Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies
Katia Beider, Orit Itzhaki, Jacob Schachter, Ania Hava Grushchenko-Polaq, Valeria Voevoda-Dimenshtein, Evgenia Rosenberg, Olga Ostrovsky, Olivia Devillers, Ronnie Shapira Frommer, Li‐at Zeltzer, Amos Toren, Elad Jacoby, Avichai Shimoni, Abraham Avigdor, Arnon Nagler, Michal J. Besser
Abstract
Despite the high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, its full capacity is currently limited by the generation of dysfunctional CAR T cells. Senescent or exhausted CAR T cells possess poor targeting and effector functions, as well as impaired cell proliferation and persistence in vivo. Strategies to detect, prevent or reverse T cell exhaustion are therefore required in order to enhance the effectiveness of CAR T immunotherapy. Here we report that CD19 CAR T cells from non-responding patients with B cell malignancies show enrichment of CD8+ cells with exhausted/senescent phenotype and display a distinct transcriptional signature with dysregulation of genes associated with terminal exhaustion. Furthermore, CAR T cells from non-responding patients exhibit reduced proliferative capacity and decreased IL-2 production in vitro, indicating functional impairment. Overall, our work reveals potential mediators of resistance, paving the way to studies that will enhance the efficacy and durability of CAR T therapy in B cell malignancies.