Although clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve mechanisms of CAR T-cell failure. Because T-cell dysfunction is thought to contribute to CAR T-cell treatment failure, understanding what mechanisms drive T cells into this dysfunctional state may aid optimal design of efficacious CAR T cells. Dysfunctional CAR T cells have been characterized as having upregulated inhibitory receptors and decreased cytolytic capabilities. Previous studies have identified a role for sustained CAR CD3ζ signaling in CAR T-cell dysfunction. Here, we demonstrate a mechanism that drives dysfunction in CAR T cells through excessive costimulation. Fully activated CD19-targeted CAR T cells were rendered dysfunctional upon stimulation with both endogenous CD28 stimulation and CAR-mediated CD28 costimulation. Costimulation-driven dysfunction of CAR T cells was demonstrated in a syngeneic immunocompetent mouse model, in which CAR T cells were activated with signals 1 (CD3ζ), 2 (CD28), and 3 (IL12). Thus, we show that CAR T-cell dysfunction can be driven through excessive CD28 and 4-1BB costimulation. See related article by Drakes et al., [p. 743][1] [1]: /lookup/volpage/8/743?iss=6

中文翻译：

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过度共刺激会导致过继转移 T 细胞功能障碍。

尽管在某些血液系统恶性肿瘤患者中观察到了靶向 CD19 的嵌合抗原受体 (CAR) T 细胞治疗的临床反应，但疾病的高复发率凸显了了解和改善 CAR T 细胞失败机制的必要性。由于 T 细胞功能障碍被认为是导致 CAR T 细胞治疗失败的原因，因此了解驱动 T 细胞进入这种功能障碍状态的机制可能有助于有效 CAR T 细胞的优化设计。功能失调的 CAR T 细胞的特点是抑制性受体上调和细胞溶解能力下降。先前的研究已经确定了持续的 CAR CD3ze 信号传导在 CAR T 细胞功能障碍中的作用。在这里，我们展示了一种通过过度共刺激驱动 CAR T 细胞功能障碍的机制。完全激活的 CD19 靶向 CAR T 细胞在受到内源性 CD28 刺激和 CAR 介导的 CD28 共刺激的刺激后会出现功能障碍。在同基因免疫活性小鼠模型中证实了共刺激驱动的 CAR T 细胞功能障碍，其中 CAR T 细胞被信号 1 (CD3z)、2 (CD28) 和 3 (IL12) 激活。因此，我们表明 CAR T 细胞功能障碍可以通过过度的 CD28 和 4-1BB 共刺激来驱动。请参阅 Drakes 等人的相关文章，[p. 11]。743][1][1]：/lookup/volpage/8/743?iss=6