Avanzi et al. aimed to improve CAR T cell therapy in hematological and solid malignancies through activation of the immune system with “armored” CAR-delivered interleukin-18 and employed immunocompetent syngeneic mouse system for evaluation. Mouse 19m28mz-mIL18 CAR T cells enhanced long-term survival without preconditioning, showed long-term B cell aplasia, and were able to migrate and persist in the bone marrow. Survival was dependent on host macrophage, but not NK cells. Importantly, splenocytes demonstrated enhanced levels of tumor-specific endogenous CD8+ T cells.
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.
Author Info: (1) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electr
Author Info: (1) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: yekuo@mskcc.org. (3) Weill Cornell School of Medicine, New York, NY, USA. (4) Weill Cornell School of Medicine, New York, NY, USA. (5) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Department of Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. (11) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell School of Medicine, New York, NY, USA. Electronic address: brentjer@mskcc.org.
