TY - JOUR
T1 - Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies
AU - Beider, Katia
AU - Itzhaki, Orit
AU - Schachter, Jacob
AU - Grushchenko-Polaq, Ania Hava
AU - Voevoda-Dimenshtein, Valeria
AU - Rosenberg, Evgenia
AU - Ostrovsky, Olga
AU - Devillers, Olivia
AU - Frommer, Ronnie Shapira
AU - Zeltzer, Li At
AU - Toren, Amos
AU - Jacoby, Elad
AU - Shimoni, Avichai
AU - Avigdor, Abraham
AU - Nagler, Arnon
AU - Besser, Michal J.
N1 - Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
KW - B cell malignancies
KW - CAR T
KW - exhaustion
KW - molecular signature
KW - resistance
UR - http://www.scopus.com/inward/record.url?scp=85127050491&partnerID=8YFLogxK
U2 - 10.3390/cells11071140
DO - 10.3390/cells11071140
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C2 - 35406703
AN - SCOPUS:85127050491
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 7
M1 - 1140
ER -