blood).

31. The method according to any one of claims 1 to 30, further comprising administering an IL-6 inhibitor.

32. The method according to any one of claims 1 to 31, comprising at least two administrations of the TNFα inhibitor, wherein optionally, the two administrations of the TNFα inhibitor are performed at intervals of a) at least 2, 3, 4, 5, 6, or 7 days, or b) at most 4, 3, 2, or 1 week, 6, or 5 days.

33. The method according to any one of claims 1 to 32, wherein the TNFα inhibitor is administered to the individual for at least two cycles, each cycle being approximately 3 to approximately 7 days long.

34. The method according to any one of claims 2 to 33, comprising administering both a tyrosine kinase inhibitor and an SHP-1 inhibitor.

35. The method according to any one of claims 1 to 34, comprising administering: a) an SHP-1 inhibitor, optionally TPI-1 or an analog or derivative thereof; b) a TLR agonist, optionally activating TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, and / or zymosan; and c) a TNFα inhibitor, optionally an anti-TNFα antibody.

36. The method according to any one of claims 1 to 35, comprising administering: a) an SHP-1 inhibitor, which optionally is TPI-1 or an analog or derivative thereof; b) a STING activator; and c) a TNFα inhibitor, which optionally is an anti-TNFα antibody.

37. The method according to any one of claims 1 to 36, comprising: a) administering an SHP-1 inhibitor, which optionally is TPI-1 or an analog or derivative thereof; b) performing radiotherapy; and c) administering a TNFα inhibitor, which optionally is an anti-TNFα antibody thereof.

38. The method according to any one of claims 2 to 37, wherein the individual is administered an inhibitor of the SHP-1 pathway and the myeloid cell activator or myeloid cell activation therapy until the individual experiences tumor disappearance.

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

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

41. The method according to claim 39 or claim 40, wherein the cytokine and / or the anti-PD-1 antibody is administered to the individual daily for at least 2, 3, 4, 5, 6, or 7 days, and optionally, the cytokine and / or the anti-PD-1 antibody is administered to the individual for at least 2 cycles, each cycle being approximately 3 to approximately 20 days.

42. The method according to any one of claims 1 to 41, wherein the individual does not develop grade 2 to 4 cytokine release syndrome or pro-inflammatory organ injury.

43. The method according to any one of claims 1 to 42, wherein administration of the TNFα inhibitor does not impair or slightly impairs tumor disappearance.

44. The aforementioned cancer, a) It is a solid tumor or a blood cancer. b) Having terminal cancer, and / or c) The method according to any one of claims 1 to 43, wherein the method is resistant to or unresponsive to radiotherapy, chemotherapeutic agents, and / or checkpoint inhibitors.

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

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