B 细胞恶性肿瘤患者中与 CAR-T 细胞耗竭及临床应答受损相关的分子与功能特征

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.