Quantitative characterization of T-cell repertoire alteration in Chinese patients with B-cell acute lymphocyte leukemia after CAR-T therapy
Quantitative characterization of T-cell repertoire alteration in Chinese patients with B-cell acute lymphocyte leukemia after CAR-T therapy
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中国 B 细胞急性淋巴细胞白血病患者 CAR-T 治疗后 T 细胞库改变的定量特征
DOI：
10.1038/s41409-019-0625-y
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发表时间：
2019-12-01
影响因子：
4.8
通讯作者：
Huang, He
中科院分区：
文献类型：
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作者：
Wang, Xiujian;Hu, Yongxian;Huang, He
嵌合抗原受体（CAR）T细胞疗法在急性淋巴细胞白血病（ALL）中显示出有效的抗白血病活性，为难治性/复发性患者带来了新的希望。然而，CAR-T疗法对宿主免疫系统的影响尚未得到很好的阐明。因此，我们应用高通量T细胞受体β链测序来追踪B细胞ALL患者中CAR-T疗法诱导的T细胞库的动态变化。正在观察 6 名完全缓解的中国患者，在 CAR-T 治疗前后的连续时间点采集其血液样本、骨髓样本和输注 CAR-T 样本。我们观察到 CAR-T 给药后，外周血和骨髓中 T 细胞库的 TCR 多样性降低，克隆性增加。血液和骨髓中的持久性 T 细胞克隆在白血病细胞破坏后扩增，但在 CAR T 细胞池中几乎检测不到。我们的结果首次证明 CAR-T 疗法可以刺激患者体内 CAR 阴性 T 细胞的克隆增殖。考虑到其他研究组的动物实验结果表明，CAR-T疗法可以促进肿瘤抗原特异性T细胞的增殖，并且这些T细胞克隆是在白血病细胞被破坏后出现的，因此它们很可能是肿瘤抗原特异性的。
Chimeric antigen receptor (CAR) T-cell therapy has displayed potent anti-leukemia activity in acute lymphocytic leukemia (ALL), acting as a new ray of hope to refractory/relapsed patients. However, the influence of CAR-T therapy on host immune system has not been well elucidated. Thus, We applied high-throughput T cell receptor beta chain sequencing to track the dynamic change of T-cell repertoire induced by CAR-T therapy in B-cell ALL patients. Six Chinese patients achieving complete remission were under observation, whose blood samples, bone marrow samples and infused CAR-T samples were collected at serial time points before and after CAR-T therapy. We observed decreased TCR diversity and increased clonality of T-cell repertoire in both peripheral blood and bone marrow after CAR-T administration. The persistent T cell clones in blood and bone marrow expanded following leukemic cell destruction and were barely detected in CAR T-cell pool. For the first time, our results demonstrated CAR-T therapy could stimulate the clonal proliferation of CAR-negative T cells in patients. Considering other groups' animal results indicating that CAR-T therapy could facilitate the proliferation of tumor antigen-specific T cells and that the emergence of these T cell clones followed the destruction of leukemic cells, they are most likely tumor antigen-specific.