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J Clin Invest. 2019 Feb 25;129(4):1551-1565. doi: 10.1172/JCI121491. eCollection 2019 Feb 25.

T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy.

Author information

1
Center for Cancer Research and.
2
Center for Cell-Based Therapy, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
3
Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
4
Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
5
Experimental Transplantation and Immunology Branch, NCI, NIH, Bethesda, Maryland, USA.
6
Children's Hospital Colorado, University of Colorado Denver, Aurora, Colorado, USA.
7
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
8
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
9
Parker Institute for Cancer Immunotherapy, New York, New York, USA.
10
Center for Cell Engineering and Department of Medicine, MSKCC, New York, New York, USA.
11
Weill Cornell Medical College, New York, New York, USA.

Abstract

Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand-receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells coengineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior antitumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies.

KEYWORDS:

Cancer gene therapy; Cancer immunotherapy; Immunology; Oncology

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