Tolerance to self-antigens prevents the elimination of cancer by the immune system^1,2. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27⁺CD45RO^-CD8⁺ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27⁺PD-1^-CD8⁺ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.

中文翻译：

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慢性淋巴细胞白血病对CD19嵌合抗原受体（CAR）T细胞疗法的反应和耐药性的决定因素。

对自身抗原的耐受性可防止免疫系统消除癌症^1,2。我们使用合成嵌合抗原受体（CARs）来克服免疫耐受并介导慢性淋巴细胞性白血病（CLL）患者的肿瘤排斥反应。在部分受试者中诱发了缓解，但是大多数没有反应。尚未探索对患者衍生的CAR T细胞进行全面评估以鉴定治疗成功和失败的机制。我们进行了基因组，表型和功能评估，以确定反应的决定因素。转录组分析显示，来自完全应答的CLL患者的CAR T细胞富含记忆相关基因，包括IL-6 / STAT3签名，而来自无应答者的T细胞则上调了涉及效应子分化，糖酵解，力竭和细胞凋亡的程序。持续缓解与CD27频率升高有关⁺ CD45RO ^- CD8 ⁺ T细胞先于CAR T细胞生成，这些淋巴细胞具有记忆样特征。来自患者的高功能CAR T细胞产生STAT3相关的细胞因子，血清IL-6与CAR T细胞扩增相关。IL-6 / STAT3阻滞减少了CAR T细胞的增殖。此外，表达高水平的IL-6受体的CD27 ⁺ PD-1 ^- CD8 ⁺ CAR T细胞在机械上相关的群体可预测治疗反应，并负责控制肿瘤。这些发现揭示了CAR T细胞生物学的新特征，并强调了使用预处理的反应生物标志物进行先进的免疫治疗的潜力。