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Cell Rep. 2018 May 15;23(7):2130-2141. doi: 10.1016/j.celrep.2018.04.051.

Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System.

Author information

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
Department of Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
5
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.

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.

KEYWORDS:

B-ALL; CAR T cell; IL-18; MUC16; adoptive transfer; armored CAR; chimeric antigen receptor; interleukin-18; ovarian cancer

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