biostudies-literatureAvanzi MPCarson Family Charitable TrustCanada Club of New YorkMemorial Sloan KetteringKate’s TeamThe Experimental Therapeutics Center of Memorial Sloan Kettering Cancer CenterWilliam Lawrence and Blanche Hughes FoundationNIHEmerald FoundationJake Wetchler FoundationNCI NIH HHSThe Lymphoma FoundationThe Leukemia and Lymphoma SocietyNIH HHS2130-2141https://www.ebi.ac.uk/biostudies/studies/S-EPMC5986286biostudies-literatureUnknown23(7)Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy.Cell reportsEngineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System.PMC5986286T32 CA009207P01CA23766P01CA059350P01CA00878R25 CA020449R01CA55349DP5 OD023056P30 CA008748R01CA138738-05P50 CA192937-02P50 CA192937P01 CA190174P01 CA059350P01 CA0237665T32-CA009207-38K12 CA184746DP5OD023056R01 CA138738P01CA190174-03Avanzi MPLi Xvan Leeuwen DGPark HBrentjens RJWijewarnasuriya DPDaniyan AFYeku OPurdon TJCheung KSpitzer MHfalseEngineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System.Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy.2018-01-01T00:00:00Z2018 May2026-05-03T11:54:32.675Z2019-03-26T23:39:56ZS-EPMC59862862976821010.1016/j.celrep.2018.04.051