Chimeric antigen receptor (CAR)-expressing T cells induce durable remissions in patients with relapsed/refractory B cell malignancies. CARs are synthetic constructs that, when introduced into mature T cells, confer a second, non-major histocompatibility complex-restricted specificity in addition to the endogenous T cell receptor (TCR). The implications of TCR activation on CAR T cell efficacy has not been well defined. Using an immunocompetent, syngeneic murine model of CD19-targeted CAR T cell therapy for pre-B cell acute lymphoblastic leukemia in which the CAR is introduced into T cells with known TCR specificity, we demonstrate loss of CD8 CAR T cell efficacy associated with T cell exhaustion and apoptosis when TCR antigen is present. CD4 CAR T cells demonstrate equivalent cytotoxicity to CD8 CAR T cells and, in contrast, retain in vivo efficacy despite TCR stimulation. Gene expression profiles confirm increased exhaustion and apoptosis of CD8 CAR T cells upon dual receptor stimulation compared to CD4 CAR T cells and indicate inherent differences between CD4 and CD8 CAR T cells in the use of T cell-associated signaling pathways. These results provide insights into important aspects of CAR T cell immune biology and indicate opportunities to rationally design CAR constructs to optimize clinical efficacy.

中文翻译：

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TCR参与会对CD8产生负面影响，但对CD4 CAR T细胞扩增和白血病清除没有影响。

表达嵌合抗原受体（CAR）的T细胞在患有复发/难治性B细胞恶性肿瘤的患者中诱导持久的缓解。CAR是合成的构建体，当将其引入成熟的T细胞时，除了内源性T细胞受体（TCR）之外，还赋予了第二种非主要的组织相容性复合物限制的特异性。TCR活化对CAR T细胞功效的影响尚未明确。使用针对CD19靶向CAR T细胞治疗B前细胞急性淋巴细胞白血病的免疫功能，同系小鼠模型（其中将CAR引入具有已知TCR特异性的T细胞中），我们证明了CD8 CAR T细胞与T细胞相关的功效丧失存在TCR抗原时，精疲力竭和凋亡。CD4 CAR T细胞表现出与CD8 CAR T细胞同等的细胞毒性，相反，尽管有TCR刺激，仍可保持体内功效。基因表达谱证实了与CD4 CAR T细胞相比，双重受体刺激后CD8 CAR T细胞的耗竭和凋亡增加，并表明在使用T细胞相关信号通路时CD4和CD8 CAR T细胞之间存在固有差异。这些结果提供了对CAR T细胞免疫生物学重要方面的见识，并为合理设计CAR结构以优化临床疗效提供了机会。