Upon finding that the apoptosis-inducing ligand FasL is overexpressed in most cancer types, and that its receptor Fas is highly expressed on T cells used in clinical adoptive cell transfer, Yamamoto et al. transduced T cells with dominant negative Fas variants that do not recruit FADD (Fas-associated via death domain), disrupting apoptotic signaling. T cells with engineered CAR or TCR and an overexpressed mutant Fas variant were protected from apoptosis in vitro, and showed enhanced persistence and antitumor effect upon adoptive transfer in mice with solid or liquid tumors, without inducing abnormal lymphoproliferation or autoimmunity.
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 anti-tumor 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 co-engineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior anti-tumor 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.