SHP-1 inhibitors and activators of t cells

Abstract

The present application provides a method of treating a cancer in an individual that involves administering to the individual a lymphocyte activating agent (e.g., a T cell activating agent) and an agent that inhibits SHP-1 signaling (e.g., TPI-1, PTP-1). In some cases, the method optionally further involves administering a TNFα inhibitor and / or a pro-inflammatory agent (such as TLR or STING agonists).

Description

Attorney Docket No.24516-20012.40 SHP-1 INHIBITORS AND ACTIVATORS OF T CELLS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 562,250, filed March 6, 2024, entitled “SHP-1 INHIBITORS AND ACTIVATORS OF T CELLS,” U.S. Provisional Patent Application No. 63 / 562,140, filed March 6, 2024, entitled “SHP-1 INHIBITOR CONJUGATES WITH PRO-INFLAMMATORY COMPOUNDS,” U.S. Provisional Patent Application No.63 / 562,133, filed March 62024, entitled “TYROSINE PHOSPHATASE INHIBITOR 1 (TPI-1) DERIVATIVES,” and U.S. Provisional Patent Application No.63 / 562,237, filed March 6, 2024, entitled “LOCAL APPLICATION OF AGENTS INHIBITING TYROSINE KINASE OR SHP-1 SIGNALING,” the contents of each of which are herein incorporated by reference in their entirety for all purposes. FIELD OF THE INVENTION

[0002] The present invention relates to compositions and methods for treating cancer involving activating T cells with a lymphocyte activating agent and an inhibitor of the tyrosine kinase / SHP-1 pathway. BACKGROUND OF THE INVENTION

[0003] In cancers such as solid tumors, intratumoral myeloid leukocytes, including macrophages (i.e., tumor-associated macrophage or TAM) and myeloid-derived suppressive cells (MDSC), play critical roles in controlling the tumor microenvironment (TME) immunosuppression that supports tumor growth and also confers tumor resistance to immunotherapeutic treatments. One important mechanism for myeloid leukocytes to adapt an immunosuppressive phenotype, or to strengthen their immunosuppressive capacity following tumor therapies, is through their cell surface inhibitory receptors (iRs), which upon activation are also driven by their extracellular ligand binding that triggers multi-pathways of negative regulation via their cytoplasmic domain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that activate SHP-1, the central signal modulator, to dephosphorylate and hence deactivate a number of signal transduction molecules. This diminishes therapeutics-induced anti-cancer pro-inflammatory responses. In solid tumors, essential cell surface iRs, such as SIRP^, Siglecs, LilRBs, PirB, LAIR1, lectin receptors, SLAM family receptors, etc. (see, e.g., Kang, X.L. et al., Cell Cycle 2016;15:25-40; and Zarrin, A.A. et al., Front Immunol. 2020;11, each of which is hereby incorporated by reference), which also show increased ny-2916766Attorney Docket No.24516-20012.40 expression in the TME with tumor progression to advanced stages, conduct their regulations via activation of SHP-1, which then mediates downstream inhibition.

[0004] Furthermore, TAMs and MDSCs suppress the anticancer activities of tumor infiltrating lymphocytes (TILs), often by inducing lymphocyte exhaustion, in particular T-cell exhaustion. Exhausted T cells are unable to produce cytokine or kill target cancer cells, and typically this state is driven by the induction of iRs (e.g., PD-1, CTLA-4, LAG-3, TIM-3). Accordingly, T cells can infiltrate the TME but are rapidly rendered incompetent and unable to mount an effective anti-tumor response, thereby allowing the tumor cells to evade the adaptive immune system.

[0005] Given these inhibitory mechanisms elucidated within previous years, pipelines of therapeutic developments aiming to blockade iRs (e.g., anti-LilRB1 / 2 and anti-SIRP^) and their ligands (e.g., anti-CD47) are being undertaken (see, e.g., Carosella, E.D. et al., Trends Cancer 2021;7:389-392; Yanagita, T.Y. et al., JCI Insight 2017;2; and Zhang, W. et al., Front Immunol.2020;11:18, each of which is hereby incorporated by reference). However, these efforts of targeting each iR or its ligand singularly, but not all inhibitory pathways at once, achieve weak-to-partial efficacies in controlling solid tumors. Therefore, safe and effective novel anti-cancer therapeutics are needed.

[0006] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety. BRIEF SUMMARY OF THE INVENTION

[0007] The present application in one aspect provides a method of treating a cancer in a human individual in need thereof, comprising administering to the human individual immune cells deficient in SHP-1 expression or activity. In some embodiments, the immune cells deficient in SHP-1 expression or activity comprise a reduced level of SHP-1 protein, optionally wherein the level of the SHP-1 protein is less than about 50%, 40%, 30%, 20%, 10% or 5% compared to the level of SHP-1 protein in reference immune cells.

[0008] In some embodiments according to any of the methods described above, the immune cells deficient in SHP-1 expression or activity comprise a mutant SHP-1 gene or SHP-1 protein. In some embodiments, the mutant SHP-1 gene or SHP-1 protein comprises a mutation in a catalytic site or a nucleotide within a nucleic acid sequence encoding the catalytic site. In some embodiments, the mutant SHP-1 gene or SHP-1 protein comprises a ny-2916766Attorney Docket No.24516-20012.40 mutation in Tyr 536, Tyr 564, or Ser591 or a nucleotide within a nucleic acid sequence encoding Tyr536, Tyr564 or Ser591.

[0009] In some embodiments according to any of the methods described above, the immune cells deficient in SHP-1 expression or activity comprise an inhibitory nucleic acid that specifically target SHP-1, optionally wherein the inhibitory nucleic acid comprises a siRNA or shRNA.

[0010] In some embodiments according to any of the methods described above, the method further comprises administering to the individual an agent that inhibits SHP-1 signaling (referred to as “SHP-1I”, e.g., a SHP-1 inhibitor, a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a perdeuterated TPI-1, referred to as “dTPI-1”). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor. In some embodiments, the SHP-1 inhibitor is a TPI-1 or an analog thereof. In some embodiments, the TPI-1 is deuterated TPI-1. In some embodiments, the deuterated TPI-1 is TPI-1-d6. In some embodiments, the agent is a tyrosine kinase inhibitor. In some embodiments, the agent is administered intermittently. In some embodiments, the method further comprises administering a TNFa inhibitor to the individual prior to (e.g., within 14, 7, 5, 3, 2, 1 day prior to, e.g., within 24, 18, 12, 6, 3 hours prior to) or shortly after (e.g., within 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes after) the administration of the agent that inhibits the SHP-1 signaling pathway. In some embodiments, the method further comprises administering a pro-inflammatory agent (PIA) or a lymphocyte activating agent (LAA) (together: PI / LA agent) described herein. In some embodiments, the agent that inhibits SHP-1 signaling is associated (e.g., conjugated, e.g, fused) with the PI / LA agent. In some embodiments, the agent that inhibits SHP-1 signaling is conjugated to the PI / LA agent according to a formula. In some embodiments, the formula is PI / LAA-LA-R1wherein PI / LAA is a pro-inflammatory agent or a lymphocyte activating agent, LAis an optional linker, and R1is a SHP-1 inhibitor. In some embodiments, the agent that inhibits SHP-1 signaling conjugated to the PI / LA agent is R848-linker-TPI-1 ester conjugate (1-6) or R848-linker-TPI-1 amide conjugate (2-6).

[0011] In another aspect is provided a method of producing a population of activated T cells in a plurality of cells, comprising treating the T cells with an agent that inhibits SHP-1 signaling, wherein the plurality of cells comprises tumor cells, myeloid-derived suppressor cells (MDSCs), or tumor-associated macrophages (TAMs). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling. ny-2916766Attorney Docket No.24516-20012.40

[0012] In another aspect is provided a method of treating a cancer in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a lymphocyte activating agent. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling.

[0013] In some embodiments according to any of the methods provided above, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of 40 µm, 35 µm, 30 µm, 20 µm, 15 µm, or 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1 (e.g., dTPI-1). In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50.

[0014] In some embodiments according to any of the methods described above, the SHP-1 inhibitor comprises a genome editing agent comprising a genome editing enzyme and a guide RNA or a guide DNA that specifically targets SHP1. In some embodiments, the guide RNA or guide DNA targets a nucleotide within a nucleic acid sequence encoding a catalytic site. In some embodiments, the guide RNA or guide DNA targets a nucleic acid sequence encoding Tyr536, Tyr564 or Ser591.

[0015] In some embodiments according to any of the methods described above, the SHP-1 inhibitor comprises an inhibitory nucleic acid that specifically target SHP-1, optionally the inhibitory nucleic acid comprises a siRNA or shRNA.

[0016] In some embodiments according to any of the methods described above, the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism-modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, a lymphocyte-activating antibody, a small molecule, a calcium ionophore, and any combination thereof. In some embodiments, the lymphocyte activating agent comprises a cytokine. In some embodiments, the cytokine is IL-2, IL-4, IL-7, IL-15, or IL-21. In some embodiments, the lymphocyte activating agent comprises a binding moiety that binds to a T ny-2916766Attorney Docket No.24516-20012.40 cell antigen. In some embodiments, the binding moiety comprises an antibody. In some embodiments, the T cell antigen is CD3 or CD28. In some embodiments, the lymphocyte activating agent comprises an anti-CD3 antibody and / or an anti-CD28 antibody. In some embodiments, the lymphocyte activating agent comprises an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor comprises an antibody that targets an immune checkpoint selected from the group consisting of PD-1, CTLA4, LAG-3, and TIM-3. In some embodiments, the lymphocyte activating agent comprises an anti-PD-1 antibody and / or an anti-CTLA4 antibody.

[0017] In some embodiments according to any of the methods described above, the immune cells (e.g., T cells) are obtained from the same individual. In some embodiments, the immune cells (e.g., T cells) are obtained from a different individual. In some embodiments, the immune cells comprise T cells. In some embodiments, the T cells comprise CD8+ T cells. In some embodiments, the T cells comprise CD4+ T cells. In some embodiments, the T cells comprise tumor infiltrating lymphocytes (TILs). In some embodiments, the T cells comprise a TCR that targets one or more tumor-associated antigens.

[0018] In some embodiments, the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously.

[0019] In some embodiments according to any of the methods described above, the method further comprises administering a pro-inflammatory agent. In some embodiments, the pro- inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. ny-2916766Attorney Docket No.24516-20012.40

[0020] In some embodiments according to any of the methods described above, the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are associated. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are associated. In some embodiments, a) the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are fused via a linker; and / or b) the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are fused via a linker; optionally wherein the linker is a cleavable linker, further optionally wherein the linker is a pH sensitive linker. In some embodiments, a) the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are covalently conjugated; and / or b) the agent that inhibits SHP-1 signaling and the pro- inflammatory agent are covalently conjugated. In some embodiments, a) the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are conjugated via an ester bond or via an amide bond; and / or b) the agent that inhibits SHP-1 signaling and the pro- inflammatory agent are conjugated via an ester bond or via an amide bond. In some embodiments, the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are conjugated via an ester bond. In some embodiments, the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are conjugated via an amide bond. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are conjugated via an ester bond. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are conjugated via an amide bond. In some embodiments, a) the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are conjugated via a PEG moiety; and / or b) the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are conjugated via a PEG moiety. In some embodiments, the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are conjugated via a PEG moiety. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are conjugated via a PEG moiety.

[0021] In some embodiments according to any of the methods described above, the method further comprises administering a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor. In some embodiments, the method further comprises administering a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti- TNF^ antibody. In some embodiments, the TNF^ inhibitor comprises a neutralizing anti- TNF^ antibody. In some embodiments, the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. ny-2916766Attorney Docket No.24516-20012.40

[0022] In some embodiments according to any of the methods described above, the TNF^ inhibitor is administered to the individual prior to the administration of the agent that inhibits SHP-1 signaling or within about 3 hours post the administration of the agent that inhibits SHP-1 signaling, wherein the individual has been subject to the pro-inflammatory agent and / or the lymphocyte activating agent, optionally wherein the TNF^ inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the agent that inhibits SHP-1 signaling.

[0023] In some embodiments according to any of the methods described above, the TNF^ inhibitor is administered to the individual prior to the administration of the pro-inflammatory agent and / or the lymphocyte activating agent or within about 3 hours post the administration of the pro-inflammatory agent and / or the lymphocyte activating agent, wherein the individual has been subject to the agent that inhibits SHP-1 signaling, optionally wherein the TNF^ inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the pro- inflammatory agent and / or the lymphocyte activating agent.

[0024] In some embodiments according to 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 a late-stage cancer. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor. In some embodiments, the individual is human. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG.1 shows the efficacy of SHP-1 inhibition to rescue tumor infiltrating lymphocytes (TILs) from suppression of TCR-induced activation and proliferation by the tumor microenvironment (TME). TILs isolated from KPC pancreatic adenocarcinoma were labeled with CFSE and induced to proliferate by CD3 / CD28 ligation of the T cell receptor (TCR) in the absence (row B) or presence of tumor dissociates (TME) (rows C-M). Proliferation was measured by assessing the degree of CFSE dilution (i.e., the reduced fluorescence intensity detected by flow cytometry, peak shifted toward left). Control TILs cultured without CD3 / CD28 ligation are shown in row A. TILs cultured with the SHP-1 inhibitors TPI-1 or PTP-1 are shown in rows D-G. TILs cultured with SHP-2 or SHIP inhibitors are shown in rows H-M. TME, tumor microenvironment; iSHP-1, SHP-1 inhibitor; ny-2916766Attorney Docket No.24516-20012.40 iSHP-2, SHP-2 inhibitor; iSHIP-1, SHIP-1 inhibitor; *, p < 0.05; **, p < 0.001; ***, p < 0.0001.

[0026] FIG.2 shows the ability of SHP-1, SHP-2, or SHIP-1 inhibition to rescue CD4 and CD8 TIL from suppression of TCR-induced activation and proliferation by myeloid derived suppressor cells (MDSCs). TILs isolated from KPC were labeled with CFSE and induced to proliferate for 4 days by CD3 / CD28 ligation of TCR in the absence (row B) or presence of MDSCs (rows C-J). Proliferation was measured by assessing the degree of CFSE dilution (i.e., the reduced fluorescence intensity detected by flow cytometry, peak shifted toward left). Control TILs cultured without CD3 / CD28 ligation are shown in row A. TILs cultured with the SHP-1 inhibitor TPI-1 are shown in rows D-E. TILs cultured with SHP-2 or SHIP inhibitors are shown in rows F-J. TME, tumor microenvironment; ctl, control; MDSC, myeloid derived suppressor cell; iSHP-1, SHP-1 inhibitor; iSHP-2, SHP-2 inhibitor; iSHIP, SHIP-1 inhibitor; TCR, T cell receptor; *, p < 0.05.

[0027] FIG.3 shows the ability of SHP-1 inhibition or deletion to rescue the suppression of T cell activation and proliferation induced by the tumor microenvironment. Splenic T cells isolated from WT, SHP1+ / -, or SHP1- / -mice were stimulated with anti-CD3 / CD28 antibodies to induce T cell activation and proliferation (rows B, F and J, respectively). MC38 tumor dissociates (TME) were added to WT, SHP1+ / -, or SHP1- / -T cell cultures and the T cells stimulated with anti-CD3 / CD28 antibodies (rows C, G, and K, respectively). WT, SHP1+ / -, or SHP1- / -T cell cultures were also cultured with TME and the SHP-1 inhibitor, TPI-1 (D, H, and L, respectively). Control experiments were WT, SHP1+ / -, or SHP1- / -T cells cultured in the absence of CD3 / CD28 stimulation, TME, or TPI-1 (rows A, E, and I, respectively). WT, wildtype; TME, tumor microenvironment; ***, p < 0.0001.

[0028] FIGs.4A-4D show the therapeutic anti-cancer efficacy of combined SHP-1 inhibition and T cell activation. MC38 colorectal carcinoma was established in C57Bl / 6 mice. After tumor formation, the tumors were treated by intratumoral (i.t.) injection with (i) anti-PD-1 Ab alone (^PD-1, 50^g, every 3 days) or ^PD-1 in combination with the SHP-1 inhibitor, TPI-1 (1mg / kg, every 2 days) (FIG.4A), (ii) a single dose of anti-CD3 and anti-CD28 antibodies (50^g each) or anti-CD3 / anti-CD28 antibodies in combination with TPI-1 (FIG.4B), or (iii) IL-2 (30,000IU, every 3 days) alone or in combination with TPI-1 or IL-2 with TPI-1 in combination with anti- TNF^ and anti-IL-6 antibodies (50^g each) (FIG.4C). Addition of neutralizing anti-TNF^ and anti-IL-6 antibodies did not affect treatment efficacy. (FIG.4D) ny-2916766Attorney Docket No.24516-20012.40 shows that treating mice with TPI-1 alone did not stop tumor progression. iSHP-1, SHP-1 inhibitor; V, volume. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present application in one aspect provides methods of treating a cancer in a human individual in need thereof, comprising administering to the human individual immune cells deficient in SHP-1 expression or activity. The present application in some embodiments provides methods of treating a cancer in an individual that further comprises administering to the individual a lymphocyte activating agent. In another aspect is provided a method of treating a cancer in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a lymphocyte activating agent. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling. In some embodiments, the SHP-1 inhibitor comprises TPI-1 or an analog or derivative thereof (e.g., deuterated TPI-1, e.g., a dTPI-1). In some embodiments, the inhibitor of the SHP-1 signaling pathway is administered systemically or locally. In some embodiments, the method comprises administering the inhibitor of the SHP-1 signaling pathway daily for at least 7 days or intermittently. In some embodiments, the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism-modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, a lymphocyte-activating antibody, a small molecule, a calcium ionophore, and any combination thereof. In some embodiments, the pro- inflammatory agent comprises an agent selected from the group consisting of: a STING activator, a Toll-like receptor (TLR) agonist, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, a radiation treatment, a radiopharmaceutical treatment, an electrostatic treatment, an antibody drug conjugate, and any combination thereof.

[0030] The present application is at least partly based upon a striking finding that combination of a SHP-1 inhibitor, which potentially inhibits the activation of a “master” ny-2916766Attorney Docket No.24516-20012.40 inhibitory executor SHP-1, with a lymphocyte activating treatment that activates T cells (e.g., tumor infiltrating T cells, TILs) leads to drastic reprogramming of the tumor microenvironment (TME) and dramatically bolsters activation of adaptive immune cells (i.e., T cells) to promote anti-cancer immunity. Specifically, it was found that the administration of i) an exemplary agent that inhibits SHP-1 signaling, TPI-1 and ii) a lymphocyte activating agent (e.g., anti-PD-1 antibody, e.g., IL-2, e.g., anti-CD3 / anti-CD28 antibodies) in a preclinical model dramatically improved the tumor burden. This finding is particularly striking because the same effect was not seen upon administering TPI-1 alone, anti-PD-1 antibody alone, or IL-2 alone or anti-CD3 / anti-CD28 antibodies. See FIGs.4A-4D. This finding underscores the potential of targeting the SHP-1 pathway in TILs in order to ameliorate or eliminate tumors.

[0031] Accordingly, this application provides novel methods that can effectively rewire tumor condition-imposed immunosuppression and license innate and adaptive immunity against cancer while significantly preventing therapeutic-induced toxicity, thereby achieving a remarkable and safe anti-tumor efficacy. I. Definitions

[0032] In general, terms used in the claims and the specification are intended to be construed as having the plain meaning understood by a person of ordinary skill in the art. Certain terms are defined below to provide additional clarity. In case of conflict between the plain meaning and the provided definitions, the provided definitions are to be used.

[0033] The term “individual,” “subject,” or “patient” is used synonymously herein to describe an animal, for example a reptile, a bird, a fish, or a mammal, (e.g., a human). An individual includes, but is not limited to, fish, reptile, bird, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is human. In some embodiments, the individual is selected from the group consisting of fish, reptile, bird, human, bovine, horse, feline, canine, or primate. In some embodiments, an individual suffers from a disease, such as cancer. In some embodiments, the individual is in need of treatment.

[0034] A “reference” as used herein, refers to any sample, standard, or level that is used for comparison purposes. A reference may be obtained from a healthy and / or non-diseased sample. In some examples, a reference may be obtained from an untreated sample. In some examples, a reference is obtained from a non-diseased or non-treated sample of an individual. In some examples, a reference is obtained from one or more healthy individuals who are not ny-2916766Attorney Docket No.24516-20012.40 the individual or individuals under treatment. For example, as used herein, reference immune cells can refer to corresponding immune cells in a healthy individual; or corresponding immune cells from the same individual that are not found in tumor tissue, i.e., that are found in healthy tissues.

[0035] As used herein, the term “intermittent” or “intermittently” in the context of dosing refers to a non-continuous dosing. For example, in some cases, “intermittent” dosing refers to a dosing where the treatment is administered at least two times, and the two administrations are separated by at least one day (i.e., Day 1 and Day 3).

[0036] As used herein, the term “cycle” in the context of dosing refers to a time period during which there is at least one administration of a treatment. Day 1 of a cycle is defined as the day when the first administration of a treatment happens during that time period. When there are a few daily consecutive administrations of the treatment, then Day 1 of the cycle is defined as the day when first administration among the few daily consecutive administrations happens. The last day of the cycle is defined as the day before the next non-consecutive administration of the treatment happens. The cycles do not have to have the same length of time. For example, the first cycle can have five days, and the second cycle can have seven days. Each cycle may have different numbers of administrations of the treatment. For example, the first cycle, which may have five days, may have one administration of the treatment, and the second cycle, which may have seven days, may have two administrations of the treatment. Wherein the treatment involves the administration of more than one compound, then each compound can follow the same or different cycles as described above. In some examples, each compound may have cycles that are a combination of the same and different cycles as the cycles of any other compound.

[0037] As used herein the term “immunogenic” is the ability to elicit an immune response, e.g., via T-cells, B cells, or both.

[0038] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the ny-2916766Attorney Docket No.24516-20012.40 disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. Also encompassed by “treatment” is a reduction of pathological consequence of cancer. The methods of the invention contemplate any one or more of these aspects of treatment.

[0039] As used herein, “delaying” the development of cancer means to defer, hinder, slow, retard, stabilize, and / or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. A method that “delays” development of cancer is a method that reduces probability of disease development in a given time frame and / or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of individuals. Cancer development can be detectable using standard methods, including, but not limited to, computerized axial tomography (CAT Scan), Magnetic Resonance Imaging (MRI), abdominal ultrasound, clotting tests, arteriography, or biopsy. Development may also refer to cancer progression that may be initially undetectable and includes occurrence, recurrence, and onset.

[0040] The term “simultaneous administration,” as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes. When the first and second therapies are administered simultaneously, the first and second therapies may be contained in the same composition (e.g., a composition comprising both a first and second therapy) or in separate compositions (e.g., a first therapy in one composition and a second therapy is contained in another composition).

[0041] As used herein, the term “sequential administration” means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first therapy or the second therapy may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits. ny-2916766Attorney Docket No.24516-20012.40

[0042] As used herein, the term “concurrent administration” means that the administration of the first therapy and that of a second therapy in a combination therapy overlap with each other.

[0043] As used herein, by “pharmaceutically acceptable” or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0044] It is understood that embodiments of the application described herein include “consisting of” and / or “consisting essentially of” embodiments.

[0045] Ranges: throughout this disclosure, various aspects of the application can be presented in a range format. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0046] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0047] As used herein, reference to “not” a value or parameter generally means and describes “other than” a value or parameter. For example, the method is not used to treat cancer of type X means the method is used to treat cancer of types other than X.

[0048] The term “about X-Y” used herein has the same meaning as “about X to about Y.”

[0049] It should be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. ny-2916766Attorney Docket No.24516-20012.40

[0050] Any terms not directly defined herein shall be understood to have the meanings commonly associated with them as understood within the art of the invention. Certain terms are discussed herein to provide additional guidance to the practitioner in describing the compositions, devices, methods and the like of aspects of the invention, and how to make or use them. It will be appreciated that the same thing may be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. No significance is to be placed upon whether or not a term is elaborated or discussed herein. Some synonyms or substitutable methods, materials and the like are provided. Recital of one or a few synonyms or equivalents does not exclude use of other synonyms or equivalents, unless it is explicitly stated. Use of examples, including examples of terms, is for illustrative purposes only and does not limit the scope and meaning of the aspects of the invention herein. II. Methods of treatment

[0051] The present application in one aspect provides methods of treating a cancer in an individual (e.g., a human individual) in need thereof, comprising administering to individual immune cells deficient in SHP-1 expression or activity. In some embodiments, the method further comprises administering a lymphocyte activating agent to the individual. In some embodiments, the method further comprises administering an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a tyrosince kinase inhibitor, e.g., a TPI-1 or a derivative or analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1) to the individual. In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the immune cells deficient in SHP-1 expression or activity comprise a reduced level of SHP-1 protein, optionally wherein the level of the SHP-1 protein is less than about 50%, 40%, 30%, 20%, 10% or 5% compared to the level of SHP-1 protein in reference immune cells. In some embodiments, the immune cells are obtained from the same individual. In some embodiments, the immune cells are obtained from a different individual. In some embodiments, the immune cells comprise T cells. In some embodiments, the T cells comprise CD8+ T cells. In some embodiments, the T cells comprise CD4+ T cells. In some embodiments, the T cells comprise tumor infiltrating lymphocytes (TILs). In some embodiments, the T cells comprise a chimeric antigen receptor (CAR), wherein the CAR specifically binds to a tumor-associated antigen. In some embodiments, the T cells comprise a TCR that targets one or more tumor-associated antigens. In some embodiments, the cancer ny-2916766Attorney Docket No.24516-20012.40 is a hematological cancer. In some embodiments, the cancer is a late-stage cancer. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0052] In some embodiments, there is provided a method of treating a cancer in a human individual in need thereof, comprising administering to the human individual immune cells deficient in SHP-1 expression or activity, wherein the immune cells deficient in SHP-1 expression or activity comprise a mutated SHP-1 gene or SHP-1 protein. In some embodiments, the method further comprises administering a lymphocyte activating agent to the individual. In some embodiments, the method further comprises administering a pro- inflammatory agent to the individual. In some embodiments, the method further comprises administering an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a tyrosince kinase inhibitor, e.g., a TPI-1 or a derivative or analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1) to the individual. In some embodiments, the agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the immune cells deficient in SHP-1 expression or activity comprise a reduced level of SHP-1 protein, optionally wherein the level of the SHP-1 protein is less than about 50%, 40%, 30%, 20%, 10% or 5% compared to the level of SHP-1 protein in reference immune cells. In some embodiments, the mutant SHP-1 gene or SHP-1 protein comprises a mutation in a catalytic site or a nucleotide within a nucleic acid sequence encoding the catalytic site. In some embodiments, the mutant SHP-1 gene or SHP-1 protein comprises a mutation in Tyr 536, Tyr 564, or Ser591 or a nucleotide within a nucleic acid sequence encoding Tyr536, Tyr564 or Ser591. In some embodiments, the immune cells are obtained from the same individual. In some embodiments, the immune cells are obtained from a different individual. In some embodiments, the immune cells comprise T cells. In some embodiments, the T cells comprise CD8+ T cells. In some embodiments, the T cells comprise CD4+ T cells. In some embodiments, the T cells comprise tumor infiltrating lymphocytes (TILs). In some embodiments, the T cells comprise a chimeric antigen receptor (CAR), wherein the CAR specifically binds to a tumor-associated antigen. In some embodiments, the T cells comprise a TCR that targets one or more tumor-associated antigens. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a ny-2916766Attorney Docket No.24516-20012.40 sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the method further comprises administering a TNF^ inhibitor, a TNF- like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor. In some embodiments, the method further comprises administering a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the TNF^ inhibitor is administered to the individual prior to the administration of the immune cells deficient in SHP-1 expression or activity or within about 3 hours post the administration of the immune cells deficient in SHP-1 expression or activity, wherein the individual has been subject to the pro-inflammatory agent and / or the immune cells deficient in SHP-1 expression or activity, optionally wherein the TNF^ inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the immune cells deficient in SHP-1 expression or activity. In some embodiments, the TNF^ inhibitor is administered to the individual prior to the administration of the pro-inflammatory agent and / or the immune cells deficient in SHP-1 expression or activity or within about 3 hours post the administration of the pro-inflammatory agent and / or the immune cells deficient in SHP-1 expression or activity, wherein the individual has been subject to the immune cells deficient in SHP-1 expression or activity, optionally wherein the TNF^ inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the pro-inflammatory agent and / or immune cells deficient in SHP-1 expression or activity. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a late-stage cancer. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0053] In some embodiments, there is provided a method of treating a cancer in a human individual in need thereof, comprising administering to the human individual immune cells deficient in SHP-1 expression or activity, wherein the immune cells deficient in SHP-1 expression or activity comprise an inhibitory nucleic acid that specifically target SHP-1, optionally wherein the inhibitory nucleic acid comprises a siRNA or shRNA. In some embodiments, the method further comprises administering a lymphocyte activating agent to the individual. In some embodiments, the method further comprises administering an agent ny-2916766Attorney Docket No.24516-20012.40 that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a tyrosince kinase inhibitor, e.g., a TPI-1 or a derivative or analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1) to the individual. In some embodiments, the agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the method further comprises administering a pro- inflammatory agent to the individual. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the immune cells deficient in SHP-1 expression or activity comprise a reduced level of SHP-1 protein, optionally wherein the level of the SHP-1 protein is less than about 50%, 40%, 30%, 20%, 10% or 5% compared to the level of SHP-1 protein in reference immune cells. In some embodiments, the immune cells are obtained from the same individual. In some embodiments, the immune cells are obtained from a different individual. In some embodiments, the immune cells comprise T cells. In some embodiments, the T cells comprise CD8+ T cells. In some embodiments, the T cells comprise CD4+ T cells. In some embodiments, the T cells comprise tumor infiltrating lymphocytes (TILs). In some embodiments, the T cells comprise a chimeric antigen receptor (CAR), wherein the CAR specifically binds to a tumor-associated antigen. In some embodiments, the T cells comprise a TCR that targets one or more tumor-associated antigens. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the method further comprises administering a TNF^ inhibitor, a TNF- like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor. In some embodiments, the method further comprises administering a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the TNF^ inhibitor is administered to the individual prior to the administration of the immune cells deficient in SHP-1 expression or activity or within about 3 hours post the administration of the immune cells deficient in SHP-1 expression or activity, wherein the individual has been subject to the pro-inflammatory agent and / or the immune cells deficient in SHP-1 expression or activity, optionally wherein the TNF^ inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the immune cells deficient in SHP-1 expression or activity. In some embodiments, the TNF^ inhibitor is ny-2916766Attorney Docket No.24516-20012.40 administered to the individual prior to the administration of the pro-inflammatory agent and / or the immune cells deficient in SHP-1 expression or activity or within about 3 hours post the administration of the pro-inflammatory agent and / or the immune cells deficient in SHP-1 expression or activity, wherein the individual has been subject to the immune cells deficient in SHP-1 expression or activity, optionally wherein the TNF^ inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the pro-inflammatory agent and / or immune cells deficient in SHP-1 expression or activity. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a late-stage cancer. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0054] The present application in another aspect provides methods of treating a cancer in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a lymphocyte activating agent. In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1 (e.g., a dTPI-1). In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5- fold, or 10-fold of its EC50. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0055] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a ny-2916766Attorney Docket No.24516-20012.40 SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a lymphocyte activating agent, wherein the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism- modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, a lymphocyte-activating antibody, a small molecule, a calcium ionophore, and any combination thereof. In some embodiments, the method further comprises administering a pro- inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 ny-2916766Attorney Docket No.24516-20012.40 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the lymphocyte activating agent. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the lymphocyte activating agent. In some embodiments, the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 ny-2916766Attorney Docket No.24516-20012.40 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the lymphocyte activating agent and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0056] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) a SHP-1 inhibitor, and b) a lymphocyte activating agent, wherein the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism-modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, a lymphocyte-activating antibody, a small molecule, a calcium ionophore, and any combination thereof. In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the SHP- 1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog ny-2916766Attorney Docket No.24516-20012.40 thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5- fold, or 10-fold of its EC50. In some embodiments, SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered at an interval of no more than once every two days. In some embodiments, the SHP-1 inhibitor is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP-1 inhibitor is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the SHP-1 inhibitor is administered regularly. In some embodiments, the SHP- 1 inhibitor is administered daily. In some embodiments, the SHP-1 inhibitor is administered twice daily. In some embodiments, SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the SHP-1 inhibitor. In some embodiments, the SHP-1 inhibitor is administered simultaneously with the lymphocyte activating agent. In some embodiments, the SHP-1 inhibitor is administered concurrently with the lymphocyte activating agent. In some embodiments, the SHP-1 inhibitor and the lymphocyte activating agent are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the SHP-1 inhibitor has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the SHP-1 inhibitor is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected ny-2916766Attorney Docket No.24516-20012.40 from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the lymphocyte activating agent and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the SHP-1 inhibitor comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0057] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), and b) a lymphocyte activating agent, wherein the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism- modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, a lymphocyte-activating antibody, a small molecule, a calcium ionophore, and any combination thereof. In some embodiments, the method further comprises administering a pro- inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the concentration of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered intermittently. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered at an interval of no more than once every two days. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., ny-2916766Attorney Docket No.24516-20012.40 a deuterated TPI-1) is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered regularly. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered daily. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered twice daily. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1). In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered simultaneously with the lymphocyte activating agent. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is administered concurrently with the lymphocyte activating agent. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) and the lymphocyte activating agent are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor ny-2916766Attorney Docket No.24516-20012.40 comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1) and / or the lymphocyte activating agent and / or the pro-inflammatory agent. In some embodiments, the pro- inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M- 852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0058] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) PTP-1 or a derivative or analog thereof, and b) a lymphocyte activating agent, wherein the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism-modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, a lymphocyte-activating antibody, a small molecule, a calcium ionophore, and any combination thereof. In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the concentration of PTP-1 or a derivative or analog thereof in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, PTP-1 or a derivative or analog thereof is administered intermittently. In some embodiments, PTP-1 or a derivative or analog thereof is administered at an interval of no more than once every two days. In some embodiments, PTP-1 or a derivative or analog thereof is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In ny-2916766Attorney Docket No.24516-20012.40 some embodiments, PTP-1 or a derivative or analog thereof is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, PTP-1 or a derivative or analog thereof is administered regularly. In some embodiments, PTP-1 or a derivative or analog thereof is administered daily. In some embodiments, PTP-1 or a derivative or analog thereof is administered twice daily. In some embodiments, PTP-1 or a derivative or analog thereof is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering PTP-1 or a derivative or analog thereof. In some embodiments, PTP-1 or a derivative or analog thereof is administered simultaneously with the lymphocyte activating agent. In some embodiments, PTP-1 or a derivative or analog thereof is administered concurrently with the lymphocyte activating agent. In some embodiments, PTP-1 or a derivative or analog thereof and the lymphocyte activating agent are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, PTP-1 or a derivative or analog thereof has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, PTP-1 or a derivative or analog and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, PTP-1 or a derivative or analog and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, PTP-1 or a derivative or analog thereof is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of PTP-1 or a derivative or analog thereof and / or the lymphocyte activating agent and / or the ny-2916766Attorney Docket No.24516-20012.40 pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0059] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a cytokine (e.g., an IL-2, IL-4, IL-7, IL-15, or IL-21 cytokine or biologically active fragment or derivative thereof). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5- ny-2916766Attorney Docket No.24516-20012.40 fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the cytokine. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the cytokine. In some embodiments, the agent that inhibits SHP-1 signaling and the cytokine agent are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, ny-2916766Attorney Docket No.24516-20012.40 adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the cytokine and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0060] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a chemokine (e.g., CXCL9, CXCL10, or CXCL11). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the ny-2916766Attorney Docket No.24516-20012.40 SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the chemokine. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the chemokine. In some embodiments, the agent that inhibits SHP-1 signaling and the chemokine are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering ny-2916766Attorney Docket No.24516-20012.40 to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the chemokine and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0061] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a metabolism-modulating drug (such as any of the metabolism- modulating drugs described herein). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro- inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor ny-2916766Attorney Docket No.24516-20012.40 selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the metabolism-modulating drug. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the metabolism-modulating drug. In some embodiments, the agent that inhibits SHP-1 signaling and the metabolism-modulating drug are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or ny-2916766Attorney Docket No.24516-20012.40 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the metabolism-modulating drug and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0062] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a metabolite antagonist (such as any of the metabolite antagonists described herein). In some embodiments, the method further comprises administering a pro- inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, ny-2916766Attorney Docket No.24516-20012.40 a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the metabolite antagonist. In ny-2916766Attorney Docket No.24516-20012.40 some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the metabolite antagonist. In some embodiments, the agent that inhibits SHP-1 signaling and the metabolite antagonist agent are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the metabolite antagonist and / or the pro- inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0063] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, ny-2916766Attorney Docket No.24516-20012.40 e.g., a dTPI-1), and b) an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, e.g., an anti-CTLA4 antibody). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is ny-2916766Attorney Docket No.24516-20012.40 administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the immune checkpoint inhibitor. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the immune checkpoint inhibitor. In some embodiments, the agent that inhibits SHP-1 signaling and the immune checkpoint inhibitor are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro- inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the immune checkpoint inhibitor and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some ny-2916766Attorney Docket No.24516-20012.40 embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0064] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) an immune cell (such as any of the immune cells described herein). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no ny-2916766Attorney Docket No.24516-20012.40 more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the immune cell. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the immune cell. In some embodiments, the agent that inhibits SHP-1 signaling and the immune cell are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or ny-2916766Attorney Docket No.24516-20012.40 simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the immune cell and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0065] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a cancer vaccine (such as any of the cancer vaccines described herein). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- ny-2916766Attorney Docket No.24516-20012.40 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the cancer vaccine. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the cancer vaccine. In some embodiments, the agent that inhibits SHP-1 signaling and the cancer vaccine are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half- life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a ny-2916766Attorney Docket No.24516-20012.40 JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the cancer vaccine and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0066] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a bacterium or component thereof (such as any of the bacteria or components thereof described herein, e.g., LPS). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), ny-2916766Attorney Docket No.24516-20012.40 and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5- fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the bacterium or component thereof. In some embodiments, the agent that inhibits SHP- 1 signaling is administered concurrently with the bacterium or component thereof. In some embodiments, the agent that inhibits SHP-1 signaling and the bacterium or component thereof are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently ny-2916766Attorney Docket No.24516-20012.40 or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half- life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the bacterium or component thereof and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0067] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a virus or component thereof (such as any of the viruses or components thereof described herein, e.g., an oncolytic virus). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In ny-2916766Attorney Docket No.24516-20012.40 some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the virus or component thereof. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the ny-2916766Attorney Docket No.24516-20012.40 virus or component thereof. In some embodiments, the agent that inhibits SHP-1 signaling and the virus or component thereof are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the virus or component thereof and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0068] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a fungus or component thereof (such as any of the fungi or ny-2916766Attorney Docket No.24516-20012.40 components thereof described herein). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro- inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits ny-2916766Attorney Docket No.24516-20012.40 SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the fungus or component thereof. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the fungus or component thereof. In some embodiments, the agent that inhibits SHP-1 signaling and the fungus or component thereof are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the fungus or component thereof and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some ny-2916766Attorney Docket No.24516-20012.40 embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0069] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a bispecific T cell engager (BiTE; such as any of the BiTEs described herein). In some embodiments, the method further comprises administering a pro- inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no ny-2916766Attorney Docket No.24516-20012.40 more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the bispecific T cell engager. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the bispecific T cell engager. In some embodiments, the agent that inhibits SHP-1 signaling and the bispecific T cell engager are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 ny-2916766Attorney Docket No.24516-20012.40 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the bispecific T cell engager and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0070] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) an antibody drug conjugate (ADC; such as any of the ADCs described herein). In some embodiments, the method further comprises administering a pro- inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- ny-2916766Attorney Docket No.24516-20012.40 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the antibody drug conjugate. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the antibody drug conjugate. In some embodiments, the agent that inhibits SHP-1 signaling and the antibody drug conjugate are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ ny-2916766Attorney Docket No.24516-20012.40 inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the antibody drug conjugate and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0071] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a lymphocyte activating antibody (e.g., an anti-CD3 antibody and / or an anti-CD28 antibody). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent ny-2916766Attorney Docket No.24516-20012.40 that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the lymphocyte activating antibody. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the lymphocyte activating antibody. In some embodiments, the agent that inhibits SHP-1 signaling and the lymphocyte activating antibody are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some ny-2916766Attorney Docket No.24516-20012.40 embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the lymphocyte activating antibody and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0072] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a lymphocyte activating small molecule (e.g., PMA, PHA, Concanavalin A, PWM, or PQDN). In some embodiments, the method further comprises administering a pro-inflammatory agent to the individual. In some embodiments, the pro- inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is ny-2916766Attorney Docket No.24516-20012.40 under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP-1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the lymphocyte activating small molecule. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the lymphocyte activating small molecule. In ny-2916766Attorney Docket No.24516-20012.40 some embodiments, the agent that inhibits SHP-1 signaling and the lymphocyte activating small molecule are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti- TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the lymphocyte activating small molecule and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0073] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late-stage cancer) in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., a TPI-1 or a derivative or an analog thereof, e.g., a deuterated TPI-1, e.g., a dTPI-1), and b) a calcium ionophore (e.g., ionomycin, A23187, ryanodine, or ny-2916766Attorney Docket No.24516-20012.40 thapsigargin). In some embodiments, the method further comprises administering a pro- inflammatory agent to the individual. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment. In some embodiments, the individual is under an inflammation reaction. In some embodiments, the agent that inhibits SHP-1 signaling is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1). In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor selected from the group consisting of TPI-1 or an analog or a derivative thereof (e.g., a deuterated TPI-1), vitamin E derivative, phomoxanthone A (PXA), and a PKC^ activator. In some embodiments, the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 signaling (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site. In some embodiments, the SHP-1 inhibitor is an allosteric inhibitor. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less. In some embodiments, the SHP- 1 inhibitor is a TPI-1 or a derivative or analog thereof. In some embodiments, the SHP-1 inhibitor comprises a deuterated TPI-1. In some embodiments, the SHP-1 inhibitor is PTP-1 or a derivative or analog thereof. In some embodiments, the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50. In some embodiments, agent that inhibits SHP-1 signaling is administered intermittently. In some embodiments, the agent that inhibits SHP-1 signaling is administered at an interval of no more than once every two days. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the agent that inhibits SHP-1 signaling is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the agent that inhibits SHP-1 signaling is administered regularly. In some embodiments, the agent that inhibits SHP-1 signaling is administered daily. In some embodiments, the agent that inhibits SHP-1 signaling is ny-2916766Attorney Docket No.24516-20012.40 administered twice daily. In some embodiments, agent that inhibits SHP-1 signaling is administered at least three, four, or five times. In some embodiments, the method comprises systemically (e.g., intravenously or subcutaneously) or locally (e.g., intratumorally, topically) administering the agent that inhibits SHP-1 signaling. In some embodiments, the agent that inhibits SHP-1 signaling is administered simultaneously with the calcium ionophore. In some embodiments, the agent that inhibits SHP-1 signaling is administered concurrently with the calcium ionophore. In some embodiments, the agent that inhibits SHP-1 signaling and the calcium ionophore are administered sequentially and within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or the same day). In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered within about 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other. In some embodiments, the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously. In some embodiments, the agent that inhibits SHP-1 signaling has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days). In some embodiments, the agent that inhibits SHP-1 signaling is effective in inhibiting more than 50% of the SHP-1 expression or activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm (e.g., a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor). In some embodiments, the method further comprises administering to the individual a TNF^ inhibitor, optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, optionally wherein the anti- TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept. In some embodiments, the anti-TNF^ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the agent that inhibits SHP-1 signaling (e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI-1) and / or the calcium ionophore and / or the pro- inflammatory agent. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine, and Vesatolimod. In some embodiments, the agent that inhibits SHP-1 signaling comprises TPI-1. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor. ny-2916766Attorney Docket No.24516-20012.40

[0074] In some embodiments according to 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 a late-stage cancer. In some embodiments, the cancer is a cutaneous or subcutaneous malignancy. In some embodiments, the cutaneous or subcutaneous malignancy is a primary malignancy or a secondary malignancy. In some embodiments, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor. In some embodiments, the individual is a human. Tumor microenvironment (TME) immunosuppression and SHP-1 signaling

[0075] Src homology region 2 (SH-2) domain-containing phosphatase 1 (SHP-1) is a non- receptor tyrosine phosphatase. SHP-1 is encoded by the PTPN6 gene (on chromosome 12p13). As there are two promoter regions, one on exon 1 (active in cells of non- hematopoietic lineage) and one on exon 2 (active in cells of hematopoietic lineage), there are two forms of SHP-1 which have different N-terminal sequences, but which both have phosphatase activity. Both promoters may be active in epithelial cancer cells, giving rise to alternative SHP-1 transcripts. Form I of SHP-1 is primarily found in the nucleus, while form II is primarily found in the cytoplasm, and presumably they have different substrates.

[0076] SHP-1 is a 595 amino acid protein. It has two tandem N-terminal SH2 domains (N- SH2 and C-SH2), and a classic catalytic protein tyrosine phosphatase (PTP) domain. The C- terminal tail has multiple sites for phosphorylation. Structural analysis of SHP-1 indicates that its N-SH2 is bound to and auto-inhibits the catalytic site in its inactive state. When phosphotyrosine residues bind to the SH2 domains, the electrostatic interactions between N- SH2 and the catalytic site is disrupted, allowing the enzyme to become active. Thus, substrate interaction plays a role in regulating the activity of SHP-1. Phosphorylation of amino acids Tyr536, Tyr564 and Ser591 also increase SHP-1 activity. Ser591 may also play a role in down-regulating SHP-1 activity, via phosphorylation by protein kinase C (PKC) or mitogen-activated protein kinases (MAPKs).

[0077] SHP-1 activity in solid cancers and blood cancers is altered, and this alteration may be due to mutations or changes in epigenetic regulation. SHP-1 is involved in multiple signal transduction pathways related to development and progression of cancer. Presumably, disruption of the normal, highly regulated phosphorylation patterns involved in SHP-1 regulation is a factor in SHP-1’s role in cancer. ny-2916766Attorney Docket No.24516-20012.40

[0078] Inhibition of SHP-1, however, can also cause deleterious effects. Motheaten mice (me / me or mev / mev) which are genetically deficient in SHP-1 show abnormal immune function, including hyperactivation of immune cells, and such mice have shortened life spans. Depletion of SHP-1 in adult wild-type mice also caused pathology, including enlarged spleens and inflammation of the lungs. Thus, approaches to treatment of cancer by inhibition of SHP-1 require careful balancing of the need for normal SHP-1 activity versus preventing abnormal SHP-1 activity.

[0079] Inhibitors of SHP-1 phosphatase activity include TPI-1, suramine, NSC-87877, and sodium stibogluconate. Sodium stibogluconate entered Phase I clinical trials for malignant melanoma, but showed severe side effects. To date, no SHP-1 inhibitors have progressed to Phase II trials.

[0080] One or more agents that inhibit SHP-1 signaling described herein can be administered (e.g., both a SHP-1 inhibitor and an inhibitor of a tyrosine kinase that is involved in SHP-1 signaling). In some embodiments, the method comprises administering (e.g., locally or systemically) to the individual an effective amount of an agent that inhibits SHP-1 signaling (e.g., a SHP-1 inhibitor, e.g., TPI-1 or an analog or derivative thereof, e.g., a deuterated TPI- 1). In some embodiments, two or more agents that inhibits SHP-1 signaling are administered simultaneously. In some embodiments, two or more agents that inhibits SHP-1 signaling are administered sequentially (e.g., prior to or after). Lymphocyte activating agents

[0081] In some embodiments, the methods of treatment described herein comprise administering to the individual an effective amount of a lymphocyte activating agent. In some embodiments, the lymphocyte activating agent is a T cell (e.g., a CD4+ T cell, a CD8+ T cell, a regulatory T cell, a helper T cell, a cytotoxic T cell, a memory T cell, an effector T cell, a naïve T cell, a genetically engineered T cell) activating agent. In some embodiments, the lymphocyte activating agent is an NKT cell (e.g., a CAR-NKT cell) activating agent.

[0082] In some embodiments, the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism-modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), a lymphocyte-activating antibody, an antibody drug conjugate, a small molecule, a calcium ionophore, and any combination thereof. ny-2916766Attorney Docket No.24516-20012.40

[0083] Cancer vaccines, bacteria and components thereof, viruses (e.g., oncolytic viruses) and components thereof, fungi and components thereof, and antibody drug conjugates and derivatives thereof are described above as pro-inflammatory agents. These same components can also be capable of activating lymphocytes and are included herein by reference. Cytokines and chemokines

[0084] In some embodiments, the lymphocyte activating agent is a cytokine or chemokine (e.g., a cytokine or chemokine that promotes T cells, such as CD8+ cytotoxic T cells).

[0085] In some embodiments, the cytokine promotes T cell survival and / or expansion, such as IL-2, IL-7, IL-15, and IL-21. In some embodiments, the cytokine promotes T cell stimulation, such as CD27L or 4-1BBL. See, e.g., Zhang, Y. et al., Front Immunol.2020 Dec 14; 11:594609; and Vazquez, M. et al., Cytokine 2015 Aug;74(2):318-326.

[0086] In some embodiments, the lymphocyte activating agent comprises a chemokine. In some embodiments, the chemokine can include chemokines that signal for cells, e.g., T cells or NK cells, to migrate into the tumor or to migrate to DCs for priming. For example, CXCL9, CXCL10, and CXCL11 can attract T cells and are produced by dendritic cells to induce T cells to migrate to dendritic cells where the T cells can be primed, e.g., against tumor cells. Additional chemokines can include, but are not limited to, CCL2, CCL3, CCL4, CCL5, CCL21, CCL27, CCL28, CXCL1, CXCL2, CXCL8, CXCL16, and LTB4. Immune checkpoint inhibitors

[0087] In some embodiments, the lymphocyte activating agent is an immune checkpoint inhibitor. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described immune checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). See e.g., Marin-Acevedo et al., J Hematol Oncol 14, 45 (2021).

[0088] In some embodiments, the immune checkpoint inhibitor targets CLTA-4, PD-1 or PD- L1 (e.g., an antibody targeting CTLA-4, PD-1 or PD-L1).

[0089] In some embodiments, the immune checkpoint inhibitor targets LAG-3, TIM-3, B7- H3, B7-H4, A2aR, CD73, NKG2A, PVRIG / PVRL2, CEACAM1, CEACAM 5 / 6, FAK, CCL2 / CCR2, LIF, CD47 / SIRP^, CSF-1(M-CSF) / CSF-1R, IL-1 / IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine. ny-2916766Attorney Docket No.24516-20012.40

[0090] In some embodiments, the immune checkpoint inhibitor comprises or is ipilimumab, Cemiplimab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO-201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, Lanotuzumab (MCS110), LY3022855, SNDX-6352, Emactuzumab (RG7155), Pexidartinib (PLX3397), CAN04, Canakinumab (ACZ885), BMS- 986253, Pepinemab (VX15 / 2503), Trebananib, FP-1305, Enapotamab vedotin(EnaV), or Bavituximab. Metabolism-modulating drugs and metabolite antagonists

[0091] Tumors are highly metabolically active and have high metabolic demands. Similarly, immune cells become highly metabolically active once the immune cells (e.g., T cells) are activated. The metabolic demands of cancer cells and immune cells, however, are not identical, thereby creating the opportunity to target specific metabolic pathways. Similar to metabolism-modulating drugs, metabolites can be similarly targeted to promote antitumor immunity.

[0092] Examples of metabolism-modulating drugs to target cancer cells include, but are not limited to: drugs that target mutant isocitrate dehydrogenases (e.g., Enasidenib, Ivosidenib, Indoximod, Epacadostat); glutaminase inhibitor, CB-839; inhibitor of LAT1-dependent neutral amino acid transport, JPH203 or KYT-0353; kidney-type glutaminase (GLS1)- specific inhibitors, such as the allosteric inhibitor BPTES or CB-839; lactate dehydrogenase A inhibitor, NCGC00420737-09; monocarboxylate transporter 1 (MCT1) inhibitor, AZ3965; RNA to DNA conversion inhibitor, hydroxyurea; purine synthesis inhibitor, 6- Mercaptopurine; etc.

[0093] Examples of metabolite antagonists include, but are not limited to, folate antagonists (e.g., aminopterin, methotrexate, pemetrexed); ASCT2 / glutamine antagonist (V-9302); reactive diazo glutamine analogue, DON; DON prodrugs JHU-083 (ethyl 2-(2-amino-4- methylpentanamido)-DON) or DRP-104; 2-amido-6-benzenesulfonamide glucosamine inhibitor, GSK compound 27; nucleotide analogues (e.g., Gemcitabine, Fludarabine); etc.

[0094] See, e.g., Stine, Z.E. et al. Nat Rev. Drug Discov. 2022 Feb.; 21(2): 141-162. ny-2916766Attorney Docket No.24516-20012.40 Lymphocyte-activating antibodies

[0095] In some embodiments, the lymphocyte activating agent is a lymphocyte-activating antibody. Such antibodies activate pathways with lymphocyte-stimulatory features. Examples of lymphocyte-activating antibodies include, but are not limited to, anti-CD3 antibodies and anti-CD28 antibodies.

[0096] Exemplary anti-human CD3 antibodies with cross reactivity to human and monkey CD3 include, but are not limited to, SP34 mouse monoclonal antibody (see, for example, Pressano, S. The EMBO J.4:337-344, 1985; Alarcon, B. EMBO J.10:903-912, 1991; Salmeron A. et al., J. Immunol.147:3047-52, 1991; Yoshino N. et al., Exp. Anim 49:97-110, 2000; Conrad M L. et al., Cytometry 71A:925-33, 2007; Yang et al., J. Immunol.137:1097- 1100: 1986; US 8,846,042; US 11,013,800; and US 10,870,701). Exemplary anti-CD3 antibodies that lack cross reactivity to monkey CD3 include, but are not limited to, the Cris-7 monoclonal antibody (Reinherz, E. L. et al. (eds.), Leukocyte typing II, Springer Verlag, New York, (1986)), BC3 monoclonal antibody (Anasetti et al. (1990) J. Exp. Med. 172:1691), OKT3 (Ortho multicenter Transplant Study Group (1985) N. Engl. J. Med. 313:337) and derivatives thereof such as OKT3 ala-ala (Herold et al. (2003) J. Clin. Invest. 11:409), visilizumab (Carpenter et al. (2002) Blood 99:2712), and 145-2C11 monoclonal antibody (Hirsch et al. (1988) J. Immunol.140: 3766). Further CD3 binding molecules contemplated herein include UCHT-1 (Beverley, P C and Callard, R. E. (1981) Eur. J. Immunol.11: 329-334) and CD3 binding molecules described in WO2004 / 106380; WO2010 / 037838; WO2008 / 119567; WO2007 / 042261; WO2010 / 0150918; the contents of each of which are incorporated herein by reference in their entirety.

[0097] Exemplary anti-CD28 antibodies that bind to human CD28 include, but are not limited to, CD28.2 monoclonal antibody, CD28.6 monoclonal antibody, 10F3 monoclonal antibody, HL1589 monoclonal antibody, RM404 monoclonal antibody, 007 monoclonal antibody, CB28 monoclonal antibody, 204.12 monoclonal antibody, C28 / 74 monoclonal antibody, C28 / 75 monoclonal antibody, C28 / 1636 monoclonal antibody, C28 / 76 monoclonal antibody, C28 / 77 monoclonal antibody, OTI5G3 monoclonal antibody, OTI9G10 monoclonal antibody, OTI4G8 monoclonal antibody, OTI1A2 monoclonal antibody, OTI8C4 monoclonal antibody, YTH913.12 monoclonal antibody, B-23 monoclonal antibody, 2C1 monoclonal antibody, 1H3 monoclonal antibody, 1E5 monoclonal antibody, 4G3 monoclonal antibody, 1D5 monoclonal antibody, 3E12 monoclonal antibody, 8D7 monoclonal antibody, 2E6 monoclonal antibody, 4G11 monoclonal antibody, 1D7 monoclonal antibody, 4B5 ny-2916766Attorney Docket No.24516-20012.40 monoclonal antibody, TGN1412 (Theralizumab; see, e.g., Lin et al. (2004), Blood (ASH Annual Meeting Abstracts) 104 (11): Abstract 2519) and VEL-101 (see, e.g., clinical trial NCT05238493). Small molecules

[0098] In some embodiments, the lymphocyte activating agent comprises a small molecule. Such small molecules activate components of the T cell activation pathway. Examples of lymphocyte-activating small molecules include, but are not limited to, PMA, PHA, Concanavalin A, PWM, and PQDN.

[0099] Phorbol myristate acetate (PMA; phorbol ester, also known as 12-O- tetradecanoylphorbol 13-acetate (TPA)) crosses the cell membrane and activates protein kinase C (e.g., PKC isoforms ^, ^I, ^II, ^), a critical component of the TCR activation pathway. PMA in combination with ionomycin (described below) bypass the T cell receptor complex to activate T cells. In some embodiments, the lymphocyte activating agent is PMA.

[0100] Phytohemagglutinin (PHA) binds to the TCR / CD3 complex, mimicking all intracellular activation events triggered by anti-CD3 antibodies and stimulating metabolic activity and cell division. PHA can also be utilized to activate natural killer (NK) cells in vitro. In some embodiments, the lymphocyte activating agent is PHA.

[0101] Concanavalin A (ConA) binds to the mannose residues of various glycoproteins and activates T cells and NK cells. In some embodiments, the lymphocyte activating agent is ConA.

[0102] In some embodiments, the lymphocyte activating agent is PWM.

[0103] PQDN is a small molecule that activates CD8 T cells after TCR engagement, even when antigen stimulation is too weak for their activation. PQDN improves the T cell activation threshold. See, e.g., Dotsu, et al. (2022), J Immunother Cancer, 10(2):e003958. In some embodiments, the lymphocyte activating agent is PQDN. Calcium ionophores

[0104] In some embodiments, the lymphocyte activating agent is a calcium ionophore. Ionophores are a class of compounds that form complexes with specific ions and facilitate their transport across cell membranes. An ionophore typically has a hydrophilic pocket (or hole) that forms a binding site specific for a particular ion. Such calcium ionophores activate T cell calcium flux, which is initiated by TCR signaling and leads to a sequence of events ny-2916766Attorney Docket No.24516-20012.40 culminating in the release of Ca2+stores from the endoplasmic reticulum (ER) and an influx of extracellular Ca2+into the cell. Examples of lymphocyte-activating calcium ionophores include, but are not limited to, ionomycin, A23187, ryanodine, and thapsigargin.

[0105] Ionomycin is a membrane permeable calcium ionophore. The calcium ionophore ionomycin, which is an activator of ADAM10, can directly trigger the secretion of plasma membrane-derived EVs or exosomes. Ionomycin increases intracellular Ca2+levels in cells by activating Ca2+ / calmodulin-dependent signaling pathways, inducing the hydrolysis of phosphoinositides, and the activating PKC in human T cells. See, e.g., Chatila et al. (1989) J Immunol.143(4): 1283-1289. In some embodiments, the lymphocyte activating agent is ionomycin.

[0106] A23187 is a calcium ionophore that mimic early signal transduction pathways and activate purified human T cells. In some embodiments, the lymphocyte activating agent is A23187.

[0107] Ryanodine binds to ryanodine receptors (RyRs) that co-localize with the plasmalemmal store-operated Ca2+channels of the Orai family and endoplasmic reticulum Ca2+sensing Stim family proteins and are activated by store-operated Ca2+entry and pyridine nucleotide metabolites to release intracellular Ca2+stores. See, e.g., Fomina (2021) J Physiol. 599(19): 4415-4426. In some embodiments, the lymphocyte activating agent is ryanodine.

[0108] Thapsigargin is an endosomal Ca(2+)-ATPase inhibitor. Thapsigargin stimulates MAP kinase signaling via Src and Raf-1. In some embodiments, the lymphocyte activating agent is thapsigargin. Bispecific T cell engagers

[0109] In some embodiments, the lymphocyte activating agent comprises a bispecific T cell engager (BiTe). Bispecific T cell engagers redirect T cells to target the cancer cells for T cell-mediated cytolysis of the cancer cells by binding to T cells (e.g., through an anti-CD3 antigen binding moiety) and binding to cancer cells (e.g., through an anti-tumor antigen binding moiety, for example CD19 or CD22 to target B cell malignancies), thereby creating an immunological synapse to drive T cell-mediated cytolysis of the cancer cells. Bispecific T cell engagers generally include two single-chain variable fragments (scFvs) that are connected to each other in tandem by a short linker.

[0110] Exemplary BiTes include but are not limited to, Blinatumomab, Pasotuxizumab, Cibisatamab, AMV564, AMG 160, AMG 330, AMG 673, AMG 420, AMG 701, AMG 596, ny-2916766Attorney Docket No.24516-20012.40 AMG 757, AMG 199, AMG 910, HPN424, M701, M802, and ERY974. Any BiTe known in the art may be used as described herein. See, e.g., Zhou, S. et al., Biomarker Res 2021;9:38. Cells

[0111] In some embodiments, the lymphocyte activating agent comprises cells that trigger or otherwise activate lymphocytes. In some embodiments, the cells are APCs (e.g., macrophages or dendritic cells). In some embodiments, the cells are macrophages (e.g., tumor-infiltrating). In some embodiments, the cells are dendritic cells. In some embodiments, the cells are SIRPant-macrophages. In some embodiments, the immune cells comprise monocytes or macrophages described herein. In some embodiments, the macrophages are identified by F4 / 80 expression. In some embodiments, the macrophages have a M1 phenotype. In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%) of the macrophages in the immune cells have a M1 phenotype.

[0112] In some embodiments, the myeloid cells (e.g., monocytes or macrophages) are engineered to be deficient in SHP-1 expression and / or activity. In some embodiments, the myeloid cells (e.g., monocytes or macrophages) are engineered to be deficient in SHP-1 expression and / or activity (e.g., via methods described herein). In some embodiments, the monocytes or macrophages express a reduced level of SHP-1 and / or tyrosine kinase for at least a period of time (e.g., for at least 1, 2, 3, 4, or 5 days) or are resistant to activation for at least a period of time (e.g., for at least 1, 2, 3, 4, or 5 days). In some embodiments, the period of time is no more than about 10, 9, 8, 7, 6, 5, 4, or 3 days. In some embodiments, the myeloid cells (e.g., monocytes or macrophages) have reduced SHP-1 and / or tyrosine kinase activity for no more than about 5 consecutive days (e.g., for no more than 5, 4, or 3 days) before the SHP-1 and / or tyrosine kinase activity level returns to normal.

[0113] Methods to engineer myeloid cells (e.g., monocytes or macrophages) to transiently express a reduced level of tyrosine kinase are well-known in the field. Exemplary methods include contacting the monocytes or macrophages with an agent that inhibits a tyrosine kinase involved in the SHP-1 signaling pathway or SHP-1 signaling described herein (such as a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1, tyrosine kinases, or activated tyrosine kinase)) in vivo or in vitro.

[0114] In some embodiments, the myeloid cells express a high level of MHC-I, MHC-II, CD80 and / or CD86. In some embodiments, the myeloid cells express a high level of MHC-I, ny-2916766Attorney Docket No.24516-20012.40 MHC-II, CD80, and / or CD86 when the expression level of MHC-I, MHC-II, CD80 and / or CD86 on the immune cells is comparable (e.g., at least more than 50%) of that on activated antigen presenting cells (APCs). In some embodiments, the myeloid cells express a pro- inflammatory cytokine, optionally wherein the pro-inflammatory cytokine comprises IL-12. In some embodiments, the myeloid cells do not express a significant level of TGF^ and / or IL-10.

[0115] In some embodiments, the cells are tumor-infiltrating lymphocytes. In some embodiments, the cells specifically recognize a tumor antigen (e.g., being engineered to express a CAR recognizing a tumor antigen). In some embodiments, the cells are T cells. In some embodiments, the cells are CAR-T cells. In some embodiments, the cells are NK cells (e.g., CAR-NK cells). In some embodiments, the cells are neutrophils (e.g., CAR-expressing neutrophils cells). In some embodiments, the cells are TCR-T cells. In some embodiments, the cells are CAR-macrophages or CAR-monocytes.

[0116] In some embodiments, the cells are stem cells. In some embodiments, the cells are allogenic. In some embodiments, the cells are autologous.

[0117] In some embodiments, the agent that inhibits SHP-1 signaling, the lymphocyte activating agent (e.g., the immune cells), and / or a pro-inflammatory agent described above are administered within 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, 1 hour, or 0.5 hour) of each other. In some embodiments, the lymphocyte activating agent (e.g., the immune cells) are administered simultaneously or concurrently with the agent that inhibits SHP-1 signaling, and / or the pro-inflammatory agent. Inhibitory agents of SHP-1 signaling

[0118] Agents that inhibt SHP-1 signaling described herein can be any agent that achieves the inhibition of SHP-1 signaling, which in some embodiments can be assessed by e.g., evaluating expression and / or phosphorylation of SHP-1. In some embodiments, the agent that inhibits SHP-1 signaling comprises an inhibitor of a tyrosine kinase involved in the SHP-1 signaling pathway (“SHP-1 signaling inhibitor”), optionally wherein the SHP-1 signaling inhibitor is an inhibitor of a tyrosine kinase of a Src family member. In some embodiments, the agent that inhibits SHP-1 signaling comprises a SHP-1 inhibitor (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1). In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of 100, 90, 80, 70, 60, 50, 40, 35, 30, 25, 20, 15, 5µm or less. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of 40, 35, 30, 25, 20, ny-2916766Attorney Docket No.24516-20012.40 15, 5µm or less. In some embodiments, the SHP-1 inhibitor inhibits SHP-1 with an IC50 of 5µm or less. SHP-1 inhibitors

[0119] In some embodiments, an agent that inhibits SHP-1 signaling comprises a SHP-1 inhibitor. A SHP-1 inhibitor as referred to herein is an agent of any kind or sort that inhibits the expression or activity of SHP-1. In some embodiments, the SHP-1 inhibitor directly targets SHP-1. In some embodiments, the SHP-1 inhibitor comprises a binding moiety that specifically binds to SHP-1 (such as any SHP-1 inhibitor described here, e.g., TPI-1 or a derivative or an analog thereof) associated with a proteolysis-targeting chimeras (PROTAC) (e.g., ARV-110 and ARV-471). See e.g., Nature Reviews Drug Discovery volume 21, pages181–200 (2022). In some embodiments, the SHP-1 inhibitor targets a molecule involved in SHP-1 signaling pathway in lymphocytes (e.g., T cells) that is distinct from SHP- 1.

[0120] In some embodiments, the SHP-1 inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%, e.g., 20%-50%, 20%-30%, 20%-40%, 30%-40%, 30%-50%, or 40%-50%) of the SHP-1 activity. In some embodiments, the SHP-1 inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%, e.g., 20%- 50%, 20%-30%, 20%-40%, 30%-40%, 30%-50%, or 40%-50%) of the SHP-1 expression.

[0121] In some embodiments, the SHP-1 inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1, e.g., a dominant negative SHP-1 or a constitutively active SHP-1 mutant), a protein agent that contains a SH2 domain (by competing for binding to ITIM motif so to inhibit SHP-1 activity), and an inhibitor of a tyrosine kinase involved in the SHP-1 signaling pathway that inhibits ITIM phosphorylation.

[0122] In some embodiments, the SHP-1 inhibitor does not significantly inhibit SHP-2 (e.g., does not inhibit the SHP-2 activity for more than 50%, 40%, 30%, or 20%).

[0123] In some embodiments, the SHP-1 inhibitor also inhibits SHP-2.

[0124] In some embodiments, the SHP-1 inhibitor does not significantly inhibit SHIP-1 (e.g., does not inhibit the SHIP-1 activity for more than 50%, 40%, 30%, or 20%).

[0125] In some embodiments, the SHP-1 inhibitor also inhibits SHIP-1. ny-2916766Attorney Docket No.24516-20012.40

[0126] In some embodiments, the SHP-1 inhibitor has a half-life of no more than about 10, 9, 8, or 7 days (e.g., a half-life of no more than about 7, 6, 5, 4, 3, 2 or 1 day).

[0127] In some embodiments, the SHP-1 inhibitor is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 10, 9, 8, 7, 6, or 5 days. In some embodiments, the SHP-1 inhibitor is effective in inhibiting more than 50% of the SHP-1 activity for no more than 4, 3, 2 or 1 day.

[0128] In some embodiments, the SHP-1 inhibitor is a covalent inhibitor. In some embodiments, the SHP-1 inhibitor is a noncovalent inhibitor.

[0129] In some embodiments, the SHP-1 inhibitor is a competitive inhibitor. In some embodiments, the SHP-1 inhibitor is Phomoxanthone A (PXA) or Phomoxanthone B (PXB). See e.g., Yang et al., ACS Omega.2020 Sep 29;5(40):25927-25935

[0130] In some embodiments, the SHP-1 inhibitor targets the catalytic site. In some embodiments, the SHP-1 inhibitor binds to the catalytic site (e.g., covalently or competitively binds to the catalytic site). Exemplary catalytic site inhibitors include TPI-1 or TPI analogs such as those shown in Kundu et al. (e.g., TPI-1a1-10). See J Immunol.2010 Jun 1; 184(11): 6529–6536. Methods for screening and identifying SHP-1 inhibitors (e.g., SHP-1 inhibitors targeting the catalytic site) are known in the field. For example, recombinant protein of SHP- 1 catalytic domain can be used to screen and identify SHP-1 inhibitors that target the catalytic site. SHP-1 inhibition activities can be evaluated with various methods such as rapid SHP-1 PTP assay. See “materials and methods” in Kundu et al.

[0131] In some embodiments, the SHP-1 inhibitor targets the allosteric or regulatory site. See e.g., Wang et al. J Cell Biochem.2011 Aug; 112(8): 2062–2071 for the structure of SHP-1.

[0132] In some embodiments, the SHP-1 inhibitor is TPI-1, a derivative thereof or an analog thereof. Exemplary analogs include those disclosed in Kundu et al. (J Immunol.2010 Jun 1; 184(11): 6529–6536.) See, e.g., FIG.6 of Kundu et al.

[0133] In some embodiments, the SHP-1 inhibitor comprises TPI-1. In some embodiments, the TPI-1 is a deuterated TPI-1. TPI-1, a derivative thereof or an analog thereof

[0134] In some embodiments, the SHP-1 inhibitor is TPI-1, a derivative thereof or an analog thereof. Exemplary analogs include those disclosed in Kundu et al. (J Immunol.2010 Jun 1; 184(11): 6529–6536.) See, e.g., FIG.6 of Kundu et al. ny-2916766Attorney Docket No.24516-20012.40

[0135] In some embodiments, the SHP-1 inhibitor comprises TPI-1. In some embodiments, the TPI-1 is a deuterated TPI-1.

[0136] The compound 2-(2,5-dichlorophenyl)benzoquinone (which is also referred to as 2- (2,5-dichlorophenyl)cyclohexa-2,5-diene-1,4-dione, Tyrosine Phosphatase Inhibitor 1 or TPI- 1; CAS Registry No.79756-69-7) is an inhibitor of SHP-1. TPI-1 has the following structure:.

[0137] TPI-1 can be derivatized with a functional group for facile attachment to other compounds, for use in conjugate compounds. For example, a carboxyl group can be introduced at the 3-position of the dichlorophenyl ring to provide:

[0138] which can be readily coupled to an amino or hydroxy group on another molecule, such as a therapeutic molecule, or a linker to another molecule. Derivatives and analogs of TPI-1 include compounds of the following structure: ny-2916766Attorney Docket No.24516-20012.40

[0139] where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof.

[0140] Various methods for preparing TPI-1 analogs are available. In one such method, an RC-substituted 2,5-dichloroaniline is suitably protected on its RC group (the protected RC group is indicated as RCP in the scheme below). Then the amino group is converted to the corresponding diazonium ion and coupled with quinone to give the TPI-1 scaffold. An example of the experimental conditions that can be adapted for this reaction is shown in the synthesis in Jones et al., Journal of Organic Chemistry 58(8):2035 (1993) for 2-(4- carboxyphenyl)-3,6-dichloro-2,5-cyclohexadiene-1,4-dione. The Jones et al. reaction can be adapted to preparation of carboxylic acid-functionalized TPI-1 derivatives by replacing the 2,5-dichloro-2,5-cyclohexadiene-1,4-dione reagent with 1,4-benzoquinone, and replacing the 4-aminobenzoic acid reagent with 2-amino-3,6-dichlorobenzoic acid, 3-amino-3,6- dichlorobenzoic acid, or 4-amino-3,6-dichlorobenzoic acid, to yield 2-(2-carboxy-3,6- dichlorophenyl)-2,5-cyclohexadiene-1,4-dione, 2-(5-carboxy-3,6-dichlorophenyl)-2,5- cyclohexadiene-1,4-dione, or 2-(4-carboxy-3,6-dichlorophenyl)-2,5-cyclohexadiene-1,4- dione, respectively. Should a longer linker be desired between the TPI-1 derivative and the molecule conjugated through the carboxylic acid, 2-amino-3,6-dichlorobenzoic acid can be replaced by 2-(2-amino-3,6-dichlorophenyl)acetic acid, 3-(2-amino-3,6- dichlorophenyl)propanoic acid, etc., and similarly for the other positional isomers. Deprotection affords the TPI-1 analog ready for conjugation to a linker or PIA. Suitable protecting group approaches for RCA include esters where RCA = -COOH, carbamates or cleavable alkyl groups where RCA = -NH2, and silyl ethers, cleavable alkyl groups, or esters where RCA = -OH. ny-2916766Attorney Docket No.24516-20012.40

[0141] Alternatively, an approach through Pd-catalyzed biaryl coupling may be utilized. An RC substituted 2,5-dichloroaniline is suitably protected on its RC group (the protected RC group is indicated as RCP in the scheme below). The amino group is converted to a halide through a diazonium intermediate using t-butyl nitrite and copper halide (CuX2, e.g., CuBr2) (Sandmeyer reaction). Treatment of the aryl halide with Pd-catalyst and 2,5-dimethoxyphenyl boronic acid provides the biaryl structure of TPI-1. Oxidative conditions, such as ceric ammonium nitrate, give the quinone. Deprotection affords the TPI-1 analog ready for conjugation to a linker or PIA. Suitable protecting group approaches for the RCA group include esters where RCA = -COOH, carbamates or cleavable alkyl groups where RCA = - NH2, and silyl ethers, cleavable alkyl groups, or esters where RCA = -OH. ny-2916766Attorney Docket No.24516-20012.40ny-2916766Attorney Docket No.24516-20012.40

[0142] In addition to TPI-1 functionalized for conjugation, perdeuterated TPI-1 (i.e., dTPI-1) can be used in methods in place of TPI-1 at natural isotopic abundance. Perdeuterated TPI-1 has the following structure (referred to as TPI-1-d6), wherein D is deuterium (i.e., 2H):, and can be used in non-salt form or as a pharmaceutically acceptable salt.

[0143] In addition to the perdeuterated compound (i.e., TPI-1-d6), there are 62 possible deuterated compounds with deuterium at one, two, three, four, or five positions out of the 3, 4, 6, 3’, 4’, and 6’ positions on TPI-1, which are all provided herein. (The compound without any specific deuteration will have deuterium at natural isotopic abundance.) In view of the results demonstrated in Examples, the various deuterated compounds (d1, d2, d3, d4, d5, d6) are expected to be effective for inhibiting SHP-1 and treating cancer (e.g., via systemic administration, e.g., in a topical application).

[0144] In some embodiments, the deuterated TPI-1 is TPI-1-d1. In some embodiments, the TPI-1-d1 is selected from TPI-1-3-d1, TPI-1-4-d1, TPI-1-6-d1, TPI-1-3’-d1, TPI-1-4’-d1, or TPI-1-6’-d1.

[0145] In some embodiments, the deuterated TPI-1 is TPI-1-d2. In some embodiments, the TPI-1-d2 is selected from TPI-1-3,4-d2, TPI-3,6-d2, TPI-1-3,3’-d2, TPI-1-3,4’-d2, TPI-3,6’-d2, TPI-1-4,6-d2, TPI-1-4,3’-d2, TPI-1-4,4’-d2, TPI-4,6’-d2, TPI-1-6,3’-d2, TPI-1-6,4’-d2, TPI- 6,6’-d2, TPI-1-3’,4’-d2, TPI-3,6’-d2, or TPI-4’,6’-d2.

[0146] In some embodiments, the deuterated TPI-1 is TPI-1-d3. In some embodiments, the TPI-1-d3 is selected from TPI-1-3,4,6-d3, TPI-1-3,4,3'-d3, TPI-1-3,4,4’-d3, TPI-1-3,4,6’-d3, TPI-1-3,6,3’-d3, TPI-1-3,6,4’-d3, TPI-1-3,6,6’-d3, TPI-1-3,3’,4’-d3, TPI-1-3,3’,6’-d3, TPI-1- 3,4’,6’-d3, TPI-1-4,6,3’-d3, TPI-1-4,6,4’-d3, TPI-1-4,6,6’-d3, TPI-1-4,3’,4’-d3, TPI-1-4,3’,6’- d3, TPI-1-4,4’,6’-d3, TPI-1-6,3’,4’-d3, TPI-1-6,3’,6’-d3, TPI-1-6,4’,6’-d3, or TPI-1-3’,4’,6’-d3. ny-2916766Attorney Docket No.24516-20012.40

[0147] In some embodiments, the deuterated TPI-1 is TPI-1-d4. In some embodiments, the TPI-1-d4 is selected from TPI-1-3,4,6,3’-d4, TPI-1-3,4,6,4'-d4, TPI-1-3,4,6,6’-d4, TPI-1- 3,4,3’,4’-d4, TPI-1-3,4,3’,6’-d4, TPI-1-3,4,4’6’-d4, TPI-1-3,6,3’,4’-d4, TPI-1-3,6,3’,6’-d4, TPI-1-3,6,4’,6’-d4, TPI-1-4,6,3’,4’-d4, TPI-1-4,6,3’,6’-d4, TPI-1-4,6,4’,6’-d4, TPI-1- 3,3’,4’,6’-d4, TPI-1-4,3’,4’,6’-d4, or TPI-1-6,3’,4’,6’-d4.

[0148] In some embodiments, the deuterated TPI-1 is TPI-1-d5. In some embodiments, the TPI-1-d5 is selected from TPI-1-3,4,6,3’,4’-d5, TPI-1-3,4,6,3’,6’-d5, TPI-1-3,4,6,4’,6’-d5, TPI-1-4,6,3’,4’,6’-d5, TPI-1-3,6,3’,4’,6’-d5, or TPI-3,4,3’,4’,6’-d6.

[0149] In some embodiments, the deuterated TPI-1 is TPI-1-d6, i.e., perdeuterated TPI-1, or TPI-1- 3,4,6,3’,4’,6’-d6.

[0150] Perdeuterated TPI-1 can also be functionalized as described above for conjugation, as a compound of the formula:

[0151] where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. Deuterated and perdeuterated TPI-1 derivatives can be prepared by using appropriately deuterated compounds in the synthetic preparations of the TPI-1 derivatives disclosed herein.

[0152] As another example, the perdeuterated TPI-1 compound ny-2916766Attorney Docket No.24516-20012.40can be conjugated to a pro-inflammatory agent, either directly or through a linker. Perdeuterated TPI-1 derivatives can be prepared by using appropriately deuterated compounds in the synthetic preparations of the TPI-1 derivatives disclosed herein, for instance as in Example 5.

[0153] In some embodiments, the SHP-1 inhibitor comprises the formula:

[0154] where RCis RCAor -C1-C4 alkyl-RCA, where RCAis -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. In some embodiments, where RCis RCAand RCAis -COOH, or a pharmaceutically acceptable salt thereof. In some embodiments, the SHP-1 inhibitor comprises the formula: ny-2916766Attorney Docket No.24516-20012.40

[0155] or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, RC is RCA and RCA is -NH2, or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, RC is RCA and RCA is -OH, or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, RC is -C1-C4 alkyl-RCA and RCA is -COOH, or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, RC is -C1-C4 alkyl-RCA and RCA is -NH2, or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, RC is -C1-C4 alkyl-RCA and RCA is -OH, or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the SHP-1 inhibitor comprises a compound of the formula:or a pharmaceutically acceptable salt thereof. ny-2916766Attorney Docket No.24516-20012.40

[0162] In some embodiments, the SHP-1 inhibitor comprises a compound of the formula:

[0163] where RC is RCA or -C1-C4 alkyl-RCA, where RCA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, RCis RCAand RCAis -COOH, or a pharmaceutically acceptable salt thereof. In some embodiments,or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, RCis RCAand RCAis -NH2, or a pharmaceutically acceptable salt thereof. ny-2916766Attorney Docket No.24516-20012.40

[0166] In some embodiments, RCis RCAand RCAis -OH, or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, RCis -C1-C4alkyl-RCAand RCAis -COOH, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, RCis -C1-C4alkyl-RCAand RCAis -NH2, or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, RCis -C1-C4 alkyl-RCAand RCAis -OH, or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the SHP-1 inhibitor is PTP-I.

[0171] In some embodiments, the SHP-1 inhibitor is vitamin E. In some embodiments, the SHP-1 inhibitor is tocofersolan (TPGS). In some embodiments, the SHP-1 inhibitor is ^- tocopherol acetate (^TA). In some embodiments, the SHP-1 inhibitor is ^-tocopheryl succinate (^TOS).

[0172] In some embodiments, the SHP-1 inhibitor is phomoxanthone A (PXA).

[0173] In some embodiments, the SHP-1 inhibitor is a PKC^ activator (such as PMA).

[0174] In some embodiments, the SHP-1 inhibitor is an siRNA or an shRNA that inhibits or knocks down the amount of endogenous SHP-1 protein. See e.g., WO2009 / 023333.

[0175] In some embodiments, the SHP-1 inhibitor is a dominant negative SHP-1 or a constitutively active SHP-1 mutant. See e.g., WO2009 / 023333.

[0176] In some embodiments, the SHP-1 inhibitor is a nucleic acid editing system (such as a CRISPR system). In some embodiments, the CRISPR components are introduced into the cell (e.g., the monocytes and the macrophages) but no DNA encoding a guide RNA or Cas9 are incorporated into the cell’s genome. Under this approach, the CRISPR system only cleave the cell’s genomic DNA for a limited period of time. See e.g., Fister et al., Front Plant Sci.2018 Mar 2;9:268.

[0177] In some embodiments, the SHP-1 inhibitor is a chemical inducer of dimerization. See e.g., Buck et. al., ACS Omega.2022 Apr 11;7(16):14180-14188.

[0178] In some embodiments, the SHP-1 inhibitor (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1) is administered at least two times (such as at least 3, 4, 5, or ny-2916766Attorney Docket No.24516-20012.40 6 times, e.g., 2-10 times, 2-9 times, 2-8 times, 2-7 times, 2-6 times, 2-5 times, 2-4 times, 3-10 times, 3-9 times, 3-8 times, 3-7 times, 3-6 times, 3-5 times).

[0179] In some embodiments, the method comprises administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1) at an interval of no more than once every two days for at least twice (such as at least three times, four times, five times, or six times, such as 2-10 times, 2-9 times, 2-8 times, 2-7 times, 2-6 times, 2-5 times, 2-4 times, 3-10 times, 3-9 times, 3-8 times, 3-7 times, 3-6 times, or 3-5 times).

[0180] In some embodiments, the method comprises administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1) at an interval of no more than once every three days for at least twice (such as at least three times, four times, five times, or six times, such as 2-10 times, 2-9 times, 2-8 times, 2-7 times, 2-6 times, 2-5 times, 2-4 times, 3-10 times, 3-9 times, 3-8 times, 3-7 times, 3-6 times, or 3-5 times).

[0181] In some embodiments, the method comprises administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1) for at least two cycles. In some embodiments, SHP-1 inhibitor (e.g., TPI-1 or an analog or a derivative thereof, e.g., a deuterated TPI-1) is administered for at least once (e.g., for twice, three times, four times) in each cycle. In some embodiments, each cycle has about three to about 50 days (e.g., about 3- 40 days, about 3-30 days, about 3-20 days, about 3-15 days, about 3-10 days, or about 2-10 days).

[0182] In some embodiments, the SHP-1 inhibitor is administered locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor is administered locally (e.g., topically).

[0183] In some embodiments, the SHP-1 inhibitor is complexed with a delivery vehicle before being administered into the individual. In some embodiments, the delivery vehicle promotes the delivery into the tumor.

[0184] In some embodiments, the SHP-1 inhibitor modulates a lymphocyte (e.g., T cell) in vitro.

[0185] In some embodiments, the SHP-1 inhibitor and the lymphocyte activating agent described above are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of each other. In some embodiments, the SHP-1 inhibitor and the lymphocyte activating agent are administered simultaneously, concurrently, or sequentially. In some embodiments, the SHP-1 inhibitor is administered prior to the lymphocyte activating agent. ny-2916766Attorney Docket No.24516-20012.40 In some embodiments, the SHP-1 inhibitor is administered following the lymphocyte activating agent.

[0186] In some embodiments, when the method further involves administration of a pro- inflammatory agent, the SHP-1 inhibitor and the pro-inflammatory agent described below are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of each other. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered simultaneously, concurrently, or sequentially. In some embodiments, the SHP-1 inhibitor is administered prior to the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor is administered following the pro-inflammatory agent. Tyrosine kinase inhibitors

[0187] In some embodiments, the agent that inhibits SHP-1 signaling comprises or is a tyrosine kinase inhibitor (e.g., a tyrosine kinase that specifically inhibits SHP-1 signaling). The tyrosine kinase inhibitors referred to herein are an agent of any kind or sort that inhibits the expression or activity of a tyrosine kinase. In some embodiments, the tyrosine kinase inhibitor is a competitive inhibitor, a partial non-competitive inhibitor, a covalent inhibitor, a noncovalent inhibitor, an allosteric inhibitor, an inhibitor that targets the catalytic site, or an inhibitor that targets a regulatory site of tyrosine kinase.

[0188] In some embodiments, the tyrosine kinase inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%, e.g., 20%-50%, 20%-30%, 20%-40%, 30%-40%, 30%-50%, or 40%-50%) of the tyrosine kinase activity. In some embodiments, the tyrosine kinase inhibitor is capable of inhibiting at least about 20% (e.g., at least any of 20%, 30%, 40%, or 50%, e.g., 20%-50%, 20%-30%, 20%-40%, 30%-40%, 30%-50%, or 40%- 50%) of the tyrosine kinase expression.

[0189] In some embodiments, the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling.

[0190] In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., an siRNA, an shRNA, an antisense RNA, a microRNA), a nucleic acid base inhibitor (e.g., a circular RNA inhibitor), a nucleic acid editing system (e.g., CRISPR, ZFN, or TALENS systems), a peptide agent, a protein agent (e.g., an antibody agent that targets tyrosine kinase or activated tyrosine kinase, e.g., an antibody agent that targets tyrosine kinase or activated tyrosine kinase, e.g., a dominant negative tyrosine kinase or a constitutively active tyrosine kinase mutant), a protein ny-2916766Attorney Docket No.24516-20012.40 degrading or destabilizing agent, a protein modified with an unnatural amino acid, an antibody directed therapy, an antibody drug conjugate (ADC), and any combination thereof.

[0191] In some embodiments, the tyrosine kinase inhibitor has a half-life of no more than about 10, 9, 8, or 7 days (e.g., a half-life of no more than about 7, 6, 5, 4, 3, 2 or 1 day).

[0192] In some embodiments, the tyrosine kinase inhibitor is effective in inhibiting more than 50% of the tyrosine kinase activity for no more than about 10, 9, 8, 7, 6, or 5 days. In some embodiments, the tyrosine kinase inhibitor is effective in inhibiting more than 50% of the tyrosine kinase activity for no more than 4, 3, 2 or 1 day.

[0193] In some embodiments, the tyrosine kinase inhibitor is a covalent inhibitor. In some embodiments, the tyrosine kinase inhibitor is a noncovalent inhibitor.

[0194] In some embodiments, the tyrosine kinase inhibitor is a competitive inhibitor.

[0195] In some embodiments, the tyrosine kinase inhibitor is a nucleic acid editing system (such as a CRISPR system). In some embodiments, the CRISPR components are introduced into the cell (e.g., the monocytes and the macrophages) but no DNA encoding a guide RNA or Cas9 are incorporated into the cell’s genome. Under this approach, the CRISPR system only cleaves the cell’s genomic DNA for a limited period of time. See, e.g., Fister et al., Front Plant Sci.2018 Mar 2;9:268.

[0196] In some embodiments, the tyrosine kinase inhibitor is administered at least two times (such as at least 3, 4, 5, or 6 times).

[0197] In some embodiments, the tyrosine kinase inhibitor is administered at least two times (such as at least 3, 4, 5, or 6 times). In some embodiments, the method comprises administering the tyrosine kinase inhibitor at a daily interval for at least twice (such as at least three times, four times, five times, or six times).

[0198] In some embodiments, the tyrosine kinase inhibitor is administered at least two times (such as at least 3, 4, 5, or 6 times). In some embodiments, the method comprises administering the tyrosine kinase inhibitor at an interval of no more than once every two days for at least twice (such as at least three times, four times, five times, or six times).

[0199] In some embodiments, the tyrosine kinase inhibitor is administered at least two times (such as at least 3, 4, 5, or 6 times). In some embodiments, the method comprises administering the tyrosine kinase inhibitor at an interval of no more than once every three days for at least twice (such as at least three times, four times, five times, or six times). ny-2916766Attorney Docket No.24516-20012.40

[0200] In some embodiments, the method comprises administering the tyrosine kinase inhibitor for at least two cycles. In some embodiments, the tyrosine kinase inhibitor is administered for at least once (e.g., for twice, three times, four times) in each cycle. In some embodiments, each cycle has about one to about 50 days (e.g., about 1-40 days, about 1-30 days, about 1-20 days, about 1-15 days, about 1-10 days, or about 2-10 days).

[0201] In some embodiments, the tyrosine kinase inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, intraperitoneally). In some embodiments, the tyrosine kinase inhibitor is administered locally (e.g., intratumorally). In some embodiments, the tyrosine kinase inhibitor is administered both systemically and locally.

[0202] In some embodiments, the tyrosine kinase inhibitor is complexed with a delivery vehicle before being administered into the individual. In some embodiments, the delivery vehicle promotes the delivery into the tumor.

[0203] In some embodiments, the tyrosine kinase inhibitor modulates a monocyte or macrophage (e.g., a monocyte or macrophage derived from the individual to be treated) in vitro.

[0204] In some embodiments, the tyrosine kinase is a tyrosine kinase of the Src family. Src- family kinases have a similar structure, comprised of an N-terminal Src-homology (“SH”) 4 (“SH4”) domain, a “unique” domain, an SH3 domain, an SH2 domain, a catalytic domain (also known as the SH1 domain or the kinase domain) and a short C-terminal tail. Activity is regulated by tyrosine phosphorylation at two sites. Phosphorylation of a tyrosine (Tyr-505, Src numbering) in the C-terminal tail leads to down-regulation by promoting an intramolecular interaction between the tail and the SH2 domain. The eight known mammalian members of the Src-family break down into two sub-families. Lck is most similar to Hck, Lyn, and Blk (identities greater than 65% between any two members). The other sub- family consists of Src, Yes, Fyn, and Fgr (identities greater than 70% between any two members). Residues that are important for Src-family kinase activity and / or substrate specificity have been identified by X-ray crystal structures and by structural modeling studies, and are highly conserved among family members.

[0205] In some embodiments, the tyrosine kinase inhibitor is a Src inhibitor. In some embodiments, the tyrosine kinase inhibitor is a Syk inhibitor. In some embodiments, the tyrosine kinase inhibitor is an Hck inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits any one or more (such as any of 2, 3, 4, 5, or 6) of: Src, Syk, Hck, Lck, Lyn, ny-2916766Attorney Docket No.24516-20012.40 JAK, and Yes. In some embodiments, the tyrosine kinase inhibitor does not or weakly inhibits one or more kinases involved in T cell activation. In some embodiments, the one or more kinases involved in T cell activation comprises any one or more of: Lck, Fyn, Zap70, Syk and Csk. In some embodiments, the tyrosine kinase inhibitor inhibits Bcr-Abl. In some embodiments, the tyrosine kinase inhibitor is selected from the group consisting of RK- 20449, Dasatinib, R406, Entospletinib, Fostamatinib, Cerdulatinib, TAK-659, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105, RK-20449, RK-20693, RK- 24466, RK-20444, RK-20445, RK-20466, Masitinib, Ponatinib, and NVP-BEP800. These tyrosine kinase inhibitors are further discussed below. Src inhibitors

[0206] Src is a member of non-receptor protein tyrosine kinases, and has an activity that phosphorylates a specific tyrosine residue in a target protein. The Src may be originated from any species of animals (e.g., mammals), and for example may be at least one selected from the group consisting of primate Src including human Src (e.g., Accession No. NP_005408), monkey Src (e.g., Accession No. XP_002830325), and the like, and rodent Src including mouse Src (e.g., Accession No. NP_001020566), rat Src (e.g., Accession No. NP_114183), and the like, but not be limited thereto.

[0207] In some embodiments, the Src inhibitor (SRCi) may be an inhibitor of Src gene or Src protein expression; or an inhibitor of Src protein activity. The Src gene or Src protein expression inhibitor may be one or more selected from the group consisting of antisense nucleotides complementarily binding to mRNA of the gene, short interfering RNA (siRNA), short hairpin RNA (shRNA) and ribozyme, but not limited thereto. Further, the Src protein activity inhibitor may be one or more selected from the group consisting of a compound, a peptide, peptide mimetics, aptamers, antibodies, and natural products that specifically bind to the protein, but not limited thereto. The antibody includes a monoclonal antibody, a polyclonal antibody, or a recombinant antibody capable of specifically binding to the Src protein and can be constructed by methods known to those skilled in the art or purchased and used. According to the present disclosure, the compound may be one or more selected from the group consisting of dasatinib, bosutinib, ponatinib, saracatinib, WH-4-023, KX2-391, and WZ3105.

[0208] In one embodiment, the Src inhibitor may be at least one selected from the group consisting of dasatinib, saracatinib, and bosutinib, or any combination thereof. ny-2916766Attorney Docket No.24516-20012.40

[0209] KX2-391 (Tirbanibulin), which is also called N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, has the following structure:

[0210] Dasatinib, which is also called N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2- hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate, has the following structure:

[0211] Saracatinib, which is also called AZD0530 (4-Quinazolinamine, N-(5-Chloro-1,3- benzodioxol-4-yl)-7-[2-(4-methyl-1-piperazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]- 4-quinazolinamine), has the following structure:

[0212] Bosutinib, which is also called 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, has the following structure:Syk inhibitors

[0213] Spleen tyrosine kinase (Syk) is a cytosolic non-receptor protein tyrosine kinase (PTK). The human SYK gene is located in the region of chromosome 9 q22. Syk, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non- ny-2916766Attorney Docket No.24516-20012.40 receptor tyrosine kinases share a characteristic dual SH2 domain separated by a linker domain.

[0214] In some embodiments, the Syk inhibitor may be an inhibitor of Syk gene or Syk protein expression; or an inhibitor of Syk protein activity. The Syk gene or Syk protein expression inhibitor may be one or more selected from the group consisting of antisense nucleotides complementarily binding to mRNA of the gene, short interfering RNA (siRNA), short hairpin RNA (shRNA) and ribozyme, but not limited thereto. Further, the Syk protein activity inhibitor may be one or more selected from the group consisting of a compound, a peptide, peptide mimetics, aptamers, antibodies, and natural products that specifically bind to the protein, but not limited thereto. The antibody includes a monoclonal antibody, a polyclonal antibody, or a recombinant antibody capable of specifically binding to the Syk protein and can be constructed by methods known to those skilled in the art or purchased and used.

[0215] In some embodiments, the Syk inhibitor is a small molecule inhibitor. In some embodiments, the Syk inhibitor is selected from the group consisting of Entospletinib (GS- 9973), Fostamatinib (R788), R406, Cerdulatinib (PRT0626070), and TAK-659.

[0216] In some embodiments, the Syk inhibitor is R406 having the formula as follows:Hck inhibitors

[0217] Hck is a member of the Src-family of non-receptor tyrosine kinases, which plays many roles in signaling pathways involved in the regulation of cell processes. Hck is expressed in cells of hematopoietic origin, specifically myelomonocytic cells and B lymphocytes. It participates in phagocytosis, adhesion, migration, regulation of protrusion formation on cell membrane, lysosome exocytosis, podosome formation and actin polymerization. High levels of Hck are present in chronic myeloid leukemia and other hematologic tumors. Hck could also play a role in the genesis of acute myeloid leukemia. ny-2916766Attorney Docket No.24516-20012.40

[0218] In some embodiments, the Hck inhibitor may be an inhibitor of Hck gene or Hck protein expression; or an inhibitor of Hck protein activity. The Hck gene or Hck protein expression inhibitor may be one or more selected from the group consisting of antisense nucleotides complementarily binding to mRNA of the gene, short interfering RNA (siRNA), short hairpin RNA (shRNA) and ribozyme, but not limited thereto. Further, the Hck protein activity inhibitor may be one or more selected from the group consisting of a compound, a peptide, peptide mimetics, aptamers, antibodies, and natural products that specifically bind to the protein, but not limited thereto. The antibody includes a monoclonal antibody, a polyclonal antibody, or a recombinant antibody capable of specifically binding to the Hck protein and can be constructed by methods known to those skilled in the art or purchased and used.

[0219] In some embodiments, the Hck inhibitor is a small molecule inhibitor. In some embodiments, the Hck inhibitor is selected from the group consisting of RK-20449, RK- 20693, RK-24466, RK-20444, RK-20445, and RK-20466. In other embodiments, the HCK inhibitor is selected from RK-20449, RK-20693, RK-24466, RK-20444, RK-20445, RK- 20466, RK-20730, RK-20690, RK-20781, RK-20786, RK-20888, RK-20658, RK-20686, RK-20696, RK-20709, RK-20721, RK-20694, RK-20703, RK-20718, RK-20744, and compounds having Hck inhibitory activity disclosed in WO2014 / 017659, incorporated herein by reference. Hck inhibitors are also disclosed in WO2018 / 052120, which are incorporated herein by reference.

[0220] RK-20449 (also known as A 419259): 7-((1R,4R)-4-(4-methylpiperazin-l- yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-amine has a structure as follows:Lck inhibitors

[0221] Lck (or lymphocyte-specific protein tyrosine kinase) is a member of Src kinase family important for the activation of the T-cell receptor signaling in both naive T cells and effector T cells. The N-terminal tail of Lck is myristoylated and palmitoylated, which tethers ny-2916766Attorney Docket No.24516-20012.40 the protein to the plasma membrane of the cell. The protein furthermore contains a SH3 domain, a SH2 domain and in the C-terminal part the tyrosine kinase domain.

[0222] In some embodiments, the Lck inhibitor may be an inhibitor of Lck gene or Lck protein expression; or an inhibitor of Lck protein activity. The Lck gene or Lck protein expression inhibitor may be one or more selected from the group consisting of antisense nucleotides complementarily binding to mRNA of the gene, short interfering RNA (siRNA), short hairpin RNA (shRNA) and ribozyme, but not limited thereto. Further, the Lck protein activity inhibitor may be one or more selected from the group consisting of a compound, a peptide, peptide mimetics, aptamers, antibodies, and natural products that specifically bind to the protein, but not limited thereto. The antibody includes a monoclonal antibody, a polyclonal antibody, or a recombinant antibody capable of specifically binding to the Lck protein, and can be constructed by methods known to those skilled in the art or purchased and used.

[0223] In some embodiments, the Lck inhibitor is a small molecule inhibitor. In some embodiments, the Lck inhibitor is selected from the group consisting of Saractinib, Masitinib, and NVP-BEP800. Bcr-Abl inhibitor

[0224] BCR-ABL, a fusion gene created as a consequence of a reciprocal translocation mutation in the long arms of Chromosome 9 and 12, encodes the BCR-ABL protein, a constitutively active cytoplasmic tyrosine kinase present in >90% of all patients with chronic myelogenous leukemia (CML) and in 15-30% of adult patients with acute lymphoblastic leukemia (ALL). Exemplary Bcr-Abl inhibitors include, but are not limited to, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, rebastinib, tozasertib, danusertib, HG-7- 85-01, GNF-2, and 1,3,4-thiadiazole derivatives. Additional Bcr-Abl inhibitors can be found, for example, at WO2006 / 052810, specifically incorporated herein by reference.

[0225] Ponatinib (AP24534) is a dual Src / Abl inhibitor having the following structure.ny-2916766Attorney Docket No.24516-20012.40 Pro-inflammatory agents

[0226] In some embodiments, the methods described herein for treating a disease such as cancer further comprises administering to the individual a pro-inflammatory agent.

[0227] Infection and tissue injury are the two classic instigators of inflammation. See e.g., Medzhitov, Nature.2008 Jul 24;454(7203):428-35. Pro-inflammatory agents described herein include at least two overlapping categories: 1) an agent or therapy of any kind or sort that can promote an inflammation (e.g., by promoting one or more pro-inflammatory cytokines or chemokines, inhibiting one or more anti-inflammatory cytokines or chemokines, recruiting macrophages, NK cells, neutrophils, effector T cells, or B cells to the tissue or activating any of these cells, or suppressing regulatory / suppressive immune cells such as regulatory T cells or MDSC), and 2) an agent or therapy that can cause damage of cancer cells (e.g., necrosis of cancer cells).

[0228] In some embodiments, the pro-inflammatory agent triggers a pro-inflammatory signal on macrophages. In some embodiments, the pro-inflammatory agent activates a TLR, a TNFR, or ITAM-R. See Lionel et al., Eur J Immunol.2011 Sep; 41(9): 2477–2481. The pro- inflammatory can activate a pro-inflammatory signal on macrophages via a direct manner or indirect manner. For example, a TLR agonist, which directly activates TLR on macrophages, or a radiotherapy which indirectly activates a pro-inflammatory signal on macrophages, when used with an agent that inhibits SHP-1 signaling both demonstrated remarkable anti-tumor effects.

[0229] Exemplary pro-inflammatory agents include TLR agonists, STING activators, radiation therapies, PAMP / DAMP activators, pro-inflammatory cytokines or chemokines, chemotherapies, bacteria components, cancer vaccines, antibody-drug conjugates, and oncolytic viruses. Other exemplary pro-inflammatory agents include cryotherapies, surgeries, thermotherapies, sound treatments (e.g., high intensity focused ultrasound), magnetic therapies, electrical treatments, and electrostatic treatments that can kill cancer cells. See e.g., Naud et al., Nanoscale Adv., 2020, 2, 3632-3655; Rominiyi et al., Br J Cancer.2021 Feb;124(4):697-709; Zandi et al., Cancer Med.2021 Nov; 10(21): 7475–7491.

[0230] In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of TLR agonists, STING activators, radiation therapies, PAMP / DAMP activators, pro-inflammatory cytokines or chemokines, chemotherapies, bacteria components, cancer vaccines, oncolytic viruses, antibody-drug conjugates, cryotherapies, surgeries, ny-2916766Attorney Docket No.24516-20012.40 thermotherapies, sound treatments (e.g., high intensity focused ultrasound), magnetic therapies, electrical treatments, and electrostatic treatments.

[0231] In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of TLR agonists, STING activators, PAMP / DAMP activators, pro- inflammatory cytokines or chemokines, bacteria components, cancer vaccines, oncolytic viruses, antibody-drug conjugates, cryotherapies, surgeries, thermotherapies, sound treatments (e.g., high intensity focused ultrasound), magnetic therapies, electrical treatments, and electrostatic treatments.

[0232] In some embodiments, the pro-inflammatory agent is a sound treatment (e.g., high intensity focused ultrasound (HIFU), e.g., low intensity focused ultrasound (LIPUS)). See e.g., Wood et al., Ultrasound Med Biol.2015 Apr; 41(4): 905–928; Sengupta et al., J Adv Res.2018 Nov; 14: 97–111.

[0233] In some embodiments, the pro-inflammatory agent is a magnetic therapy (e.g., pulsed magnetic field, e.g., static magnetic field). See e.g., Tatarov et al., Comp Med.2011 Aug; 61(4): 339–345; Sengupta et al., J Adv Res.2018 Nov; 14: 97–111.

[0234] In some embodiments, the pro-inflammatory agent is an electrical treatment or electrochemical treatment. See e.g., Ciria et al., Chin J Cancer Res.2013 Apr; 25(2): 223– 234; Das et al., Front Bioeng Biotechnol.2021; 9: 795300.

[0235] In some embodiments, the pro-inflammatory agent is an electrostatic treatment. See e.g., Zandi et al., Cancer Med.2021 Nov; 10(21): 7475–7491.

[0236] In some embodiments, the pro-inflammatory agent is a thermoacoustic treatment. See e.g., Wen et al., Theranostics.2017; 7(7): 1976–1989.

[0237] In some embodiments, the pro-inflammatory agent comprises a microbe (e.g., a fragment or lysate of a microbe). Examples of microbe include bacteria, fungi, and viruses.

[0238] In some embodiments, the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a cytokine (e.g., IFN-gamma).

[0239] In some embodiments, the pro-inflammatory agent is a cryotherapy.

[0240] In some embodiments, the pro-inflammatory agent is a surgery.

[0241] In some embodiments, the pro-inflammatory agent is a thermotherapy. ny-2916766Attorney Docket No.24516-20012.40 TLR agonists

[0242] In some embodiments, the pro-inflammatory agent comprises or is a TLR agonist.

[0243] TLRs play a vital role in activating immune responses. TLRs recognize conserved pathogen-associated molecular patterns (PAMPs) expressed on a wide array of microbes, as well as endogenous DAMPs released from stressed or dying cells. TLR1, -2, -4, -5, -6, and - 10 are expressed on the cell surface, whereas TLR3, -7, -8, and -9 are situated on endosomal membranes within the cell. TLR1 and TLR2 can heterodimerize to recognize a variety of bacterial lipid structures and cell wall components, such as triacylated lipoproteins, lipoteichoic acid, and ^-glucans. TLR2 also heterodimerizes with TLR6 to bind diacylated lipopeptides. Additionally, TLR2 can bind various endogenous DAMPs, such as HSPs, HMGB1, uric acid, fibronectin, and other extracellular matrix proteins. It has also been suggested that TLR1 and TLR6 can heterodimerize with TLR10; however, the TLR agonist recognized by this dimer remains to be identified. TLR3 recognizes viral dsRNA, as well as synthetic analogs of dsRNA, such as ligand Poly I:C. TLR4 binds LPS in complex with lipid A binding protein, CD14, and myeloid differentiation protein 2, MD2 as well as recognizing various DAMPs. Endogenous TLR4 ligands, which have been described, include ^-defensin 2, fibronectin extra domain A EDA, HMGB1, Snapin, and tenascin C. TLR5 recognizes bacterial flagellin, TLR7 and TLR8 bind viral ssRNA, whereas TLR9 interacts with unmethylated CpG DNA from bacteria and some viruses. Additional TLRs have been identified more recently in mice based on sequence homology of the highly conserved TIR domain. TLR10 is a surface receptor whose natural ligand remains unknown. TLR11, -12, and -13 are present in mice but not in humans. TLR11 was shown to bind a T. gondii profilin and uropathogenic E. coli. The ligand for TLR12 has not yet been identified, whereas TLR13 is an endosomal receptor that recognizes VSV. See e.g., Kaczanowska et al., J Leukoc Biol. 2013 Jun;93(6):847-63.

[0244] TLR signaling can act as a double-edged sword in cancer. It was found that TLR stimulation of cancer cells can lead to either tumor progression or inhibition. For example, stimulation of TLR2, -4, and -7 / 8 was found to lead to tumor progression via production of immunosuppressive cytokines, increased cell proliferation and resistance to apoptosis. R848- stimulation of TLR7 / 8 overexpressing pancreatic cancer cell line resulted in increased cell proliferation and reduced chemosensitivity. On the other hand, stimulation of TLR2, -3, -4, - 5, -7 / 8, and -9, often combined with chemotherapy or immunotherapy, can lead to tumor ny-2916766Attorney Docket No.24516-20012.40 inhibition via different pathways. See e.g., Grimmig et al., Int J Oncol. (2015) 47:857–66; Urban-Wojciuk et al., Front Immunol.2019; 10: 2388.

[0245] In some embodiments, the TLR agonist activates any of the TLRs.

[0246] In some embodiments, the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and / or Pam3CSK4.

[0247] In some embodiments, the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, optionally wherein the TLR agonist comprises a diacylated lipopeptide, a hot shock protein, HMGB1, uric acid, fibronectin, and / or ECM protein.

[0248] In some embodiments, the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and / or CBLB612.

[0249] In some embodiments, the TLR agonist activates TLR3, optionally wherein the TLR agonist comprises dsRNA, Poly I:C, PolyICIC, Poly-IC12U, IPH302, ARNAX, and / or MPLA.

[0250] In some embodiments, the TLR agonist activates TLR4, optionally wherein the TLR agonist comprises LPS, lipoteichoic acid beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, FP20, G100, and / or GLA-SE.

[0251] In some embodiments, the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and / or M-VM3.

[0252] In some embodiments, the TLR agonist activates TLR6.

[0253] In some embodiments, the TLR agonist activates TLR7 or TLR8, optionally wherein the TLR agonist comprises ssRNA, CpG-A, poly G10, poly G3, and / or 324 BDB001.

[0254] In some embodiments, the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and / or R848.

[0255] In some embodiments, the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and / or R848.

[0256] In some embodiments, the TLR agonist activates TLR9, optionally wherein the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and / or ODN M362. ny-2916766Attorney Docket No.24516-20012.40

[0257] In some embodiments, the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam3CSK4.

[0258] In some embodiments, the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises Toxoplasma gondii profilin.

[0259] In some embodiments, the TLR agonist activates TLR12.

[0260] In some embodiments, the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV.

[0261] In some embodiments, the TLR agonist activates a TLR on a macrophage.

[0262] In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and / or TLR9.

[0263] In some embodiments, the TLR comprises TLR1, TLR4, and / or TLR9. In some embodiments, the TLR comprises TLR9.

[0264] In some embodiments, the TLR comprises TLR2, TLR4, TLR7, and / or TLR8.

[0265] In some embodiments, the TLR agonist comprises CpG. In some embodiments, the TLR agonist comprises polyI:C. In some embodiments, the TLR agonist comprises CpG and / or polyI:C. In some embodiments, the TLR agonist comprises CpG, polyI:C and / or R848.

[0266] In some embodiments, the TLR agonist is R848, 3M-852A, Motolimod, Bropirimine, or Vesatolimod. In some embodiments, the TLR agonist is R848.

[0267] In some embodiments, the method described herein further comprises assessing whether the individual has an ongoing infection. In some embodiments, a reduced amount of the TLR agonist is administered when the individual has an ongoing infection. In some embodiments, the administration of TLR agonist can be avoided when the individual has an ongoing infection. Radiation therapy

[0268] In some embodiments, the pro-inflammatory agent comprises or is a radiation therapy. Radiation activates the interconnected network of cytokines, adhesion molecule, ROS / RNS and DAMPs leading to a self-amplified cascade, which generates pro- inflammatory, pro-oxidant tumor microenvironment and ultimately tumor cell death. See e.g., McKelvey et al., Mamm Genome.2018; 29(11): 843–865. ny-2916766Attorney Docket No.24516-20012.40

[0269] In some embodiments, the radiation therapy comprises irradiation at site of the cancer to be treated.

[0270] In some embodiments, the radiation therapy comprises irradiation at a site that is different from the site of the cancer to be treated.

[0271] In some embodiments, the radiation therapy is intraoperative radiation therapy (“IORT”). In particular embodiments, the radiation is localized to a tumor site. The patient may be subjected to intraoperative radiation prior to resection of the tumor or following resection of the tumor. The tumor site may comprise different types of cells including cancerous and benign cells. In certain embodiments, the radiation therapy is stereotactic body radiotherapy (“SBRT”) or stereotactic radiosurgery (“SRS”).

[0272] In some embodiments, the radiation is ionizing radiation such as particle beam radiation. The particle beam radiation may be selected from any of electrons, protons, neutrons, heavy ions such as carbon ions, or pions. The ionizing radiation may be selected from x-rays, UV-light, ^-rays, or microwaves. In some embodiments, the radiation therapy may comprise subjecting the patient to one or more types of radiation therapy.

[0273] In some embodiments, a radio sensitizer is used to sensitize the tumor cells to radiation. The use of such pharmaceuticals, called radiosensitizers, provides a method of increasing the radiosensitivity of tumors to radiation therapy, avoiding the need to increase radiation dosages to levels that are harmful to surrounding organs and tissues. See e.g., US9656098B2.

[0274] In some embodiments, the dose of the radiation therapy is non-ablative, insufficient to eliminate the tumor (kill all tumor cells). In some embodiments, the radiation therapy is selected from the group consisting of external-beam radiation therapy, internal radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectors.

[0275] In some embodiments, the radiation therapy is external-beam radiation therapy, optionally comprising three-dimensional conformal radiation therapy (3D-RT), intensity modulated radiation therapy (IMRT), photon beam therapy, image-guided radiation therapy (IGRT), and sterotactic radiation therapy (SRT).

[0276] In some embodiments, the radiation therapy comprises administering a radiopharmaceutical. The radiopharmaceuticals can be delivered via any vehicle such as a cell, a protein, or a small molecule complex. In some embodiments, the radiopharmaceutical ny-2916766Attorney Docket No.24516-20012.40 is administered to the tumor tissue. See e.g., Sgouros et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19, 589–608 (2020).

[0277] In some embodiments, the radiation therapy is brachytherapy, optionally comprising interstitial brachytherapy, intracavitary brachytherapy, intraluminal radiation therapy, and radioactively tagged molecules given intravenously. STING activator

[0278] In some embodiments, the pro-inflammatory agent comprises or is a STING activator.

[0279] Stimulator of IFN genes (STING, also known as TMEM173, MITA, MPYS or ERIS) is a pattern recognition receptor (PRR) that recognizes cytosolic DNA in the form of cyclic dinucleotides (CDNs), such as the bacterial product cyclic-guanosine monophosphate- adenosine monophosphate (3’3’ cGAMP). In addition to bacterial components, other forms of DNA from viruses, or the host cell, that find their way into the cytosol are recognized by an enzyme c-GMP-AMP (cGAMP) synthase (cGAS). Upon cytosolic DNA binding, cGAS converts ATP and GTP into the metazoan-specific CDN 2’3’-cGAMP for STING recognition and activation. STING is a transmembrane protein that exists as dimers anchored within the endoplasmic reticulum membrane and forms a V-shaped pocket that enables cytosolic CDN binding. Ligand binding results in significant conformational changes in the C-terminal domain of STING, mediating its transport to Golgi compartments. At the Golgi, STING recruits TANK-binding kinase 1 (TBK1), which facilitates IRF3 phosphorylation, nuclear translocation and the strong induction of transcription of type I IFNs (e.g., IFN-^). STING also triggers a robust pro-inflammatory cytokine response (e.g., tumor necrosis factor (TNF)) by activating Nuclear Factor-kappa B (NF-^B) and this part of the pathway can be mediated independent of TBK1 via a closely related homologue protein, IKK^. See e.g., Peng et al., Front Immunol.2022 Feb 25;13:794776; Amougezar et al., Cancers (Basel).2021 May 30;13(11):2695.

[0280] In some embodiments, the STING activator is a cyclic-guanosine monophosphate- adenosine monophosphate (cGAMP, e.g., 3’3’ cGAMP, e.g., 2’3’ cGAMP).

[0281] In some embodiments, the STING activator is a bacterial vector (e.g., SYNB1891, STACT-TREX-1).

[0282] In some embodiments, the STING activator is a CDN compound (e.g., ADU-S100, BI-STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3’3’-cyclic AIMP). ny-2916766Attorney Docket No.24516-20012.40

[0283] In some embodiments, the STING activator is a non-CDN small molecule (e.g., ALG- 031048, E7755, JNJ-6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI- 10001).

[0284] In some embodiments, the STING activator is a nanovaccine (e.g., PC7A NP, cCAMP-NP, ONM-500).

[0285] In some embodiments, the STING activator is an antibody-drug conjugate (e.g., XMT-2056, CRD-5500).

[0286] In some embodiments, the STING activator is an ATR inhibitor (e.g., berzosertib). See e.g., Cancer Commun (Lond).2023 Apr; 43(4): 435–454. In some embodiments, the ATR inhibitor is used in combination with a radiation therapy.

[0287] Other exemplary STING activators can be found in Amougezar et al., Cancers (Basel).2021 May 30;13(11):2695, which is incorporated by reference here by its entirety. PAMP / DAMP activators

[0288] In some embodiments, the pro-inflammatory agent comprises or is a PAMP / DAMP activator.

[0289] The organism senses microbial infection through innate receptors encoded in the genome, called pattern-recognition receptors, including the Toll-like receptors (TLRs), the nucleotide-binding and oligomerization domain (NOD)-like receptors, and retinoic acid– inducible gene I (RIG-I)-like receptors. These receptors recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, fungi, and viruses, but also bind damage- associated molecular patterns (DAMPs), which are molecules released by sterile injury. Thus, PAMPs and DAMPs that bind to the same type of receptors initiate identical intracellular pathways terminating in identical effector functions. See e.g., Alisi et al., Hepatology.2011 Nov;54(5):1500-2.

[0290] In some embodiments, the pro-inflammatory agent is a PAMP activator. Exemplary PAMP activator includes triacyl lipopeptides, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porins, lipoarabinomannan, double- stranded RNA, poly(I:C), trepanosomal lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial / viral DNA, CpG DNA, ureobacteria, and toxoplasma LPS. ny-2916766Attorney Docket No.24516-20012.40

[0291] In some embodiments, the pro-inflammatory agent is a DAMP activator. Exemplary DAMP activator includes defensins, HSP60, HSP70, messenger RNA, low-molecular-weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, and unmethylated CpG DNA. Chemotherapeutic agent

[0292] In some embodiments, the pro-inflammatory agent comprises or is a chemotherapeutic agent.

[0293] In some embodiments, the chemotherapeutic agent is an alkylating agent. Exemplary alkylating agents include nitrogen mustard (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkyl sulfonate (e.g., busulfan), and ethyleneimine (e.g., thiotepa).

[0294] In some embodiments, the chemotherapeutic agent is an antimetabolite. Exemplary antimetabolites include cytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (prodrug of 5-FU)).

[0295] In some embodiments, the chemotherapeutic agent is an antimicrotubular agent. Exemplary antimicrotubular agents include topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin).

[0296] Other exemplary chemotherapeutic agents include hydroxyurea, tretinoin, arsenic trioxide, and proteasome inhibitors (e.g., bortezomib). Pro-inflammatory cytokines

[0297] In some embodiments, the pro-inflammatory agent is a pro-inflammatory cytokine.

[0298] In some embodiments, the pro-inflammatory cytokine promotes the M1 macrophages. See e.g., Duque et al., Front Immunol.2014; 5: 491. In some embodiments, the pro- inflammatory cytokine comprises or is TNF, IFN^, and / or GM-CSF. ny-2916766Attorney Docket No.24516-20012.40

[0299] In some embodiments, the pro-inflammatory cytokine comprises IL-6, TNF^, a cytokine from IL-1 family (e.g., IL-1^, IL-1^, IL-18, IL-33, and IL-36), and / or IFN^.

[0300] In some embodiments, the pro-inflammatory cytokine comprises a cytokine from IL-1 family. In some embodiments, the pro-inflammatory cytokine comprises any one or more of IL-1^, IL-1^, IL-18, IL-33, and IL-36. See e.g., Sims, J., Smith, D. The IL-1 family: regulators of immunity. Nat Rev Immunol 10, 89–102 (2010). Antibody drug conjugates

[0301] In some embodiments, the pro-inflammatory agent comprises an antibody drug conjugate (ADC). In some embodiments, the ADC presents a payload to the cancer cells. In some embodiments, the payload is a cytotoxic drug. In some embodiments, the ADC enhances cancer cell killing and thereby induces antigen spreading and activation of antigen- presenting cells. Exemplary ADCs include, but are not limited to, brentuximab vedotin, enfortumab vedotin, gemtuzumab ozogamicin, inotuzumab ozogamicin, polatuzumab vedotin, sacituzumab govitecan, trastuzumab deruxtecan, trastuzumab emtansine, and belantamab mafodotin. Any ADC known in the art may be used as described herein. See, e.g., Baah, S. et al., Molecules 2021; 26(10):2943. Cancer vaccine

[0302] In some embodiments, the pro-inflammatory agent comprises or is a cancer vaccine. Cancer vaccine stimulates anti-tumor immunity with tumor antigens, which could be delivered in the form of whole cells, peptides, nucleic acids, etc. Ideal cancer vaccines could overcome the immune suppression in tumors and induce both humoral immunity and cellular immunity.

[0303] In some embodiments, the cancer vaccine comprises a cell-based vaccine, a peptide- based vaccine, a viral-based vaccine, and / or a nucleic acid-based vaccine. See e.g., Liu et al., J Hematol Oncol 15, 28 (2022).

[0304] Cell-based vaccines are the form of cancer vaccines initially. Cell-based cancer vaccines are often prepared from whole cells or cell fragments, containing almost tumor antigens, inducing a broader antigen immune response. DC vaccine is an important branch of cell-based vaccines. Personalized neoantigen cancer vaccines based on DC have shown promising anti-tumor effects in clinical. Viruses are naturally immunogenic, and their genetic material can be engineered to contain sequences encoding tumor antigens. Several recombinant viruses, such as adenovirus, can infect immune cells as vectors. The engineered ny-2916766Attorney Docket No.24516-20012.40 virus vaccines can present tumor antigens in large quantities in the immune system and produce anti-tumor immunity. Furthermore, the oncolytic virus can be used as a vector as well. Except for providing tumor antigens, the virus itself can also lyse the tumor, release tumor antigens, further increase the vaccine's effectiveness, and produce long-term immune memory.

[0305] Peptide-based subunit vaccines, including chemical and biosynthetic preparations of predicted or known specific tumor antigens, induce a robust immune response against the particular tumor antigen site. Peptide-based subunit vaccine combined with adjuvants can efficiently provoke humoral immune response, suitable for preventing and treating viral infectious diseases.

[0306] HBV and HPV vaccines for liver and cervical cancers were primarily peptide-based subunit vaccines. Especially, virus-like particles (VLP)-based subunit vaccines that can activate cellular immune responses have shown good anti-tumor activity in recent years.

[0307] The nucleic acid vaccine induces strong MHC I mediated CD8+^T cell responses; thus, it is a desirable cancer vaccine platform. Nucleic acid vaccines can simultaneously deliver multiple antigens to trigger humoral and cellular immunity. Additionally, nucleic acid vaccines can encode full-length tumor antigens, allowing APC to cross-present various epitopes or present several antigens simultaneously. Finally, the nucleic acid vaccine preparation is simple and fast, which is suitable for developing personalized neoantigen cancer vaccines. Oncolytic virus

[0308] In some embodiments, the pro-inflammatory agent is an oncolytic virus (OV). The oncolytic viruses (OVs) are organisms able to identify, infect, and lyse different cells in the tumor environment, aiming to stabilize and decrease the tumor progression. They can present a natural tropism to the cancer cells or be oriented genetically to identify specific targets. See e.g., Apolonio et al., World J Virol.2021 Sep 25; 10(5): 229–255.

[0309] Oncolytic viruses represent an exciting new avenue of cancer therapy. Such viruses have the remarkable ability to hunt and terminate cancer cells while leaving healthy cells unharmed, as well as enhancing the immune system's ability to recognize and terminate cancer cells. See e.g., Cancer Cell.2022 Aug 15;S1535-6108(22)00357-9.

[0310] In some embodiments, the oncolytic virus comprises or is an adenovirus (e.g., ONYX-15, LOAd703 virus), a protoparvovirus, a parvovirus (e.g., H-1PV), a vaccinia virus ny-2916766Attorney Docket No.24516-20012.40 (VACV), a Reovirus (e.g., Reolysin), or a Herpes simplex virus (HSV, e.g., HSV-1, HSV-2, G207, L1BR1, HF10, T-VEC, Orien X010).

[0311] Other exemplary oncolytic viruses include JX-593, Coxsackievirus A21 (CVA21), marabá virus or its MG1 variant, DNX2440 adenovirus, fowl pox virus, and Sendai virus. Cells

[0312] In some embodiments, the pro-inflammatory agent comprises cells that trigger inflammatory factors. In some embodiments, the cells are tumor-infiltrating lymphocytes. In some embodiments, the cells specifically recognize a tumor antigen (e.g., being engineered to express a CAR recognizing a tumor antigen). In some embodiments, the cells are T cells. In some embodiments, the cells are CAR-T cells. In some embodiments, the cells are NK cells (e.g., CAR-NK cells). In some embodiments, the cells are neutrophils (e.g., CAR-expressing neutrophils cells). In some embodiments, the cells are TCR-T cells. In some embodiments, the cells are APCs (e.g., macrophages or dendritic cells). In some embodiments, the cells are CAR-macrophages or CAR-monocytes. In some embodiments, the cells are SIRPant- macrophages. In some embodiments, the cells are stem cells. In some embodiments, the cells are allogenic. In some embodiments, the cells are autologous. Associated agent that inhibits SHP-1 signaling and pro-inflammatory agent / lymphocyte activating agent

[0313] In some embodiments, the agent that inhibits SHP-1 signaling comprises an agent (e.g., a conjugate) comprising an agent that inhibits SHP-1 signaling (such as a SHP-1 inhibitor, such as a TPI-1 or a derivative or an analog thereof, such as a deuterated TPI-1, such as dTPI-1) associated (e.g., fused or conjugated) with a pro-inflammatory agent or lymphocyte activating agent (PI / LA agent, or PI / LAA) are associated. In some embodiments, the agent that inhibits SHP-1 signaling and the PI / LA agent are fused via a linker. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker is a pH sensitive linker.

[0314] In some embodiments, the agent that inhibits SHP-1 signaling comprises a SHP-1 inhibitor or a tyrosine kinase inhibitor that specifically inhibits SHP-1 (“SHP-1I”). In some embodiments, the SHP-1I and the PI / LA agent are covalently conjugated, e.g., via a linker. In some embodiment, the linker is a PEG linker. In some embodiments, the SHP-1 inhibitor and the PI / LA agent are conjugated via an ester bond or via an amide bond. ny-2916766Attorney Docket No.24516-20012.40

[0315] In some embodiments, more than one agent that inhibits SHP-1 pathway (i.e., SHP- 1I) are associated with one PI / LA agent. For example, two or more TPI-1 or derivative or analog thereof (e.g., deuterated TPI-1 discussed here) are associated (e.g., conjugated) with a PI / LA agent (e.g., a TLR agonist, e.g., Poly I:C, R848, R847, CpG, e.g., a STING activator, e.g., 2’3’-cGAMP). Exemplary structure of SHP1I-PI / LAA Conjugates

[0316] Exemplary SHP1I-PI / LAA conjugates are of the following formula: PI / LAA-LA-R1wherein PI / LAA is a pro-inflammatory agent or a lymphocyte activating agent, LAis an optional linker, and R1is a SHP-1 inhibitor.

[0317] In some embodiments, the pro-inflammatory agent comprises a TLR agonist, a STING activator, a PAMP / DAMP molecule, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic agent, or a bacterial component.

[0318] In some embodiments, the PI / LAA is a TLR agonist. In some embodiments, the TLR agonist activates a TLR on a macrophage. In some embodiments, the TLR agonist activates TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and / or TLR9. In some embodiments, the TLR agonist comprises a DNA molecule or an RNA molecule. In some embodiments, the TLR agonist comprises a cytosine–phosphate–guanine (CpG) oligodeoxynucleotide, polyinosinic-polycytidylic acid (polyI:C), R837, R848, flagellin, zymosan, or HMGB1. In some embodiments, the TLR agonist comprises R837. In some embodiments, the TLR agonist comprises R848.

[0319] In some embodiments, the conjugate comprises the following formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1I. In some embodiments, R1is a TPI-1 or a derivative or analog thereof (e.g., those discussed above).

[0320] In some embodiments, the conjugate comprises the formula: ny-2916766Attorney Docket No.24516-20012.40or a salt thereof.

[0321] In some embodiments, the conjugate comprises the formula:or a salt thereof.

[0322] In some embodiments, the conjugate comprises the formula:or a salt thereof.

[0323] In some embodiments, the pro-inflammatory agent comprises a STING activator. In some embodiments, the STING activator comprises 2’3’-cGAMP. ny-2916766Attorney Docket No.24516-20012.40

[0324] In some embodiments, the conjugate comprises the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1I. In some embodiments, R1is a SHP-1 inhibitor. In some embodiments, R1is a TPI-1 or a derivative or analog thereof (e.g., those discussed above).

[0325] In some embodiments, the conjugate comprises the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1I. In some embodiments, R1is a TPI-1 or a derivative or analog thereof (e.g., those discussed above).

[0326] In some embodiments, the conjugate comprises the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1I. In some embodiments, R1is a TPI-1 or a derivative or analog thereof (e.g., those discussed above). ny-2916766Attorney Docket No.24516-20012.40

[0327] In some embodiments, the conjugate comprises the formula:or a salt thereof, wherein one G substituent is -LA-R1and the other two G substituents are H, LAis an optional linker, and R1is a SHP-1I. In some embodiments, R1is a TPI-1 or a derivative or analog thereof (e.g., those discussed above).

[0328] In some embodiments, the conjugate comprises the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1I (e.g., SHP-1 inhibitor). In some embodiments, R1is a TPI-1 or a derivative or analog thereof (e.g., those discussed above). Optional Linkers of the SHP1I-PI / LAA conjugates

[0329] A SHP-1I (e.g., SHP-1 inhibitor) can be directly conjugated to the pro-inflammatory agent or the T cell activating agent through functional groups on the SHP-1I (e.g., SHP-1 inhibitor) and the PI / LA agent. However, an optional linker can also be used to covalently link a SHP1I and a PI / LA agent.

[0330] The optional linker, when present, can link a SHP-1I (e.g., SHP-1 inhibitor) and a PI / LA agent by attachment to a functional group on the PI / LA agent at one end of the linker and attachment to a functional group on the SHP-1I (e.g., SHP-1 inhibitor) at the other end of the linker. Typical functional groups for attachment include amino, hydroxy, sulfhydryl, or carboxyl groups. Alternatively, the linker may be attached to either the PI / LA agent, the ny-2916766Attorney Docket No.24516-20012.40 SHP-1I (e.g., SHP-1 inhibitor), or both, at a valence opened on the PI / LA agent, the SHP-1I (e.g., SHP-1 inhibitor), or both by replacement of a hydrogen, halogen, or methyl group with a bond to the linker.

[0331] A wide variety of linkers are available. When the optional linker LAis present in the conjugate of form PI / LAA-LA-R1, where PI / LAA is a pro-inflammatory agent or a lymphocyte activating agent and R1is a SHP-1I (e.g., SHP-1 inhibitor), the optional linker LAcan be between 1 and 25 atoms in length. The length is defined by the chain that connects the PIA moiety to the R1moiety; there may be other substituents that define shorter chains. For example, the following linker:where the bonds crossed by a wavy line indicate where the linker attached to the PIA moiety on one end and the R1moiety on the other end, has a length of 9, from the first carbon marked with asterisk * to the second carbon marked with asterisks **.

[0332] The linker can comprise any number of carbon atoms and heteroatoms, such as N, O, or S. PEG linkers, such as –(CH2CH2O)n- or –(OCH2CH2)n- , where n is between 1 and 8 inclusive, are useful linkers. PEG compounds terminated with functional groups such as hydroxy groups, amino groups, and carboxy groups are commercially available and can be readily used in synthesis. For example, when LAis –(CH2CH2O)n- or –(OCH2CH2)n-, where n is an integer between 1 and 8 inclusive, a PEG compound of the form OH–(CH2CH2O)n-H or HO2C–(OCH2CH2)n-NH2can be used to connect to appropriate functional groups on the pro-inflammatory agent or SHP-1 inhibitor.

[0333] In other embodiments, LAcan be C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or heteroalkyl containing between two to twelve chain atoms total and one, two, or three chain atoms selected from the group consisting of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups, where RAis C1-C4alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2. A wide variety of functional groups may be present on the reagent used to form the LA group. For example, sebacic acid, HO2C-(CH2)8-CO2H, may react with functional groups on the pro-inflammatory agent and ny-2916766Attorney Docket No.24516-20012.40 SHP-1 inhibitor to provide a linker of the structure -C(=O)-(CH2)8-C(=O)-, which is a C10 alkyl chain substituted with two oxo groups.

[0334] LAcan be composed of multiple regions, such as when LAis L1-L2-L3, where: L1is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, or heteroalkyl containing between two to eight chain atoms total and one, two, or three chain atoms selected from the group consisting of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; L2is C3-C8 cycloalkyl, C6-C10 aryl, three-to-twelve-membered heterocyclyl, or five-to- twelve-membered heteroaryl, wherein the cycloalkyl or heterocyclyl are optionally substituted with one, two, or three RAgroups, and the aryl or heteroaryl are optionally substituted with one, two, or three RBgroups; and L3is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or heteroalkyl containing between two to eight chain atoms total and one, two, or three chain atoms selected from the group consisting of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups;

[0335] where RAis C1-C4 alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2, and

[0336] RBis C1-C4alkyl, -OH, -O-C1-C6, F, Cl, Br, I, -CN, or -NO2.

[0337] LAcan also be –O-(CH2CH2O)n-, –(OCH2CH2)n–O–, or -L4-PEG-L4-, where n is an integer between 1 and 8 inclusive, PEG is ethylene glycol or polyethylene glycol having between 2 and 8 ethylene glycol units, and each L4 is independently absent or -O-, -NH-, - CH2-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or -(C=O)-NH-; or

[0338] LAcan be L5-L6-L7-L8-L9,

[0339] where L5is -O-, -NH-, -CH2-, -(C=O)-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or - (C=O)-NH-; L6is absent or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or heteroalkyl containing between two to eight chain atoms total and one, two, or three chain atoms selected from the group consisting of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; L7is absent or C3-C8cycloalkyl, C6-C10aryl, three-to-twelve-membered heterocyclyl, or five- to-twelve-membered heteroaryl, wherein the cycloalkyl or heterocyclyl are optionally ny-2916766Attorney Docket No.24516-20012.40 substituted with one, two, or three RAgroups, and the aryl or heteroaryl are optionally substituted with one, two, or three RBgroups; L8is absent or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or heteroalkyl containing between two to eight chain atoms total and one, two, or three chain atoms selected from the group consisting of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; with the proviso that at least one of L6, L7, or L8is not absent; and L9is -O-, -NH-, -CH2-, -(C=O)-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or -(C=O)-NH-; where RAis C1-C4alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2, and RBis C1-C4 alkyl, -OH, -O-C1-C6, F, Cl, Br, I, -CN, or -NO2.

[0340] Additional groups which can be used as LAlinkers include:wherein the wavy bonds indicate the bonds attaching LAto the remainder of the molecule.

[0341] Additional examples of chemistry that can be used to form linkers between various functional groups on different molecules can be found in publications such as “Chemistry of Protein and Nucleic Acid Cross-Linking and Conjugation” by Shan S. Wong and David M. Jameson (CRC Press: Boca Raton, Florida, USA, 2012), and Bargh et al., Chem. Sci., 2020, 11, 2375–2380. ny-2916766Attorney Docket No.24516-20012.40 An agent that reduces systemic inflammation

[0342] In some cases, individuals develop systemic inflammation, i.e., cytokine release syndrome (CRS) after receiving (e.g.) immunotherapeutic treatment, however the inflammatory disorder is not fully understood. CRS can be induced by direct target cell lysis and the consecutive release of cytokines like TNF^ or IFN^, or by activation of T cells due to therapeutic stimuli that is followed by subsequent cytokine release. These cytokines trigger a chain reaction due to the activation of innate immune cells like macrophages and endothelial cells, which then induces further cytokine release. In particular, IL-6, IL-10, and IFN^ are most commonly found to be elevated in patients with CRS.

[0343] The methods described herein can further comprises administration of an agent that reduces systemic inflammation (including, for example, an agent that reduces inflammatory cytokine cascade or cytokine storm), in order to curb down systemic inflammation and reduce adverse toxicity. The agents that reduce systemic inflammation include, but are not limited to, inhibitors of TNF^, IL-6, IL-10, and IFN^. In some embodiments, the agent that reduces systemic inflammation is administered simultaneously with the agent that inhibits SHP-1 signaling. In some embodiments, the agent that reduces systemic inflammation is administered sequentially (e.g., prior to or after) with the SHP-1I (e.g., SHP-1 inhibitor). In some embodiments, the administration of the agent that reduces systemic inflammation follows the same dosing schedule as the SHP-1I (e.g., SHP-1 inhibitor). In some embodiments, the agent that reduces systemic inflammation is administered at a sub- therapeutic dose, namely, at a dose that is lower than an effective amount for treating a disease when administered alone. In some embodiments, the administration of the agent that reduces systemic inflammation allows more frequent administration of the SHP-1I and / or the pro-inflammatory agent (e.g., daily, once every two days, once every three days, etc.).

[0344] The agent can include any anti-inflammatory agent known in the art, including inhibitors of or antagonists to pro-inflammatory agents. For example, the agent can be an inhibitor or antagonist, including but not limited to, a small molecule inhibitor, a neutralizing antibody, a receptor blockade antibody, a soluble receptor, a targeting short interfering RNA (siRNA), a chemical inhibitor of mRNA stability, derivatives thereof, and any combination thereof, including combinations of agents targeting one or more molecules (e.g., targeting via the inhibition of TNF^ alone, IL-6 alone, TNF^ and IL-6 in combination). ny-2916766Attorney Docket No.24516-20012.40

[0345] In some embodiments, the methods described herein further comprise administering a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor. See e.g., Arthritis Rheum.2012 Dec; 64(12): 3856–3866. Cytokine release syndrome and the role of TNF^

[0346] TNF^, a major pro-inflammatory cytokine, is secreted by activated macrophages, monocytes, and lymphocytes. TNF^ plays a role in the non-specific immune response, but it is still not completely understood what role, if any, TNF^ plays in the specific, cell-mediated immune response. TNF^, as well as various other cytokines, has been identified as a potential inducer of such biological reactions as cytokine release syndrome (CRS). CRS can be induced by direct target cell lysis and the consecutive release of cytokines like TNF^ or IFN^, or by activation of T cells due to therapeutic stimuli that is followed by subsequent cytokine release. These cytokines trigger a chain reaction due to the activation of innate immune cells like macrophages and endothelial cells, which then induces further cytokine release.

[0347] IL-6, IL-10, and IFN^ are most commonly found to be elevated in patients with CRS. IFN^ causes fever, chills, headache, dizziness, and fatigue. IFN^ induces activation of macrophages, which in turn produce excessive amounts of additional cytokines such as IL-6, TNF^, and IL-10.

[0348] TNF^ elicits flu-like symptoms similar to IFN^, i.e., fever, general malaise, and fatigue. TNF^ further has been linked to watery diarrhea, vascular leakage, cardiomyopathy, lung injury, and the synthesis of acute phase proteins. However, the mechanism of action and the degree to which TNF^ overproduction contributes to the development and / or the severity of CRS remains elusive.

[0349] IL-6 in particular is believed to play an integral role in CRS pathophysiology and patient symptoms. The IL-6R targeting antibody, tocilizumab, has become standard care for the initial treatment of severe CRS in patients receiving CAR T cells, and additional therapies include corticosteroids. In cases where IL-6 blockage has been ineffective, some patients have responded to TNF^ blockade in conjunction with IL-6 blockade and corticosteroids. See, e.g., Shimabukuro-Vornhagen, A. et al., J Immunother Cancer.2018 Jun 15;6(1):56. Anti-TNF^ antagonist

[0350] TNF^, a major pro-inflammatory cytokine, is secreted by activated macrophages, monocytes and lymphocytes. Inventors surprisingly found that the administration of an anti- ny-2916766Attorney Docket No.24516-20012.40 TNF^ antibody to an individual who has been administered with an agent that inhibits SHP-1 signaling and a pro-inflammatory agent alleviates toxicity caused by systemic inflammation without compromising the efficacy of the therapeutic agents.

[0351] The methods of the present application therefore in some embodiments comprises administration of TNF^ inhibitor, e.g., an anti-TNF^ antagonist (e.g., in the context where the proinflammatory agent is not TNF^). In some embodiments, the TNF^ inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNF^ receptor blockade antibody, a soluble TNF^ receptor, a TNF-like ligand 1a (TL1a), a TNF^- targeting short interfering RNA (siRNA), a chemical inhibitor of TNF^ mRNA stability, an inhibitor of TNF^ converting enzyme (TACE), and derivatives thereof. In some embodiments, the TNF^ inhibitor is an anti-TNF^ neutralizing antibody. In some embodiments, the TNF^ inhibitor is an anti-TNF^ receptor blockade antibody. In some embodiments, the anti-TNF^ antibody is a monoclonal antibody. In some embodiments, anti- TNF^ antibody is a chimeric, humanized, and / or fully human antibody. In some embodiments, the TNF^ inhibitor is a TNF-like ligand 1a (TL1a).

[0352] Suitable antibodies for use in the methods provided herein include, but are not limited to, Remicade® (Infliximab (Centocor)), and those antibodies described, for example, in U.S. Patent No.6,835,823; 6,790,444; 6,284,471; 6,277,969; 5,919,452; 5,698,195; 5,656,272; and 5,223,395 and in EP Patent No.0610201, the contents of each of which are hereby incorporated by reference in their entirety, or antibodies that bind to the same epitope as Remicade®. Others suitable anti-TNF^ antibodies for use in the methods provided herein are, by way of non- limiting example, Humira (Adalimumab (Abbott Laboratories, Esai)) as described in U.S. Patent No.6,090,382; 6,258,562; or 6,509,015 and related patents and applications, the contents of which are hereby incorporated by reference in their entirety; Simponi™ (Golimimab, CNTO 148 (Centocor)) as described in PCT Publication No. WO 02 / 12502 and related patents and applications, the contents of which are hereby incorporated by reference in their entirety; ART621 (Arana Therapeutics), SSS 07 (Epitopmics and 3SBio) or antibodies that bind to the same epitope as Humira, Simponi, ART621, or SSS07.

[0353] In some embodiments, the TNF^ inhibitor, e.g., anti-TNF^ antagonist, is a fusion protein. Suitable fusion proteins for use in the methods provided herein include, but are not limited to, Enbrel (Etanercept (Amgen)) and other fusion proteins or fragments thereof described in U.S. Patent No.5,712,155, PCT Publication No. WO 1991 / 03553, and related 111 ny-2916766Attorney Docket No.24516-20012.40 patents and applications, the contents of which are hereby incorporated by reference in their entirety.

[0354] In some embodiments, the TNF^ inhibitor, e.g., anti-TNF^ antagonist, is a modified antibody antagonist or a non-antibody-based antagonist. Such antagonists include advanced antibody therapeutics, such as antibody fragments including, but not limited to, Cimzia™ (Certolizumab pegol, CDP870 (Enzon)), bispecific antibodies, Nanobodies® such as ABX 0402 (Ablynx), immunotoxins, and radiolabeled therapeutics; peptide therapeutics; gene therapies, particularly intrabodies; oligonucleotide therapeutics such as aptamer therapeutics, antisense therapeutics, interfering RNA therapeutics; and small molecules such as LMP-420 (LeukoMed) as described in EP Patent No.0767793, and related patents and applications, the contents of which are hereby incorporated by reference in their entirety.

[0355] In some embodiments, the TNF^ inhibitor (e.g., an anti-TNF^ antibody) is administered within two weeks, 10 days, or one week prior to the administration of the SHP- 1 inhibitor and / or pro-inflammatory agent described herein. Exemplary TNF^ inhibitors such an anti-TNF^ antibody is usually stable for at least one or two weeks. In some embodiments, the TNF^ inhibitor (e.g., an anti-TNF^ antibody) is administered concurrently or simultaneously with the SHP-1 inhibitor and / or proinflammatory agent. In some embodiments, the TNF^ inhibitor (e.g., an anti-TNF^ antibody) is administered immediately after (e.g., within 1 hour or 30 minutes) the administration of the SHP-1I (e.g., SHP-1 inhibitor) and / or pro-inflammatory agent.

[0356] In some embodiments, the TNF^ inhibitor is administered systemically. In some embodiments, the TNF^ inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNF^ inhibitor is administered intermittently. In some embodiments, the TNF^ inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days. In some embodiments, the individual does not develop cytokine release syndrome or pro- inflammatory organ damage. In some embodiments, administration of the TNF^ inhibitor does not compromise or weakly compromises tumor clearance. Anti-IL6 antagonist

[0357] An “anti-IL-6 antagonist” or “IL-6 inhibitor” refers to an agent that inhibits or blocks IL-6 biological activity via binding to IL-6 or IL-6 receptor. In some embodiments, the anti- IL-6 antagonist is an antibody. In one embodiment, the anti-IL-6 antagonist is an antibody ny-2916766Attorney Docket No.24516-20012.40 that binds IL-6 receptor. Antibodies that bind IL-6 receptor include tocilizumab (including intravenous, i.v., and subcutaneous, s.c., formulations thereof) (Chugai, Roche, Genentech), satralizumab (Chugai, Roche, Genentech), sarilumab (Sanofi, Regeneron), NI-1201 (Novimmune and Tiziana), and vobarilizumab (Ablynx). In one embodiment, the anti-IL-6 antagonist is a monoclonal antibody that binds IL-6. Antibodies that bind IL-6 include sirukumab (Centecor, Janssen), olokizumab (UCB), clazakizumab (BMS and Alder), siltuximab (Janssen), and EBI-031 (Eleven Biotherapeutics and Roche). In one embodiment, the IL-6 antagonist is olamkicept.

[0358] In some embodiments, the IL-6 inhibitor is administered systemically. In some embodiments, the IL-6 inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the IL-6 inhibitor is administered intermittently. In some embodiments, the IL-6 inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days. Immunogenic cell death

[0359] In some embodiments, the individual has immunogenic cell death when being treated with the methods described herein.

[0360] Immunogenic cell death (ICD) is a type of cancer cell death that can be induced by different stressors, including but not limited to (1) intracellular pathogens; (2) conventional chemotherapeutics such as anthracyclines, DNA-damaging agents, and proteasomal inhibitors; (3) targeted anti-cancer agents such as the tyrosine kinase inhibitor crizotinib, the epidermal growth factor receptor-specific monoclonal antibody cetuximab and poly-ADP- ribose polymerase (PARP) inhibitors; and (4) numerous physical modalities, encompassing hypericin- and redaporfin-based photodynamic therapy, extracorporeal photochemotherapy, various forms of ionizing radiation, high hydrostatic pressure, and severe heat shock. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor-specific immune responses, thus eliciting long-term efficacy of anti-cancer drugs by combining direct cancer cell killing and antitumor immunity. DAMPs include the cell surface exposure of calreticulin (CRT) and heat-shock proteins (HSP70 and HSP90), extracellular release of adenosine triphosphate (ATP), high-mobility group box-1 (HMGB1), type I IFNs and members of the IL-1 cytokine family. See e.g., ny-2916766Attorney Docket No.24516-20012.40 Ahmed et al., Mol Oncol.2020 Dec;14(12):2994-3006 and Fucikova et al., Cell Death Dis. 2020 Nov 26;11(11):1013.

[0361] Key DAMPs for cell death to be perceived as immunogenic include calreticulin, high- mobility group box 1 (HMGB1), ATP, annexin A1 (ANXA1), and type I IFN. The main hallmarks of immunogenic cell death (ICD) can be assessed by flow cytometry, (immuno)fluorescence microscopy, immunoblotting, or luminometry, based on a variety of different approaches. See e.g., Cell Death Dis.2020 Nov 26;11(11):1013.

[0362] In some embodiments, the individual has ICD (e.g., in the tumor, e.g., in a site distinct from the tumor) within about one week, 6 days, 5 days, 4 days, 3 days, 2 days, or one day prior to and / or after the administration of the SHP-1 inhibitor and / or the tyrosine kinase inhibitor.

[0363] In some embodiments, the individual has ongoing ICD (e.g., in the tumor, e.g., in a site distinct from the tumor) when the SHP-1 inhibitor and / or the tyrosine kinase inhibitor are administered.

[0364] In some embodiments, the individual has ICD when a sample from the cancer has a higher level of one or more (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% more) DAMPs than a reference sample (e.g., a corresponding sample in a healthy control, e.g., a sample from the cancer prior to the administration of a therapy that induces ICD. In some embodiments, the DAMPs are selected from the group consisting of endoplasmic reticulum (ER) chaperones (e.g., calreticulin (CALR), e.g., heat-shock proteins (HSPs)), the non-histone chromatin-binding protein high-mobility group box 1 (HMGB1), the cytoplasmic protein annexin A1 (ANXA1), and the small metabolite ATP, and type I interferons (IFNs). Individuals

[0365] In some embodiments, the individual has a solid tumor. In some embodiments, the individual has a hematologic cancer.

[0366] In some embodiments, the individual has an advanced cancer. In some embodiments, the individual has a late-stage cancer. In some embodiments, the individual has a malignant cancer. In some embodiments, the individual has a cancer that is in stage II, III or IV. In some embodiments, the individual has an inoperable tumor and / or metastases. In some embodiments, the individual is a terminally ill individual. ny-2916766Attorney Docket No.24516-20012.40

[0367] In some embodiments, the individual has been subjected (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days before the administration of the agent that inhibits SHP-1 signaling) to a therapy that induces an inflammation reaction or an immunogenic cell death (e.g., radiotherapy). In some embodiments, the individual is to be subjected to (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days after the administration of the agent that inhibits SHP-1 signaling) a therapy that induces an inflammation reaction or an immunogenic cell death (e.g., radiotherapy).

[0368] In some embodiments, the individual has been subjected (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days before the administration of the agent that inhibits SHP-1 signaling) to a pro-inflammatory agent (such as any of the pro- inflammatory agents described herein). In some embodiments, the individual is to be subjected to (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days after the administration of agent that inhibits SHP-1 signaling) a pro-inflammatory agent (such as any of the pro-inflammatory agents described herein).

[0369] In some embodiments, the individual has been subjected (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days before the administration of the agent that inhibits SHP-1 signaling) to a lymphocyte activating agent (such as any of the lymphocyte activating agents described herein). In some embodiments, the individual is to be subjected to (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days after the administration of the agent that inhibits SHP-1 signaling) a lymphocyte activating agent (such as any of the lymphocyte activating agents described herein).

[0370] In some embodiments, the individual does not have an autoimmune disease.

[0371] In some embodiments, the individual is a female. In some embodiments, the individual is a male.

[0372] In some embodiments, the individual is a human. In some embodiments, the individual is at least about 50, 55, 60, 65, 70 or 75 years old.

[0373] In some embodiments, the individual is selected for treatment based upon a high expression level and / or a high activity level of SHP-1 in the tumor tissue. In some embodiments, the individual has a high expression level and / or a high activity level of SHP-1 when the expression level and / or the activity level is at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or 200% more than a reference expression level and / or a reference activity level of SHP-1. In some embodiments, the individual has a ny-2916766Attorney Docket No.24516-20012.40 high expression level and / or a high activity level of SHP-1 when the expression level and / or the activity level is at least about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 500-fold, or 1000-fold more than a reference expression level and / or a reference activity level of SHP-1. In some embodiments, the reference expression level or the reference activity level of SHP-1 is the corresponding expression or activity level of SHP-1 in a reference state, wherein the individual is not treated with a pro-inflammatory agent (or any immune therapy).

[0374] In some embodiments, the individual is at risk of developing systemic inflammation and / or CRS. In some embodiments, the individual develops systemic inflammation and / or CRS prior to the administration of an agent that reduces systemic inflammation. Cytokine release syndrome can damage or cause organ failure in most organ systems. For example, organs that can become damaged due to CRS may include, but are not limited to, the lungs, the kidneys, the liver, the brain, the heart, the spleen, or any combination thereof, for example multi-organ failure.

[0375] In some embodiments, the individual is administered an agent that reduces systemic inflammation. In some embodiments, the administration occurs prior to the development of systemic inflammation in the individual. In some embodiments, the individual develops mild cytokine release syndrome. In some embodiments, the individual develops CRS of grade 1. Mild symptoms of CRS can include fever, fatigue, headache, rash, arthralgia, and myalgia. Mild CRS can be treated by treating the symptoms or by administration of anti-inflammatory drugs such as corticosteroids. Mild CRS can often be resolved within one to two weeks and does not require or necessitate hospitalization.

[0376] In some embodiments, the individual does not develop severe cytokine release syndrome. In some embodiments, the individual does not develop CRS of grade 2. In some embodiments, the individual does not develop CRS of grade 3. In some embodiments, the individual does not develop CRS of grade 4. More severe cases are characterized by hypotension and high fever, and severe CRS can progress to an uncontrolled systemic inflammatory response with vasopressor-requiring circulatory shock, vascular leakage, disseminated intravascular coagulation, and multi-organ system failure. More severe cases of CRS often require hospitalization of symptoms. Laboratory abnormalities that are common in patients with CRS include cytopenias, elevated creatinine and liver enzymes, deranged coagulation parameters, and a high CRP. There are four grading systems currently used for cytokine release syndrome, as shown in Table 1 below. See, e.g., Liu, D. and Zhao, J., J ny-2916766Attorney Docket No.24516-20012.40 Hematol Oncol.2018 Sep 24;11(1):121; and Shimabukuro-Vornhagen, A. et al., J Immunother Cancer.2018 Jun 15;6(1):56, hereby incorporated by reference in their entirety.

[0377] In some embodiments, the individual has developed CRS prior to administration of an agent that reduces systemic inflammation. In some embodiments, the individual has developed CRS of grade 1. In some embodiments, the individual has developed CRS of grade 2. In some embodiments, the individual has developed CRS of grade 3. In some embodiments, the individual has developed CRS of grade 4. In some embodiments, the individual who has developed CRS is administered an agent that reduces systemic inflammation. In some embodiments, the agent that reduces systemic inflammation ameliorates, eliminates, or reverses the CRS, including organ damage, for example pro- inflammatory organ damage (e.g., nephritis, hepatitis, pneumonitis, myocarditis, appendicitis). Table 1. Cytokine release syndrome medical grading systems.ny-2916766Attorney Docket No.24516-20012.40

[0378] In some embodiments, the individual does not develop cytokine storm. In some embodiments, the individual develops mild cytokine storm. In some embodiments, the individual does not develop severe or life-threatening cytokine storm. Cytokine storm appears to be mainly a result of non-specific T cell activation, whereas CRS is more often a direct consequence of antigen-specific T cell activation. The clinical manifestations of cytokine storm and CRS can be similar (Liu, D. and Zhao, J., J Hematol Oncol.2018 Sep 24;11(1):121).

[0379] In some embodiments, the individual is an animal, for example a reptile, a bird, a fish, or a mammal. In some embodiments, the individual is a mammal. In some embodiments, the ny-2916766Attorney Docket No.24516-20012.40 individual includes human and veterinary subjects. In some embodiments, the individual is a mammal, including, but not limited to, humans, rodents, simians, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets. In some embodiments, the individual is a human. Cancer

[0380] Cancer described here can be any type or kind. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic cancer.

[0381] In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a late-stage cancer. In some embodiments, the cancer is a terminal cancer. In some embodiments, the cancer is in stage II, III or IV. In some embodiments, the cancer is an inoperable tumor and / or is malignant.

[0382] In some embodiments, the tumor is at least 0.2cm, 0.4cm, 0.6cm, 0.8cm, 1cm, 2 cm, 3cm, 4cm or 5cm in length.

[0383] Examples of cancers described herein include, but are not limited to, adrenocortical carcinoma, agnogenic myeloid metaplasia, AIDS-related cancers (e.g., AIDS-related lymphoma), anal cancer, appendix cancer, astrocytoma (e.g., cerebellar and cerebral), basal cell carcinoma, bile duct cancer (e.g., extrahepatic), bladder cancer, bone cancer, (osteosarcoma and malignant fibrous histiocytoma), brain tumor (e.g., glioma, brain stem glioma, cerebellar or cerebral astrocytoma (e.g., pilocytic astrocytoma, diffuse astrocytoma, anaplastic (malignant) astrocytoma), malignant glioma, ependymoma, oligodenglioma, meningioma, craniopharyngioma, haemangioblastomas, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, and glioblastoma), breast cancer, bronchial adenomas / carcinoids, carcinoid tumor (e.g., gastrointestinal carcinoid tumor), carcinoma of unknown primary, central nervous system lymphoma, cervical cancer, colon cancer, colorectal cancer, chronic myeloproliferative disorders, endometrial cancer (e.g., uterine cancer), ependymoma, esophageal cancer, Ewing’s family of tumors, eye cancer (e.g., intraocular melanoma and retinoblastoma), gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, (e.g., extracranial, extragonadal, ovarian), gestational trophoblastic tumor, head and neck cancer, hepatocellular (liver) cancer (e.g., hepatic carcinoma and heptoma), hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), ny-2916766Attorney Docket No.24516-20012.40 laryngeal cancer, laryngeal cancer, leukemia, lip and oral cavity cancer, oral cancer, liver cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), lymphoid neoplasm (e.g., lymphoma), medulloblastoma, melanoma, mesothelioma, metastatic squamous neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, oropharyngeal cancer, ovarian cancer (e.g., ovarian epithelial canc...

Claims

Attorney Docket No.24516-20012.40 CLAIMS What is claimed is:

1. A method of treating a cancer in an individual in need thereof, comprising administering to the individual a) an agent that inhibits SHP-1 signaling, and b) a lymphocyte activating agent.

2. The method of claim 1, wherein the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or an inhibitor of a tyrosine kinase involved in the SHP-1 signaling pathway, optionally wherein: a. the SHP-1 inhibitor targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site; or b. the SHP-1 inhibitor is an allosteric inhibitor; further optionally wherein the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less.

3. The method of claim 1 or claim 2, wherein the SHP-1 inhibitor is: a. a TPI-1 or a derivative or analog thereof, optionally wherein the SHP-1 inhibitor comprises a deuterated TPI-1; or b. PTP-1 or a derivative or analog thereof.

4. The method of claim 2 or claim 3, wherein the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50.

5. The method of claim 1-4, wherein the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism-modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, a lymphocyte-activating antibody, a small molecule, a calcium ionophore, and any combination thereof, optionally wherein the lymphocyte activating agent is a T cell activating agent, further optionally wherein: a. the T cell activating agent comprises a cytokine, further optionally wherein the cytokine is IL-2, IL-4, IL-7, IL-15, or IL-21; and / or b. the T cell activating agent comprises a binding moiety that binds to a T cell antigen, further optionally wherein the binding moiety comprises an antibody, further ny-2916766Attorney Docket No.24516-20012.40 optionally wherein the T cell antigen is a CD3 or CD28, further optionally wherein the T cell activating agent comprises an anti-CD3 antibody and / or an anti-CD28 antibody.

6. The method of any one of claims 1-5, wherein the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are administered within 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other; or the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are administered concurrently or simultaneously.

7. The method of any one of claims 1-6, wherein the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are associated, optionally wherein: a. the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are fused via a linker, optionally wherein the linker is a cleavable linker, further optionally wherein the linker is a pH sensitive linker; or b. the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are covalently conjugated; optionally wherein the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are conjugated via an ester bond or via an amide bond or the agent that inhibits SHP-1 signaling and the lymphocyte activating agent are conjugated via a PEG moiety.

8. The method of any one of claims 1-7, wherein the method further comprises administering a pro-inflammatory agent or therapy, optionally wherein the pro-inflammatory agent or therapy comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment.

9. The method of claim 8, wherein the agent that inhibits SHP-1 signaling and the pro- inflammatory agent are administered within 7 days, 5 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of each other; or wherein the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are administered concurrently or simultaneously.

10. The method of claim 8 or claim 9, wherein the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are associated; optionally wherein: ny-2916766Attorney Docket No.24516-20012.40 a. the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are fused via a linker, optionally wherein the linker is a cleavable linker, further optionally wherein the linker is a pH sensitive linker; or b. the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are covalently conjugated, optionally wherein the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are conjugated via an ester bond or via an amide bond or the agent that inhibits SHP-1 signaling and the pro-inflammatory agent are conjugated via a PEG moiety.

11. The method of any one of claims 1-10, wherein the method further comprises administering a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor, optionally wherein the method comprises administering a TNF^ inhibitor, further optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, further optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept.

12. The method of claim 11, wherein the TNF^ inhibitor is administered to the individual prior to the administration of the agent that inhibits SHP-1 signaling or within about 3 hours post the administration of the agent that inhibits SHP-1 signaling, wherein the individual has been subject to the lymphocyte activating agent, optionally wherein the TNF^ inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the agent that inhibits SHP-1 signaling.

13. A method of treating a cancer in an individual in need thereof, comprising administering to the individual a population of immune cells deficient in SHP-1 expression or activity.

14. The method of claim 13, wherein the population of immune cells are obtained from the same individual or obtained from a different individual than the individual to be treated, optionally wherein the population of immune cells comprises: a. T cells, optionally wherein the T cells comprise CD8+ T cells and / or CD4+ T cells; b. NK cells; and / or ny-2916766Attorney Docket No.24516-20012.40 c. tumor infiltrating lymphocytes (TILs).

15. The method of claim 13 or claim 14, wherein the population of immune cells comprises: a. a chimeric antigen receptor (CAR), wherein the CAR specifically bind to a tumor-associated antigen; and / or b. TCR that target one or more tumor-associated antigens.

16. The method of any one of claims 13-15 wherein the population of immune cells deficient in SHP-1 expression or activity comprises: a. a reduced level of SHP-1 protein, optionally wherein the level of the SHP-1 protein is no more than 50%, 40%, 30%, 20%, 10% or 5% as compared to that in reference immune cells. b. a mutant SHP-1 gene or SHP-1 protein, optionally wherein the mutant SHP-1 gene or SHP-1 protein comprises a mutation in a catalytic site or a nucleotide within a nucleic acid sequence encoding the catalytic site, further optionally wherein the mutant SHP-1 gene or SHP-1 protein comprises a mutation in Tyr 536, Tyr 564, or Ser591 or a nucleotide within a nucleic acid sequence encoding Tyr536, Tyr564 or Ser591; or c. an inhibitory nucleic acid that specifically targets SHP-1, optionally the inhibitory nucleic acid comprises a siRNA or shRNA.

17. The method of any one of claims 13-16, wherein the method further comprises administering a lymphocyte activating agent, optionally wherein wherein the lymphocyte activating agent is selected from the group consisting of a cytokine, a chemokine, a metabolism-modulating drug, a metabolite antagonist, an immune checkpoint inhibitor, an immune cell, a cancer vaccine, a bacteria or component thereof, a virus or component thereof, a fungus or component thereof, a bispecific T cell engager (BiTE), an antibody drug conjugate, a lymphocyte-activating antibody, a small molecule, a calcium ionophore, and any combination thereof, optionally wherein the lymphocyte activating agent is a T cell activating agent, further optionally wherein: a) the T cell activating agent comprises a cytokine, further optionally wherein the cytokine is IL-2, IL-4, IL-7, IL-15, or IL-21; and / or b) the T cell activating agent comprises a binding moiety that binds to a T cell antigen, further optionally wherein the binding moiety comprises an antibody, further ny-2916766Attorney Docket No.24516-20012.40 optionally wherein the T cell antigen is a CD3 or CD28, further optionally wherein the T cell activating agent comprises an anti-CD3 antibody and / or an anti-CD28 antibody.

18. The method of claim 17, wherein the method further comprises administering a pro- inflammatory agent or therapy, optionally wherein the pro-inflammatory agent or therapy comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a radiation therapy, a PAMP / DAMP activator, a chemotherapeutic agent, a pro-inflammatory cytokine, a cancer vaccine, a cryotherapy, a surgery, a thermotherapy, a bacteria component, a virus, a viral component, a sound treatment, a magnetic therapy, an electrical treatment, and an electrostatic treatment.

19. The method of claim 17 or claim 18, wherein the method further comprises administering a TNF^ inhibitor, a TNF-like ligand 1a (TL1a), a JAK inhibitor, a steroid, or an IL-6 inhibitor, optionally wherein the method comprises administering a TNF^ inhibitor, further optionally wherein the TNF^ inhibitor comprises an anti-TNF^ antibody, further optionally wherein the anti-TNF^ antibody is selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and etanercept.

20. The method of any one of claims 11-12 and 19, wherein the TNF^ inhibitor is administered to the individual prior to the administration of the lymphocyte activating agent or within about 3 hours post the administration of the lymphocyte activating agent, wherein the individual has been subject to the agent that inhibits SHP-1 signaling, optionally wherein the TNF^ inhibitor is administered to the individual at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or 3 hours prior to the administration of the lymphocyte activating agent.

21. The method of any one of claims 1-20, wherein the cancer is a solid tumor or a hematological cancer, optionally wherein the cancer is a late-stage cancer.

22. The method of any one of claims 1-21, wherein the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

23. The method of any one of claims 1-22, wherein the individual is a human.

24. A method of producing a population of activated T cells in a plurality of cells, comprising treating the T cells with an agent that inhibits SHP-1 signaling, wherein the ny-2916766Attorney Docket No.24516-20012.40 plurality of cells comprises tumor cells, myeloid-derived suppressor cells (MDSCs) or tumor- associated macrophages (TAMs).

25. The method of claim 24, wherein the agent that inhibits SHP-1 signaling is a SHP-1 inhibitor or an inhibitor of a tyrosine kinase involved in the SHP-1 signaling pathway, optionally wherein the SHP-1 inhibitor: a. targets a catalytic site, optionally wherein the SHP-1 inhibitor binds to the catalytic site; or b. is an allosteric inhibitor; further optionally wherein the SHP-1 inhibitor inhibits SHP-1 with an IC50 of about 30, 25, 20, 15, 10, 5µm or less.

26. The method of claim 25, wherein the SHP-1 inhibitor is: a. a TPI-1 or a derivative or analog thereof, optionally wherein the SHP-1 inhibitor comprises a deuterated TPI-1; or b. PTP-1 or a derivative or analog thereof; optionally wherein the concentration of the SHP-1 inhibitor in cancer tissue is at least 2-fold, 5-fold, or 10-fold of its EC50.

27. The method of claim 25 or claim 26, wherein the SHP-1 inhibitor comprises a genome editing agent comprising a genome editing enzyme and a guide RNA or a guide DNA that specifically targets SHP1, optionally wherein the guide RNA or guide DNA targets a nucleotide within a nucleic acid sequence encoding a catalytic site, further optionally wherein the guide RNA or guide DNA targets a nucleic acid sequence encoding Tyr536, Tyr564 or Ser591.

28. The method of any one of claims 25-27, wherein the SHP-1 inhibitor comprises an inhibitory nucleic acid that specifically targets SHP-1, optionally the inhibitory nucleic acid comprises an siRNA or shRNA.

29. The method of any one of claims 24-28, wherein the method further comprises treating the T cells with a lymphocyte activating agent or a pro-inflammatory agent. ny-2916766

Images