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

TN Yamamoto, PH Lee, SK Vodnala… - The Journal of …, 2019 - Am Soc Clin Investig
TN Yamamoto, PH Lee, SK Vodnala, D Gurusamy, RJ Kishton, Z Yu, A Eidizadeh, R Eil
The Journal of clinical investigation, 2019Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation