Differential susceptibility to senescence in CART cells based on co-stimulatory signaling

Abstract

CD19-directed chimeric antigen receptor (CART19) cells have emerged as a potentially curative immunotherapy in a subset of patients with hematological malignancies. While initial responses are impressive, the majority of responsive patients relapse within a year. Recent studies suggest that CART cells are susceptible to states of dysfunction.

We aimed to study the development of T cell senescence in CART cells using similar constructs to the FDA-approved therapies, CART19-BBζ and CART19-28ζ, to determine the impact of co-stimulatory domains on CART cell senescence. We developed an in vitro model for repeated CART cell activation followed by rest to study the development of senescence and its impact on effector T cell functions. We examined CART cell immunophenotype, cell cycle regulators, and transcriptomic profile on days 0 (T cell), D8 (standard CART cell), 15 (after one activation cycle) and 22 (after two activation cycles).