Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
Nat Med. 2022 Sep;28(9):1860-1871. doi: 10.1038/s41591-022-01960-7. Epub 2022 Sep 12.
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 CD4Helios 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) cells. Validation cohort analysis upheld the link between higher CAR T 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 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.
约 60%接受靶向 CD19 的嵌合抗原受体 (CAR) T 细胞疗法治疗的大 B 细胞淋巴瘤患者会出现疾病进展，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有限。在这项研究中，对 32 名接受 CD19-CAR 治疗的患者的循环 CAR T 细胞进行单细胞蛋白质组学分析，发现输注后第 7 天的 CD4Helios CAR T 细胞与进行性疾病和较轻的神经毒性相关。深入分析表明，该群体是非克隆的，表现出 T 调节 (T) 细胞的标志性特征。验证队列分析支持 CAR T 细胞与临床进展和较轻的神经毒性之间存在更高关联的观点。与仅依赖于每个特征的模型相比，将该亚群的扩增与乳酸脱氢酶水平（作为肿瘤负担的替代物）相结合的模型更能预测持久的临床反应。这些数据证明 CAR T 细胞扩增是 CAR T 细胞治疗后反应和毒性的新型生物标志物，并提出了该亚群可能在人类中调节 CAR T 细胞反应的可能性。
