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BackgroundDespite the remarkable efficacy achieved by CAR-T therapy in hematologic malignancies, application in solid tumors has been challenging. We previously developed human CAR-M and demonstrated that adoptive transfer of CAR-M into xenograft models of human cancer controls tumor progression and improves overall survival.1 Given that CAR-M are M1-polarized macrophages with the potential to remodel the tumor microenvironment (TME) and act as professional antigen presenting cells, we developed an immunocompetent animal model to evaluate the interaction of CAR-M with the TME and the adaptive immune system.MethodsMurine bone marrow-derived macrophages were engineered to express an anti-HER2 CAR using the chimeric adenoviral vector Ad5f35. To evaluate the safety and efficacy of CAR-M therapy, immunocompetent mice were engrafted with HER2+ tumors and treated with syngeneic CAR-M monotherapy or in combination with a PD1 blocking antibody. Tumors were collected at various time points and dynamic changes in the TME were assessed using flow cytometry, immunohistochemistry, and gene expression analysis.ResultsIn addition to efficient gene delivery, Ad5f35 transduction promoted a pro-inflammatory (M1) phenotype in murine macrophages. CAR-M, but not control macrophages, phagocytosed and killed HER2-overexpressing tumor cell lines. CAR-M induced MHC-I expression on tumor cells and enhanced the cytotoxicity of CD8+ T cells. In vivo, CAR-M led to significant tumor regression and improved overall survival in multiple syngeneic models. Analysis of the TME showed that CAR-M led to increased infiltration of intratumoral CD4+ and CD8+ T, NK, and dendritic cells – as well as an increase in T cell responsiveness to tumor-associated antigens, indicating enhanced epitope spreading. Given the impact of CAR-M on the endogenous adaptive immune system, we evaluated the combination of CAR-M with anti-PD1 in the CT26-HER2 model, which is resistant to anti-PD1 monotherapy, and found that the combination further reprogrammed the TME, enhanced tumor control, and improved overall survival compared to monotherapy with either agent. Mice that achieved complete responses (CRs) after CAR-M therapy were protected against antigen-negative relapse, indicating long-term anti-tumor immunity. Finally, the combination of CAR-M with anti-PD1 did not trigger sustained elevations of any serum analyte associated with cytokine release syndrome (CRS) and was well tolerated across numerous safety assessmentsConclusionsThese results demonstrate that CAR-M reprogram the TME, induce epitope spreading, and orchestrate a systemic immune response against solid tumors. Moreover, our findings provide rationale for the combination of CAR-M with immune checkpoint inhibitors for the treatment of solid tumors.ReferenceKlichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38(8):947–953

A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive ‘macroenvironment’ mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis. Tumour progression is promoted by the generation of an immunosuppressive macroenvironment. Here, the authors demonstrate that the Inhibitor of Differentiation 1 promotes the switch from dendritic cell differentiation towards myeloid-derived suppressor cell expansion during tumour progression.

Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment (TME). Interleukin (IL)-6 is particularly and highly produced by triple-negative breast cancer (TNBC) cells, and has been considered as an important contributor to immune suppression in the TME. Therefore, we hypothesized that IL-6 reduction may improve efficacy of vaccination against TNBC cancer through improved T-cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL-6 production, on vaccination of a highly attenuated Listeria monocytogenes (Listeria(at)), encoding tumor-associated antigens (TAA) Mage-b in a TNBC model 4T1. Two therapeutic vaccination strategies with Listeria(at)-Mage-b and curcumin were tested. The first immunization strategy involved all Listeria(at)-Mage-b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with Listeria(at)-Mage-b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of Listeria(at)-Mage-b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL-6 was significantly decreased and IL-12 increased by myeloid-derived suppressor cells (MDSC), in correlation with improved CD4 and CD8 T-cell responses in blood. Our study suggests that curcumin improves the efficacy of Listeria(at)-Mage-b vaccine against metastases in TNBC model 4T1 through reversal of tumor-induced immune suppression.

Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment (TME). Interleukin (IL)‐6 is particularly and highly produced by triple‐negative breast cancer (TNBC) cells, and has been considered as an important contributor to immune suppression in the TME. Therefore, we hypothesized that IL‐6 reduction may improve efficacy of vaccination against TNBC cancer through improved T‐cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL‐6 production, on vaccination of a highly attenuated Listeria monocytogenes (Listeriaat), encoding tumor‐associated antigens (TAA) Mage‐b in a TNBC model 4T1. Two therapeutic vaccination strategies with Listeriaat‐Mage‐b and curcumin were tested. The first immunization strategy involved all Listeriaat‐Mage‐b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with Listeriaat‐Mage‐b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of Listeriaat‐Mage‐b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL‐6 was significantly decreased and IL‐12 increased by myeloid‐derived suppressor cells (MDSC), in correlation with improved CD4 and CD8 T‐cell responses in blood. Our study suggests that curcumin improves the efficacy of Listeriaat‐Mage‐b vaccine against metastases in TNBC model 4T1 through reversal of tumor‐induced immune suppression. This study is focused on improving cancer vaccination by reducing immune suppression. Here we demonstrate that curcumin improves vaccine efficacy of Listeria‐Mage‐b by converting myeloid‐derived suppressor cells into an immune stimulating phenotype, that is, through reducing IL‐6 and increasing IL‐12 production, in correlation with improved T cell responses and a dramatic reduction in the number of metastases. The novel results of this study may be a platform for improvement of other cancer vaccines by curcumin.

Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment ( TME ). Interleukin ( IL )‐6 is particularly and highly produced by triple‐negative breast cancer ( TNBC ) cells, and has been considered as an important contributor to immune suppression in the TME . Therefore, we hypothesized that IL ‐6 reduction may improve efficacy of vaccination against TNBC cancer through improved T‐cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL ‐6 production, on vaccination of a highly attenuated L isteria monocytogenes ( L isteria at ), encoding tumor‐associated antigens ( TAA ) Mage‐b in a TNBC model 4T1. Two therapeutic vaccination strategies with L isteria at ‐ M age‐b and curcumin were tested. The first immunization strategy involved all L isteria at ‐ M age‐b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with L isteria at ‐ M age‐b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of L isteria at ‐ M age‐b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL ‐6 was significantly decreased and IL ‐12 increased by myeloid‐derived suppressor cells ( MDSC ), in correlation with improved CD 4 and CD 8 T‐cell responses in blood. Our study suggests that curcumin improves the efficacy of L isteria at ‐ M age‐b vaccine against metastases in TNBC model 4T1 through reversal of tumor‐induced immune suppression.