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

Yamamoto TN, Lee PH, Vodnala SK, Gurusamy D, Kishton RJ, Yu Z, Eidizadeh A, Eil R, Fioravanti J, Gattinoni L, Kochenderfer JN, Fry TJ, Aksoy BA, Hammerbacher JE, Cruz AC, Siegel RM, Restifo NP, Klebanoff CA (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 129

Pages Range: 1551-1565

Journal Issue: 4

DOI: 10.1172/JCI121491

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.

Involved external institutions

National Cancer Institute (NCI) US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) University of Colorado System US United States (USA) (US) Medical University of South Carolina (MUSC) US United States (USA) (US) US National Institutes of Health (NIH) US United States (USA) (US) Parker Institute for Cancer Immunotherapy US United States (USA) (US)

How to cite

APA:

Yamamoto, T.N., Lee, P.-H., Vodnala, S.K., Gurusamy, D., Kishton, R.J., Yu, Z.,... Klebanoff, C.A. (2019). T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy. Journal of Clinical Investigation, 129(4), 1551-1565. https://doi.org/10.1172/JCI121491

MLA:

Yamamoto, Tori N., et al. "T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy." Journal of Clinical Investigation 129.4 (2019): 1551-1565.

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