1. Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System
- Author
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Avanzi, Mauro P, Yeku, Oladapo, Li, Xinghuo, Wijewarnasuriya, Dinali P, van Leeuwen, Dayenne G, Cheung, Kenneth, Park, Hyebin, Purdon, Terence J, Daniyan, Anthony F, Spitzer, Matthew H, and Brentjens, Renier J
- Subjects
armored CAR ,adoptive transfer ,Cell Survival ,T-Lymphocytes ,MUC16 ,Adoptive ,Medical Physiology ,Antineoplastic Agents ,Inbred C57BL ,SCID ,interleukin-18 ,Mice ,Neoplasms ,Tumor Microenvironment ,Animals ,Humans ,Cell Proliferation ,B-Lymphocytes ,chimeric antigen receptor ,Animal ,B-ALL ,Xenograft Model Antitumor Assays ,Autocrine Communication ,ovarian cancer ,CAR T cell ,Immune System ,Disease Models ,Immunotherapy ,Biochemistry and Cell Biology ,IL-18 ,Signal Transduction - Abstract
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.
- Published
- 2018