Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma.
Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma.
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DOI：
10.1038/s41591-022-01959-0
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发表时间：
2022-09
期刊：
影响因子：
82.9
通讯作者：
Maus, Marcela, V
中科院分区：
文献类型：
--
作者：
Haradhvala, Nicholas J.;Leick, Mark B.;Maurer, Katie;Gohil, Satyen H.;Larson, Rebecca C.;Yao, Ning;Gallagher, Kathleen M. E.;Katsis, Katelin;Frigault, Matthew J.;Southard, Jackson;Li, Shuqiang;Kann, Michael C.;Silva, Harrison;Jan, Max;Rhrissorrakrai, Kahn;Utro, Filippo;Levovitz, Chaya;Jacobs, Raquel A.;Slowik, Kara;Danysh, Brian P.;Livak, Kenneth J.;Parida, Laxmi;Ferry, Judith;Jacobson, Caron;Wu, Catherine J.;Getz, Gad;Maus, Marcela, V
嵌合抗原受体（CAR）-T细胞疗法彻底改变了血液恶性肿瘤的治疗。大约一半的难治性大B细胞淋巴瘤患者从靶向CD 19的CAR-T治疗中获得了持久的应答;然而，仅在一小部分病例中确定了失败机制。为了获得对临床反应基础的新见解，我们对105个治疗前和治疗后的外周血单核细胞样本进行了单细胞转录组测序，并从32个接受两种CD 19 CAR-T产品治疗的大B细胞淋巴瘤患者中收集了输注产品：axicabtagene ciloleucel（axi-cel）或tisagenlecleucel（tisa-cel）。增殖性记忆样CD 8克隆的扩增是组织细胞应答的标志，而axi-cel应答者显示出更异质的群体。在axi-cel无应答者中检测到CAR-T调节细胞（CAR-Tcells）的升高，并且这些群体能够抑制常规CAR-T细胞扩增并在体内模型中驱动晚期复发。我们的分析揭示了对CAR-T治疗的有效反应的时间动态，具有不同设计的CAR-T细胞的不同分子表型，以及CAR-T细胞即使微小增加也能驱动复发的能力。来自接受CD 19 CAR-T产品治疗的患者的治疗前和治疗后外周血单核细胞的单细胞转录组学分析揭示了CAR-T调节细胞在治疗复发中的作用。
Chimeric Antigen Receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B-cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain novel insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pre- and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B-cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells (CAR-Tregs) among non-responders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-Tregs to drive relapse. Single-cell transcriptomics analyses of pre- and post-treatment peripheral blood mononuclear cells from patients treated with CD19 CAR-T products reveals a role for CAR-T regulatory cells in treatment relapse.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1097/cji.0b013e3181ac6138
发表时间：
2009-09
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Kochenderfer JN;Feldman SA;Zhao Y;Xu H;Black MA;Morgan RA;Wilson WH;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
82.9
作者：
Deng Q;Han G;Puebla-Osorio N;Ma MCJ;Strati P;Chasen B;Dai E;Dang M;Jain N;Yang H;Wang Y;Zhang S;Wang R;Chen R;Showell J;Ghosh S;Patchva S;Zhang Q;Sun R;Hagemeister F;Fayad L;Samaniego F;Lee HC;Nastoupil LJ;Fowler N;Eric Davis R;Westin J;Neelapu SS;Wang L;Green MR
通讯作者：
Green MR
影响因子：
5.6
作者：
Golab, Karolina;Leveson-Gower, Dennis;Witkowski, Piotr
通讯作者：
Witkowski, Piotr
影响因子：
20.3
作者：
Dufva, Olli;Koski, Jan;Mustjoki, Satu
通讯作者：
Mustjoki, Satu