Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy
Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy
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DOI：
10.1038/s41591-022-01960-7
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发表时间：
2022-09-12
期刊：
影响因子：
82.9
通讯作者：
Mackall, Crystal L.
中科院分区：
文献类型：
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作者：
Good, Zinaida;Spiegel, Jay Y.;Mackall, Crystal L.
在以CD19为靶点的嵌合抗原受体(CAR)T细胞疗法治疗的大B细胞淋巴瘤患者中，大约60%的患者经历了疾病进展，神经毒性仍然是一个挑战。与耐药性和毒性相关的生物标志物是有限的。在这项研究中，对接受CD19-CAR治疗的32名患者循环CAR T细胞的单细胞蛋白质组图谱表明，输注后第7天的CD4(+)Helios(+)CAR T细胞与疾病进展和较轻的神经毒性有关。深度分析表明，这一群体是非克隆性的，并表现出T调节(T-REG)细胞的特征。验证队列分析支持较高的CAR T-REG细胞与临床进展和较不严重的神经毒性之间的联系。将这一亚群的扩大与乳酸脱氢酶水平相结合的模型，作为肿瘤负担的替代指标，与单独依赖每个特征的模型相比，在预测持久的临床反应方面更好。这些数据证明CAR T-REG细胞扩增是CAR T细胞治疗后反应和毒性的新生物标记物，并提出了这一亚群可能调节人类CAR T细胞反应的可能性。接受CD19-CAR治疗的患者循环CAR T细胞的单细胞蛋白质组图谱显示，输注后第7天的CD4(+)Helios(+)CAR T细胞与疾病进展和较不严重的神经毒性有关。
Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4(+)Helios(+) CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (T-Reg) cells. Validation cohort analysis upheld the link between higher CAR T-Reg cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR T-Reg cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.Single-cell proteomic profiling of circulating CAR T cells in patients treated with CD19-CAR shows that CD4(+)Helios(+) CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity.