肿瘤细胞治疗研究
英文原题：Integrative single-cell multi-omics of CD19-CAR(pos) and CAR(neg) T cells suggest drivers of immunotherapy response in B cell neoplasias.
完全缓解患者 IP 时的 CAR 阳性 T 细胞表现出显著更高的 CD4:CD8 比值，并在更大的 B-ALL 患者队列（n = 47）中得到验证。
嵌合抗原受体（CAR）T细胞的表型、克隆和功能异质性对临床结局的影响尚未得到充分研究。本研究整合克隆动力学与单细胞组学解析的转录组异质性，考察5例接受CD19 CAR-T细胞（varni-cel）治疗的B细胞急性淋巴细胞白血病（B-ALL）患者中，输注制剂（IP）内未转导（CAR阴性）和已转导（CAR阳性）T细胞，以及CAR-T细胞扩增峰值时的细胞动态。我们发现治疗应答过程中细胞动态存在显著差异。达到完全缓解患者的输注制剂中，CAR阳性T细胞CD4:CD8比值显著较高；这一结果在更大规模的B-ALL患者队列（n=47）中得到验证。相反，在扩增峰值时，CD8+效应记忆T细胞和细胞毒性T细胞发生克隆扩增。细胞毒性CAR阳性T细胞的扩增与治疗疗效相关；这一发现分别在B-ALL患者队列（n=18）和弥漫大B细胞淋巴瘤（DLBCL）患者队列（n=58）中得到验证。我们的数据揭示CAR-T细胞治疗后T细胞应答的复杂性，并提示了可能驱动免疫治疗应答的因素。
The impact of phenotypic, clonal, and functional heterogeneity of chimeric antigen receptor (CAR)-T cells on clinical outcome remains understudied. Here, we integrate clonal kinetics with transcriptomic heterogeneity resolved by single-cell omics to interrogate cellular dynamics of non-transduced (CAR neg ) and transduced (CAR pos ) T cells, in the infusion product (IP) and at the CAR-T cell expansion peak in five B cell acute lymphoblastic leukemia (B-ALL) patients treated with CD19CAR-T cells (varni-cel). We identify significant differences in cellular dynamics in response to therapy. CAR pos T cells at IP of complete response patients exhibit a significantly higher CD4:CD8 ratio, validated in a larger cohort B-ALL patients (n = 47). Conversely, at the expansion peak, there is a clonal expansion of CD8 + effector memory and cytotoxic T cells. Cytotoxic CAR pos -T cells expansion correlates with treatment efficacy validated in a cohort of B-ALL (n = 18) and diffuse large B cell lymphoma (DLBCL) patients (n = 58). Our data provide insights into the complexity of T cell responses following CAR-T cell therapy and suggest drivers of immunotherapy response.
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