SHP-1 inhibitors for cancer treatment

Abstract

The present application provides methods of treating cancer in an individual, the method comprising administering to the individual an SHP-1 inhibitor (such as TPI-1 or an analog or derivative thereof) and an inflammatory agent (such as a TLR agonist, radiation therapy, or an immune checkpoint inhibitor). In some cases, the method involves administering the SHP-1 inhibitor when the individual is under inflammatory control. In one aspect, the present application provides methods of treating cancer in an individual, the method comprising administering an SHP-1 inhibitor to the individual, where the individual a) has previously been administered, is currently being administered, or will be administered an inflammatory agent, or b) is experiencing an inflammatory response or persistent infection.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 404,392, filed September 7, 2022, and U.S. Provisional Application No. 63 / 491,008, filed March 17, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to compositions and methods for treating cancer comprising administering an SHP-1 inhibitor and, optionally, an inflammation-inducing agent. [Background technology]

[0003] In cancers, including solid tumors, intratumoral myeloid leukocytes (IL-1), including macrophages (i.e., tumor-associated macrophages or TAMs) and myeloid-derived suppressor cells (MDSCs), play a crucial role in regulating the immunosuppressive tumor microenvironment (TME) that supports tumor growth and contributes to tumor resistance to immunotherapy. One of the key mechanisms by which IL-1 acquires an immunosuppressive phenotype and enhances its immunosuppressive capacity after tumor treatment is the multiple pathways of negative regulation mediated by inhibitory receptors (iRs) on the cell surface. Under tumor treatment, phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) present in the cytoplasmic domain of iRs activates the central signal regulator SHP-1, which then mediates the dephosphorylation and subsequent inactivation of numerous signaling molecules, thereby attenuating the proinflammatory response induced by the treatment (Figure 1). In solid tumors, key cell surface iRs (1, 2), including SIRPα, Siglecs, LilRBs, PirB, LAIR1, lectin receptors, and SLAM family receptors, are upregulated in the TME as tumor progression progresses, and these receptors regulate SHP-1 activation, suppressing downstream signaling.

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

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

[0006] In one aspect, the present application provides a method of treating cancer in an individual, comprising administering to the individual: a) an SHP-1 inhibitor; and b) an inducing agent, wherein the method comprises intermittently administering the SHP-1 inhibitor to the individual. In some embodiments, the method comprises administering the SHP-1 inhibitor systemically or locally (e.g., intratumorally). In some embodiments, the inducing agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP molecule, a checkpoint inhibitor, a proinflammatory cytokine, a proinflammatory cell, a cell, a cancer vaccine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

[0007] In another aspect, the application provides methods of treating cancer in an individual, comprising administering to the individual: a) an SHP-1 inhibitor; and b) an inducing agent, wherein the method comprises systemically administering the SHP-1 inhibitor. In some embodiments, the method comprises intermittently administering the SHP-1 inhibitor to the individual. In some embodiments, the inducing agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a proinflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

[0008] In another aspect, the application provides methods of treating cancer in an individual, comprising administering to the individual: a) an SHP-1 inhibitor; and b) an inducing agent, wherein the inducing agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP / DAMP activator, chemotherapy, a proinflammatory cytokine, a cancer vaccine, a bacterial component, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy. In some embodiments, the method comprises intermittently administering the SHP-1 inhibitor to the individual. In some embodiments, the method comprises systemically administering the SHP-1 inhibitor.

[0009] In another aspect, the application provides methods of treating cancer in an individual, comprising administering to the individual an SHP-1 inhibitor, wherein the individual is exhibiting an inflammatory response or has a persistent infection. In some embodiments, the method comprises intermittently administering the SHP-1 inhibitor to the individual. In some embodiments, the method comprises systemically administering the SHP-1 inhibitor. In some embodiments, the method further comprises immune cells.

[0010] In some embodiments of any one of the aforementioned methods, the method comprises administering to the individual the SHP-1 inhibitor at least twice, not more than once every three days.

[0011] In some embodiments of any one of the aforementioned methods, the method comprises administering to the individual the SHP-1 inhibitor in at least two cycles, each cycle lasting from about 3 days to about 20 days.

[0012] In some embodiments of any of the aforementioned methods, the SHP-1 inhibitor has a half-life of about 5 days or less, and optionally, the SHP-1 inhibitor has a half-life of about 3 days or less.

[0013] In some embodiments of any of the above methods, the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation within about 5 days, and optionally, the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation within about 3 days.

[0014] In some embodiments of any of the above-described methods, the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR), and protein agents (e.g., antibody agents targeting SHP-1 or activated SHP-1) or SH2 domain-containing protein agents (which compete for binding to ITIM motifs and inhibit SHP-1 activation), and tyrosine kinase inhibitors that inhibit SHP-1 activation by inhibiting ITIM phosphorylation. In some embodiments, the SHP-1 inhibitor is selected from the group consisting of TPI-1 or an analog or derivative thereof, vitamin E derivatives, homoxanthone A (PXA), and PKC theta activators. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0015] In some embodiments of any of the aforementioned methods, the SHP-1 inhibitor is administered at least three times. In some embodiments of any one of the aforementioned methods, the method comprises systemic and local administration of the SHP-1 inhibitor, and optionally, the method comprises intratumoral administration of the SHP-1 inhibitor.

[0016] In some embodiments of any of the methods described above, systemic administration of SHP-1 comprises oral administration, intravenous administration, subcutaneous administration, and / or intraperitoneal administration.

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

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

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

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

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

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

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

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

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

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

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

[0028] In some embodiments of any of the above methods, the pro-inflammatory agent and the SHP-1 inhibitor are administered simultaneously or concurrently.

[0029] In some embodiments of any of the above methods, the pro-inflammatory agent comprises immune cells. In some embodiments, the immune cells are derived from the same individual. In some embodiments, the immune cells comprise or are macrophages, optionally, the macrophages have a pro-inflammatory (M1) phenotype. In some embodiments, the immune cells are derived from monocytes. In some embodiments, the immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86. In some embodiments, the immune cells express one or more pro-inflammatory cytokines, optionally, the one or more pro-inflammatory cytokines include TNFα and / or IL-12. In some embodiments, the immune cells do not express significant levels of TGFβ and / or IL-10. In some embodiments, the immune cells comprise T cells. In some embodiments, the immune cells are engineered to express a chimeric antigen receptor, optionally, the chimeric antigen receptor specifically binds to a tumor antigen. In some embodiments, the macrophages are engineered to be deficient in expression and / or activation of SHP-1. In some embodiments, the SHP-1 inhibitor and the immune cells are administered within about 24 hours of each other, and optionally, the SHP-1 inhibitor and the immune cells are administered within about 4 hours of each other, in some embodiments, the immune cells are administered simultaneously or concurrently with the SHP-1 inhibitor.

[0030] In some embodiments of any of the above-described methods, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm, including, but not limited to, an anti-TNFα antibody and an anti-IL6 antibody. In some embodiments, the agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm is administered simultaneously with the tyrosine kinase inhibitor. In some embodiments, the agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm is administered sequentially with the tyrosine kinase inhibitor (e.g., before or after administration of the tyrosine kinase inhibitor). In some embodiments, administration of the agent that reduces systemic inflammation and / or suppresses inflammatory cytokine cascades or cytokine storm follows the same administration schedule as the tyrosine kinase inhibitor.

[0031] In some embodiments of any of the aforementioned methods, the cancer is a solid tumor.

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

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

[0034] In some embodiments of any of the aforementioned methods, the cancer is resistant or refractory to radiation therapy, chemotherapy, and / or checkpoint inhibitors.

[0035] In some embodiments of any of the above methods, the individual is a human.

[0036] In another aspect, the application provides a composition comprising an SHP-1 inhibitor and an inducing agent, optionally wherein the inducing agent comprises an agent selected from the group consisting of an immune cell, a TLR agonist, a STING activator, an agent used in radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a proinflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, and an agent used in acoustic therapy, magnetic therapy, electrical therapy, or electrostatic therapy. [Brief explanation of the drawings]

[0037] [Figure 1] We demonstrate that SHP-1 functions as a "master" signaling mediator downstream of multiple inhibitory receptors on myeloid leukocytes in the tumor microenvironment (TME). Activation of SHP-1 attenuates proinflammatory pathways and the anticancer effects of RT and immunotherapy, maintaining the immunosuppressive phenotype of myeloid leukocytes. Our approach of SHP-1 inhibition as an anticancer strategy (shown in red) is illustrated. Examples include immunotherapy using SIRPα (SIRPα antagonists, anti-CD47 Gilead) and anti-SIRPα (Biosion) approaches, as well as companies and approaches aimed at depleting or blocking individual cell surface inhibitory receptors, such as Siglec (NextCure), LilRB (Next-IO), and SLAMF (BMS).

[0038] [Figure 2-1]Figure 2A shows that SHP-1 inhibition enhances proinflammatory responses, antigen presentation, and phagocytosis in macrophages in the tumor environment. Figure 2A shows that SHP-1 activation in macrophages is triggered by proinflammatory stimuli and extracellular ligand binding ("contact") of cancer cells (green bars). Figure 2B shows that SHP-1 activation is dose-dependently inhibited by the catalytic domain covalent inhibitor TPI-1 (1 μg / ml, A). The SHP-2 inhibitor SHP099 (1 μg / ml) was used in the assay. Figure 2C shows that TPI-1 inhibition of SHP-1 dose-dependently restores IFNγ / LPS-induced activation of STAT1 (p-STAT1) and Erk1 / 2 (p-Erk1 / 2) inactivated by SHP-1 (red lines). Figure 2D shows that inhibition of SHP-1 in macrophages by TPI-1 enhances IFNγ / LPS-induced proinflammatory cytokine production in the tumor environment. Figure 2E shows that inhibition of SHP-1 in macrophages by TPI-1 enhances the expression of immunogenic antigen-presenting machinery. Figure 2F shows that inhibition of SHP-1 promotes proinflammatory activated macrophages for phagocytosis of cancer cells. Human monocyte-derived macrophages phagocytose THP-1 leukemia cells and HT29 colon cancer cells. Figure 2G shows that inhibition of SHP-1 promotes proinflammatory activated macrophages for phagocytosis of cancer cells. Mouse bone marrow-derived macrophages phagocytose EL4 (T lymphoma), B16 (melanoma), MC38 (colorectal cancer), Pan01 and KPC (both pancreatic adenocarcinomas), and LLC (lung cancer). The SHP-1 and SHP-2 inhibitors, TPI-1 and SHP099, were each used at 1 μg / ml in the assay. [Figure 2-2] Same as above. [Figure 2-3] Same as above.

[0039] [Figure 3-1]We demonstrate the regulation of SHP-1 activation in proinflammatory macrophages in cancer. Macrophages cocultured with cancer cells were stimulated with IFNγ / LPS or TLR agonists (αTLR) including CpG, polycytidylic acid (i.e., PolyI:C), and R848 (each at 0.4 μg / ml) in the presence or absence of different SHP-1 and SHP-2 inhibitors or activators for 30 minutes at 37°C. Cell lysis was then performed and PTP activation assays were performed. (A) The mechanism of regulation of SHP-1 activation is shown. (B) Under cancer cell ligand binding, IFNγ / LPS-induced PTP activation in macrophages was significantly reduced (>70%) by inhibition of SHP-1 (TPI-1 and PTP-I) or the pan-PTP inhibitors PTP-III and pervanadate, but only slightly reduced (<10%) by inhibition of SHP-2 (SHP099 and PHPS1). (C) PTP activation in macrophages induced by TLR agonists under cancer cell ligand binding was significantly reduced (>70%) by inhibition of SHP-1 (TPI-1 and PTP-I) or the pan-PTP inhibitors PTP-III and pervanadate, but only slightly reduced (<10%) by inhibition of SHP-2 (SHP099 and PHPS1). (D) Vitamin E derivatives and homoxanthone A (PXA) moderately inhibited SHP-1 activation in IFNγ / LPS-stimulated macrophages surrounding cancer cells in a dose-dependent manner. (E) PKCθ negatively regulates SHP-1 activation at a moderate level. Inhibition of PKCθ with PKCθ inhibitor I and VTX27 increased SHP-1 activation induced by IFNγ / LPS and cancer cell ligand binding. Conversely, activation of PKCθ with PMA reduced SHP-1 activation. [Figure 3-2] Same as above. [Figure 3-3] Same as above. [Figure 3-4] Same as above.

[0040] [Figure 4-1]Pulse inhibition of SHP-1 transiently promotes proinflammatory signaling in macrophages. (A) Mouse macrophages (bone marrow-derived macrophages, or "BMDM") were treated with TPI-1 for 15 minutes, followed by complete removal of TPI-1 by washing. At different time points after TPI-1 treatment, macrophages were stimulated with IFNγ / LPS for 20 minutes in the presence of viable cancer cells (at a 1:1 ratio to BMDM). Cells were lysed, and SHP-1 activation was measured using pNpp. Total protein levels and phosphorylation status of STAT1 and Erk1 / 2 were detected by WB. (B) Macrophages were stimulated with IFNγ / LPS at different time points under the same conditions as in (A), except that TPI-1 was partially (50%) or not removed from the medium after TPI-1 treatment. [Figure 4-2] Same as above.

[0041] [Figure 5-1]The signaling mechanism of targeting SHP-1 in solid tumors is shown. (A) An overview of the SHP-1 mechanism in solid tumors. SHP-1 remains inactivated or hypoactivated in solid tumors until treatment is administered. SHP-1 is activated through a tumor-protective feedback loop: proinflammatory signaling → tyrosine kinase (TK) → ITIM phosphorylation → SHP-1 activation. SHP-1 activation then inhibits proinflammatory signaling, conferring tumor resistance to therapy. TPI-1 inhibits SHP-1 activation, restoring proinflammatory signaling and promoting antitumor innate and adaptive immunity. (B) An example is seen with SIRPα. Src family TK(s) induced by proinflammatory signals mediate phosphorylation of ITIMs within the cytoplasmic domain that dock to SHP-1, resulting in SHP-1 activation. C shows that proinflammatory stimuli phosphorylate ITIM, an iR, leading to the exclusive binding of SHP-1 to pITIM, activating SHP-1. On the other hand, immunosuppressive signals from IL-4, IL-10, and TGFβ promote ITIM phosphorylation and induce SHP-1 binding. Macrophage iRs LilRB and SIRPα are shown as examples. [Figure 5-2] Same as above.

[0042] [Figure 6-1]We demonstrate that SHP-1 inhibition promotes antitumor or protumorigenic effects under various conditions. (A) Intratumoral macrophages upregulate the expression of IRs (Pir-B, Siglec E, F, and G, and SIRPα) during late-stage tumor progression. Small KPC pancreatic tumors (<150 mm3) and larger KPC pancreatic tumors (>800 mm3) were dissociated into single cells, followed by flow cytometry analysis of cell surface protein expression in macrophages (gate F4 / 80+). (B) Inhibition of SHP-1 alone promotes TME immunosuppression. Resected MC38 solid tumor pieces were treated with the SHP-1 inhibitor TPI-1 (100 nM) or vehicle (DMSO) under cell culture conditions. After 24 hours, tumor-derived cytokines secreted into the culture medium were measured by ELISA. As shown, TPI-1 treatment increased tumor production of IL-6 and IL-10. (C) TPI-1 and PTP-1 dose-dependently inhibited SHP-1, enhancing IL-10 and TGF-β production in macrophages stimulated with IL-4 / 13 or IL-10 in the presence of cancer cell ligand binding. (D) In ​​the same experimental setting, TPI-1 and PTP-1 dose-dependently enhanced the inflammatory response of macrophages, increasing IL-12 and TNF-α induced by IFN-γ and LPS. [Figure 6-2] Same as above.

[0043] [Figure 7-1]Inhibition of SHP-1 induces proinflammatory responses and antigen presentation in therapeutic solid tumors. (A) Intratumoral treatment of KPC pancreatic tumors with TLR agonists (including αTLR, CpG, poly I:C, and R848, 1 μg each), proinflammatory cytokines (IL-1β, IL-6, TNFα, and IFNγ, 10 ng each), and the STING activator 2'3'-cGAMP (1 μg) for 30 minutes induced a rapid increase in PTP activation, which was suppressed by the SHP-1 inhibitor TPI-1. Untreated homeostatic tumors showed low PTP / SHP-1 activation. (B) Similarly, PTP / SHP-1 activation in KPC tumors was induced by 8 Gy of RT, azathioprine (AZA), or chemotherapy with anti-PD-L1 antibody (αPD-L1), and this activation was attenuated by cotreatment with TPI-1. (C) Depletion of intratumor macrophages with clodronate liposomes abolished SHP-1 activation induced by various tumor treatments. (D) SHP-1 inhibition significantly enhanced TLR agonist- and RT-induced proinflammatory cytokines. (E) SHP-1 inhibition significantly enhanced the immunogenic antigen-presenting capacity of intratumor macrophages. Treatment of tumors with TLR agonists or RT without SHP-1 inhibition only slightly increased proinflammatory cytokines, but significantly increased IL-10 and TGFβ. (F) Transcriptional profiling revealed that tumor responses to TLR agonists and RT differed significantly depending on whether intratumor SHP-1 was inhibited. Without SHP-1 inhibition, KPC tumors exhibited increased immunosuppressive TGFβ signaling and MDSC infiltration, making them resistant to therapy, whereas tumors treated with SHP-1 inhibition exhibited reduced TGFβ but high expression of proinflammatory cytokines, antigen-presenting molecules, and chemokines that attract neutrophils, NK cells, and T cells, but not MDSCs, reprogramming the TME into a robust inflammatory niche. Similar data were obtained by examining colorectal carcinoma MC38. [Figure 7-2] Same as above. [Figure 7-3] Same as above.

[0044] [Figure 8-1] Inhibition of SHP-1 in combination with a TLR agonist (αTLR) reprograms the TME of MC38 colorectal cancer. (A) A shows a treatment scheme for MC38 tumors. (B) and (C) TME analysis results demonstrate that treatment with TPI-1 and αTLR reprograms the TME, resulting in a reduction in tumor cells and an increase in immune infiltrates, particularly tumor-associated CD8 T cells, neutrophils (PMNs), and NK cells, while also reducing macrophages, MDSCs, and Tregs. (D) A significant reduction in intratumoral macrophages after treatment with TPI-1 and αTLR. (E) Ex vivo treatment of resected MC38 tumors with TPI-1 and αTLR induced CD8 T cell proliferation and induced antigen presentation in situ. [Figure 8-2] Same as above. [Figure 8-3] Same as above.

[0045] [Figure 9-1] We demonstrate that the combination of SHP-1 inhibition by TPI-1 and tumor-focused RT reprogrammed the TME of KPC pancreatic ductal adenocarcinoma toward the elimination of pro-inflammatory cancer. (A) Treatment scheme and TME analysis at day 5. The table shows the percentage of various cell populations among total CD45+ cells. The bar graph shows the percentage of various populations within total cells. (A) TPI-1 and RT combined treatment promoted neutrophil (PMN) infiltration, increased NK cells, and induced CD8+ T cell proliferation. (B) TPI-1 and RT combined treatment induced a significant proliferation of CD8+ T cells with high frequency of reactivity to the tumor-specific antigen p15E. (C) Intratumoral macrophages exhibited a pro-inflammatory phenotype and increased antigen-presenting capacity after TPI-1 and RT combined treatment. [Figure 9-2] Same as above. [Figure 9-3] Same as above.

[0046] [Figure 10-1] Figure 1 shows a pulse-intermittent SHP-1 inhibition (iShp-1) strategy for metastatic solid tumors. (A) A preclinical metastatic solid tumor model is established in syngeneic WT mice by multiple-site transplantation. After tumor formation, mice are treated with an SHP-1 inhibitor in combination with a pro-inflammatory modality to activate anti-cancer immunity. Treatment is administered via i.p. or sc to achieve systemic efficacy. Treatment can also be administered via intratumoral (it) injection. (B) Treatment scheme and evaluation are shown. In the pulse-intermittent scheme, an SHP-1 inhibitor is administered once at the start of each cycle, or two or three consecutive times (pulse 1, 2, or 3), followed by a 2- to 9-day intermittent period before the next treatment cycle. Combined modalities are not limited to the following list and may be administered simultaneously (e.g., TLR agonists as indicated in the figure) or according to a specific dosing schedule. Tumor control efficacy, side effects, and toxicity are evaluated throughout the experiment. Immunogenic changes in the TME are also evaluated to elucidate mechanisms. [Figure 10-2] Same as above.

[0047] [Figure 11-1]The effects of continuous or intermittent iShp-1 treatment on efficacy and adverse toxicity are shown. A shows the study design. KPC pancreatic cancer mice were administered TPI-1 continuously (once daily) or intermittently with an interval between two treatments (intermittent). Three doses, 1, 3, and 10 mg / kg (ip), were tested. A TLR agonist (CpG + poly I:C, 10 μg each, ip, once every 3 days) was administered to initiate the inflammatory response. B shows the tumor treatment effect. C shows the tumor treatment effect. Tumor imaging (B) and volume change recording (C) show similar efficacy in both continuous and intermittent iShp-1 treatment schemes. D shows side effects. E shows side effects. Daily weight records, blood hemoglobin, proteinuria, serum alanine aminotransferase (ALT), and splenomegaly analysis at the final time point (day 11) indicated that continuous administration of iSHP-1 was associated with a high risk of anemia, renal dysfunction, splenomegaly, and pneumonia (not shown), whereas intermittent administration of iSHP-1 was associated with a low risk of side effects. [Figure 11-2] Same as above.

[0048] [Figure 12-1] Pulse-intermittent inhibition of SHP-1 (iSHP-1) in combination with a TLR agonist (αTLR) and / or an anti-PD-L1 checkpoint inhibitor effectively treated multifocal MC38 colorectal cancer. (A) Treatment scheme. Bilaterally MC38 tumor-implanted (sc) mice were treated with TPI-1 and various combinations via either i.p. or subcutaneous (sc) administration for two days. Mice with residual tumors were treated with a 5-day intermittent period before receiving a second cycle of treatment. (B) and (C) Tumor control effects measured by changes in tumor volume (B) and TME reprogramming, indicating an increase in tumor-attacking immune cell populations while alleviating immunosuppression. (D) Acute adverse toxicity measured by body weight, proteinuria, serum ALT levels, and splenomegaly. [Figure 12-2] Same as above. [Figure 12-3] Same as above.

[0049] [Figure 13-1] Pulse-intermittent SHP-1 inhibition (iSHP-1) combined with RT and αPD-L1 for the treatment of pancreatic and lung cancers. Figure A shows the experimental scheme. On day 1, mice bearing bilateral KPC pancreatic cancer or LLC lung cancer were treated with a single pulse dose of TPI-1 (3 mg / kg) via i.p. administration to inhibit SHP-1 (iSHP-1) systemically. Simultaneously, tumors in the right flank were treated with 8 Gy of X-ray radiation (RT). After a 2-day intermittent period, on day 4, mice were treated with the same dose of TPI-1 (i.p.) in the second cycle, while RT was reduced to 4 Gy in the right flank tumors. In the third cycle (day 7), iSHP-1 and RT were combined, and RT was reduced to 2 Gy. Anti-PD-L1 Ab (100 μg, i.p.) was administered the day after TPI-1 + RT treatment. (B) shows luminescence images tracing the changes in KPC-luc and LLC-luc tumors after treatment. (C) shows records of tumor volume changes and animal survival rates up to 45 days after treatment. (D) shows that treatment did not cause splenomegaly, weight loss, or anemia. (E) shows that treatment did not induce pneumonia. [Figure 13-2] Same as above. [Figure 13-3] Same as above.

[0050] [Figure 14-1]This figure shows the treatment of advanced KPC pancreatic ductal adenocarcinoma by combined pulse-intermittent inhibition of SHP-1 (iSHP-1). (A) The treatment scheme is shown. Mice bearing large KPC tumors were treated (ip) with TPI-I plus TLR agonists (CpG, PolyIC, and R848, 50 μg each) for three consecutive days. The first pulse treatment was followed by a 9-day intermittent period, followed by a second cycle of 2 days of treatment with TPI plus TLR agonists. (B) Luminescence images of KPC tumor-bearing mice over the course of treatment. (C) Changes in tumor volume are shown. (D) TME analysis on day 4 revealed a decrease in intratumoral immunosuppressive populations, including macrophages (Mφ) and MDSCs, and an increase in tumor-attacking CD8+ T cells (Tc), inflammatory neutrophils (PMN), and NK cells. (E) The treatment scheme resulted in minor side effects and temporary weight loss, followed by recovery. [Figure 14-2] Same as above.

[0051] [Figure 15] 1 shows a proteomic analysis of protein tyrosine phosphatase expression in macrophages.

[0052] [Figure 16-1] Figure 1 shows activation of macrophage proinflammatory responses and antigen presentation in the tumor environment by a combined regimen of SHP-1 inhibition (iShp1). A shows the test system. B shows the effect of interferon with or without TPI-1. C shows the effect of interferon with or without TPI-1. D shows the effect of various agents, including IL-1 family cytokines (IL-1β, IL-18), TNFα, and TLR ligands, in combination with TPI-1. [Figure 16-2] Same as above.

[0053] [Figure 17A]We show that inhibition of SHP-1 (iSHP1) suppresses tumor-induced immunosuppression under pro-inflammatory stimuli. Figure 1 shows neutrophil infiltration in various organs measured at various time points after αTLR stimulation. [Figure 17B] We show that inhibition of SHP-1 (iSHP1) suppresses tumor-induced immunosuppression under pro-inflammatory stimuli. We also show neutrophil infiltration in tumor tissues of mice treated with αTLR+TPI-1. [Figure 17C] We demonstrate that inhibition of SHP-1 (iSHP1) suppresses tumor-induced immunosuppression under pro-inflammatory stimuli. We also demonstrate the phenotype of intratumoral macrophages.

[0054] [Figure 18-1]This shows that anti-TNFα mAb reduces systemic inflammation and adverse toxicity. Figure A shows the experimental design. Mice with established MC38 colorectal carcinoma (200–400 mm3) were treated with αTLR, TPI-1, and dasatinib (sc), and then either untreated or treated with anti-TNFα mAb or anti-IL-6 mAb (150 μg, ip). The treatment was repeated once (d1 and d2). Changes in tumor volume were recorded, and immune infiltration in the tumor TME was analyzed 6 days after treatment. Figure B shows the changes in tumor volume after various treatments. Figure C shows the results of TME analysis. Figure D shows the results of TME analysis. Treatment with anti-TNFα mAb or anti-IL-6 mAb did not affect the increase in CD8 T cells (Tc) and NK cells, or the decrease in macrophages and MDSCs in the TME, induced by αTLR / TPI-1 / dasatinib therapy. (E) Treatment of mice with anti-TNFα mAb, but not anti-IL-6 mAb, significantly reduced the induction of proinflammatory cytokines (TNFα, IL-6, IL-1β, IL-10, IFNα, and IFNγ) associated with αTLR / TPI-1 / dasatinib combination therapy. (F) Anti-TNFα treatment significantly reduced circulating monocyte and PMN chemokines CCL2, CCL5, and CXCL1, but not CXCL10, which is essential for T cell migration. (G) Anti-TNFα treatment protected mice from the development of splenomegaly and intestinal inflammation normally associated with αTLR / TPI-1 / dasatinib therapy. [Figure 18-2] Same as above. [Figure 18-3] Same as above. [Figure 18-4] Same as above. [Figure 18-5] Same as above.

[0055] [Figure 19] A-C show the mechanism by which tumor cells inhibit macrophage proinflammatory responses in the TME. [Figure 20] We demonstrate the mechanism by which tumor cells inhibit macrophage proinflammatory responses in the TME.

[0056] [Figure 21A] Figure 1 shows upregulation of iRs and their ligands when tumors progress to later stages. [Figure 21B] Figure 1 shows upregulation of iRs and their ligands when tumors progress to later stages. [Figure 21C] Figure 1 shows upregulation of iRs and their ligands when tumors progress to later stages. [Figure 21D] Figure 1 shows upregulation of iRs and their ligands when tumors progress to later stages. [Figure 21E] Figure 1 shows upregulation of iRs and their ligands when tumors progress to later stages.

[0057] [Figure 22A] We show that cancer cell and tumor TME-produced factors (secritome) induce increased macrophage expression of iR. [Figure 22B] We show that cancer cell and tumor TME-produced factors (secritome) induce increased macrophage expression of iR. [Figure 22C] We show that cancer cell and tumor TME-produced factors (secritome) induce increased macrophage expression of iR. [Figure 22D] We show that cancer cell and tumor TME-produced factors (secritome) induce increased macrophage expression of iR. [Figure 22E] We show that cancer cell and tumor TME-produced factors (secritome) induce increased macrophage expression of iR.

[0058] [Figure 23A] We show that inhibition of SHP-1 triggers a proinflammatory response in the KPC tumor TME. [Figure 23B] We show that inhibition of SHP-1 triggers a proinflammatory response in the KPC tumor TME.

[0059] [Figure 24]We show that treating MC38 tumors with a TLR agonist (αTLR) plus SHP-1 inhibition resulted in pro-inflammatory polarization in the TME.

[0060] [Figure 25A] Figure 1 shows the inhibitory effect of the iR→SHP-1 inhibitory axis. Figure 2 shows Western blot analysis of activation and protein phosphorylation of the JAK-STAT, NFκB, MAPK, and PI3K-Akt signaling pathways induced by stimulation with LPS (1 μg / ml) + IFNγ (40 ng / ml). [Figure 25B] Inhibition of the iR→SHP-1 pathway is shown. Densitometry analysis of protein phosphorylation and thus activation of signal transduction is shown.

[0061] [Figure 26A] We show that SHP1- / - macrophages resist the inhibition imposed by cancer cells under TLR and IFNγ stimulation and induce a pro-inflammatory response. [Figure 26B] We show that SHP1- / - macrophages resist the inhibition imposed by cancer cells under TLR and IFNγ stimulation and induce a pro-inflammatory response. [Figure 26C] We show that SHP1- / - macrophages resist the inhibition imposed by cancer cells under TLR and IFNγ stimulation and induce a pro-inflammatory response.

[0062] [Figure 27A] We present cell surface blockade of iR or ligand as an alternative strategy to remove the inhibitory effects of the iR→SHP-1 pathway. [Figure 27B] We present cell surface blockade of iR or ligand as an alternative strategy to remove the inhibitory effects of the iR→SHP-1 pathway. [Figure 27C] We present cell surface blockade of iR or ligand as an alternative strategy to remove the inhibitory effects of the iR→SHP-1 pathway. DETAILED DESCRIPTION OF THE INVENTION

[0063] In one aspect, the application provides a method of treating cancer in an individual, comprising administering to the individual an SHP-1 inhibitor, wherein the individual a) has previously been, is currently being, or will be administered an inflammatory agent, or b) is exhibiting an inflammatory response or has a persistent infection. In another aspect, the application provides a method of treating cancer in an individual, comprising administering to the individual monocytes or macrophages with deficient SHP-1 expression or inhibited activation, wherein the individual a) has previously been, is currently being, or will be administered an inflammatory agent, or b) is exhibiting an inflammatory response or has a persistent infection. In some embodiments, the SHP-1 inhibitor is administered systemically. In some embodiments, the method comprises administering to the individual an SHP-1 inhibitor at least twice, no more frequently than once every three days. In some embodiments, the method comprises administering to the individual an SHP-1 inhibitor in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts for about 3 to about 20 days. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, radiation therapy, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

[0064] This application is based, at least in part, on the remarkable discovery that combining the "pivotal" inhibitor SHP-1 with proinflammatory treatments activates proinflammatory signaling in the tumor environment, particularly in tumor-infiltrating macrophages, leading to a radical remodeling of the TME and promoting the activation of innate and adaptive immune cells, enhancing anti-cancer immunity. Specifically, we found that intratumoral iR and SHP-1-mediated inhibitory regulation is significantly enhanced under tumor therapy because these treatments often induce ITIM hyperphosphorylation, thereby promoting SHP-1 "hyperactivation," which functions as a feedback loop protecting tumors from therapeutic damage and inflammatory responses and further inducing wound healing responses to promote tumor progression. See, for example, Figures 1 and 5A. This finding strongly supports the need for SHP-1 inhibition as a combination in tumor immunotherapy to achieve efficacy.

[0065] Combining SHP-1 inhibitors (e.g., TPI-1) with proinflammatory agents (e.g., TLR agonists, proinflammatory cytokines, radiation therapy, checkpoint inhibitors) has been shown to convert the immunosuppressive TME to an inflammatory TME, activating various types of immune cells (e.g., macrophages, T cells, and B cells), and completely eliminating tumors. (See, e.g., Figures 11C and 12B.) This combination therapy also produced an abscopal effect (e.g., Figure 13B) and was demonstrated to be effective in treating large, advanced tumors (e.g., Figure 14C).

[0066] Furthermore, intermittent administration of SHP-1 inhibitors has the same significant antitumor efficacy as continuous administration of SHP-1 inhibitors, while significantly reducing side effects (e.g., anemia, kidney damage, and liver damage) (see Figures 11A-11D). This is particularly remarkable given the severe side effects associated with SHP-1 inhibitors shown in previous studies. Furthermore, administration of drugs that reduce systemic inflammation (e.g., anti-TNFα mAb) further suppresses systemic inflammation and reduces adverse toxicities (see Figures 18A-18G).

[0067] Therefore, the present application provides a novel method for effectively reconstructing immunosuppression caused by the tumor microenvironment and activating innate and adaptive immunity against cancer, thereby achieving significant cancer-suppressing effects.

[0068] I. Definition In general, the terms used in the claims and the specification are intended to be interpreted as having their ordinary meanings as understood by those of ordinary skill in the art. However, certain terms are defined below for clarity. If there is a conflict between the ordinary meaning and a given definition, the given definition shall govern.

[0069] The terms "individual," "subject," or "patient" are used synonymously herein and refer to a mammal, including a human. An individual includes, but is not limited to, a human, a cow, a horse, a cat, a dog, a rodent, or a primate. In some embodiments, the individual is human. In some embodiments, the individual is suffering from a disease, such as cancer. In some embodiments, the individual is in need of treatment.

[0070] As used herein, a "reference value" refers to any sample, standard, or level used for comparison purposes. The reference can be obtained from a healthy sample and / or a non-diseased sample. In some examples, the reference value may be obtained from an untreated sample. In some examples, the reference value is obtained from a non-diseased or untreated sample from an individual. In some examples, the reference value is obtained from one or more healthy individuals who are not the individual or the individual.

[0071] As used herein, the terms "intermittent" or "intermittently" in the context of dosing refer to discontinuous dosing as shown in Figure 11A (lower panel), Figure 12A, Figure 12A, Figure 13A, and Figure 14A. In some instances, "intermittent" administration refers to a) administering the SHP-1 inhibitor for fewer than 12 consecutive days (e.g., fewer than 11, 10, 9, 8, 7, 6, 5, 4, and 3 days), and b) administering the SHP-1 inhibitor at least twice, with the two administrations separated by at least one day (i.e., days 1 and 3). In some embodiments, the SHP-1 inhibitor is administered daily for no more than three consecutive days, with the at least two administrations separated by at least one day.

[0072] As used herein, the term "cycle" in the context of administration refers to a period during which an SHP-1 inhibitor is administered at least once. Day 1 of a cycle is defined as the day on which the first administration of the SHP-1 inhibitor occurs during that period. When an SHP-1 inhibitor is administered continuously over several days, day 1 of the cycle is defined as the day on which the first of several consecutive administrations occurs. The last day of a cycle is defined as the day before the next non-consecutive administration of the SHP-1 inhibitor. See Figures 12A and 14A for exemplary cycles. The duration of each cycle does not have to be the same. For example, the first cycle is 5 days, and the second cycle is 7 days. Each cycle may differ in the number of administrations of the SHP-1 inhibitor. For example, in a first cycle with a 5-day duration, the SHP-1 inhibitor may be administered once, and in a second cycle with a 7-day duration, the SHP-1 inhibitor may be administered twice.

[0073] As used herein, the term "immunogenic" refers to the ability to elicit an immune response, for example, via T cells, B cells, or both.

[0074] As used herein, "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing one or more symptoms attributable to the disease; reducing the extent of the disease; stabilizing the disease (e.g., preventing or slowing the progression of the disease); preventing or slowing the spread of the disease (e.g., metastasis); preventing or slowing the onset or recurrence of the disease; slowing or slowing the progression of the disease; improving the condition of the patient; providing remission (whether partial or total) of the disease; reducing the dose of one or more other drugs required to treat the disease; slowing the progression of the disease; improving quality of life; and / or extending survival. "Treatment" also encompasses reducing the pathological consequences of cancer. The methods of the present invention take into account any one or more of these therapeutic aspects.

[0075] As used herein, "delaying" the onset of cancer means extending, preventing, slowing, inhibiting, stabilizing, and / or postponing the onset of the disease. This delay can be of varying duration depending on the disease history and / or the individual being treated. As will be apparent to one skilled in the art, a sufficient or significant delay can essentially encompass prevention, in the sense that the individual does not develop the disease. A method that "delays" the onset of cancer is one that reduces the likelihood of disease onset in a given timeframe and / or reduces the extent of disease in a given timeframe compared to the absence of the method. Such comparisons are usually based on clinical studies using a statistically significant number of individuals. Cancer onset can be detected using standard methods, including, but not limited to, computed tomography (CAT scan), magnetic resonance imaging (MRI), abdominal ultrasound, coagulation studies, arteriography, or biopsy. Onset also refers to cancer progression, which may be undetectable initially, and includes onset, recurrence, and onset.

[0076] The term "co-administration," as used herein, means that the first and second therapies in a combination therapy are administered at a time interval of about 15 minutes or less, e.g., about 10 minutes or less, 5 minutes or less, or 1 minute or less. When the first and second therapeutic agents are administered at the same time, the first and second therapeutic agents may be contained in the same composition (e.g., a composition containing both the first and second therapeutic agents) or may be contained in separate compositions (e.g., one composition containing the first therapeutic agent and another composition containing the second therapeutic agent).

[0077] As used herein, the term "sequential administration" means that the first and second therapeutic agents in a combination therapy are administered at intervals of more than about 15 minutes, e.g., more than about 20 minutes, more than 30 minutes, more than 40 minutes, more than 50 minutes, more than 60 minutes, or more. Either the first 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.

[0078] As used herein, "concurrent administration" means that the administration of a first therapeutic agent and the administration of a second therapeutic agent in a combination therapy overlap with each other.

[0079] As used herein, "pharmaceutically acceptable" or "pharmaceutically compatible" means a material that is biologically or otherwise undesirable; e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. A pharmaceutically acceptable carrier or excipient preferably has met the required standards of toxicology and manufacturing testing and / or is listed in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0080] It is understood that the embodiments of the present application described herein include embodiments that include "consisting of" and / or "consisting essentially of."

[0081] Reference herein to "about" a value or parameter includes (and describes) a variation about that value or parameter itself. For example, a reference to "about X" includes a reference to "X."

[0082] As used herein, reference to "not being" a value or parameter generally means and describes "other than" a value or parameter. For example, a method is not used to treat cancer type X means that the method is used to treat cancer types other than X.

[0083] As used herein, the term "about X to Y" has the same meaning as "about X to about Y."

[0084] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0085] Any term not directly defined herein will be understood to have the general meaning understood in the art of the present invention. Certain terms are explained herein to provide additional guidance to practitioners in describing the compositions, devices, methods, etc. of the present invention, as well as methods for making or using them. It will be understood that the same meaning may be expressed differently. Accordingly, alternative and synonymous terms may be used for any one or more of the terms discussed herein. No importance should be placed on whether a term is detailed or discussed herein. Some synonyms or alternative methods, materials, etc. are provided. The description of one or more synonyms or equivalents allows for the use of other synonyms or equivalents unless expressly stated otherwise. Various examples, including examples of terms, are used for illustrative purposes only and do not limit the scope and meaning of the inventive embodiments described herein.

[0086] II. Treatment method In one aspect, the present application provides a method of treating cancer by administering an SHP-1 inhibitor, e.g., TPI-1 or an analog or derivative thereof. The SHP-1 inhibitors described herein (e.g., TPI-1 or an analog or derivative thereof) include any agent comprising an SHP-1 inhibitor moiety (e.g., an agent comprising a TPI-1 moiety or a derivative or analog thereof). In some embodiments, the SHP-1 inhibitor comprises TPI-1. In some embodiments, the individual to be treated has previously received, is currently receiving, or will receive, e.g., any of the pro-inflammatory agents described herein. In some embodiments, the individual is experiencing an inflammatory response or has a persistent infection.

[0087] In some embodiments, the method comprises administering both an SHP-1 inhibitor and a pro-inflammatory agent to an individual. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between doses. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with two, three, four, five, six, seven, eight, nine, or two days between doses. In some embodiments, the SHP-1 inhibitor is administered at least one day between each dose of the previous or next SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor systemically.

[0088] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) to the individual, where the individual a) has previously received, is currently receiving, or will receive an inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy), or b) is experiencing an inflammatory response or ongoing infection, and the SHP-1 inhibitor is administered systemically (e.g., intravenously or subcutaneously). In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally administered at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, the SHP-1 inhibitor is administered at least 1 day apart from the previous or next administration of the SHP-1 inhibitor, respectively. In some embodiments, the SHP-1 inhibitor is administered no more than once every two days. In some embodiments, the SHP-1 inhibitor is administered two or more times but not more than five times within 10 consecutive days (e.g., two times in 10 days, three times in 10 days, four times in 10 days, or five times in 10 days). In some embodiments, the SHP-1 inhibitor is administered simultaneously with the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor is administered concurrently with the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered sequentially within two weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or on the same day). In some embodiments, the SHP-1 inhibitor has a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less). In some embodiments, the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation for no more than about 7 days (e.g., about 5, 4, or 3 days).In some embodiments, the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein formulations (e.g., antibody formulations targeting 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 derivative thereof, vitamin E derivatives, homoxanthone A (PXA), and PKC theta activators. In some embodiments, the method further comprises locally (e.g., intratumorally) administering to the individual an inflammation-inducing agent. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further includes administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or pro-inflammatory agent. In some embodiments, the pro-inflammatory agent includes or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the pro-inflammatory agent includes a TLR agonist (e.g., R848) and a pro-inflammatory cytokine (e.g., IFN-gamma). In some embodiments, the SHP-1 inhibitor includes TPI-1.

[0089] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy), wherein the SHP-1 inhibitor is administered intravenously or subcutaneously, and optionally, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally administered at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day after each previous or subsequent administration of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the SHP-1 inhibitor is administered twice every 7 to 20 days (e.g., on two consecutive days). In some embodiments, the SHP-1 inhibitor is administered three times every 10 to 20 days (e.g., on three consecutive days). In some embodiments, the SHP-1 inhibitor is administered no more than once every two days. In some embodiments, the SHP-1 inhibitor is administered two or more times but no more than five times within 10 consecutive days (e.g., twice every 10 days, three times every 10 days, four times every 10 days, or five times every 10 days). In some embodiments, the SHP-1 inhibitor is administered simultaneously with a pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor is administered concurrently with a pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered sequentially within 2 weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the SHP-1 inhibitor has a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less).In some embodiments, the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein formulations (e.g., antibody formulations targeting 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 derivative thereof, vitamin E derivatives, homoxanthone A (PXA), and PKC theta activators. In some embodiments, the method further comprises locally (e.g., intratumorally) administering to the individual an inflammation-inducing agent. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further includes administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0090] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy), wherein the SHP-1 inhibitor is administered intravenously or subcutaneously, and optionally, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally administered at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day after the previous or next administration of the SHP-1 inhibitor, respectively. In some embodiments, the method includes administering the SHP-1 inhibitor to the individual in at least two cycles, and further optionally, the SHP-1 inhibitor is administered at least once in each cycle, each cycle lasting from about 3 to about 20 days. In some embodiments, the SHP-1 inhibitor is administered at least two times in each cycle (e.g., on at least two consecutive days). In some embodiments, the SHP-1 inhibitor is administered at least three times in each cycle (e.g., on at least three consecutive days). In some embodiments, the SHP-1 inhibitor is administered simultaneously with the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor is administered concurrently with the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered sequentially within two weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or on the same day). In some embodiments, the SHP-1 inhibitor has a half-life of about 10 days or less (eg, about 7, 5, 4, or 3 days or less).In some embodiments, the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein formulations (e.g., antibody formulations targeting 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 derivative thereof, vitamin E derivatives, homoxanthone A (PXA), and PKC theta activators. In some embodiments, the method further comprises locally (e.g., intratumorally) administering to the individual an inflammation-inducing agent. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or reduces the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further includes administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0091] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising intravenously, subcutaneously, and / or intratumorally administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy), optionally wherein the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation within about 5 days, and optionally wherein the method comprises administering the SHP-1 inhibitor to the individual at least twice (e.g., at least 3, 4, 5, or 6 times), no more than once every 3 days. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than 2 or 3 consecutive days, optionally with at least 2 doses separated by at least 1 day. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, the SHP-1 inhibitor is administered at least one day apart from the previous or next dose of the SHP-1 inhibitor, respectively. In some embodiments, the SHP-1 inhibitor is administered no more than twice every 7 to 20 days. In some embodiments, the SHP-1 inhibitor is administered no more than three times every 7 to 20 days. In some embodiments, the SHP-1 inhibitor is administered about one to three times every 7 to 20 days for at least 14 to 20 days. In some embodiments, the SHP-1 inhibitor is administered at least about two, three, four, five, or six times within a period of about 14 to about 40 days (e.g., about 14 to about 20 days). In some embodiments, the SHP-1 inhibitor is administered simultaneously with the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor is administered concurrently with the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered sequentially within 2 weeks (e.g., within 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or on the same day).In some embodiments, the SHP-1 inhibitor has a half-life of about 10 days or less (e.g., about 7 days, 5 days, 4 days, or 3 days or less). In some embodiments, the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days). In some embodiments, the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein formulations (e.g., antibody formulations targeting 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 derivative thereof, vitamin E derivatives, homoxanthone A (PXA), and PKC theta activators. In some embodiments, the method further comprises locally (e.g., intratumorally) administering to the individual an inducing agent. In some embodiments, the SHP-1 inhibitor is administered systemically and the inducing agent is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0092] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising intravenously, subcutaneously, and / or intratumorally administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy), wherein the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation within about 5 days (e.g., within 5 days, 4 days, 3 days), and wherein the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than 2 or 3 consecutive days, optionally administered at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least 3, 4, or 5 times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, the SHP-1 inhibitor is administered at least one day apart from the previous or next administration of the SHP-1 inhibitor, respectively. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 to about 20 days. In some embodiments, the SHP-1 inhibitor is administered at least twice in each cycle (e.g., on at least two consecutive days). In some embodiments, the SHP-1 inhibitor is administered at least three times in each cycle (e.g., on at least three consecutive days). In some embodiments, the SHP-1 inhibitor is administered simultaneously with a pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor is administered concurrently with a pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered sequentially within 2 weeks (e.g., within 10, 7, 6, 5, 4, 3, 2 days, or on the same day). In some embodiments, the SHP-1 inhibitor has a half-life of about 10 days or less (e.g., about 7, 5, 4, or 3 days or less).In some embodiments, the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein formulations (e.g., antibody formulations targeting 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 derivative thereof, vitamin E derivatives, homoxanthone A (PXA), and PKC theta activators. In some embodiments, the method further comprises administering to the individual a pro-inflammatory agent locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor is administered systemically and the pro-inflammatory agent is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further includes administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0093] In some embodiments, provided are methods of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering (e.g., intravenously, subcutaneously, and / or intratumorally) to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and immune cells (e.g., any immune cell described herein). In some embodiments, the individual has previously received, is currently receiving, or will receive an inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy). In some embodiments, the individual is exhibiting an inflammatory response or has a persistent infection. In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, the method comprising administering (e.g., intravenously, subcutaneously, and / or intratumorally) to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof), an inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy), and immune cells. In some embodiments, the immune cells are derived from the individual. In some embodiments, the immune cells comprise monocytes or macrophages. In some embodiments, the immune cells comprise T cells (e.g., CAR-T cells). In some embodiments, the immune cells comprise NK cells (e.g., CAR-NK cells). In some embodiments, the immune cells comprise neutrophils (e.g., CAR-expressing neutrophil cells). In some embodiments, the immune cells comprise antigen-presenting cells (APCs). In some embodiments, the immune cells are engineered to express a chimeric receptor that specifically binds to a tumor antigen. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between doses. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between doses.In some embodiments, the SHP-1 inhibitor is administered at least one day after the previous or next administration of the SHP-1 inhibitor, respectively. In some embodiments, the SHP-1 inhibitor, immune cells, and / or pro-inflammatory agent are administered within 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the SHP-1 inhibitor and immune cells are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor, immune cells, and / or pro-inflammatory agent are administered simultaneously. In some embodiments, the SHP-1 inhibitor, immune cells, and / or pro-inflammatory agent are administered in parallel. In some embodiments, the SHP-1 inhibitor, immune cells, and / or pro-inflammatory agent are administered sequentially. In some embodiments, the SHP-1 inhibitor is administered systemically and the pro-inflammatory agent is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0094] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a TLR agonist (e.g., R848), wherein the SHP-1 inhibitor is administered at least twice (e.g., at least three, four, or five times). In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally with at least one day between each administration. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each administration. In some embodiments, each administration of the SHP-1 inhibitor is separated by at least one day from the previous or next administration of the SHP-1 inhibitor. In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a TLR agonist, wherein the SHP-1 inhibitor and TLR agonist are administered within 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the method comprises administering to the individual the SHP-1 inhibitor at least twice, no more than once every three days. In some embodiments, the method comprises administering to the individual the SHP-1 inhibitor in at least two cycles, wherein the SHP-1 inhibitor is administered at least once (e.g., at least two or three times) in each cycle, each cycle lasting from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously or subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor and the TLR agonist are administered simultaneously, concurrently, or sequentially.In some embodiments, the TLR agonist activates TLR1 or TLR2, and optionally, the TLR agonist comprises a triacylated lipoprotein, peptidoglycan, zymosan, and / or Pam3CSK4. In some embodiments, the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, and optionally, the TLR agonist comprises a diacylated lipopeptide, a heat shock protein, HMGB1, uric acid, fibronectin, and / or an ECM protein. In some embodiments, the TLR agonist activates TLR2, and optionally, the TLR agonist comprises Pam3Cys, SMP-105, and / or CBLB612. In some embodiments, the TLR agonist activates TLR3, and optionally, the TLR agonist comprises dsRNA, poly I:C, poly ICIC, poly-IC12U, IPH302, ARNAX, and / or MPLA. In some embodiments, the TLR agonist activates TLR4, and optionally, the TLR agonist comprises LPS, lipoteichoic acid beta-defensin-2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, and / or GLA-SE. In some embodiments, the TLR agonist activates TLR5, and optionally, the TLR agonist comprises flagellin, CBLB502, and / or M-VM3. In some embodiments, the TLR agonist activates TLR6. In some embodiments, the TLR agonist activates TLR7 or TLR8, and optionally, the TLR agonist comprises ssRNA, CpG-A, polyG10, and / or polyG3. In some embodiments, the TLR agonist activates TLR7, and optionally, the TLR agonist comprises bistriazolyl and / or R848. In some embodiments, the TLR agonist activates TLR8, and optionally, the TLR agonist comprises VTX1463 and / or R848.In some embodiments, the TLR agonist activates TLR9, and optionally, the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and / or ODN M362. In some embodiments, the TLR agonist activates TLR10, and optionally, the TLR agonist comprises Pam3CSK4. In some embodiments, the TLR agonist activates TLR11, and optionally, the TLR agonist comprises Toxoplasma gondiiprofilin. In some embodiments, the TLR agonist activates TLR12. In some embodiments, the TLR agonist activates TLR13, and optionally, the TLR agonist comprises VSV. In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and / or TLR9. In some embodiments, the TLR agonist activates TLR9, TLR4, and TLR7 / 8. In some embodiments, the TLR agonist comprises CpG, poly I:C, and / or R848. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, the SHP-1 inhibitor is administered systemically and the TLR agonist is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody).In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0095] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering TPI-1 or an analog or derivative thereof and a TLR agonist (e.g., R848), where optionally the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7, and TLR8. In some embodiments, TPI-1 or an analog or derivative thereof and the TLR agonist are administered on the same day. In some embodiments, TPI-1 or an analog or derivative thereof is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally administered at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, each administration of the SHP-1 inhibitor is administered at least 1 day apart from the previous or next administration of the SHP-1 inhibitor. In some embodiments, the TPI-1 or analog or derivative thereof and / or the TLR agonist are administered at least twice (e.g., at least 3, 4, 5, or 6 times). In some embodiments, the TPI-1 or analog or derivative thereof and the TLR agonist are administered in at least two cycles (e.g., at least 3 cycles), optionally with the TPI-1 or analog or derivative thereof and the TLR agonist administered on the same day for at least 2 consecutive days (e.g., at least 3 consecutive days) per cycle. In some embodiments, each cycle lasts from about 7 to about 20 days. In some embodiments, the TLR agonist activates TLRs on macrophages, optionally the TLRs include TLR 9. In some embodiments, the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9).In some embodiments, the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4, and TLR7 / 8). In some embodiments, the TLR agonist comprises CpG, poly I:C, and / or R848. In some embodiments, the pro-inflammatory agent comprises or is selected from the group consisting of R848, 3M-852A, motolimod, bropirimine, and vesatolimod. In some embodiments, TPI-1 or an analog or derivative thereof is administered systemically and the TLR agonist is administered intratumorally. In some embodiments, TPI-1 or an analog or derivative thereof is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0096] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a STING activator (e.g., cGAMP, e.g., MSA-2), optionally wherein the SHP-1 inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a STING activator (e.g., cGAMP, e.g., MSA-2), optionally wherein the SHP-1 inhibitor and STING activator are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of each other. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day between each subsequent dose of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (eg, intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally).In some embodiments, the SHP-1 inhibitor and the STING activator are administered sequentially, simultaneously, or concurrently. In some embodiments, the STING activator is a compound selected from the group consisting of cyclic guanosine monophosphate and cyclic adenosine monophosphate (cGAMP, e.g., 3'3'cGAMP, e.g., 2'3'cGAMP), bacterial vectors (e.g., SYNB1891, STACT-TREX-1), CDN compounds (e.g., ADU-S100, BI-STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB 11285, 3'3'-cyclic AIMP), non-CDN small molecules (e.g., ALG-031048, E7755, JNJ-'6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI-10001), nanovaccines (e.g., PC7ANP, cCAMP-NP, ONM-500), or antibody-drug conjugates (e.g., XMT-2056, CRD-5500). In some embodiments, the SHP-1 inhibitor is administered systemically and the STING activator is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0097] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and radiation therapy, optionally comprising administering to the individual at least two cycles of the SHP-1 inhibitor, wherein the SHP-1 inhibitor is administered at least once per cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the method comprises administering to the individual the SHP-1 inhibitor at least twice, no more than once every 3 days. In some embodiments, during the administration period, the SHP-1 inhibitor is administered at least three times. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor and radiation therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of each other. In some embodiments, the radiation therapy comprises irradiating the site of the cancer being treated. In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated. In some embodiments, the radiation therapy dose is insufficient to kill tumor cells. In some embodiments, the radiation therapy is selected from the group consisting of external beam radiation therapy, internal radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectants. In some embodiments, the radiation therapy is external beam radiation therapy, optionally including three-dimensional conformal radiation therapy (3D-RT), intensity-modulated radiation therapy (IMRT), photon beam therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT). In some embodiments, the radiation therapy is brachytherapy, optionally including interstitial brachytherapy, intracavitary brachytherapy, intracavitary radiation therapy, and intravenously administered radiolabeled molecules, hi some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally.In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0098] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and radiation therapy, wherein the radiation therapy comprises irradiation to a site different from the site of the cancer being treated. In some embodiments, the SHP-1 inhibitor is administered at least twice (at least three, four, five, or six times). In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally with at least one day between each administration. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each administration. In some embodiments, the SHP-1 inhibitor is administered at least one day after each previous or subsequent administration of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor and radiation therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one administration. In some embodiments, the radiation therapy comprises irradiating the site of the cancer being treated. In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated. In some embodiments, the dose of radiation therapy is insufficient to kill tumor cells.In some embodiments, the radiation therapy is selected from the group consisting of external beam radiation therapy, internal radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectants. In some embodiments, the radiation therapy is external beam radiation therapy, optionally including three-dimensional conformal radiation therapy (3D-RT), intensity-modulated radiation therapy (IMRT), photon beam therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT). In some embodiments, the radiation therapy is brachytherapy, optionally including interstitial brachytherapy, intracavitary brachytherapy, intraluminal radiation therapy, and intravenously administered radiolabeled molecules. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0099] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering TPI-1 or an analog or derivative thereof and radiation therapy. In some embodiments, the TPI-1 or analog or derivative thereof is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally administered at least twice with at least one day between doses. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between doses. In some embodiments, each dose of the SHP-1 inhibitor is administered at least one day after the previous or next dose of the SHP-1 inhibitor. In some embodiments, the TPI-1 or analog or derivative thereof and radiation therapy are administered on the same day. In some embodiments, the TPI-1 or analog or derivative thereof and / or radiation therapy are administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the TPI-1 or analog or derivative thereof and radiation therapy are administered in at least two cycles (e.g., at least three cycles), optionally with the TPI-1 or analog or derivative thereof and radiation therapy administered on the same day for at least two consecutive days (e.g., at least three consecutive days) per cycle. In some embodiments, each cycle lasts from about 7 to about 20 days. In some embodiments, the SHP-1 inhibitor and radiation therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of each other. In some embodiments, the radiation therapy comprises irradiating the site of the cancer being treated. In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated. In some embodiments, the dose of radiation therapy is insufficient to kill tumor cells.In some embodiments, TPI-1 or an analog or derivative thereof is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0100] In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a PAMP / DAMP activator, optionally administering the SHP-1 inhibitor at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a PAMP / DAMP activator, optionally administering the SHP-1 inhibitor and PAMP / DAMP activator within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one administration of the other. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day between each subsequent dose of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the pro-inflammatory agent is a PAMP activator.In some embodiments, the PAMP activator is triacyl lipopeptide, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipid, Pam3Cys porin, lipoarabinomannan, double-stranded RNA, poly(I:C), trepanosome lipid, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptide, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial / viral DNA, CpG DNA, urea bacteria, or Toxoplasma LPS. In some embodiments, the pro-inflammatory agent is a DAMP activator. In some embodiments, the DAMP activator is a defensin, HSP60, HSP70, messenger RNA, small hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, or unmethylated CpG DNA. In some embodiments, the SHP-1 inhibitor is administered systemically and the PAMP / DAMP activator is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0101] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a checkpoint inhibitor (e.g., an anti-PD-1 agent, an anti-PD-L1 agent, an anti-CTLA-4 agent), optionally wherein the SHP-1 inhibitor is administered at least two times (at least three, four, five, or six times). In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a checkpoint inhibitor (e.g., an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent), wherein the SHP-1 inhibitor and the checkpoint inhibitor are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally administered at least twice with an interval of at least one day between each. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, the SHP-1 inhibitor is administered at least one day apart from the previous or next administration of the SHP-1 inhibitor, respectively. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally).In some embodiments, the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG / PVRL2, CEACAM1, CEACAM5 / 6, FAK, CCL2 / CCR2, LIF, CD47 / SIRPα, CSF-1 (M-CSF) / CSF-1R, IL-1 / IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVA-1, Axl, or phosphatidylserine. In some embodiments, the checkpoint inhibitor is selected from the group consisting of ipilimumab, cemiplimab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, LAG525 (IMP701), REGN3767, BI754,091, tebotelimab (MGD013), eftiragimod alfa (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, monalizumab, COM701, CM24, NEO-201, The inhibitor may include or be defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, lanotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), pexidartinib (PLX3397), CAN04, canakinumab (ACZ885), BMS-986253, pepinemab (VX15 / 2503), trebananib, FP-1305, enapotamab vedotin (EnaV), or bavituximab. In some embodiments, the SHP-1 inhibitor is administered systemically and the checkpoint inhibitor is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody).In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0102] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a pro-inflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and / or TNFα), optionally wherein the SHP-1 inhibitor is administered at least two times (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a proinflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and / or TNFα), wherein the SHP-1 inhibitor and the proinflammatory cytokine are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally administered at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, the SHP-1 inhibitor is administered at least one day apart from the previous or next administration of the SHP-1 inhibitor, respectively. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally).In some embodiments, the proinflammatory cytokine promotes M1 macrophages. In some embodiments, the proinflammatory cytokine includes or is TNF, IFNγ, and / or GM-CSF. In some embodiments, the proinflammatory cytokine includes IFNγ. In some embodiments, the proinflammatory cytokine includes IL-1. In some embodiments, the proinflammatory cytokine includes TNF-α. In some embodiments, the proinflammatory cytokine includes IL-6. In some embodiments, the SHP-1 inhibitor is administered systemically and the proinflammatory cytokine is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further includes administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0103] In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a chemotherapeutic agent (e.g., azathioprine), optionally administering the SHP-1 inhibitor at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a chemotherapeutic agent (e.g., azathioprine), wherein the SHP-1 inhibitor and the chemotherapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day between each subsequent dose of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the chemotherapeutic agent is an alkylating agent.In some embodiments, the alkylating agent is selected from the group consisting of nitrogen mustards (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkylsulfonates (e.g., busulfan), and ethylenimines (e.g., thiotepa). In some embodiments, the chemotherapeutic agent is an antimetabolite. In some embodiments, the antimetabolite is selected from the group consisting of a cytidine analog (e.g., azacitidine, decitabine, cytarabine, gemcitabine), a folate antagonist (e.g., methotrexate, pemetrexed), a purine analog (e.g., cladribine, clofarabine, nelarabine), a pyrimidine analog (e.g., fluorouracil (5-FU), capecitabine (a prodrug of 5-FU)). In some embodiments, the chemotherapeutic agent is an anti-microtubule agent. In some embodiments, the anti-microtubule agent is selected from the group consisting of a topoisomerase II inhibitor (e.g., anthracycline, doxorubicin, daunorubicin, idarubicin, mitoxantrone), a topoisomerase I inhibitor (e.g., irinotecan, topotecan), a taxane (e.g., paclitaxel, docetaxel, cabazitaxel), a vinca alkaloid (e.g., vinblastine, vincristine, vinorelbine), or an antibiotic (e.g., actinomycin D, bleomycin, daunomycin). In some embodiments, the chemotherapeutic agent is hydroxyurea, tretinoin, arsenic trioxide, or a proteasome inhibitor (e.g., bortezomib). In some embodiments, the SHP-1 inhibitor is administered systemically and the chemotherapeutic agent is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody).In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0104] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a cancer vaccine, optionally administering the SHP-1 inhibitor at least twice. In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a cancer vaccine, wherein the SHP-1 inhibitor and the cancer vaccine are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day between each subsequent dose of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the cancer vaccine comprises a cell-based vaccine, a peptide-based vaccine, a virus-based vaccine, and / or a nucleic acid-based vaccine.In some embodiments, the SHP-1 inhibitor is administered systemically and the cancer vaccine is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses an inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0105] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an oncolytic virus, optionally administering the SHP-1 inhibitor at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an oncolytic virus, wherein the SHP-1 inhibitor and oncolytic virus are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day between each subsequent dose of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (eg, intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally).In some embodiments, the oncolytic virus comprises or is an adenovirus (e.g., ONYX-15, LOAd703 virus), a protoparvovirus, a parvovirus (e.g., H-1PV), a vaccinia virus (VACV), a reovirus (e.g., leolysin), or a herpes simplex virus (HSV, e.g., HSV-1, HSV-2, G207, L1BR1, HF10, T-VEC, Oren X010). In some embodiments, the oncolytic virus comprises JX-593, coxsackievirus A21 (CVA21), Maraba virus or its MG1 variant, DNX2440 adenovirus, fowlpox virus, or Sendai virus. In some embodiments, the SHP-1 inhibitor is administered systemically and the oncolytic virus is administered intratumorally. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0106] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and acoustic therapy (e.g., high intensity focused ultrasound (HIFU), e.g., low intensity focused ultrasound (LIPUS)), optionally wherein the SHP-1 inhibitor is administered at least two times (at least three, four, five, or six times). In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and acoustic therapy (e.g., high-intensity focused ultrasound (HIFU), e.g., low-intensity focused ultrasound (LIPUS)), wherein the SHP-1 inhibitor and acoustic therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally administered at least twice with at least one day between each. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, the SHP-1 inhibitor is administered at least one day apart from the previous or next administration of the SHP-1 inhibitor, respectively. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally).In some embodiments, the SHP-1 inhibitor is administered systemically, and the method includes administering acoustic therapy to the site of the cancer being treated. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further includes administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further includes administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor includes TPI-1.

[0107] In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and magnetic therapy (e.g., a pulsed magnetic field, e.g., a static magnetic field), optionally administering the SHP-1 inhibitor at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and magnetic therapy (e.g., a pulsed magnetic field, e.g., a static magnetic field), wherein the SHP-1 inhibitor and magnetic therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day between each subsequent dose of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor is administered systemically and the method comprises administering magnetic therapy to the site of the cancer being treated.In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0108] In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and electrical or electrochemical therapy, optionally administering the SHP-1 inhibitor at least twice (at least three, four, five, or six times). In some embodiments, methods are provided for treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer), comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and electrical or electrochemical therapy, wherein the SHP-1 inhibitor and electrical or electrochemical therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day between each subsequent dose of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor is administered systemically and the method comprises administering electrical or electrochemical therapy to the site of the cancer being treated.In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0109] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and electrostatic therapy, optionally administering the SHP-1 inhibitor at least twice (at least three, four, five, or six times). In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual is provided, comprising administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and electrostatic therapy, wherein the SHP-1 inhibitor and electrostatic therapy are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice with at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice with 2, 3, 4, 5, 6, 7, 8, 9, or 2 days between each dose. In some embodiments, the SHP-1 inhibitor is administered at least one day between each subsequent dose of the SHP-1 inhibitor. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor is administered systemically and the method comprises administering electrostatic therapy to the site of the cancer being treated. In some embodiments, the SHP-1 inhibitor is administered systemically and intratumorally.In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0110] In some embodiments, a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual comprises administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof), wherein the individual is selected for treatment based on the individual exhibiting an inflammatory response. In some embodiments, the individual exhibits an acute inflammatory response. In some embodiments, the inflammatory response occurs within the tumor. In some embodiments, the inflammatory response occurs at a site separate from the tumor. In some embodiments, the individual exhibits an inflammatory response as defined by: a) an increase in one or more (e.g., at least 1, 2, 3, 4, 5) pro-inflammatory cytokines (e.g., IFNγ, IL-12b, TNFα, IL-6, IL-1b, IFN-a1, IFN-a2, IFN-b1, etc.); b) a decrease in one or more (e.g., at least 1, 2, or 3) anti-inflammatory cytokines (e.g., TGFb1, TGFb2, TGFb3, etc.); c) an increase in infiltrating immune cells (e.g., T cells, NK cells, macrophages, etc.); In some embodiments, the patient exhibits an inflammatory response accompanied by at least two (e.g., two, three, four, or five) events selected from the group consisting of: a) an increase in immune cells (e.g., lymphocytes, neutrophils, etc.), b) a decrease in inhibitory immune cells (e.g., MDSCs), and / or c) an increase in one or more (e.g., at least one, two, three, four, or five) immunogenic costimulatory molecules (e.g., CD80, CD86, OX40L, CD40, ICOS-L, PD-L1, GITRL, etc.) in tissue (e.g., tumor tissue) or immune cells (e.g., macrophages). In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for a period not exceeding two or three consecutive days, optionally administered at least twice with an interval of at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, the SHP-1 inhibitor is administered at least 1 day apart from the previous or next administration of the SHP-1 inhibitor, respectively.In some embodiments, the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein formulations (e.g., antibody formulations targeting 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 derivative thereof, vitamin E derivatives, homoxanthone A (PXA), and PKC theta activators. In some embodiments, the SHP-1 inhibitor is administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to an individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0111] In some embodiments, a method of treating cancer in an individual (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) comprises administering to the individual an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof), wherein the individual is selected for treatment on the basis that the individual is experiencing immunogenic cell death (ICD). In some embodiments, the individual is determined to be experiencing ICD if a sample obtained from the cancer contains a higher level (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) of one or more DAMPs than a reference sample (e.g., a corresponding sample from a healthy control, e.g., a sample from the cancer prior to administration of an ICD-inducing therapy). In some embodiments, the SHP-1 inhibitor is administered intermittently. In some embodiments, the SHP-1 inhibitor is administered daily for no more than two or three consecutive days, optionally at least twice, with an interval of at least one day between each dose. In some embodiments, the SHP-1 inhibitor is administered at least three, four, or five times. In some embodiments, the SHP-1 inhibitor is administered at least twice, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 2 days apart. In some embodiments, the SHP-1 inhibitor is administered at least one day after each administration of the previous or next SHP-1 inhibitor. In some embodiments, the DAMP is selected from the group consisting of endoplasmic reticulum (ER) chaperones (e.g., calreticulin (CALR), e.g., heat shock proteins (HSPs)), the non-histone chromatin-binding protein high mobility group box 1 (HMGB1), the cytoplasmic protein annexin A1 (ANXA1), and the small molecule metabolites ATP and type I interferon (IFN). In some embodiments, the SHP-1 inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., siRNA, shRNA, antisense RNA, microRNA), a nucleic acid editing method (e.g., CRISPR method), and a protein formulation (e.g., an antibody formulation targeting 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 derivative thereof, a vitamin E derivative, homoxanthone A (PXA), and a PKCθ activator. In some embodiments, the SHP-1 inhibitor is administered at least twice (e.g., at least three, four, five, or six times). In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual at least twice, no more than once every three days. In some embodiments, the method comprises administering the SHP-1 inhibitor to the individual in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 to about 20 days. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously, e.g., subcutaneously) and / or locally (e.g., intratumorally). In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0112] In some embodiments, the present application provides a method of treating cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a terminal cancer) in an individual, the method comprising administering to the individual: a) monocytes or macrophages with deficient expression or inhibited activation of SHP-1, and b) a pro-inflammatory agent (e.g., a TLR agonist, e.g., R848, e.g., radiation therapy). In some embodiments, the monocytes or macrophages are derived from the same individual. In some embodiments, the monocytes or macrophages are engineered to express a chimeric receptor that targets a tumor antigen. In some embodiments, the monocytes or macrophages and the pro-inflammatory agent are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of one another. In some embodiments, the monocytes or macrophages and the pro-inflammatory agent are administered simultaneously, concurrently, or sequentially. In some embodiments, the monocytes or macrophages are administered before the administration of the pro-inflammatory agent. In some embodiments, the monocytes or macrophages are administered after administration of the pro-inflammatory agent. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0113] The present application also provides a method for modulating monocytes or macrophages from an individual with cancer, the method comprising contacting the monocytes or macrophages with an SHP-1 inhibitor and an inflammation-inducing agent. In some embodiments, the monocytes or macrophages are derived from the same individual. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, 10 days, 1 week, 48 hours, or 24 hours), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the inflammation-inducing agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0114] The present application also provides a method for activating phagocytosis of tumor cells in an individual bearing a tumor, comprising administering an SHP-1 inhibitor to the individual, wherein the individual a) has previously received, is currently receiving, or will soon receive an inflammatory agent, or b) is exhibiting an inflammatory response or has a persistent infection. In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., intravenously or subcutaneously). The present application also provides a method for activating tumor-infiltrating T cells in an individual bearing a tumor, comprising administering an SHP-1 inhibitor to the individual, wherein the individual a) has previously received, is currently receiving, or will soon receive an inflammatory agent, or b) is exhibiting an inflammatory response or has a persistent infection. In some embodiments, the method comprises administering an SHP-1 inhibitor to the individual at least twice, no more frequently than once every three days. In some embodiments, the method comprises administering to the individual an SHP-1 inhibitor in at least two cycles, wherein the SHP-1 inhibitor is administered at least once in each cycle, and each cycle lasts from about 3 days to about 20 days. In some embodiments, the pro-inflammatory agent and the SHP-1 inhibitor are administered within 24 hours of each other. In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, and an oncolytic virus. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and / or suppresses the inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNFα antibody or an anti-IL6 antibody).In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally administered prior to (e.g., within 2 weeks, within 10 days, within 1 week, within 48 hours, or within 24 hours of), concurrently or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hours of) administering the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and / or the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0115] We also found that the potent inhibitory control mediated by intratumoral iR and SHP-1 primarily relies on physical contact between cancer cells and macrophages. Separating cancer cells from macrophages using a transwell, which prevents contact between cancer cells and macrophages while allowing the delivery of soluble factors, did not result in strong inhibition of macrophage proinflammatory responses. For example, see Figure 19. Combining iR blockade (e.g., antibodies, fusion proteins, or other agents that block a) interacting sialic acid proteoglycan-derived SIGLECs, b) interacting LILRB or MHC, c) CD47 or SIRPa, d) lectin receptors, or e) signaling lymphocyte activation molecule family (SLAMF) receptors or their ligands) effectively suppresses iR-mediated inhibition, allowing macrophages to activate toward inflammation (as evidenced by the increase in cytokines shown in Figure 27).

[0116] Thus, it is contemplated that iR blocking agents (e.g., antibodies, fusion proteins, or other agents that block the interaction of SIGLEC with sialic acid proteoglycan ligands, LILRB with MHC, CD47 with SIRPα, lectins with lectin receptors, or signaling lymphocyte activation molecule family (SLAMF) receptors and their ligands), particularly combinations of these blocking agents, may be used as an alternative to SHP-1 inhibitors in the methods described herein. See, e.g., Figure 27C. In some embodiments, methods of treating cancer are provided, comprising administering at least two or three blocking agents that block various interactions selected from the group consisting of SIGLEC with sialic acid proteoglycans, LILRB with MHC, CD47 with SIRPa, lectins with lectin receptors, signaling lymphocyte activation molecule family (SLAMF) receptors and their ligands, and optionally, pro-inflammatory agents.

[0117] Blocking agents described herein include, for example, any agent that can a) reduce binding of an inhibitory receptor to its ligand as measured by spectroscopic assays, isothermal titration calorimetry (ITC), optical biosensors such as surface plasmon resonance (SPR), biolayer interferometry (BLI), or grating binding interferometry (GCI), and / or b) any agent that can suppress activation of an inhibitory receptor by at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as measured by, for example, Western blot of activated downstream signaling. Exemplary blocking agents include, for example, blocking antibodies that bind to an iR or its ligand.

[0118] In some embodiments, the method comprises administering to an individual in need thereof a) a CD47 and SIRPa blocker (e.g., an anti-CD47 antibody (e.g., B6H12) or an anti-SIRPa antibody), b) a LILRB and MHC blocker (e.g., an antibody against LILRB1, LILRB2, and / or LILRB3, e.g., an antibody against HLA-A, HLA-B, and / or HLA-C), c) a SIGLEC and sialic acid proteoglycan blocker (e.g., anti-Siglec-9, anti-Siglec-7, anti-Siglec-8, e.g., neuraminidase), and optionally d) a pro-inflammatory agent (e.g., a TLR agonist, a STING activator). In some embodiments, the methods comprise administering a) neuraminidase, b) anti-CD47 antibody, c) anti-HLA-A / B / C, and optionally d) a pro-inflammatory agent (e.g., a TLR agonist, a STING activator) to an individual in need thereof. Exemplary antibodies against iR or its ligand are shown in Figure 27B. In some embodiments, the individual has a persistent infection and does not require treatment with a pro-inflammatory agent. Tumor microenvironment (TME) immunosuppression and SHP-1 signaling

[0119] Src homology region 2 (SH-2) domain-containing phosphatase 1 (SHP-1) is a non-receptor tyrosine phosphatase encoded by the PTPN6 gene, located on human chromosome 12p13 and containing two promoter regions (in exons 1 and 2). Two forms of SHP-1 are produced, differing in their N-terminal amino acid sequences but possessing similar phosphatase activity. Promoter I is activated in non-hematopoietic cells, whereas promoter II is activated in hematopoietic-derived cells. In some epithelial cancer cells, both promoters are functional, generating various alternative SHP-1 transcripts. The two SHP-1 isoforms exhibit distinct subcellular localizations: type I is primarily located in the nucleus, while type II is present in the cytoplasm, suggesting that they have distinct targets.

[0120] SHP-1 is a 595-amino acid protein consisting of two consecutive N-terminal SH2 domains (N-SH2 and C-SH2), a classical catalytic protein tyrosine phosphatase (PTP) domain, and a C-terminal tail containing multiple phosphorylation sites. Its crystal structure revealed a structure in which the N-SH2 domain binds to the catalytic site of the protein via charge-charge interactions. In this autoinhibited, inactive state, substrate access to the activation site is blocked. However, binding of a phosphotyrosine residue to the SH2 domain induces a conformational change that impairs the interaction between the N-SH2 domain and the catalytic domain. This opens the conformation, allowing substrate access to the activation site, which is further stabilized by new interactions between the SH2 domain and the catalytic domain. These molecular rearrangements determine the sophisticated regulatory mechanisms controlled by substrate recruitment.

[0121] An additional activation mechanism is mediated by phosphorylation of amino acids within the C-terminal tail. Three phosphorylation sites have been identified: two tyrosines (Tyr536 and Tyr564) and a serine (Ser591) residue. Tyr536 and Tyr564 ​​are phosphorylated upon various stimuli (i.e., insulin stimulation or apoptosis-inducing agents), resulting in increased SHP-1 activation. Although the molecular mechanism is unclear, it has been proposed that Tyr phosphorylation induces interaction with the N-SH2 domain, thereby relieving the inhibitory effect of this domain on PTPase activation. SHP-1 activation can also be negatively regulated by protein kinase C (PKC) or mitogen-activated protein kinase (MAPK) via phosphorylation of Ser591, although the inhibitory mechanism is not fully understood.

[0122] Protein tyrosine phosphorylation is a reversible post-translational modification that is tightly controlled by both kinases and phosphatases. Any deviation in the phosphorylation / dephosphorylation balance can promote the intracellular accumulation of tyrosine-phosphorylated proteins, resulting in altered regulation of cellular processes, including cell proliferation, migration, invasion, differentiation, survival, and trafficking. In this scenario, SHP-1 acts as a classic tumor suppressor, primarily involved in the homeostatic maintenance of all of these processes. Indeed, SHP-1 function is altered in both human solid and hematologic cancers via somatic mutations or epigenetic mechanisms. In addition to its well-documented role in regulating hematopoietic cell biology, SHP-1 has now been shown to correlate with several signaling pathways associated with cancer initiation and progression.

[0123] However, inhibition of SHP-1 is associated with severe side effects. SHP-1 gene-deficient mice, mothaten mice (me / me or me v / me v Studies of SHP-1 have shown that the total loss of SHP-1 is associated with severe immunological abnormalities and immune cell hyperactivation (6, 7). Motheaten mice typically suffer from life-threatening autoimmune inflammatory diseases during infancy. Even partial depletion of SHP-1 in WT mice after they reached adulthood resulted in the development of inflammatory disease characteristics, including widespread lung inflammation and splenomegaly. Although SHP-1 inhibition may enhance anti-cancer immunity, it is a double-edged sword that inevitably endangers the host by enhancing inflammatory responses, cytokine storms, and autoimmunity.

[0124] Development of inhibitors targeting SHP-1 phosphatase activation has been ongoing, with several currently in preclinical studies, including NSC-87877, sodium stibogluconate (SSG), tyrosine phosphatase inhibitor 1 (TPI-1 or its analogs or derivatives), and suramin. However, only a few of these have demonstrated activity in experimental tumor models. SSG has undergone Phase I trials for both malignant melanoma (NCT00498979) and advanced malignancies (NCT00629200). This drug has been administered in combination with interferon, with or without chemotherapy. Unfortunately, no effect on tumor development has been observed, and the most common toxic side effects are thrombocytopenia, elevated serum lipase, fatigue, fever, chills, anemia, hypokalemia, pancreatitis, and skin rash (observed in up to 68% of patients). Currently, no SHP-1 inhibitors are in Phase II trials. Drugs that reduce systemic inflammation

[0125] In some cases, individuals develop systemic inflammation, i.e., cytokine release syndrome (CRS), after receiving (for example) immunotherapy treatment, a poorly understood inflammatory disease. CRS can be induced by direct target cell lysis and the sequential release of cytokines such as TNFα or IFNγ, or by therapeutic stimulation-induced T cell activation and subsequent cytokine release. These cytokines trigger a chain reaction by activating innate immune cells such as macrophages and endothelial cells, which then induces the release of additional cytokines. In particular, IL6, IL10, and IFNγ are most commonly found elevated in CRS patients.

[0126] The methods described herein may further include administering an agent that reduces systemic inflammation (e.g., including an agent that suppresses the inflammatory cascade or cytokine storm) to suppress systemic inflammation and reduce harmful toxicity. Agents that reduce systemic inflammation include, but are not limited to, inhibitors of TNFα, IL6, IL10, and IFNγ. In some embodiments, the agent that reduces systemic inflammation is administered simultaneously with the SHP-1 inhibitor. In some embodiments, the agent that reduces systemic inflammation is administered sequentially with (e.g., before or after) the SHP-1 inhibitor. In some embodiments, the administration of the agent that reduces systemic inflammation follows the same dosing schedule as the SHP-1 inhibitor. In some embodiments, the agent that reduces systemic inflammation is administered at a sub-therapeutic dose, i.e., a dose lower than the amount that would be effective to treat the disease if administered alone. In some embodiments, the administration of the agent that reduces systemic inflammation allows for more frequent administration of the SHP-1 inhibitor and / or the pro-inflammatory agent (e.g., daily, once every two days, once every three days, etc.).

[0127] The agent can include any anti-inflammatory agent known in the art, including an inhibitor of an inflammatory agent or an antagonist to an inflammatory agent. For example, the agent can include, but is not limited to, a small molecule inhibitor, a neutralizing antibody, a receptor-blocking antibody, a soluble receptor, a targeting short interfering RNA (siRNA), a chemical inhibitor of mRNA stability and its derivatives, and any combination thereof (e.g., a combination of agents targeting one or more molecules (e.g., TNFα inhibition alone, IL6 inhibition alone, TNFα and IL6 inhibition combined, etc.)). Anti-TNFα antagonists

[0128] TNFα, a major pro-inflammatory cytokine, is secreted by activated macrophages, monocytes, and lymphocytes. The present inventors have surprisingly found that administering an anti-TNFα antibody to an individual treated with an SHP-1 inhibitor and an inflammation-inducing agent mitigates the toxicity caused by systemic inflammation without compromising the efficacy of the therapeutic agent.

[0129] Thus, in some embodiments, the methods of the present application comprise administering a TNFα inhibitor, e.g., an anti-TNFα antagonist (e.g., when the pro-inflammatory agent is not TNFα). In some embodiments, the TNFα inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNFα receptor-blocking antibody, a soluble TNFα receptor, a TNFα-targeting short interfering RNA (siRNA), a chemical inhibitor of TNFα mRNA stability, a TNFα-converting enzyme (TACE) inhibitor, and derivatives thereof. In some embodiments, the TNFα inhibitor is an anti-TNFα neutralizing antibody. In some embodiments, the TNFα inhibitor is an anti-TNFα receptor-blocking antibody. In some embodiments, the anti-TNFα antibody is a monoclonal antibody. In some embodiments, the anti-TNFα antibody is a chimeric antibody, a humanized antibody, and / or a fully human antibody.

[0130] Suitable antibodies for use in the methods provided herein include, but are not limited to, Remicade® (infliximab (Centocor)) and antibodies described in, for example, U.S. Pat. Nos. 6,835,823, 6,790,444, 6,284,471, 6,277,969, 5,919,452, 5,698,195, 5,656,272, and 5,223,395, and European Patent No. 0610201 (the contents of each of which are incorporated herein by reference in their entirety), or antibodies that bind to the same epitope as Remicade®. Other suitable anti-TNFα antibodies for use in the methods provided herein include, by way of non-limiting example, Humira (adalimumab (Abbott Laboratories, Esai)), described in U.S. Pat. Nos. 6,090,382, 6,258,562, or 6,509,015, and related patents and applications, the contents of which are incorporated herein by reference in their entireties; Simponi™ (golimumab, CNTO148 (Centocor)), described in PCT Publication No. WO 02 / 12502, and related patents and applications, the contents of which are incorporated herein by reference in their entireties; ART621 (Arana Therapeutics); SSS 07 (Epitopmics and 3SBio); or an antibody that binds to the same epitope as Humira, Simponi, ART621, or SSS 07.

[0131] In some embodiments, the TNFα inhibitor, e.g., an anti-TNFα antagonist, is a fusion protein. Suitable fusion proteins for use in the methods provided herein include, but are not limited to, Enbrel (etanercept (Amgen)) and other fusion proteins or fragments thereof described in U.S. Patent No. 5,712,155, PCT Publication No. WO 91 / 03553, and related patents and applications, the contents of which are incorporated herein by reference in their entireties.

[0132] In some embodiments, the TNFα inhibitor, e.g., anti-TNFα antagonist, is a modified antibody antagonist or a non-antibody-based antagonist. Such antagonists include Cimzia™ (certolizumab pegol, CDP870 (Enzon)), bispecific antibodies, Nanobodies® such as ABX0402 (Ablinx), immunotoxins, and radiolabeled therapeutics; peptide therapeutics; gene therapy, particularly intrabodies; oligonucleotide therapeutics such as aptamer therapy, antisense therapy, and interfering RNA therapy; and advanced antibody therapeutics such as antibody fragments, including but not limited to small molecules such as LMP-420 (LeukoMed), as described in EP 0767793 and related patents and applications (the contents of which are incorporated herein by reference in their entirety).

[0133] In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered 2 weeks, 10 days, or 1 week prior to administration of the SHP-1 inhibitor and / or pro-inflammatory agent described herein. Exemplary TNFα inhibitors, such as anti-TNFα antibodies, are typically stable for at least 1 or 2 weeks. In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered in parallel or simultaneously with the SHP-1 inhibitor and / or pro-inflammatory agent. In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered shortly (e.g., within 1 hour or 30 minutes) after administration of the SHP-1 inhibitor and / or pro-inflammatory agent.

[0134] In some embodiments, the TNFα inhibitor is administered systemically. In some embodiments, the TNFα inhibitor is administered at least once weekly, once every 5 days, once every 3 days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα inhibitor is administered to the individual in at least two cycles, each cycle lasting from about 3 to about 7 days. In some embodiments, the individual does not develop cytokine release syndrome or inflammation-induced organ damage. In some embodiments, administration of the TNFα inhibitor does not impair or only slightly impairs tumor clearance.

[0135] Anti-IL6 antagonist An "anti-IL6 antagonist" or "IL6 inhibitor" refers to an agent that inhibits or blocks the biological activation of IL6 through binding to IL6 or the IL6 receptor. In some embodiments, the anti-IL6 antagonist is an antibody. In one embodiment, the anti-IL6 antagonist is an antibody that binds to the IL6 receptor. Antibodies that bind to the IL-6 receptor include tocilizumab (including their intravenous, i.v., and subcutaneous, sc, formulations) (Chugai, Roche, Genentech), satralizumab (Chugai, Roche, Genentech), sarilumab (Sanofi, Regeneron), NI-1201 (Novimmune and Tiziana), and bovalilizumab (Ablinx). In one embodiment, the anti-IL6 antagonist is a monoclonal antibody that binds to IL6. Antibodies that bind to IL-6 include sirukumab (Centecor, Janssen), olokizumab (UCB), clazakizumab (BMS and Alder), siltuximab (Janssen), and EBI-031 (Eleven Biotherapeutics and Roche). In one embodiment, the IL6 antagonist is olamuxcept.

[0136] In some embodiments, the IL6 inhibitor is administered systemically. In some embodiments, the IL6 inhibitor is administered at least once a week, once every 5 days, once every 3 days, or daily. In some embodiments, the IL6 inhibitor is administered intermittently. In some embodiments, the IL6 inhibitor is administered to an individual in at least two cycles, each cycle lasting from about 3 to about 7 days.

[0137] SHP-1 inhibitors The SHP-1 inhibitor referred to herein is any type of agent that inhibits the expression or activation of SHP-1. In some embodiments, the SHP-1 inhibitor directly targets SHP-1. In some embodiments, the SHP-1 inhibitor targets a molecule other than SHP-1 that is involved in the SHP-1 signaling pathway in macrophages.

[0138] In some embodiments, the SHP-1 inhibitor is capable of inhibiting SHP-1 activation by at least about 20% (e.g., at least 20%, 30%, 40%, or 50%). In some embodiments, the SHP-1 inhibitor is capable of inhibiting SHP-1 expression by at least about 20% (e.g., at least 20%, 30%, 40%, or 50%).

[0139] In some embodiments, the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein formulations (e.g., antibody formulations that target SHP-1 or activated SHP-1 (e.g., dominant-negative SHP-1 or constitutively active SHP-1 mutants)), protein formulations containing an SH2 domain (which compete for binding to ITIM motifs and inhibit SHP-1 activation), and tyrosine kinase inhibitors that inhibit ITIM phosphorylation.

[0140] In some embodiments, the SHP-1 inhibitor does not significantly inhibit SHP-2 (eg, inhibits SHP-2 activation by no more than 50%, 40%, 30%, or 20%).

[0141] In some embodiments, the SHP-1 inhibitor also inhibits SHP-2.

[0142] In some embodiments, the SHP-1 inhibitor has a half-life of about 10 days, 9 days, 8 days, or 7 days or less (e.g., a half-life of about 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day or less).

[0143] In some embodiments, the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation within about 10, 9, 8, 7, 6, or 5 days, hi some embodiments, the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation within about 4, 3, 2, or 1 day.

[0144] In some embodiments, the SHP-1 inhibitor is a covalent inhibitor. In some embodiments, the SHP-1 inhibitor is a non-covalent inhibitor.

[0145] In some embodiments, the SHP-1 inhibitor is a competitive inhibitor. In some embodiments, the SHP-1 inhibitor is homoxanthone A (PXA) or homoxanthone B (PXB). See, for example, Yang et al., ACS Omega. 2020 Sep 29; 5(40): 25927-25935.

[0146] 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 described by 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 that target the catalytic site) are known in the art. For example, recombinant proteins of the SHP-1 catalytic domain can be used to screen for and identify SHP-1 inhibitors that target the catalytic site. SHP-1 inhibitory activation can be assessed by various methods, such as a rapid SHP-1 PTP assay. See "Materials and Methods" in Kundu et al.

[0147] In some embodiments, the SHP-1 inhibitor targets an allosteric or regulatory site. For example, see Wang et al. J Cell Biochem. 2011 Aug;112(8):2062-2071 for the structure of SHP-1.

[0148] In some embodiments, the SHP-1 inhibitor is TPI-1, its derivative or analog. Exemplary analogs include those disclosed in Kundu et al. (J Immunol. 2010 Jun1; 184(11):6529-6536). See, for example, Figure 6 of Kundu et al.

[0149] In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0150] In some embodiments, the SHP-1 inhibitor is a PTP-I.

[0151] In some embodiments, the SHP-1 inhibitor is vitamin E. In some embodiments, the SHP-1 inhibitor is tocophersolan (TPGS). In some embodiments, the SHP-1 inhibitor is alpha-tocopherol acetate (alphaTA). In some embodiments, the SHP-1 inhibitor is alpha-tocopheryl succinate (alphaTOS).

[0152] In some embodiments, the SHP-1 inhibitor is homoxanthone A (PXA).

[0153] In some embodiments, the SHP-1 inhibitor is a PKC theta activator (such as PMA).

[0154] In some embodiments, the SHP-1 inhibitor is an siRNA or shRNA that inhibits or knocks down the amount of endogenous SHP-1 protein. See, e.g., WO2009 / 023333.

[0155] 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.

[0156] In some embodiments, the SHP-1 inhibitor is a nucleic acid editing method (such as CRISPR method). In some embodiments, CRISPR components are introduced into cells (e.g., monocytes and macrophages), but the DNA encoding guide RNA or Cas9 is not integrated into the genome of the cell. Under this approach, the CRISPR method cuts the genomic DNA of the cell for a limited period of time. See, for example, Fister et al., Front Plant Sci. 2018 Mar2;9:268.

[0157] 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.

[0158] In some embodiments, the SHP-1 inhibitor (eg, TPI-1 or an analog or derivative thereof) is administered at least twice (eg, at least three, four, five, or six times).

[0159] In some embodiments, the method comprises administering an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) at least twice (e.g., at least three, four, five, or six times) at intervals of no more than once every two days.

[0160] In some embodiments, the method comprises administering an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) at least twice (e.g., at least three, four, five, or six times) at intervals of no more than once every three days.

[0161] In some embodiments, the method comprises administering an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) in at least two cycles. In some embodiments, the SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) is administered at least once (e.g., two, three, or four times) in each cycle. In some embodiments, each cycle lasts from about 3 to about 50 days (e.g., from about 3 to 40 days, from about 3 to 30 days, from about 3 to 20 days, from about 3 to 15 days, from about 3 to 10 days, or from about 2 to 10 days).

[0162] In some embodiments, the SHP-1 inhibitor is administered systemically (e.g., orally, intravenously, subcutaneously, intraperitoneally). In some embodiments, the SHP-1 inhibitor is administered locally (e.g., intratumorally). In some embodiments, the SHP-1 inhibitor is administered both systemically and locally (e.g., intratumorally).

[0163] In some embodiments, the SHP-1 inhibitor is complexed with a delivery vehicle prior to administration to an individual. In some embodiments, the delivery vehicle facilitates delivery into the tumor.

[0164] In some embodiments, an SHP-1 inhibitor modulates monocytes or macrophages in vitro (eg, monocytes or macrophages derived from the individual being treated).

[0165] In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered within 24 hours (e.g., within 12 hours, 8 hours, 4 hours, 2 hours, or 1 hour, or within 30 minutes) of 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 before the pro-inflammatory agent. In some embodiments, the SHP-1 inhibitor is administered after the pro-inflammatory agent.

[0166] Inflammatory agents Infection and tissue injury are two classic triggers of inflammation. See, e.g., Medzhitov, Nature. 2008 Jul 24;454(7203):428-35. Proinflammatory agents, as described herein, include at least two overlapping categories: 1) any agent or therapy that can promote inflammation (e.g., by promoting one or more proinflammatory cytokines or chemokines, inhibiting one or more anti-inflammatory cytokines or chemokines, recruiting macrophages, NK cells, neutrophils, effector T cells, or B cells to tissues, activating any of these cells, or suppressing regulatory / suppressive immune cells, such as regulatory T cells or MDSCs), and 2) any agent or therapy that can cause cancer cell damage (e.g., cancer cell necrosis).

[0167] In some embodiments, the proinflammatory agent induces proinflammatory signals on macrophages. See, e.g., Figure 5A. In some embodiments, the proinflammatory agent activates TLR, TNFR, or ITAM-R. See Lionel et al., Eur J Immunol. 2011 Sep;41(9):2477-2481. The proinflammatory agent can activate proinflammatory signals on macrophages via direct or indirect methods. For example, TLR agonists, which directly activate TLRs on macrophages, and radiation therapy, which indirectly activates proinflammatory signals on macrophages, both showed significant antitumor effects when used with SHP-1 inhibitors. See the Examples.

[0168] Exemplary pro-inflammatory agents include TLR agonists, STING activators, radiation therapy, PAMP / DAMP activators, checkpoint inhibitors, pro-inflammatory cytokines or chemokines, chemotherapeutic drugs, bacterial components, cancer vaccines, and oncolytic viruses. Other exemplary pro-inflammatory agents include acoustic therapy (e.g., high-intensity focused ultrasound), magnetic therapy, electrical therapy, and electrostatic therapy, which can kill cancer cells. See, for example, Naud et al., Nanoscale Adv., 2020, 2, 3632-3655; Rominiyi et al., Br J Cancer. 2021 Feb; 124(4): 697-709; Zandi et al., Cancer Med. 2021 Nov; 10(21): 7475-7491.

[0169] In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine or chemokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy (e.g., high intensity focused ultrasound), magnetic therapy, electrical therapy, and electrostatic therapy.

[0170] In some embodiments, the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP / DAMP activator, a pro-inflammatory cytokine or chemokine, a bacterial component, a cancer vaccine, acoustic therapy (e.g., high intensity focused ultrasound), magnetic therapy, electrical therapy, and electrostatic therapy.

[0171] In some embodiments, the pro-inflammatory agent is acoustic therapy (e.g., high intensity focused ultrasound (HIFU), e.g., low intensity focused ultrasound (LIPUS)). See, e.g., Wood et al., Ultrasound Med Biol. 2015 Apr; 41(4): 905-928; Sengupta et al., J Adv Res. 2018 Nov; 14: 97-111.

[0172] In some embodiments, the pro-inflammatory agent is magnetic therapy (e.g., a pulsed magnetic field, e.g., a static magnetic field). See, e.g., Tatarov et al., Comp Med. 2011 Aug; 61(4): 339-345; Sengupta et al., J Adv Res. 2018 Nov; 14: 97-111.

[0173] In some embodiments, the pro-inflammatory agent is an electrical or electrochemical therapy. See, e.g., Ciria et al., Chin J Cancer Res. 2013 Apr;25(2):223-234; Das et al., Front Bioeng Biotechnol. 2021;9:795300.

[0174] In some embodiments, the pro-inflammatory agent is electrostatic therapy. See, e.g., Zandi et al., Cancer Med. 2021 Nov;10(21):7475-7491.

[0175] In some embodiments, the pro-inflammatory agent is thermoacoustic therapy. See, e.g., Wen et al., Theranostics. 2017;7(7):1976-1989.

[0176] In some embodiments, the pro-inflammatory agent comprises a microorganism (e.g., a fragment or lysate of a microorganism). Examples of microorganisms include bacteria, fungi, and viruses.

[0177] In some embodiments, the pro-inflammatory agent comprises a TLR agonist (eg, R848) and a cytokine (eg, IFN-gamma).

[0178] TLR agonists In some embodiments, the pro-inflammatory agent comprises or is a TLR agonist.

[0179] TLRs play an important role in activating the immune response. They recognize not only pathogen-associated molecular patterns (PAMPs) expressed by various microorganisms but also endogenous DAMPs released by stressed or dying cells. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are expressed on the cell surface, while TLR3, TLR7, TLR8, and TLR9 are located intracellularly in the endosomal membrane. TLR1 and TLR2 heterodimerize to recognize various bacterial lipid structures and cell wall components, such as triacylated lipoproteins, lipoteichoic acid, and β-glucan. TLR2 also heterodimerizes with TLR6 to bind diacylated lipopeptides. Furthermore, TLR2 can bind to various endogenous DAMPs, such as HSPs, HMGB1, uric acid, fibronectin, and other extracellular matrix proteins. It has also been shown that TLR1 and TLR6 can form heterodimers with TLR10, but the TLR agonist recognized by this dimer has not yet been identified. TLR3 recognizes viral dsRNA as well as synthetic analogs of dsRNA, such as the ligand poly I:C. TLR4 binds to LPS in complex with lipid A-binding protein, CD14, and myeloid differentiation protein 2 (MD2), and recognizes various DAMPs. Reported endogenous TLR4 ligands include β-defensin 2, fibronectin extra domain A (EDA), HMGB1, snapin, and tenascin-C. TLR5 recognizes bacterial flagellin, while TLR7 and TLR8 bind viral ssRNA. Meanwhile, TLR9 interacts with unmethylated CpG DNA from bacteria and some viruses. More recently, additional TLRs have been identified in mice based on highly conserved sequence homology of their TIR domains. TLR10 is a surface receptor whose natural ligand remains unknown. TLR11, TLR12, and TLR13 are present in mice but not in humans. TLR11 has been shown to bind to T. gondii profilin and uropathogenic E. coli. The ligand for TLR12 has yet to be identified. Meanwhile, TLR13 is an endosomal receptor that recognizes VSV.See, e.g., Kaczanowska et al., J Leukoc Biol. 2013 Jun;93(6):847-63.

[0180] TLR signaling can act as a double-edged sword in cancer. It has become clear that stimulation of TLRs in cancer cells can contribute to either tumor progression or tumor suppression. For example, stimulation of TLR2, TLR4, and TLR7 / 8 has been shown to promote tumor progression through the production of immunosuppressive cytokines, increase cell proliferation, and increase resistance to apoptosis. R848 stimulation of TLR7 / 8-overexpressing pancreatic cancer cell lines increased cell proliferation and reduced chemosensitivity. Meanwhile, stimulation of TLR2, TLR3, TLR4, TLR5, TLR7 / 8, and TLR9, often in combination with chemotherapy or immunotherapy, can result in tumor inhibition through various pathways. See, for example, Grimmig et al., Int J Oncol. (2015) 47:857-66; Urban-Wojciuk et al., Front Immunol. 2019;10:2388.

[0181] In some embodiments, the TLR agonist activates any of the TLRs.

[0182] In some embodiments, the TLR agonist activates TLR1 or TLR2, and optionally, the TLR agonist comprises triacylated lipoprotein, peptidoglycan, zymosan, and / or Pam3CSK4.

[0183] In some embodiments, the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, and optionally, the TLR agonist comprises a diacylated lipopeptide, a heat shock protein, HMGB1, uric acid, fibronectin, and / or an ECM protein.

[0184] In some embodiments, the TLR agonist activates TLR2, and optionally, the TLR agonist comprises Pam3Cys, SMP-105, and / or CBLB612.

[0185] In some embodiments, the TLR agonist activates TLR3, and optionally, the TLR agonist comprises dsRNA, poly I:C, poly ICIC, poly-IC12U, IPH302, ARNAX, and / or MPLA.

[0186] In some embodiments, the TLR agonist activates TLR4, and optionally, the TLR agonist comprises LPS, lipoteichoic acid beta-defensin-2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, and / or GLA-SE.

[0187] In some embodiments, the TLR agonist activates TLR5, and optionally, the TLR agonist comprises flagellin, CBLB502, and / or M-VM3.

[0188] In some embodiments, the TLR agonist activates TLR6.

[0189] In some embodiments, the TLR agonist activates TLR7 or TLR8, and optionally, the TLR agonist comprises ssRNA, CpG-A, polyG10, and / or polyG3.

[0190] In some embodiments, the TLR agonist activates TLR7, and optionally, the TLR agonist comprises bistriazolyl and / or R848.

[0191] In some embodiments, the TLR agonist activates TLR8, and optionally, the TLR agonist comprises VTX1463 and / or R848.

[0192] In some embodiments, the TLR agonist activates TLR9, and optionally, the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and / or ODN M362.

[0193] In some embodiments, the TLR agonist activates TLR10, and optionally, the TLR agonist comprises Pam3CSK4.

[0194] In some embodiments, the TLR agonist activates TLR11, and optionally, the TLR agonist comprises Toxoplasma gondiiprofilin.

[0195] In some embodiments, the TLR agonist activates TLR12.

[0196] In some embodiments, the TLR agonist activates TLR13, and optionally, the TLR agonist comprises VSV.

[0197] In some embodiments, the TLR agonist activates a TLR on a macrophage.

[0198] In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and / or TLR9.

[0199] In some embodiments, the TLR comprises TLR1, TLR4, and / or TLR9. In some embodiments, the TLR comprises TLR9.

[0200] In some embodiments, the TLRs include TLR2, TLR4, TLR7, and / or TLR8.

[0201] In some embodiments, the TLR agonist comprises CpG. In some embodiments, the TLR agonist comprises poly I:C. In some embodiments, the TLR agonist comprises CpG and / or poly I:C. In some embodiments, the TLR agonist comprises CpG, poly I:C, and / or R848.

[0202] In some embodiments, the TLR agonist is R848, 3M-852A, motolimod, bropirimine, or vesatolimod. In some embodiments, the TLR agonist is R848.

[0203] In some embodiments, the methods described herein include assessing whether an individual is persistently infected. In some embodiments, if the individual is persistently infected, the dosage of the TLR agonist is reduced. In some embodiments, if the individual is persistently infected, administration of the TLR agonist is avoided.

[0204] Radiation therapy In some embodiments, the pro-inflammatory agent includes or is radiation therapy. Radiation activates an interconnected network of cytokines, adhesion molecules, ROS / RNS, and DAMPs, triggering a self-amplifying cascade that creates a pro-inflammatory, pro-oxidant tumor microenvironment and ultimately kills tumor cells. See, e.g., McKelvey et al., Mamm Genome. 2018;29(11):843-865.

[0205] In some embodiments, radiation therapy involves irradiating the site of the cancer being treated.

[0206] In some embodiments, the radiation therapy comprises irradiating a site different from the site of the cancer being treated.

[0207] In some embodiments, the radiation therapy is intraoperative radiation therapy ("IORT"). In certain embodiments, radiation is administered locally to the tumor site. The patient may receive intraoperative radiation therapy before or after tumor resection. The tumor site may contain various types of cells, including cancerous and benign cells. In certain embodiments, the radiation therapy is stereotactic body radiation therapy ("SBRT") or stereotactic radiosurgery ("SRS").

[0208] In some embodiments, the radiation is ionizing radiation, such as particle radiation. The particle radiation can be selected from electrons, protons, neutrons, heavy ions such as carbon ions, or ions. The ionizing radiation can be selected from X-rays, UV light, gamma rays, or microwaves. In some embodiments, radiation therapy can include treating the patient with one or more types of radiation therapy.

[0209] In some embodiments, radiosensitizers are used to increase the radiosensitivity of tumor cells. The use of such pharmaceuticals, called radiosensitizers, provides a method for increasing the radiosensitivity of tumors to radiation therapy, avoiding the need to increase the radiation dose to levels harmful to surrounding organs and tissues. See, e.g., US9656098B2.

[0210] In some embodiments, the radiation therapy dose is insufficient to eliminate the tumor (kill all tumor cells) without causing epidermal necrosis, hi some embodiments, the radiation therapy is selected from the group consisting of external beam radiation therapy, internal radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectants.

[0211] In some embodiments, the radiation therapy is external beam radiation therapy, optionally including three-dimensional conformal radiation therapy (3D-RT), intensity-modulated radiation therapy (IMRT), photon beam therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT).

[0212] In some embodiments, radiation therapy comprises administering a radiopharmaceutical. The radiopharmaceutical may be delivered via any vehicle, such as a cell, protein, or small molecule complex. In some embodiments, the radiopharmaceutical is administered to tumor tissue. For example, see Sgouros et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges Nat Rev Drug Discov 19, 589-608 (2020).

[0213] In some embodiments, the radiation therapy is brachytherapy, optionally including interstitial brachytherapy, intracavitary brachytherapy, intraluminal radiation therapy, and intravenously administered radiolabeled molecules.

[0214] STING activator In some embodiments, the pro-inflammatory agent comprises or is a STING activator.

[0215] Stimulator of IFN genes (STING, also known as TMEM173, MITA, MPYS, or ERIS) is a pattern recognition receptor (PRR) that recognizes cytoplasmic DNA in the form of cyclic dinucleotides (CDNs), such as the bacterial product cyclic guanosine monophosphate-adenosine monophosphate (3'3'cGAMP). Other DNA that enters the cytoplasm, including bacterial components as well as viruses and host cells, is recognized by the enzyme c-GMP-AMP (cGAMP) synthase (cGAS). Upon binding to cytoplasmic DNA, cGAS converts ATP and GTP to the metazoan-specific CDN 2'3'-cGAMP, triggering STING recognition and activation. STING is a transmembrane protein that exists as a dimer anchored within the endoplasmic reticulum membrane, forming a V-shaped pocket that allows cytoplasmic CDN binding. Ligand binding induces a conformational change in the C-terminal domain of STING, which mediates its transport to the Golgi compartment. In the Golgi, STING recruits Tank-binding kinase 1 (TBK1), which promotes IRF3 phosphorylation, nuclear translocation, and potent induction of type I IFN (e.g., IFN-β) transcription. STING also triggers a potent proinflammatory cytokine response [e.g., tumor necrosis factor (TNF)] by activating nuclear factor kappa B (NF-κB), and part of this pathway is independent of TBK1 and can be mediated through the closely related homolog protein, IKKε. See, e.g., Peng et al., Front Immunol. 2022 Feb 25; 13:794776; Amougezar et al., Cancers (Basel). 2021 May 30; 13(11):2695.

[0216] In some embodiments, the STING activator is cyclic guanosine monophosphate-adenosine monophosphate (cGAMP, e.g., 3'3'cGAMP, e.g., 2'3'cGAMP).

[0217] In some embodiments, the STING activator is a bacterial vector (e.g., SYNB1891, STACT-TREX-1).

[0218] 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).

[0219] 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).

[0220] In some embodiments, the STING activator is a nanovaccine (e.g., PC7ANP, cCAMP-NP, ONM-500).

[0221] In some embodiments, the STING activator is an antibody-drug conjugate (e.g., XMT-2056, CRD-5500).

[0222] Other exemplary STING activators include those described in Amougezar et al., Cancers (Basel). 2021 May 30; 13(11): 2695, which is incorporated herein by reference in its entirety.

[0223] PAMP / DAMP activator In some embodiments, the pro-inflammatory agent comprises or is a PAMP / DAMP activator.

[0224] Organisms sense microbial infections through genome-encoded innate immune receptors called pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), nucleotide-binding and oligomerization domain-like receptors (NOD-like receptors), and retinoic acid-inducible gene I (RIG-I)-like receptors. These receptors recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, fungi, and viruses, but also bind damage-associated molecular patterns (DAMPs), molecules released upon sterile injury. Thus, PAMPs and DAMPs that bind to the same receptor initiate the same intracellular pathways and culminate in the same effector functions. See, for example, Alisi et al., Hepatology. 2011 Nov;54(5):1500-2.

[0225] In some embodiments, the pro-inflammatory agent is a PAMP activator. Examples of PAMP activators include triacyl lipopeptides, LPS, lipoproteins, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porin, lipoarabinomannan, double-stranded RNA, poly(I:C), trepanosome lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial / viral DNA, CpG DNA, urea bacteria, and Toxoplasma LPS.

[0226] In some embodiments, the pro-inflammatory agent is a DAMP activator, examples of which include defensins, HSP60, HSP70, messenger RNA, small molecular weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, and unmethylated CpG DNA.

[0227] chemotherapy drugs In some embodiments, the pro-inflammatory agent comprises or is a chemotherapeutic agent.

[0228] In some embodiments, the chemotherapeutic agent is an alkylating agent. Examples of alkylating agents include nitrogen mustards (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkylsulfonates (e.g., busulfan), and ethylenimines (e.g., thiotepa).

[0229] In some embodiments, the chemotherapeutic agent is an antimetabolite. Examples of antimetabolites include cytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), and pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (a prodrug of 5-FU)).

[0230] In some embodiments, the chemotherapeutic agent is an anti-microtubule agent. Examples of anti-microtubule agents include topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin).

[0231] Other exemplary chemotherapeutic agents include hydroxyurea, tretinoin, arsenic trioxide, and proteasome inhibitors (eg, bortezomib). Proinflammatory cytokines

[0232] In some embodiments, the pro-inflammatory agent is a pro-inflammatory cytokine.

[0233] In some embodiments, the proinflammatory cytokine promotes M1 macrophages. See, e.g., Duque et al., Front Immunol. 2014;5:491. In some embodiments, the proinflammatory cytokine includes or is TNF, IFNγ, and / or GM-CSF.

[0234] In some embodiments, the proinflammatory cytokines include IL-6, TNFα, cytokines from the IL-1 family (e.g., IL-1α, IL-1β, IL-18, IL-33, and IL-36), and / or IFNγ.

[0235] In some embodiments, the proinflammatory cytokine comprises a cytokine from the IL-1 family. In some embodiments, the proinflammatory cytokine comprises any one or more of IL-1α, IL-1β, IL-18, IL-33, and IL-36. See, e.g., Sims, J., Smith, D. The IL-1 family: regulators of immunity. Nat Rev Immunol 10, 89-102 (2010).

[0236] Immune checkpoint inhibitors In some embodiments, the pro-inflammatory agent is a checkpoint inhibitor. Immune checkpoints are pathways with inhibitory or stimulatory characteristics that maintain self-tolerance and support immune responses. Most well-known immune checkpoints are inhibitory in nature, and examples include cytotoxic T-lymphocyte-associated molecule 4 (CTLA-4), programmed death receptor 1 (PD-1), and programmed death ligand 1 (PD-L1). See, e.g., Marin-Acevedo et al., J Hematol Oncol 14, 45 (2021).

[0237] In some embodiments, the checkpoint inhibitor targets CTLA-4, PD-1, or PD-L1 (e.g., an antibody that targets CTLA-4, PD-1, or PD-L1).

[0238] In some embodiments, the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A, PVRIG / PVRL2, CEACAM1, CEACAM5 / 6, FAK, CCL2 / CCR2, LIF, CD47 / SIRPα, CSF-1 (M-CSF) / CSF-1R, IL-1 / IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVA-1, Axl, or phosphatidylserine.

[0239] In some embodiments, the checkpoint inhibitor is selected from the group consisting of ipilimumab, cemiplimab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, LAG525 (IMP701), REGN3767, BI754,091, tebotelimab (MGD013), eftiragimod alfa (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, monalizumab, COM701, CM24, NEO-201, including or being 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.

[0240] Cancer vaccines In some embodiments, the pro-inflammatory agent includes or is a cancer vaccine. Cancer vaccines stimulate anti-tumor immunity using tumor antigens that can be delivered in the form of whole cells, peptides, nucleic acids, etc. An ideal cancer vaccine would overcome immunosuppression in tumors and induce both humoral and cellular immunity.

[0241] In some embodiments, the cancer vaccine comprises a cell-based vaccine, a peptide-based vaccine, a virus-based vaccine, and / or a nucleic acid-based vaccine. See, e.g., Liu et al., J Hematol Oncol 15, 28 (2022).

[0242] Cell-based vaccines are an early form of cancer vaccine. They are often prepared from whole cells or cell fragments and almost always contain tumor antigens, inducing a broader antigen-specific immune response. DC vaccines are an important branch of cell-based vaccines. DC-based personalized neoantigen cancer vaccines have shown promising antitumor efficacy in clinical trials. Viruses are inherently immunogenic, and their genetic material can be engineered to contain sequences encoding tumor antigens. Some recombinant viruses, such as adenoviruses, can infect immune cells as vectors. Engineered viral vaccines can present large amounts of tumor antigens to the immune system and generate antitumor immunity. In addition, oncolytic viruses can also be used as vectors. In addition to delivering tumor antigens, viruses themselves can lyse tumors, releasing tumor antigens, further enhancing vaccine efficacy and generating long-term immune memory.

[0243] Peptide-based subunit vaccines, which contain chemical and biosynthetic formulations of predicted or known tumor-specific antigens, induce potent immune responses against specific tumor antigen sites. Peptide-based subunit vaccines combined with adjuvants can efficiently induce humoral immune responses suitable for the prevention and treatment of viral infectious diseases.

[0244] HBV and HPV vaccines for liver cancer and cervical cancer have mainly been peptide-based subunit vaccines. In particular, virus-like particle (VLP)-based subunit vaccines, which can activate cellular immune responses, have shown good antitumor activity in recent years.

[0245] Nucleic acid vaccines are a desirable cancer vaccine platform because they induce strong MHC I-mediated CD8+ T cell responses

[63] . They can simultaneously deliver multiple antigens to induce humoral and cellular immunity. Furthermore, nucleic acid vaccines can encode full-length tumor antigens, allowing APCs to cross-present various epitopes or present several antigens simultaneously. Finally, nucleic acid vaccine preparation is simple and rapid, making them suitable for the development of personalized neoantigen cancer vaccines.

[0246] Oncolytic viruses In some embodiments, the pro-inflammatory agent is an oncolytic virus (OV). Oncolytic viruses (OV) are microorganisms that can identify, infect, and lyse various cells present in the tumor environment, aiming to inhibit and stabilize tumor progression. They may exhibit natural tropism for cancer cells or may be genetically engineered to identify specific targets. See, e.g., Apolonio et al., World J Virol. 2021 Sep 25; 10(5): 229-255.

[0247] Oncolytic viruses represent an exciting new field in cancer therapy. Such viruses have the remarkable ability to track and destroy cancer cells without harming normal cells, and they also enhance the immune system's ability to recognize and destroy cancer cells. See, e.g., Cancer Cell. 2022Aug15;S1535-6108(22)00357-9.

[0248] In some embodiments, the oncolytic virus comprises or is an adenovirus (e.g., ONYX-15, LOAd703 virus), a protoparvovirus, a parvovirus (e.g., H-1PV), a vaccinia virus (VACV), a reovirus (e.g., leolysin), or a herpes simplex virus (HSV, e.g., HSV-1, HSV-2, G207, L1BR1, HF10, T-VEC, Oren X010).

[0249] Other exemplary oncolytic viruses include JX-593, Coxsackievirus A21 (CVA21), Maraba virus or its MG1 variant, DNX2440 adenovirus, fowlpox virus, and Sendai virus.

[0250] cell In some embodiments, the pro-inflammatory agent comprises a cell that causes an inflammatory factor. In some embodiments, the cell is a tumor-infiltrating lymphocyte. In some embodiments, the cell specifically recognizes a tumor antigen (e.g., is engineered to express a CAR that recognizes a tumor antigen). In some embodiments, the cell is a T cell. In some embodiments, the cell is a CAR-T cell. In some embodiments, the cell is an NK cell (e.g., a CAR-NK cell). In some embodiments, the cell is a neutrophil (e.g., a CAR-expressing neutrophil cell). In some embodiments, the cell is a TCR-T cell. In some embodiments, the cell is an APC (e.g., a macrophage or dendritic cell). In some embodiments, the cell is a CAR macrophage or CAR monocyte. In some embodiments, the cell is a SIRPant macrophage. In some embodiments, the cell is a stem cell. In some embodiments, the cell is an allogeneic cell. In some embodiments, the cell is an autologous cell.

[0251] immune cells, monocytes, or macrophages The immune cells described herein encompass various types of immune cells.

[0252] In some embodiments, the immune cells comprise monocytes or macrophages as described herein. In some embodiments, the macrophages are identified by expression of F4 / 80. In some embodiments, the macrophages exhibit an M1 phenotype. In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% of the macrophages of the immune cells exhibit an M1 phenotype.

[0253] In some embodiments, macrophages are engineered to be deficient in SHP-1 expression and / or activation. In some embodiments, the monocytes or macrophages express reduced levels of SHP-1 or are resistant to activation for at least a period of time (e.g., at least 1, 2, 3, 4, or 5 days). In some embodiments, the period of time is less than about 10, 9, 8, 7, 6, 5, 4, or 3 days.

[0254] In some embodiments, the monocytes or macrophages remain in a state of reduced SHP-1 activation for up to about 5 consecutive days (e.g., 5, 4, or 3 days) until SHP-1 activation levels return to normal.

[0255] Methods for manipulating monocytes or macrophages to temporarily reduce the expression level of SHP-1 are well known in the art. Exemplary methods include contacting monocytes or macrophages in vivo or in vitro with the SHP-1 inhibitors described herein (small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein preparations (e.g., antibody preparations targeting SHP-1 or activated SHP-1)).

[0256] In some embodiments, the immune cells comprise T cells (e.g., CAR-T cells).

[0257] In some embodiments, the immune cells comprise NK cells (e.g., CAR-NK cells).

[0258] In some embodiments, the immune cells comprise neutrophils (e.g., CAR-expressing neutrophil cells).

[0259] In some embodiments, the immune cells comprise antigen-presenting cells (APCs, eg, dendritic cells).

[0260] In some embodiments, the immune cells are derived from the same individual (i.e., autologous). In some embodiments, the immune cells are allogeneic.

[0261] In some embodiments, immune cells are engineered to express a chimeric antigen receptor, optionally, the chimeric antigen receptor specifically binds to a tumor antigen.

[0262] In some embodiments, immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86. In some embodiments, immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86 when the expression levels of MHC-I, MHC-II, CD80, and / or CD86 on the immune cells are comparable (e.g., at least 50% greater) than the expression levels on activated antigen-presenting cells (APCs).

[0263] In some embodiments, the immune cells express one or more pro-inflammatory cytokines, optionally, the one or more pro-inflammatory cytokines include TNFα and / or IL-12.

[0264] In some embodiments, the immune cells do not express significant levels of TGFβ and / or IL-10.

[0265] In some embodiments, the SHP-1 inhibitor and the immune cells are administered within about 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, 1 hour, or 0.5 hours) of one another, and optionally, the SHP-1 inhibitor and the immune cells are administered within about 4 hours of one another.

[0266] In some embodiments, the SHP-1 inhibitor, immune cells, and pro-inflammatory agent are administered within about 24 hours (e.g., 12 hours, 8 hours, 4 hours, 2 hours, 1 hour, or 0.5 hours) of one another. In some embodiments, the immune cells are administered simultaneously or concurrently with the SHP-1 inhibitor and / or pro-inflammatory agent.

[0267] Inflammatory response or persistent infection There is mounting evidence that both acute and chronic inflammation are involved in the development and progression of cancer. As research on inflammation advances, the association between inflammatory processes and the development of neoplastic transformation, tumor progression, metastasis, and recurrence has become clear. Furthermore, invasive procedures (both surgery and biopsy) affect residual tumor cells by increasing their survival, proliferation, and migration. One concept that explains this phenomenon is the induction of a wound healing response. While the induction of adaptive and innate immune responses associated with wound healing is necessary for tissue repair in normal tissues, in tumor tissues, it promotes tumor cell survival, angiogenesis, and extravasation of circulating tumor cells. See, for example, Singh et al., Ann Afr Med. 2019 Jul-Sep;18(3):121-126; Piotrowski et al., Rep Pract Oncol Radiother. 2020 May-Jun;25(3):422-427.

[0268] However, as demonstrated herein, the combination of an SHP-1 inhibitor with an inflammatory agent triggers a proinflammatory response, converting the immunosuppressive tumor environment to one with an inflammatory signature. See, e.g., Figure 7F. A significant antitumor effect was achieved. These results support the use of the methods described herein to treat individuals experiencing an inflammatory response.

[0269] In some embodiments, the individual is exhibiting an inflammatory response or has a persistent infection when treated with the methods described herein. The inflammatory response described herein can be understood by, for example, a) an increase in one or more (e.g., at least 1, 2, 3, 4, or 5) pro-inflammatory cytokines (e.g., IFNγ, IL-12b, TNFα, IL-6, IL-1b, IFN-α1, IFN-α2, IFN-β, etc.); b) a decrease in one or more (e.g., at least 1, 2, or 3) pro-anti-inflammatory cytokines (e.g., TGFβ1, TGFβ2, TGFβ3, etc.); c) an increase in infiltrating immune cells (e.g., T cells, NK cells, macrophages, neutrophils, etc.); d) a decrease in inhibitory immune cells (e.g., MDSCs), and / or e) an increase in one or more (e.g., at least 1, 2, 3, 4, or 5) immunogenic costimulatory molecules (e.g., CD80, CD86, OX40L, CD40, ICOS-L, PD-L1, GITRL, etc.) in tissue (e.g., tumor tissue) or immune cells (e.g., macrophages).

[0270] In some embodiments, the inflammatory response is an acute inflammatory response.

[0271] In some embodiments, the inflammatory response occurs within a tumor. In some embodiments, the inflammatory response occurs at a site separate from the tumor.

[0272] In some embodiments, the presence of an inflammatory response refers to a) an increase in one or more (e.g., at least 1, 2, 3, 4, 5) pro-inflammatory cytokines (e.g., IFNγ, IL-12b, TNFα, IL-6, IL-1b, IFN-a1, IFN-a2, IFN-b1, etc.), b) a decrease in one or more (e.g., at least 1, 2, or 3) anti-inflammatory cytokines (e.g., TGFb1, TGFb2, TGFb3, etc.), c) an increase in infiltrating immune cells (e.g., T cells, NK cells, macrophages, etc.), d) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), e) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), f) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), g) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), h) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), i) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), i) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), ii) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), iii) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), iv) an increase in the expression of immune cells (e.g., T cells, NK cells, macrophages, etc.), iv) an increase in the expression of immune cells (e.g a) an increase in immune cells (e.g., phages, neutrophils, etc.), b) a decrease in inhibitory immune cells (e.g., MDSCs), and / or c) an increase in one or more (e.g., at least 1, 2, 3, 4, or 5) immunogenic costimulatory molecules (e.g., CD80, CD86, OX40L, CD40, ICOS-L, PD-L1, GITRL, etc.) in tissue (e.g., tumor tissue) or immune cells (e.g., macrophages).

[0273] In some embodiments, an increase as described herein refers to an increase in the amount of at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or 200% or more compared to a baseline state, optionally where the baseline state is a state in which the individual is not treated with a method described herein and is not infected with a pathogen. In some embodiments, an increase as described herein refers to an increase in the amount of at least about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 500-fold, or 1000-fold or more compared to a baseline state, optionally where the baseline state is a state in which the individual is not treated with a method described herein and is not infected with a pathogen. In some embodiments, the baseline state is a state in which a healthy individual is not infected with a pathogen.

[0274] In some embodiments, a reduction as described herein refers to a reduction of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 99.9% or less compared to a baseline state, optionally a state in which the individual is not treated with a method described herein and is not infected with a pathogen. In some embodiments, the baseline state is a state in which a healthy individual is not infected with a pathogen.

[0275] In some embodiments, the individual exhibits an inflammatory response (e.g., within a tumor, e.g., at a site distinct from the tumor) about 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before and / or after administration of the SHP-1 inhibitor.

[0276] In some embodiments, the individual has an ongoing inflammatory response (e.g., within a tumor, e.g., at a site different from the tumor) at the time the SHP-1 inhibitor is administered.

[0277] In some embodiments, the individual has an ongoing infection at the time the SHP-1 inhibitor is administered. In some embodiments, the method further comprises assessing the presence or absence of an infection in the individual, e.g., an infection associated with a virus, a fungus, and / or a bacteria.

[0278] In some embodiments, the individual has an ongoing infection (e.g., a bacterial infection, a viral infection, a fungal infection), and the method further comprises administering antibacterial therapy (e.g., an antibiotic), antiviral therapy, antimicrobial therapy, or antiprotozoal therapy.

[0279] immunogenic cell death In some embodiments, immunogenic cell death occurs in individuals when treated with the methods described herein.

[0280] Immunogenic cell death (ICD) is a type of cancer cell death induced by various stressors, including, but not limited to, (1) intracellular pathogens, (2) conventional chemotherapy such as anthracyclines, DNA-damaging agents, and proteasome inhibitors, (3) targeted anticancer drugs such as the tyrosine kinase inhibitor crizotinib, the epidermal growth factor receptor-specific monoclonal antibody cetuximab, and poly (ADP-ribose) polymerase (PARP) inhibitors, and (4) various physical modalities, including photodynamic therapy with hypericin and redaporfin, extracorporeal photochemotherapy, various forms of ionizing radiation, high hydrostatic pressure, and severe heat shock. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD involves the release of damage-associated molecular patterns (DAMPs) from dying tumor cells, which leads to the activation of tumor-specific immune responses, thus combining direct cancer cell killing with antitumor immunity to enhance the long-term efficacy of anticancer drugs. DAMPs include cell surface exposure of calreticulin (CRT) and heat shock proteins (HSP70 and HSP90), extracellular release of adenosine triphosphate (ATP), high-mobility group box-1 (HMGB1), and members of the type I IFN and IL-1 cytokine families. See, e.g., Ahmed et al., Mol Oncol. 2020 Dec;14(12):2994-3006 and Fucikova et al., Cell Death Dis. 2020 Nov 26;11(11):1013.

[0281] Major DAMPs related to cell death recognized as immunogenic include calreticulin, high mobility group box 1 (HMGB1), ATP, annexin A1 (ANXA1), and type I IFN. The main characteristics of immunogenic cell death (ICD) can be assessed by a variety of different approaches, such as flow cytometry, (immuno)fluorescence microscopy, immunoblotting, or luminometry. See, for example, Cell Death Dis. 2020 Nov 26; 11(11): 1013.

[0282] In some embodiments, the individual exhibits ICD (e.g., within a tumor, e.g., at a site distinct from the tumor) about 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before and / or after administration of the SHP-1 inhibitor.

[0283] In some embodiments, the individual has persistent ICD (e.g., within a tumor, e.g., at a site different from the tumor) at the time the SHP-1 inhibitor is administered.

[0284] In some embodiments, an individual is determined to be experiencing ICD if a sample from the cancer contains a higher level (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) of one or more DAMPs than a reference sample (e.g., a corresponding sample from a healthy control, e.g., a sample from the cancer before administration of an ICD-inducing therapy). In some embodiments, the DAMPs are selected from the group consisting of endoplasmic reticulum (ER) chaperones (e.g., calreticulin (CALR), e.g., heat shock proteins (HSPs)), the non-histone chromatin-binding protein high mobility group box 1 (HMGB1), the cytoplasmic protein annexin A1 (ANXA1), and the small molecule metabolites ATP and type I interferon (IFN).

[0285] individual In some embodiments, the individual has a solid tumor, hi some embodiments, the individual has a hematological cancer.

[0286] In some embodiments, the individual has advanced cancer. In some embodiments, the individual has terminal cancer. In some embodiments, the individual has malignant cancer. In some embodiments, the individual has stage II, III, or IV cancer. In some embodiments, the individual has inoperable tumors and / or metastases. In some embodiments, the individual is in a terminal condition.

[0287] In some embodiments, the individual has previously received a therapy (e.g., radiation therapy) that induces an inflammatory response or immunogenic cell death (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., 1, 2, 3, 4, 5, 6, or 7 days, before administration of the SHP-1 inhibitor). In some embodiments, the individual will soon receive a therapy (e.g., radiation therapy) that induces an inflammatory response or immunogenic cell death (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., 1, 2, 3, 4, 5, 6, or 7 days after administration of the SHP-1 inhibitor).

[0288] In some embodiments, the individual has previously received an inflammatory agent (e.g., any of the inflammatory agents described herein) (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., 1, 2, 3, 4, 5, 6, or 7 days, before administration of the SHP-1 inhibitor). In some embodiments, the individual will soon receive an inflammatory agent (such as any of the inflammatory agents described herein) (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., 1, 2, 3, 4, 5, 6, or 7 days after administration of the SHP-1 inhibitor).

[0289] In some embodiments, the individual has an autoimmune disease.

[0290] In some embodiments, the individual is female. In some embodiments, the individual is male.

[0291] In some embodiments, the individual is a human. In some embodiments, the individual is at least about 50, 55, 60, 65, 70, or 75 years of age.

[0292] In some embodiments, an individual is selected for treatment based on high expression and / or activation levels of SHP-1 in tumor tissue, hi some embodiments, the individual has high expression and / or activation levels of SHP-1 that are at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or 200% higher than baseline expression and / or activation levels of SHP-1. In some embodiments, the individual has a high expression and / or activation level of SHP-1, which expression and / or activation level is at least about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 500-fold, or 1000-fold higher than the baseline expression and / or activation level of SHP-1. In some embodiments, the baseline expression or activation level of SHP-1 is the corresponding expression or activation level of SHP-1 in a baseline state, and the individual is not being treated with a pro-inflammatory agent (or any immunotherapy).

[0293] In some embodiments, the individual is at risk of developing systemic inflammation and / or CRS. In some embodiments, the individual has developed systemic inflammation and / or CRS before the administration of the agent that reduces systemic inflammation. Cytokine release syndrome can damage most organ systems or cause organ failure. For example, organs that can be damaged due to CRS can include, but are not limited to, the lungs, kidneys, liver, brain, heart, spleen, or any combination thereof, such as multiple organ failure.

[0294] In some embodiments, the individual is administered an agent that reduces systemic inflammation. In some embodiments, administration occurs before the individual develops systemic inflammation. In some embodiments, the individual develops mild cytokine release syndrome. In some embodiments, the individual develops Grade 1 CRS. Symptoms of mild CRS may include fever, fatigue, headache, rash, joint pain, and muscle pain. Mild CRS may be treated by treating the symptoms or by administering anti-inflammatory medications such as corticosteroids. Mild CRS often resolves within 1-2 weeks and does not require or call for hospitalization.

[0295] In some embodiments, the individual does not develop severe cytokine release syndrome. In some embodiments, the individual does not develop Grade 2 CRS. In some embodiments, the individual does not develop Grade 3 CRS. In some embodiments, the individual does not develop Grade 4 CRS. More severe cases are characterized by hypotension and hyperthermia, and severe CRS can progress to circulatory shock requiring vasoconstrictors, vascular leakage, disseminated intravascular coagulation, and an uncontrolled systemic inflammatory response with multiple organ failure. More severe cases of CRS often require hospitalization for symptoms. Common laboratory abnormalities in CRS patients include cytopenias, elevated creatinine and liver enzyme levels, abnormal coagulation parameters, and elevated CRP levels. The GRADE system, which considers four factors, is currently used for cytokine release syndrome, as shown in Table 1 below. See, e.g., Liu, D. and Zhao, J., J Hematol Oncol. 2018 Sep 24; 11(1): 121; and Shimabukuro-Vornhagen, A. et al., J Immunother Cancer. 2018 Jun 15; 6(1): 56, which are incorporated by reference in their entireties.

[0296] In some embodiments, the individual has CRS prior to administration of the agent that reduces systemic inflammation. In some embodiments, the individual has Grade 1 CRS. In some embodiments, the individual has Grade 2 CRS. In some embodiments, the individual has Grade 3 CRS. In some embodiments, the individual has Grade 4 CRS. In some embodiments, the agent that reduces systemic inflammation is administered to the individual who has CRS. In some embodiments, the agent that reduces systemic inflammation ameliorates, eliminates, or reverses CRS, including organ damage, e.g., inflammation-induced organ damage (e.g., nephritis, hepatitis, pneumonia, myocarditis, appendicitis). [Table 1-1] [Table 1-2] [Table 1-3]

[0297] In some embodiments, the individual does not develop a cytokine storm. In some embodiments, the individual develops a mild cytokine storm. In some embodiments, the individual does not develop a severe or life-threatening cytokine storm. While cytokine storm appears to be primarily the result of non-specific T cell activation, CRS is more often the direct result of antigen-specific T cell activation. The clinical symptoms of cytokine storm and CRS can be similar (Liu, D. and Zhao, J., J Hematol Oncol. 2018 Sep 24; 11(1): 121).

[0298] cancer The cancers described herein can be of any type or variety. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer.

[0299] In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a terminal cancer. In some embodiments, the cancer is a terminal cancer. In some embodiments, the cancer is in stage II, III, or IV. In some embodiments, the cancer is an inoperable tumor and / or malignant.

[0300] In some embodiments, the tumor is at least 0.2 cm, 0.4 cm, 0.6 cm, 0.8 cm, 1 cm, 2 cm, 3 cm, 4 cm, or 5 cm in length.

[0301] Examples of cancers described herein include adrenocortical carcinoma, agnogenic myeloid metaplasia, metaplasia), AIDS-related cancer (e.g., AIDS-related lymphoma), anal cancer, appendiceal cancer, astrocytoma (e.g., cerebellar and cerebral), basal cell carcinoma, bile duct cancer (e.g., extrahepatic), bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain tumors (e.g., glioma, brain stem glioma, cerebellar or cerebral astrocytoma (e.g., pilocytic astrocytoma, diffuse astrocytoma, anaplastic (malignant) astrocytoma), malignant glioma, ependymoma, oligodendroglioma, meningioma, craniopharyngioma, hemangioblastoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, hypothalamic optic pathway glioma, and glioblastoma), breast cancer, bronchial adenoma / carcinoid, carcinoid tumor (e.g., gastrointestinal carcinoid tumor), cancer of unknown primaryprimary), central nervous system lymphoma, cervical cancer, colon cancer, colorectal cancer, chronic myeloproliferative disorders, uterine cancer (e.g., uterine cancer), ependymoma, esophageal cancer, Ewing's family of tumors, eye cancer (e.g., intraocular melanoma and retinoblastoma), gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor (e.g., extracranial, extragonadal, ovarian), gestational trophoblastic tumor, Head and neck cancer, hepatocellular (liver) cancer (e.g., hepatocarcinoma and heptoma), hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), laryngeal cancer, larynx cancer, leukemia, lip and oral cavity cancer, oral cancer, liver cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), lymphoid neoplasms (e.g., lymphoma), medulloblastoma, melanoma, mesothelioma, metastatic squamous cell neck cancer, oral cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndrome, myelodysplastic / Myeloproliferative disorders, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, oropharyngeal cancer, ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, parathyroid cancer, penile cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, pleuropulmonary blastoma, lymphoma, primary central nervous system lymphoma (microglioma), pulmonary lymphangioleiomyomatosis, rectal cancer, kidney cancer, renal pelvis and ureter cancer (transitional cell carcinoma), striated muscle These include, but are not limited to, sarcoma, salivary gland cancer, skin cancer (e.g., non-melanoma (e.g., squamous cell carcinoma), melanoma, and Merkel cell carcinoma), small intestine cancer, squamous cell carcinoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, urethral cancer, vaginal cancer, vulvar cancer, Wilms' tumor, and post-transplant lymphoproliferative disorder (PTLD), abnormal blood vessel growth associated with nevus syndrome, edema (e.g., edema associated with brain tumors), and Meigs' syndrome.

[0302] In some embodiments, the cancer is a viral infection-associated cancer. In some embodiments, the cancer is a human papillomavirus (HPV)-associated cancer (e.g., HPV-associated cervical cancer, e.g., HPV-associated head and neck cancer, e.g., HPV-associated squamous cell carcinoma). In some embodiments, the cancer is a human herpesvirus 8 (HHV8)-associated cancer (e.g., Kaposi's sarcoma). In some embodiments, the cancer is a human T-lymphotropic virus (HTLV-1)-associated cancer (e.g., adult T-cell leukemia or lymphoma). In some embodiments, the cancer is an Epstein-Barr virus (EBV)-associated cancer (e.g., Burkitt's lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, gastric cancer). In some embodiments, the cancer is a hepatitis B virus (HBV)-associated cancer (e.g., liver cancer). In some embodiments, the cancer is a hepatitis C virus-associated cancer (e.g., liver cancer, non-Hodgkin's lymphoma).

[0303] In some embodiments, the cancer is liver cancer, kidney cancer, endometrial cancer, thymic epithelial neoplasm, lung cancer, spindle cell sarcoma, chondrosarcoma, uterine smooth muscle, colon cancer, or pancreatic cancer.

[0304] In some embodiments, the cancer has previously undergone and / or failed one or more therapies, such as immune checkpoint blockade therapy (e.g., PD-1 antibodies), chemotherapy, surgery, or cell therapy (e.g., allogeneic NK cell infusion therapy).

[0305] In some embodiments, the cancer is a recurrent or refractory cancer.

[0306] In some embodiments, the cancer is resistant to one or more of radiation therapy, chemotherapy, or immunotherapy (eg, checkpoint blockade). Dosage, Administration Method, and Delivery Vehicle

[0307] The SHP-1 inhibitors, pro-inflammatory agents, and immune cells (e.g., monocytes / macrophages) described herein can be administered at any desired dosage. Exemplary dosing regimens are described, for example, in the "SHP-1 Inhibitors" section.

[0308] In some embodiments, the dosage of the pro-inflammatory agent, SHP-1 inhibitor, and / or immune cells (e.g., monocytes / macrophages) administered is determined based on one or more criteria, such as the disease burden in the subject (e.g., tumor burden, tumor mass, tumor size, or extent, extent, or type of metastasis, stage of disease, and / or the likelihood or frequency of a toxic reaction in the subject, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or a host immune response to the administered activated immune cells. For example, in some embodiments, the number of monocytes or macrophages to be included in the administered dose is determined based on the tumor burden present in the subject immediately prior to the initial administration of cells.

[0309] The pro-inflammatory agent, SHP-1 inhibitor, and / or immune cells (e.g., monocytes / macrophages) can be administered by any suitable means, e.g., bolus injection, injection, e.g., intravenous or subcutaneous injection. In some embodiments, the pro-inflammatory agent, SHP-1 inhibitor, and / or monocytes or macrophages are administered systemically (e.g., intravenously, subcutaneously, or intraperitoneally). In some embodiments, the pro-inflammatory agent, SHP-1 inhibitor, and / or monocytes or macrophages are administered locally (e.g., intratumorally).

[0310] In some embodiments, the pro-inflammatory agent, SHP-1 inhibitor, and / or immune cells (e.g., monocytes / macrophages) are administered parenterally, intrapulmonary, intranasally, or, if localized treatment is desired, intralesionally or intratumorally. Parenteral injections include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pro-inflammatory agent and / or the SHP-1 inhibitor are administered orally.

[0311] In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered simultaneously. In some embodiments, the monocytes or macrophages and the pro-inflammatory agent are administered in parallel. In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered sequentially. In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered within about 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered within about 24, 16, 12, 8, 4, 2, or 1 hour. In some embodiments, the immune cells (e.g., monocytes / macrophages) and the pro-inflammatory agent are administered within 30 minutes.

[0312] In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered simultaneously. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered concurrently. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered sequentially. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered within about 7, 6, 5, 4, 3, 2, or 1 day of each other. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered within about 24, 16, 12, 8, 4, 2, or 1 hour of each other. In some embodiments, the SHP-1 inhibitor and the pro-inflammatory agent are administered within 30 minutes of each other.

[0313] It is also contemplated that the SHP-1 inhibitors and / or pro-inflammatory agents described herein can be delivered via any suitable vehicle or method. In some embodiments, the SHP-1 inhibitors and / or pro-inflammatory agents are delivered directly to tumor tissue. Various carrier systems may be utilized for this purpose. See, for example, Manzari et al., Targeted drug delivery strategies for precision medicines. Nat Rev Mater 6, 351-370 (2021); Tewabe et al., J Multidiscip Healthc. 2021; 14:1711-1724. In some embodiments, the SHP-1 inhibitors and / or pro-inflammatory agents are delivered via nanoparticles. In some embodiments, the SHP-1 inhibitors and / or pro-inflammatory agents are delivered via a controlled release system. In some embodiments, the SHP-1 inhibitors and / or pro-inflammatory agents are delivered via a biomaterial implant scaffold. In some embodiments, the SHP-1 inhibitors and / or pro-inflammatory agents are delivered via an injectable biomaterial scaffold. In some embodiments, the SHP-1 inhibitor and / or pro-inflammatory agent is delivered via a transdermal delivery system. See, e.g., Riley et al., Nat Rev Drug Discov. 2019 Mar;18(3):175-196.

[0314] In some embodiments, the SHP-1 inhibitor and / or pro-inflammatory agent is delivered by cells. See, e.g., Millian et al., Ther Deliv. 2012 Jan;3(1):25-41. In some embodiments, the cells comprise macrophages. See, e.g., Visser et al., Front Pharmacol. 2019 Jan 25;10:22. In some embodiments, the cells comprise polymer-encapsulated human retinal pigment epithelial (aRPE) cells. See, e.g., Nash et al., Clin Cancer Res. 2022 Aug 22;CCR-22-1493. In some embodiments, the cells are encapsulated in a biocompatible material (e.g., the biocompatible alginate capsules discussed in Nash et al.).

[0315] In some embodiments, the SHP-1 inhibitor and / or pro-inflammatory agent is associated with an antibody construct. In some embodiments, the SHP-1 inhibitor and / or pro-inflammatory agent is attached to the antibody construct via a linker (e.g., a cleavable linker). In some embodiments, the antibody construct specifically recognizes a tumor-associated antigen. In some embodiments, the antibody construct comprises an antibody that recognizes a tumor antigen. In some embodiments, the antibody construct is an antibody-drug conjugate (ADC).

[0316] In some embodiments, the SHP-1 inhibitor and / or pro-inflammatory agent is delivered via a method or device that facilitates delivery to a specific organ (e.g., a tumor-bearing organ). Examples of these methods or devices include those described in, for example, Alsaggar et al., J Drug Target. 2018 Jun-Jul;26(5-6):385-397; Zhao et al., Cell. 2020 Apr 2;181(1):151-167, which are incorporated by reference in their entireties.

[0317] In embodiments, the SHP-1 inhibitor is delivered via a controlled drug delivery system (e.g., a sustained-release system or vehicle, e.g., a sustained-release system or vehicle). Examples of such systems include those described in, for example, Adepu et al., Molecules. 2021 Oct; 26(19):5905; Oh et al., Chem. Asian J. 2022, 17, e202200333, which are incorporated by reference in their entireties.

[0318] VI. COMPOSITIONS COMPRISING SHP-1 INHIBITORS The present application also provides compositions (e.g., pharmaceutical compositions) comprising an SHP-1 inhibitor, an inducing agent, and / or an immune cell for the above treatment.

[0319] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an inflammatory agent (e.g., any inflammatory agent described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0320] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a TLR agonist (e.g., CpG, poly I:C, and / or R848). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0321] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a STING activator (e.g., cGAMP, e.g., 2'3'-cGAMP, e.g., 3'3'-cGAMP). In some embodiments, the composition further comprises an immune cell (such as a monocyte or macrophage as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0322] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a chemotherapeutic agent (e.g., azathioprine (AZA), e.g., gemcitabine). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0323] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a proinflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and / or TNFα). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0324] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a checkpoint inhibitor (e.g., an anti-PD-L1 antibody, an anti-PD-1 antibody, or an anti-CLTA4 antibody). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0325] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a bacterial component (e.g., LPS). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages as described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

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

[0327] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an agent used in radiation therapy (e.g., any radiation therapy described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0328] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a PAMP / DAMP activator (e.g., any PAMP / DAMP activator described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0329] In some embodiments, provided are compositions (e.g., pharmaceutical compositions) comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a cancer vaccine (e.g., any cancer vaccine described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0330] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an oncolytic virus (e.g., any oncolytic virus described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0331] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided that includes an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an agent used in acoustic therapy (e.g., any of the acoustic therapy methods described herein). In some embodiments, the composition further includes immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further includes a pharmaceutically acceptable carrier.

[0332] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an agent for use in magnetic therapy (e.g., any of the magnetic therapies described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0333] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an electrical or electrochemical treatment (e.g., any electrical or electrochemical treatment described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0334] In some embodiments, a composition (e.g., a pharmaceutical composition) is provided comprising an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and an agent used in electrostatic treatment (e.g., any of the electrostatic treatments described herein). In some embodiments, the composition further comprises immune cells (such as monocytes or macrophages described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. [Example]

[0335] The following examples are intended to be purely illustrative of the present invention and therefore should not be construed as limiting the present invention in any way. The following examples and detailed description are offered by way of illustration and not by way of limitation.

[0336] Example 1 SHP-1 is abundantly expressed in macrophages. Proteomic studies examining the expression of non-receptor protein tyrosine phosphatases (PTPs) in macrophages reveal that SHP-1 exhibits the highest expression levels. See Figure 15. As shown, SHP-1 is the most abundant protein tyrosine phosphatase expressed in both human and mouse macrophages. SIRPα is a macrophage inhibitory receptor (iR) involved in the activation of SHP-1. Human monocyte-derived macrophages were either unstimulated (M0) or stimulated with IFNγ / LPS (M1) or IL-4 (M2) to induce phenotypic activation prior to analysis. (The housekeeping gene GAPDH was detected in parallel.)

[0337] Despite its high expression, tumor-associated macrophage assays confirmed that SHP-1 activity remained low in macrophages unless the macrophages were "surrounded by" or in contact with tumor cells and simultaneously stimulated with TLR agonists or other inflammatory activators (see Figure 2A). Under these conditions, blocking SHP-1 activation with the covalent inhibitor TPI-1 (8) prevented SHP-1-mediated protein dephosphorylation, resulting in a marked enhancement of signaling through TLRs and other factors.

[0338] As shown in Figure 2C, macrophages stimulated with IFNγ and LPS completely suppressed the phosphorylation of STAT-1 (pSTAT-1) and Erk1 / 2 (pErk1 / 2) upon tumor cell ligand binding, resulting in the inhibition of activation of these proteins. However, TPI-1 dose-dependently inhibited SHP-1, relieving tumor cell-derived inhibition and allowing signal transduction and activation of STAT-1 (pSTAT-1) and Erk1 / 2 (pErk1 / 2). Similarly, TPI-1-mediated SHP-1 inhibition resulted in increased production of proinflammatory cytokines and expression of immunogenic antigen-presenting machinery by macrophages (Figures 2D and 2E). Macrophages with high SHP-1 activation in the tumor environment reduced proinflammatory cytokine production, but produced high levels of IL-10 upon IFNγ / LPS stimulation (Figure 2D, blue bar). This enhanced immunosuppression was reversed by SHP-1 inhibition. Furthermore, SHP-1 inhibition also enabled proinflammatory activated macrophages to cross the "don't-eat-me" barrier and initiate potent phagocytosis toward cancer cells, regardless of whether the cancer cells expressed CD47 (Figure 2F and Figure 2G).

[0339] Example 2 In addition to TPI-1, we tested several other SHP-1 inhibitors, including PTP inhibitor-I, PTP inhibitor-III, the recently described vitamin E (9, 10), and homoxanthones A and B (PXA and PXB) (11). Because PKCθ regulates SHP-1 activation through phosphorylation of Ser591 (12, 13), PKCθ inhibitors and activators were also tested in various assays.

[0340] As shown in Figures 3A–3E, among these compounds, TPI-1 exhibited the strongest effect, potently inhibiting SHP-1 activation at low concentrations. PMA, a vitamin E derivative and PKCθ activator, moderately inhibited SHP-1. We also investigated the inhibitory effects of SHP-2, a close relative of SHP-1. In contrast to SHP-1 inhibition, SHP-2 inhibition did not significantly reduce PTP activation induced by proinflammatory activation or cancer cell ligand binding, nor did it confer phagocytosis of cancer cells to activated macrophages. These studies concluded that SHP-2 is differentially regulated from SHP-1 and that SHP-1, but not SHP-2, controls macrophage proinflammatory responses, immunogenic antigen presentation, and phagocytosis of cancer cells.

[0341] Example 3 SHP-1 was found to be rapidly metabolized. When macrophages were treated with the covalent inhibitor TPI-1 for 15 min and then washed out to remove the inhibitory effect, strong inhibition of SHP-1 was observed immediately after TPI-1 treatment. This effect correlated with the increase in pSTAT-1 and pErk1 / 2 induced by IFNγ / LPS. However, this pulsed SHP-1 inhibition did not persist beyond a few hours (5–8 h), and SHP-1 activity began to recover, reaching over 50% by 12–16 h, regaining its ability to suppress IFNγ / LPS-induced signaling (Figure 4A). Despite the change in SHP-1 activity, the total amount of SHP-1 protein remained unchanged. Treatment of macrophages with TPI-1 without or with partial removal of the inhibitor resulted in sustained inhibition of SHP-1 activation (Figure 4B).

[0342] Example 4 Further molecular and intracellular signaling studies have demonstrated that in the tumor environment, tumor cells ligate with macrophage iRs (e.g., SIRPα, LILRBs, and Siglecs) via counter-receptors (e.g., CD47, MHC, and carbohydrates) expressed on their cell surface. In the presence of proinflammatory stimuli, iRs undergo tyrosine phosphorylation, and their cytoplasmic ITIM domains bind to the SH2 domain of SHP-1, relieving SHP-1 autoinhibition and promoting high levels of SHP-1 activation (Figure 5A). While neither extracellular ligand binding of iRs nor inflammatory stimuli alone can induce strong ITIM phosphorylation and subsequent SHP-1 activation, the simultaneous presence of both is sufficient. The underlying mechanism suggests that extracellular ligand binding of iRs changes their cytoplasmic conformation to an "open" form, exposing the ITIMs to phosphorylation, while inflammatory signals simultaneously activate Src family tyrosine kinases (TKs) to mediate ITIM phosphorylation. Figure 5B shows a study of SIRPα, an essential macrophage iR, where phosphorylation of ITIMs requires both extracellular ligand binding of CD47 and macrophage stimulation with cytokines or TLR agonists.

[0343] These studies also revealed that macrophage iRs, such as SIRPα, can recruit both SHP-1 and SHP-2 through cytoplasmic ITIM phosphorylation. However, SHP-1 binding only occurs under proinflammatory conditions, when macrophages are stimulated with activating cytokines (TNFα, IL-17A, IL-6, or IFNγ) or TLR agonists (LPS, CpG, or polyIC), whereas SHP-2 binding is dominated by immunosuppressive IL-4, IL-10, or TGFβ (Figure 5C).

[0344] Example 5 Similar findings were also observed in solid tumors in vivo. As tumors grew, intratumoral macrophages increased their expression of iRs, while tumor cells in the same TME also increased their expression of counterreceptors such as CD47 and the T cell inhibitory molecule PD-L1 (Figure 6A). These changes in late-stage tumors suggest that immunosuppression is more strongly established than in early-stage tumors. In the absence of treatment, intratumoral macrophages, which are constitutively liganded to surrounding tumor cells, are regulated by immunosuppressive signals in the TME, resulting in phosphorylation of the cytoplasmic ITIM of macrophage iRs and binding of SHP-2, but not SHP-1 (data not shown). Our accumulated data indicate that this mode of iR-SHP-2 binding sequesters SHP-2 from accessing immunosuppressive cytokine receptors (e.g., IL-4R and IL-10R), thereby preventing SHP-2 from inhibiting anti-inflammatory signaling (14). Thus, this iR-SHP-2 binding in homeostatic solid tumors functions as a feedforward control that enhances the anti-inflammatory phenotype of macrophages, promoting immunosuppression of the TME and tumor progression.

[0345] SHP-1 in untreated solid tumors exhibits low activation (see Figures 7A–7D), which inhibits signaling from immunosuppressive receptors. Indeed, this function of SHP-1 acts synergistically with SHP-2, both of which have the ability to bind to and inactivate IL-4R and IL-10R signaling (see our previous studies and others (14–17)). Similarly, inhibition of SHP-1 in MC38 solid tumors resulted in increased production of IL-10 in the TME (Figure 6B). Interestingly, SHP-1 inhibition also increased tumor production of IL-6, a cytokine reported to play an immunosuppressive role in the TME, promoting tumor progression (18, 19). In vitro assays of macrophage activation in a tumor-associated environment using alternative activation (M2) stimuli IL-4, IL-13, and IL-10 confirmed that SHP-1 inhibition with either TPI-1 or another inhibitor, PTP-1, dose-dependently increased IL-10 and TGF-β production from macrophages (Figure 6C). In parallel experiments, the same SHP-1 inhibitor augmented macrophage responses to M1 stimuli IFN-γ and LPS, enhancing proinflammatory cytokine production.

[0346] Supporting this idea, we found that treating tumors with TLR ligands (αTLR), inflammatory cytokines (IL-1, IL-6, TNFα, IFNγ), STING activators (2'3'-cGAMP), RT, anti-PD-L1 immune checkpoint inhibitors (αPD-L1), or the chemotherapy drug azacytidine (AZA) induced a spike in SHP-1 activity. Indeed, large, late-stage tumors with high iR expression in macrophages confer the ability to potently activate SHP-1 under therapeutic treatment. We found that intratumoral macrophages are the primary source of SHP-1 activation, and that depletion of intratumoral macrophages significantly reduced the spike in SHP-1 activation upon treatment (Figure 7C). In addition to inactivating inflammatory signaling pathways, hyperactivation of SHP-1 enhances inflammatory stimuli-induced IL-10 and TGFβ production through a currently unknown mechanism (Figure 7D; see also Figure 2D), thus promoting the return of the TME to an immunosuppressive state. Consequently, in solid tumors where SHP-1 activation is strongly induced by TLR agonists and other treatments, the phenotype of intratumoral macrophages does not change from immunosuppressive to proinflammatory, nor does it reprogram the TME to antitumor immunogenicity. This phenomenon was also observed in pancreatic ductal adenocarcinoma (KPC) and colorectal cancer (MC38) tumors under treatment (Figures 7D–7F). Rather, these tumors exhibited strong resistance to treatment by increasing TGFβ and TGFβ receptors (TGFBR1 and TGFBR2) as well as the CCL2 chemokine, which attracts MDSCs (Figure 7F), resulting in enhanced wound healing and immunosuppression. Due to strong therapeutic resistance, antigen presentation was either not detected or only marginal in the TME, and antitumor T cell immunity was poorly suppressed.

[0347] In stark contrast, inhibition of SHP-1 with a single dose of TPI-1 completely altered how the TME responded to TLR agonists or RT. Just a few hours (6–18 h) after treatment (TPI-1 + αTLR or RT), intratumoral macrophage phenotypes shifted from immunosuppressive to a typical proinflammatory one, characterized by high expression of inflammatory cytokines such as TNFα, IFNα / β, IFNγ, IL-1β, IL-6, IL-12, IL-17, and IL-18, with concomitant reductions in IL-10 and TGFβ. A prominent immunogenic antigen presentation mechanism was induced, with elevations in cell surface markers MHC-I, MHC-II, and costimulatory molecules such as CD80, CD86, CD40, and OX40L. A panel of chemokines that attract neutrophils, NK cells, and T cells was also increased in the TME, whereas TGFR and CCL2 expression was reduced (Figures 7D–7F).

[0348] Example 6 In line with these changes, TME analysis of MC38 colon cancer and KPC pancreatic cancer treated with TLR agonists in combination with TPI-1 or RT (Figures 8A-8E and 9) confirmed rapid infiltration of inflammatory neutrophils (ROS high) and tumor-killing NK cells (Granz high). Furthermore, potent antigen presentation also triggered the proliferation of tumor-specific (p15E-reactive) cytotoxic T cells (Granz high) with high tumor-killing potential. The immunosuppressive compartment of the same TME, including MDSCs and Tregs, was reduced. Interestingly, the intratumoral macrophage population (F4 / 80+) also decreased to a minute size after T cell activation. Furthermore, we found that these T cell activation and proliferation events were primarily induced via in situ antigen presentation by intratumoral APCs, which in turn activated tumor-specific memory T cells (TEM / CM) within TILs. When TLR agonists and TPI-1 were combined and injected ex vivo into resected tumors, they induced a T cell proliferative response that was not observed with either agent alone. However, treatment of resected tumors did not result in an increase in neutrophils or NK cells, suggesting that the infiltration of these killer cells into tumors in vivo may be increased as a result of chemotactic recruitment from outside the tumor. Together, these results suggest that inhibiting SHP-1, eliminating a central mechanism that prevents proinflammatory signaling, unlocks intratumoral antitumor capabilities and enhances both innate and adaptive immune cells against cancer.

[0349] Furthermore, these analyses of the changes in the immune landscape in the TME after TPI-1 combination therapy guided the design of our pulsed intermittent SHP-1 inhibition strategy for metastatic solid tumors. We found that tumors treated with TPI-1 in combination with a TLR agonist or RT significantly reduced the intratumoral macrophage population in the TME after antigen presentation for T cell activation. Concomitant with the reduction in macrophages, tumor-associated SHP-1 activation also declined, a change that eliminated the need for continuous TPI-1 administration. This "intermittent" period lasted 3–6 days, depending on the dose of TPI-1 and TLR agonist / RT, as well as the type and stage of the tumor prior to treatment. During this period, the TME was dominated by tumor-killing CD8+ T cells, neutrophils, and NK cells, and treated tumors exhibited growth suppression and stable disease (SD) or tumor regression. However, if the tumor was not completely eliminated, the TME was reconstituted by "new" macrophages and an increase in MDSCs and Tregs was observed, suggesting a reconstitution of the immunosuppressive state. Consistent with these changes, tumors after the intermittent period began to grow unless another cycle of TPI-1 combination therapy was applied, but repeated intermittent application again effectively suppressed the tumors.

[0350] Example 7 Our pulsed intermittent inhibition of SHP-1 (iSHP-1) as an immunoadjuvant / neoadjuvant therapy for solid tumors was derived from the mechanistic studies described above. Based on our findings, while iSHP-1 monotherapy has limited practical application, combining iSHP-1 with a pro-inflammatory regimen is expected to have a potent tumor-suppressing effect. Recognizing that intratumoral macrophages determine TME responses and SHP-1 activation in solid tumors, our iSHP-1 strategy is designed to target intratumoral macrophages, exploiting their pro-inflammatory responses and antigen-presenting capacity to promote tumor clearance. Following the dynamics of intratumoral macrophage populations, iSHP-1 treatment is administered in a "pulse" fashion when macrophages are abundant in the TME, but is discontinued (for an "intermittent" period) once macrophages decline following antigen presentation and T cell activation. Furthermore, given our findings that macrophages reconstitute the TME after intermittent periods unless the tumor is eliminated, multiple cycles of treatment are designed, with each cycle pulsing iSHP-1 repeated immediately after the intermittent period.

[0351] Figures 10A-10B show the design and treatment scheme for pulsed intermittent iSHP-1. In preclinical tumor models, we tested three pulse treatment schemes (pulse 1, pulse 2, pulse 3) in which iSHP-1 was administered once, twice, or three consecutive times (once daily) at the beginning of each cycle, with iSHP-1 treatment discontinued for 2-9 days between cycles. Combined modalities included, but were not limited to, TLR ligands, STING activators, RT, anti-PD-1 / L1 immune checkpoint blockade (αPD-1 / L1), proinflammatory cytokines, chemotherapy, and oncolytic viruses. These combination therapies were administered in combination with SHP-1 inhibitors or according to separate dosing schedules. Murine solid tumor models with single tumors or multiple lesions (metastases) in syngeneic mice with different backgrounds were tested. These models were established by engrafting tumors at multiple locations, with single tumors reaching 200 mm in size. 3or total tumor burden of 300 mm 3 At this point, iSHP-1 treatment was initiated. These models included pancreatic adenocarcinoma (KPC and Pan02), colorectal carcinoma (MC38), metastatic breast cancer 4T1, lung carcinoma (LLC), and T-cell lymphoma (EL4). To achieve a systemic effect against metastatic lesions, all treatments administered to mice were systemically administered via intraperitoneal (ip) or subcutaneous (sc) administration. In a subset of experiments, treatment was also administered via intratumoral injection (it).

[0352] Throughout the treatment, antitumor effects (changes in tumor volume and survival rate), side effects (weight loss, proteinuria, anemia, and clinical discomfort), organ toxicity and tissue inflammation due to toxicity, and changes in the immune status in the TME were analyzed at different time points and endpoints.

[0353] As shown in the following examples, we thoroughly investigated the pulsed intermittent iSHP-1 strategy in preclinical tumor models, and in each case, pulsed iSHP-1 combined with a proinflammatory regimen induced a potent antitumor response that simultaneously activated innate and adaptive immune cells to eliminate tumors. Applying this strategy to a systemic approach resulted in the control and regression of cancer lesions throughout the body, resulting in high survival rates and durable antitumor immunity.

[0354] More importantly, the pulse-intermittent iSHP-1 strategy provides the first practical method for applying SHP-1 inhibition as an in vivo therapeutic regimen to minimize the toxicity caused by SHP-1 deficiency. While SHP-1-deficient animals or animals continuously treated with an SHP-1 inhibitor developed significant lung inflammation, kidney damage, enterocolitis, anemia, and splenomegaly, mice treated with three cycles of pulse-intermittent iSHP-1 in combination with TPI-1, a TLR ligand, a STING activator, RT, αPD-1 / L1, and proinflammatory cytokines at a dose sufficient to induce systemic tumor clearance did not exhibit severe lung or kidney damage, anemia, or splenomegaly (data presented in the case study in the next section). This high benefit-to-risk ratio is attributable to the pulsed iShp-1 design, which is specifically tailored to target intratumoral macrophages and exerts its effects locally in the tumor while avoiding long-term depletion of SHP-1 activation in major organs such as the lung, intestine, kidney, and spleen, where SHP-1 activity plays a key role in suppressing unwanted autoimmune inflammatory responses to resident microorganisms and cellular debris. Our further studies supported this idea by showing that after pulsed inhibition of SHP-1 in macrophages with the covalent inhibitor TPI-1, the macrophages regained SHP-1 activation within 24 hours.

[0355] Example 8 We tested iSHP-1 in combination with TLR agonists (αTLR), STING activators, immune checkpoint blockade (αPD-1 / L1), and / or RT for the treatment of various solid tumors, including pancreatic ductal adenocarcinoma KPC (KPC-luc) and Pan02, colorectal cancer MC38, lung cancer LLC, and metastatic breast cancer 4T1 in fully immunocompetent syngeneic mouse models. Both therapeutic efficacy and safety were evaluated according to Figure 10.

[0356] Mouse models (single or multifocal solid tumors): 1) pancreatic ductal adenocarcinoma (KPC or KPC-luc)-C57BL6 syngeneic engraftment, 2) colorectal carcinoma (MC38)-C57BL6 syngeneic engraftment, 3) lung carcinoma (LLC or LLC-luc)-C57BL6 syngeneic engraftment, and 4) metastatic breast carcinoma (4T1 or 4T1-luc)-BalbC background syngeneic engraftment.

[0357] Establishment of tumor model: Well-cultured cancer cells (1–5 × 10 5 Syngeneic models were established by subcutaneous (sc), intraperitoneal (ip), intravenous (iv), or intravenous injection into wild-type C57BL / 6 or Balb / c mice (6–8 weeks old, male and female) at the primary site. For multiple tumor lesions (metastatic models), tumor cells were implanted at multiple sites by multipoint sc injection combined with ip or iv injection. Palpable subcutaneous or orthotopic (e.g., 4T1) tumors formed after 10–14 days. The long and short diameters of the tumor were measured using calipers, and tumor volume (V) was calculated using the following formula: Volume = (major axis x minor axis 2) / 2 For luciferase-expressing tumor cells (KPC-luc, LLC-luc, 4T1-luc), whole-body luminescence intensity images were taken to visualize the tumor.

[0358] Therapeutic treatment: single tumor ≥ 200 mm 3 or total tumor burden ≥ 300 mm 3 Treatment was initiated when tumors reached a tumor size of 1000x the normal size. The covalent SHP-1 inhibitor TPI-1 was chosen for its potent inhibitory potency and relative specificity. To achieve systemic effects at sites distant from the tumor site, various doses of TPI-1 in PBS were administered by i.p. or sc injection according to different administration strategies. In a subset of experiments, TPI-1 was injected directly into the tumor (intratumoral injection (it)), and its effects were also tested. TPI-1 was administered prior to or in combination with combined modalities.

[0359] A. Study 1 (Figures 11A-11E): Therapeutic efficacy and adverse toxicity of continuous versus intermittent iSHP-1 in combination with TLR agonists Tumor model: Single engraftment of KPC pancreatic adenocarcinoma

[0360] Treatment and dosing strategy: i) iSHP-1 and TPI-1, 1, 3, and 10 mg / kg, administered ip once daily (continuously) or according to the intermittent schedule shown in Figure 11; ii) TLR agonist (αTLR)-CpG, PolyI:C, 10 μg each, administered ip every 3 days.

[0361] Results: TPI-1 demonstrated dose-dependent effects, and when combined with a TLR agonist, it inhibited KPC pancreatic tumor growth and induced tumor regression. Both continuous and intermittent administration strategies of TPI-1 achieved similar antitumor effects. However, continuous administration of TPI-1 (once daily) caused acute anemia, proteinuria, splenomegaly, and pulmonary inflammation. These adverse effects were absent or minimal in mice treated intermittently with TPI-1. In conclusion, the intermittent iSHP-1 strategy significantly reduced the risk of adverse toxicity while achieving tumor-suppressive effects.

[0362] B. Study 2 (Figures 12A-12D): Treatment, efficacy, and adverse toxicity of pulsed intermittent iSHP-1 in combination with TLR agonists and / or ICB (αPD-L1) in multiple colorectal cancer Conclusions: i) Intermittent iSHP-1 in combination with a TLR agonist (αTLR) or αTLR and αPD-L1 effectively regressed multiple MC38 colorectal cancer lesions that were resistant to TLR alone or αPD-L1. ii) TPI-1 administered ip and sc had similar systemic effects. iii) αPD-L1 enhanced iSHP-1 + αTLR-mediated T cell immune activation. iv) Intermittent iSHP-1 therapy did not cause acute adverse toxicities.

[0363] C. Study 3 (Figures 13A-13E): Treatment of multiple lesions of pancreatic ductal adenocarcinoma and lung cancer with pulsed intermittent iSHP-1 in combination with RT and αPD-L1 Modality and administration strategy: i) iSHP-1 and TPI-1, 3 or 5 mg / kg, ip, once every 3 days; ii) Local tumor RT: 8 Gy-4 Gy-2 Gy, with simultaneous iSHP-1 administration in the right flank; iii) αPD-L1: 100 μg, ip, followed by iSHP-1 + RT the next day.

[0364] Results: Systemic intermittent iSHP-1 combined with tumor-localized RT in the right flank, followed by αPD-L1, enhanced T cell immunity and induced potent antitumor immunity with abscopal effects, effectively eliminating or suppressing KPC pancreatic cancer and LLC lung cancer with distant lesions.

[0365] D. Study 4 (Figures 14A-14E): Pulse-intermittent iSHP-1 in combination with a TLR agonist to treat late-stage large KPC pancreatic cancer. Mouse model: Single large pancreatic ductal adenocarcinoma (KPC-luc) C57BL6 syngeneic

[0366] Treatment: SHP-1 inhibition (iSHP-1) combined with TLR agonist (αTLR)

[0367] Results: As shown in Figures 14A-14E, the combination of TPI-1 and αTLR enhanced anti-tumor immune cells such as CD8+ T cells, NK cells, and neutrophils, effectively eliminating large, late-stage KPC pancreatic cancers.

[0368] Example 9 In vitro macrophage assays were performed with or without TPI-1 inhibition of SHP-1 (iShp1) in the presence of tumor cells that ligand for macrophage iRs. See the test system in Figure 16A. As shown in Figures 16B and 16C, IFNα treatment alone, with or without iSHP1, did not induce antigen presentation or proinflammatory responses by macrophages. IFNγ plus iSHP1 significantly increased antigen presentation, even though this combination did not induce proinflammatory cytokine production. In contrast, IL-1 family cytokines (IL-1β, IL-18), TNFα, and TLR ligands in combination with iSHP1 demonstrated the ability to proinflammatoryly activate macrophages in the tumor environment.

[0369] Example 10 MC38 colorectal carcinoma was established (via subcutaneous administration) in syngeneic C57BL6 mice. Tumor size was 200 mm 3 After reaching 500 μg / mL, tumor-bearing mice were treated with TLR agonists (αTLR, CpG / PolyIC / R848, 25 μg each) subcutaneously at a site distal to the MC38 tumor to induce systemic inflammation. Mice were also treated with TPI-1 (1 mg / kg) subcutaneously to achieve systemic SHP-1 inhibition.

[0370] As shown in Figure 17A, MC38 tumors were protected from αTLR-induced acute inflammation via SHP-1. Neutrophil infiltration, an indicator of local tissue inflammation in each organ, was measured at various time points after αTLR stimulation. Inhibition of SHP-1 by TPI-1 relieved tumor immunosuppression and allowed neutrophil infiltration after αTLR administration (αTLR + TPI-1).

[0371] As shown in Figure 17B, TEM analysis confirmed increased neutrophil infiltration in tumor tissues of mice treated with αTLR+TPI-1.

[0372] As shown in Figure 17C, inhibition of SHP-1 by TPI-1 biased intratumoral macrophages toward proinflammatory activation via αTLR, exhibiting increased expression of TNFα and IL-12. In contrast, in the absence of TPI-1, macrophages resisted αTLR-induced inflammation but exhibited enhanced immunosuppression and increased expression of IL-10 and TGFβ.

[0373] Example 11 This example demonstrates that neutralizing TNFα suppresses systemic inflammation without compromising the antitumor effects of the combined use of TKi, SHP-1 inhibition, and αTLR.

[0374] Mice with established MC38 colorectal carcinoma (200-400 mm3) were treated with αTLR, TPI-1, and dasatinib (sc), with or without additional treatment with anti-TNFα mAb or anti-IL-6 mAb (150 μg, ip). Treatment was repeated once (d1 and d2). Changes in tumor volume were recorded, and immune infiltration in the tumor TME was analyzed 6 days after treatment. See Figure 11A.

[0375] As shown in Figure 11B, tumor volume was reduced after treatment with αTLR + TPI-1 + dasatinib, and administration of anti-TNFα or anti-IL-6 did not interfere with their anti-tumor activity. Treatment with anti-TNFα mAb or anti-IL-6 mAb did not affect the increase in CD8 T cells (Tc) and NK cells induced by αTLR / TPI-1 / dasatinib therapy, or the decrease in macrophages and MDSCs in the TME. See Figures 11C and 11D. Treatment of mice with anti-TNFα mAb, but not anti-IL-6 mAb, significantly reduced the induction of proinflammatory cytokines (TNFα, IL-6, IL-1β, IL-10, IFNα, and IFNγ) associated with αTLR / TPI-1 / dasatinib combination therapy. Anti-TNFα treatment significantly reduced circulating monocyte and PMN chemokines CCL2, CCL5, and CXCL1, but not CXCL10, which is essential for T cell migration (Figure 11E). Furthermore, as shown in Figure 11F, anti-TNFα treatment protected mice from the development of splenomegaly and intestinal inflammation typically associated with αTLR / TPI-1 / dasatinib therapy.

[0376] Taken together, these results demonstrated that neither anti-TNFα nor anti-IL-6 antibodies interfered with the induction of antitumor immunity or the achievement of therapeutic efficacy through TKi / iSHP-1 / αTLR. Furthermore, anti-TNFα significantly suppressed the cytokine storm and systemic inflammation induced by TKi / iSHP1 / αTLR, thereby exerting beneficial effects by suppressing treatment-associated adverse toxicities.

[0377] Furthermore, while the specific experiments described above used both TPI-1 and dasatinib, and both poly I:C and R848, similar effects were observed in experiments using either TPI-1 or dasatinib, or either poly I:C or R848 (data not shown). The inventors also found that the appropriate period for anti-TNFα antibody treatment ranges from at least one week prior (as long as the antibody is stable during that period) to immediately (e.g., within 0.5 to 1 hour) after SHP-1 inhibitor / αTLR treatment. The anti-TNFα antibody is preferably administered before or simultaneously with the administration of the SHP-1 inhibitor and / or αTLR to maximize blockade of TNFα induced after treatment with the SHP-1 inhibitor and an inflammatory agent.

[0378] Example 12 We investigated the mechanism by which tumor cells inhibit the proinflammatory response of macrophages in the TME. As shown in Figure 19, panel A, macrophage responses were assayed in the tumor environment. Human monocyte-derived macrophages (Mφ) were cultured alone (Configuration 1), in the presence of 50% cancer cell-conditioned medium containing secreted factors from cancer cells (Secretome condition, Configuration 2), or co-cultured with cancer cells (Cell "contact" model, Configuration 3), or in the absence of Mφ cells in a transwell (0.4 μm) without contact (Configuration 4). Macrophages in these settings were treated with the proinflammatory stimuli TLR agonist R848 (1 μg / ml), R848 plus IFNγ (40 ng / ml), or the STING activator MSA-2 (10 μg / ml).

[0379] We then examined the macrophage response to R848 / IFNγ. The presence of the cancer secretome (components 2 and 4) resulted in a partial inhibition of proinflammatory cytokine production (a 10%-40% decrease), but did not alter the pattern of macrophage proinflammatory responses. In contrast, macrophages cocultured with cancer cells exhibited suppressed proinflammatory responses and enhanced immunosuppressive effects, along with increased production of IL-10. See Figure 19, panel B.

[0380] The macrophage response to R848 or MSA-2 was also examined. Similar results as in panel B: In the presence of cancer secretome, the proinflammatory response of macrophages was partially suppressed, whereas in macrophages cocultured with cancer cells, the proinflammatory response was completely suppressed and the immunosuppressive effect was enhanced with increased production of IL-10 and TGFβ. See Figure 19, panel C.

[0381] Furthermore, as shown in Figure 20, macrophages co-cultured with cancer cells suppressed TLR agonist (R848) + IFNγ-induced macrophage antigen presentation.

[0382] Example 13 As shown in Figure 21, iRs and their ligands were found to be upregulated as tumors progressed to later stages (larger size). Panel A shows the immune cell composition and proportions within a typical MC38 colorectal carcinoma. Panel B shows the expression of multiple inhibitory receptors (iRs) on myeloid immune populations, including TAMs (F4 / 80+), MDSCs (Ly6C+), and N2-neutrophils (PMNs), in MC38 carcinomas of different sizes. Panels C and D show the expression of CD47 and PD-L1 in the same MC38 carcinomas as in Panel B but of different sizes. Panel E shows representative IHC staining of human cancer samples demonstrating increased expression of ligands for myeloid iRs.

[0383] Example 14 It has also been found that cancer cell and tumor TME-produced factors (sectomes) induce increased macrophage expression of iRs. See, e.g., Figure 22. Panel A shows increased expression of iRs in myeloid leukocytes in murine solid tumors, including 4T1 breast cancer, LLC lung cancer, and EL4 T-cell lymphoma. Treatment of murine bone marrow-derived macrophages with murine cancer cell-conditioned medium increases iR expression. Examples of cancer cells include B16 melanoma cells, MC38 colorectal cancer cells, EL4 T-cell lymphoma cells, and LLC lung cancer cells. SIRPα is an example of an iR. See, e.g., Figure 22, panel B.

[0384] Treatment of human monocyte-derived macrophages with human-derived cancer cell-conditioned medium increased the expression of iRs. Examples of cancer cells shown include colorectal cancer cells T84, HT29, and SW620T; breast cancer cells T47D; lung cancer A549; renal cancer TK10; ovarian cancer OVCAR3; and monocytic leukemia THP1. Examples of iRs tested in human macrophages include SIRPα, LILRB1, LILRB4, and Siglec7. See Panel C of Figure 22. Cytokines produced by mouse and human cancer cells in culture are shown in Panel D of Figure 22. Treatment of macrophages with cancer cell cytokines induced an increase in iR expression (e.g., SIRPα) in macrophages (bone marrow-derived macrophages (BMDM) and peritoneal macrophages (PEM)). See Panel E of Figure 22.

[0385] Example 15 Inhibition of SHP-1 induces a proinflammatory response in the KPC tumor TME, as shown in Figures 23A-23B. KPC pancreatic tumors excised from mice were cut into small pieces and treated with five different TLR agonists (R848, 3M-852A, motolimod, bropirimine, or vesatolimod, 1 μg / ml each) with or without the SHP-1 inhibitor TPI-1 (0.4 μM). After 18 hours, cytokines secreted into the culture medium were assayed.

[0386] As shown in Figure 23A, all five TLR agonists did not induce proinflammatory cytokine production but induced high levels of IL-10 and TGFβ, suggesting enhanced immunosuppression in the TME.

[0387] As shown in Figure 23B, inhibiting SHP-1 (iSHP-1) enabled TLR agonists to promote proinflammatory responses in tumor tissues. As shown, adding the SHP-1 inhibitor TPI-1 to A) induced high production of proinflammatory cytokines and suppressed the production of IL-10 and TGFβ.

[0388] Example 16 Treatment of MC38 tumors with TLR agonists (αTLR) plus SHP-1 inhibition resulted in proinflammatory polarization in the TME. MC38 colorectal tumors excised from mice were cut into small pieces and treated with CpG plus poly(I:C) plus R848 (each at 0.4 μg / ml) ± TPI-1 (0.4 μM). After 18 hours, cytokines secreted into the culture medium were assayed. As shown in Figure 24, αTLR plus TPI-1 induced a high level of proinflammatory responses while suppressing IL-10 in the TME.

[0389] Example 17 We examined the iR-SHP-1 inhibitory axis. iR-activated SHP-1 dephosphorylates the JAK-STAT, NFchB, MAPK, and PI3K-Akt activation pathways induced by inflammatory stimuli, suppressing proinflammatory signaling and conferring therapeutic resistance. Inhibition of SHP-1 suppresses multi-axis iR-mediated inhibitory control and activates proinflammatory polarization of macrophages, as shown in Figures 25A-25B.

[0390] Example 18 As shown in Figures 26B and 26C, SHP1 - / - Macrophages resist inhibition by cancer cells and activate proinflammatory responses under TLR and IFNγ stimulation. WT or homozygous Shp1 - / - Bone marrow-derived macrophages (BMDMs) from mice were treated with a TLR agonist (αTLR; R848, 1 μg / ml) plus IFNγ (40 ng / ml) in the presence of B16 melanoma cells. See Figure 26A. After 16 hours, cell culture medium was collected and assayed for cytokines. The results are shown in Figure 26B. Macrophages were also collected and assayed for inflammatory phenotypes and cell surface expression of antigen-presenting machinery. The results are shown in Figure 26C.

[0391] Example 19 As shown in Figures 27A-27C, cell surface blockade of iR or ligand is an alternative strategy to deplete the iR→SHP-1 inhibitory axis.

[0392] Experimental Setup: Human macrophages and cancer cells were cocultured and stimulated with proinflammatory factors (e.g., TLR agonists, IFNγ, STING activators, etc.) in the presence or absence of TPI-1 (SHP-1 inhibitor, or iSHP-1), mAbs blocking Siglecs (αSiglecs 7, 8, and 9), mAbs blocking LilRB-MHC interactions (αLILRB1, αLilRB2, αLilRB3, αLilRB4, or pan-HLA-A / B / C blocking antibodies), or mAbs blocking CD47-SIRPα interactions (αCD47 or αSIRPα). To remove sialic acid structures on the cancer cell surface that bind to Siglecs on macrophages, cancer cells were treated with neuraminidase (50 mU / ml, 1 hour) before use in experiments. See Figure 27A.

[0393] Information on the blocking antibodies used in the experiment is shown in Figure 27B. These antibodies are commercially available and were used at 2-10 μg / ml.

[0394] Example data (macrophages with SW260 cancer cells). As shown in Figure 27C, blocking a single iR-ligand axis was insufficient to eliminate the immune suppression of macrophages by cancer cells, whereas blocking multiple iR-ligand interactions or inhibiting SHP-1, which is downstream of all iRs in macrophages, relieved tumor cell suppression and allowed macrophages to mount a proinflammatory response. Similar results were obtained when macrophages were co-cultured with other cancer cells, including OVCAR3, MDA231, TK10, and HT29. References 1. Kang, X. L., J. Kim, M. Deng, S. John, H. Chen, G. J. Wu, H. Phan, and CC Zhang. Inhibitory leukocyte immunoglobulin-like receptors:Immune checkpoint proteins and tumor sustaining factors. Cell Cycle15:25–40. 2.Zarrin,AA,RCMonteiro. Editorial:The Role of Inhibitory Receptors in Inflammation andCancer. Front Immunol 11 . 3.Carosella,ED,S.Gregori,D.Tronic-Le Roux.2021. HLA-G / LILRBs:A Cancer Immunotherapy Challenge.Trends Cancer7:389-392. 4.Yanagita,T.,Y.Murata,D.Tanaka,SIMotegi,E.Arai,EWDaniwijaya,D.Hazama,K.Washio,Y.Saito,T.Kotani,H.Ohnishi,PAOldenborg,NVGarcia,M.Miyasaka,O. Ishikawa, Y. Kanai, T. Komori, and T. Matozaki. Anti-SIRP alpha antibodies as a potential new tool for cancer immunotherapy. Jci Insight2. 5. Zhang, W., Q. Huang, W. Xiao, Y. Zhao, J. Pi, H. Xu, H. Zhao, J. Xu, CEevas, and H. Jin. Advances inAnti-Tumor Treatments Targeting the CD47 / SIRPαlpha Axis. Front Immunol11:18. 6.Green,M.C.,and L.D.Shultz.1975. Motheaten,an immunodeficient mutant of the mouse. I.Genetics andpathology. J Hered 66:250-258. 7.Shultz,L.D.,and M.C.Green.1976. Motheaten,an immunodeficient mutant of the mouse. II. Depressedimmune competence and elevated serum immunoglobulins. J Immunol 116:936-943. 8.Kundu,S.,K.Fan,M.L.Cao,D.J.Lindner,Z.Z.J.Zhao,E.Borden,and T.L.Yi.2010. Novel SHP-1 InhibitorsTyrosine Phosphatase Inhibitor-1 and Analogs with Preclinical Anti-Tumor Activities as Tolerated Oral Agents.J Immunol 184:6529-6536. 9.Yuan,X.,Y.Duan,Y.Xiao,K.Sun,Y.Qi,Y.Zhang,Z.Ahmed,D.Moiani,J.Yao,H.Li,L.Zhang,A.E.Yuzhalin,P.Li,C.Zhang,A.Badu-Nkansah,Y.Saito,X.Liu,W.L.Kuo,H.Ying,S.C.Sun,J.C.Chang,J.A.Tainer,and D.Yu.2022. Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting CheckpointSHP-1. Cancer Discov. 10. Arabaci,G.,X.C.Guo,K.D.Beebe,K.M.Coggeshall,and D.Pei.1999.alpha-Haloacetophenone derivatives asphotoreversible covalent inhibitors of protein tyrosine phosphatases. J Am Chem Soc 121:5085-5086. 11. Yang,R.L.,Q.Dong,H.B.Xu,X.H.Gao,Z.Y.Zhao,J.C.Qin,C.Chen,and D.Q.Luo.2020. Identification ofPhomoxanthone A and B as Protein Tyrosine Phosphatase Inhibitors. Acs Omega 5:25927-25935. 12. Ben-Shmuel,A.,B.Sabag,A.Puthenveetil,G.Biber,M.Levy,T.Jubany,F.Awwad,R.K.Roy,N.Joseph,O.Matalon,J.Kivelevitz,and M.Barda-Saad.2022. Inhibition of SHP-1 activity by PKC-theta regulates NK cellactivation threshold and cytotoxicity. Elife 11. 13. Jones,M.L.,J.D.Craik,J.M.Gibbins,and A.W.Poole.2004. Regulation of SHP-1 tyrosine phosphatase inhuman platelets by serine phosphorylation at its C terminus. J Biol Chem 279:40475-40483. 14. Shi,L.,K.Kidder,Z.Bian,S.K.T.Chiang,C.Ouellette,and Y.Liu.2021. SIRPαlpha sequesters SHP-2 topromote IL-4 and IL-13 signaling and the alternative activation of macrophages. Sci Signal 14:eabb3966. 15. Huang,Z.,J.M.Coleman,Y.Su,M.Mann,J.Ryan,L.D.Shultz,and H.Huang.2005. SHP-1 regulates STAT6phosphorylation and IL-4-mediated function in a cell type-specific manner. Cytokine 29: 118-124. 16. Johnson,D.J.,L.I.Pao,S.Dhanji,K.Murakami,P.S.Ohashi,and B.G.Neel.2013. SHP-1 regulates T cellhomeostasis by limiting IL-4 signals. J Exp Med 210:1419-1431. 17. Tao,B.,W.Jin,J.Xu,Z.Liang,J.Yao,Y.Zhang,K.Wang,H.Cheng,X.Zhang,and Y.Ke.2014. Myeloid-specificdisruption of tyrosine phosphatase Shp2 promotes alternative activation of macrophages and predisposesmice to pulmonary fibrosis. J Immunol 193:2801-2811. 18. Fisher,D.T.,M.M.Appenheimer,and S.S.Evans.2014. The two faces of IL-6 in the tumormicroenvironment. Semin Immunol 26: 38-47. 19.Chonov,D.C.,M.M.K.Ignatova,J.R.Ananiev,and M.V.Gulubova.2019. IL-6 Activities in the TumourMicroenvironment. Part 1.Open Access Maced J Med Sci 7:2391-2398.

Claims

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

2. A method for treating cancer in an individual, comprising administering to the individual: a) an SHP-1 inhibitor; and b) an inflammation-inducing agent, wherein the SHP-1 inhibitor is administered systemically.

3. 1. A method for treating cancer in an individual, comprising administering to the individual: a) an SHP-1 inhibitor; and b) an inflammatory inducer, wherein the inflammatory inducer comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP / DAMP activator, chemotherapy, a proinflammatory cytokine, a cancer vaccine, a bacterial component, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

4. 1. A method of treating cancer in an individual, comprising administering to said individual an SHP-1 inhibitor, said individual exhibiting an inflammatory response.

5. The method of any one of claims 2 to 4, comprising intermittently administering the SHP-1 inhibitor to the individual.

6. The method of any one of claims 1 and 3-5, comprising systemically administering the SHP-1 inhibitor.

7. 7. The method of any one of claims 1, 5, and 6, comprising administering the SHP-1 inhibitor at least twice, not more than once every three days.

8. 8. The method of any one of claims 1 and 5-7, comprising administering to the individual the SHP-1 inhibitor in at least two cycles, each cycle lasting from about 3 days to about 20 days.

9. The method of any one of claims 1 to 8, wherein the SHP-1 inhibitor does not inhibit SHP-2.

10. 10. The method of any one of claims 1 to 9, wherein the SHP-1 inhibitor has a half-life of about 5 days or less, optionally wherein the SHP-1 inhibitor has a half-life of about 3 days or less.

11. 11. The method of any one of claims 1-10, wherein the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation within about 5 days, and optionally, the SHP-1 inhibitor is effective to inhibit greater than 50% of SHP-1 activation within about 3 days.

12. The method of any one of claims 1 to 11, wherein the SHP-1 inhibitor is selected from the group consisting of small molecules, nucleic acids (e.g., siRNA, shRNA, antisense RNA, microRNA), nucleic acid editing methods (e.g., CRISPR methods), and protein formulations (e.g., antibody formulations targeting SHP-1 or activated SHP-1).

13. 13. The method of claim 12, wherein the SHP-1 inhibitor is selected from the group consisting of TPI-1 or an analog or derivative thereof, a vitamin E derivative, homoxanthone A (PXA), and a PKCθ activator.

14. The method of claim 13, wherein the SHP-1 inhibitor comprises TPI-1.

15. The method of any one of claims 1 to 14, wherein the SHP-1 inhibitor is administered at least three times.

16. 16. The method of any one of claims 1 to 15, wherein the method comprises systemic and local administration of the SHP-1 inhibitor, and optionally, the method comprises intratumoral administration of the SHP-1 inhibitor.

17. 17. The method of any one of claims 2 and 6-16, wherein the systemic administration of SHP-1 comprises oral administration, intravenous administration, subcutaneous administration, and / or intraperitoneal administration.

18. 18. The method of any one of claims 1 to 3 and 5 to 17, wherein one of the pro-inflammatory agent and the SHP-1 inhibitor is administered within about 24 hours of the other, and optionally, one of the pro-inflammatory agent and the SHP-1 inhibitor is administered within about 4 hours of the other.

19. The method of any one of claims 1 to 3 and 5 to 18, wherein the method comprises administering the pro-inflammatory agent intratumorally.

20. 20. The method of any one of claims 1 to 3 and 5 to 19, wherein the method comprises administering an inflammation-inducing agent to a site different from the site of the cancer being treated.

21. The method of any one of claims 1 to 2 and 5 to 18, wherein the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic drug, a bacterial component, a cancer vaccine, an oncolytic virus, acoustic therapy, magnetic therapy, electrical therapy, and electrostatic therapy.

22. The method of any one of claims 1 to 3 and 5 to 21, wherein the pro-inflammatory agent comprises a TLR agonist.

23. 23. The method of claim 22, wherein the TLR agonist activates a TLR on a macrophage, and optionally the TLR comprises TLR2, TLR3, TLR7, TLR8, and / or TLR9.

24. 24. The method of claim 23, wherein the TLR agonist comprises CpG, poly I:C, and / or R848.

25. 25. The method of any one of claims 1 to 3 and 5 to 24, wherein the pro-inflammatory agent comprises a bacterial component, optionally wherein the bacterial component comprises lipopolysaccharide (LPS).

26. The method of any one of claims 1 to 3 and 5 to 25, wherein the pro-inflammatory agent comprises a STING activator.

27. The method of claim 26, wherein the STING activator comprises 2'3'-cGAMP.

28. The method of any one of claims 1 to 3 and 5 to 27, wherein the pro-inflammatory agent comprises a chemotherapeutic agent.

29. 29. The method of claim 28, wherein the chemotherapy comprises azathioprine (AZA).

30. 30. The method of any one of claims 1 to 3 and 5 to 29, wherein the pro-inflammatory agent comprises a pro-inflammatory cytokine.

31. 31. The method of claim 30, wherein the proinflammatory cytokines include IL-1b, IL-18, IL-6, and / or TNFα.

32. The method of any one of claims 1-2 and 5-31, wherein the pro-inflammatory agent comprises radiation therapy.

33. 33. The method of claim 32, wherein the radiation therapy comprises irradiating the site of the cancer being treated.

34. 34. The method of claim 32 or 33, wherein the radiation therapy comprises irradiating a site different from the site of the cancer being treated.

35. The method of any one of claims 32 to 34, wherein the dose of radiation therapy is insufficient to kill tumor cells.

36. 36. The method of any one of claims 1-2 and 5-35, wherein the pro-inflammatory agent comprises a checkpoint inhibitor.

37. 37. The method of claim 36, wherein the checkpoint inhibitor comprises an anti-PD-L1 antibody, an anti-PD-1 antibody, or an anti-CLTA4 antibody.

38. 38. The method of any one of claims 1 to 3 and 5 to 37, wherein the pro-inflammatory agent is administered intermittently.

39. 39. The method of any one of claims 1 to 3 and 5 to 38, wherein the pro-inflammatory agent and the SHP-1 inhibitor are administered simultaneously or concurrently.

40. 40. The method of any one of claims 1 to 3 and 5 to 39, wherein the pro-inflammatory agent comprises an immune cell.

41. The method of any one of claims 4 to 39, wherein the method further comprises immune cells.

42. 42. The method of claim 41, wherein the immune cells are derived from the same individual.

43. 43. The method of claim 41 or 42, wherein the immune cells comprise or are macrophages, and optionally the macrophages have an M1 phenotype.

44. The method according to any one of claims 40 to 43, wherein the immune cells are derived from monocytes.

45. The method of any one of claims 40 to 44, wherein the immune cells express high levels of MHC-I, MHC-II, CD80, and / or CD86.

46. 46. ​​The method of any one of claims 40-45, wherein the immune cells express one or more pro-inflammatory cytokines, optionally wherein the one or more pro-inflammatory cytokines comprise TNFα and / or IL-12.

47. The method of any one of claims 40 to 46, wherein the immune cells do not express significant levels of TGFβ and / or IL-10.

48. The method of any one of claims 40 to 47, wherein the immune cells comprise T cells.

49. 49. The method of any one of claims 40-48, wherein the immune cells are engineered to express a chimeric antigen receptor, optionally wherein the chimeric antigen receptor specifically binds to a tumor antigen.

50. 50. The method of any one of claims 43 to 49, wherein the macrophages are engineered to be deficient in SHP-1 expression and / or activation.

51. 51. The method of any one of claims 40-50, wherein one of the SHP-1 inhibitor and the immune cells is administered within about 24 hours after the other, and optionally, one of the SHP-1 inhibitor and the immune cells is administered within about 4 hours after the other.

52. 52. The method of any one of claims 40 to 51, wherein the immune cells are administered simultaneously or concurrently with the SHP-1 inhibitor.

53. 53. The method of any one of claims 1 to 52, further comprising administering to the individual an effective amount of an anti-TNFα antibody.

54. 54. The method of any one of claims 1 to 53, wherein the cancer is a solid tumor.

55. 54. The method of any one of claims 1 to 53, wherein the cancer is a blood cancer.

56. The method of any one of claims 1 to 55, wherein the cancer is a terminal cancer.

57. 57. The method of any one of claims 1 to 56, wherein the cancer is resistant or refractory to radiation therapy, chemotherapy, and / or checkpoint inhibitors.

58. 58. The method of any one of claims 1 to 57, wherein the individual is a human.

59. 1. A composition comprising an SHP-1 inhibitor and an inflammatory inducer, optionally wherein the inflammatory inducer comprises an agent selected from the group consisting of an immune cell, a TLR agonist, a STING activator, an agent used in radiation therapy, a PAMP / DAMP activator, a checkpoint inhibitor, a proinflammatory cytokine, a chemotherapeutic agent, a bacterial component, a cancer vaccine, an oncolytic virus, and an agent used in acoustic therapy, magnetic therapy, electrical therapy, or electrostatic therapy.

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