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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1140
JournalCells
Volume11
Issue number7
DOIs
StatePublished - 1 Apr 2022

Keywords

  • B cell malignancies
  • CAR T
  • exhaustion
  • molecular signature
  • resistance

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