Abstract PR05: T-cells engineered to overcome death signaling within the tumor microenvironment enhance adoptive cancer immunotherapy

Abstract

Across clinical trials, T-cell expansion and persistence following adoptive cell transfer (ACT) has correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis across human tumors to identify potentially actionable ligand/receptor pairs that might limit T-cell function and persistence following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments. Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T-cells used for ACT. We hypothesized that a cognate Fas-FasL interaction within the tumor microenvironment might limit both T-cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired the ability to bind FADD function as dominant negative receptors (DNRs) in Fas-competent mouse and human T-cells, rescuing cells from FasL-induced apoptosis. Fas DNR-engineered T-cells exhibited enhanced persistence within tumors following ACT, resulting in superior cancer regression and overall survival in solid and hematologic malignancies treated with TCR or CAR-modified cells. Despite enhanced longevity, Fas DNR-engineered T-cells did not undergo aberrant clonal expansion, demonstrating the safety of this approach. Thus, cell-intrinsic “insulation” of T-cells from the negative influence of FasL is a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies. Citation Format: Christopher A. Klebanoff. T-cells engineered to overcome death signaling within the tumor microenvironment enhance adoptive cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR05.