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文献精选 > 近年高分"CAR-T疗法"研究（IF≥30，近5年）

Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. ​

文献信息 ​

DOI10.1038/s41591-022-01959-0
PMID36097221
期刊Nature medicine
影响因子50.0
JCR 分区Q1
发表年份2022
被引次数122
关键词CAR-T细胞疗法, 大B细胞淋巴瘤, 单细胞转录组测序, 记忆样CD8克隆, 调节性CAR-T细胞
文献类型Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
ISSN1078-8956
页码1848-1859
期号28(9)
作者Nicholas J Haradhvala, Mark B Leick, Katie Maurer, Satyen H Gohil, Rebecca C Larson, Ning Yao, Kathleen M E Gallagher, Katelin Katsis, Matthew J Frigault, Jackson Southard, Shuqiang Li, Michael C Kann, Harrison Silva, Max Jan, Kahn Rhrissorrakrai, Filippo Utro, Chaya Levovitz, Raquel A Jacobs, Kara Slowik, Brian P Danysh, Kenneth J Livak, Laxmi Parida, Judith Ferry, Caron Jacobson, Catherine J Wu, Gad Getz, Marcela V Maus

一句话小结 ​

本研究通过单细胞转录组测序分析了32名大B细胞淋巴瘤患者在接受CD19 CAR-T治疗前后的外周血单核细胞样本，发现tisa-cel反应者中增殖记忆样CD8克隆的扩增是其有效反应的标志，而axi-cel反应者则显示出更异质的人群，且在axi-cel无反应者中发现CAR-T调节细胞的增加，这些发现揭示了CAR-T疗法反应的机制和复发的潜在风险，对优化CAR-T治疗具有重要意义。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

CAR-T细胞疗法 · 大B细胞淋巴瘤 · 单细胞转录组测序 · 记忆样CD8克隆 · 调节性CAR-T细胞

摘要 ​

嵌合抗原受体（CAR）-T细胞疗法已经彻底改变了血液恶性肿瘤的治疗。大约一半的难治性大B细胞淋巴瘤患者在接受针对CD19的CAR-T治疗后获得了持久的反应；然而，只有一小部分病例能够识别出失败机制。为了深入了解临床反应的基础，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，这些样本来自32名接受两种CD19 CAR-T产品（阿基卡戈细胞（axi-cel）或替沙尤单抗（tisa-cel））治疗的大B细胞淋巴瘤患者。增殖记忆样CD8克隆的扩增是tisa-cel反应的一个标志，而axi-cel反应者则表现出更异质的人群。在对axi-cel无反应者中检测到了CAR-T调节细胞的增加，这些细胞群能够抑制常规CAR-T细胞的扩增，并在体内模型中推动晚期复发。我们的分析揭示了CAR-T疗法有效反应的时间动态、不同设计的CAR-T细胞的独特分子表型，以及即使是小幅增加的CAR-T调节细胞也能导致复发的能力。

英文摘要 ​

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 new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment 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 among nonresponders 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-T regulatory cells to drive relapse.

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主要研究问题 ​

  1. CAR-T治疗中不同设计的CAR-T细胞如何影响患者的长期预后？
  2. 除了CD19，是否有其他靶点的CAR-T疗法在治疗难治性大B细胞淋巴瘤中显示出潜力？
  3. 如何评估CAR-T细胞中的记忆样CD8克隆扩展对治疗效果的具体影响？
  4. CAR-T调节细胞在不同患者中的作用机制是什么，如何影响治疗结果？
  5. 针对CAR-T治疗失败的机制，未来的研究方向和策略应如何制定？

核心洞察 ​

研究背景和目的 ​

CAR-T细胞疗法在血液恶性肿瘤的治疗中引起了革命性的变化，特别是在难治性大B细胞淋巴瘤患者中，约有一半的患者能够从CD19靶向CAR-T治疗中获得持久的反应。然而，只有少数病例能够识别出失败机制。为了深入了解临床反应的基础，本研究旨在通过单细胞转录组测序分析大B细胞淋巴瘤患者的外周血单核细胞样本，探讨不同CAR-T产品的治疗反应机制。

主要方法/材料/实验设计 ​

本研究的主要方法包括单细胞转录组测序，分析105个治疗前和治疗后样本以及来自32名接受两种CD19 CAR-T产品（axicabtagene ciloleucel和tisagenlecleucel）患者的输注产品。具体实验设计如下：

Mermaid diagram
  • 样本收集：收集患者的外周血单核细胞样本，包括治疗前后的样本。
  • 单细胞转录组测序：对收集的样本进行高通量测序，获取单细胞水平的基因表达信息。
  • 数据分析：通过生物信息学方法分析不同CAR-T细胞的特征和反应机制。
  • 临床反应评估：结合临床数据评估患者对治疗的反应。
  • 机制探讨：研究CAR-T细胞的增殖和抑制机制，分析不同产品的反应特征。

关键结果和发现 ​

  • 治疗反应特征：tisa-cel反应者的特征为增殖记忆样CD8克隆的扩展，而axi-cel反应者则显示出更为异质化的细胞群体。
  • CAR-T调节细胞：在axi-cel的非反应者中检测到CAR-T调节细胞的增加，这些细胞能够抑制常规CAR-T细胞的扩展，并在体内模型中驱动晚期复发。
  • 时间动态：研究揭示了CAR-T疗法有效反应的时间动态，以及不同设计的CAR-T细胞的分子表型差异。

主要结论/意义/创新性 ​

本研究的结果表明，CAR-T细胞的治疗反应不仅依赖于其数量和类型，还受到细胞微环境中调节细胞的影响。研究揭示了CAR-T细胞反应的时序动态和不同产品的分子特征，为优化CAR-T治疗策略提供了新的见解。此外，识别CAR-T调节细胞的作用机制可能为未来的治疗干预提供潜在靶点。

研究局限性和未来方向 ​

  • 局限性：本研究的样本量相对较小，可能影响结果的普遍性；单细胞测序技术的复杂性也可能导致数据解释的困难。
  • 未来方向：未来的研究应扩大样本规模，进一步探讨CAR-T调节细胞的作用机制，并评估其在不同类型淋巴瘤患者中的普遍适用性。此外，探索结合其他治疗手段以增强CAR-T疗法的效果也将是一个重要的研究方向。

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引用本文的文献 ​

  1. Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. - Brian J Sworder;David M Kurtz;Stefan K Alig;Matthew J Frank;Navika Shukla;Andrea Garofalo;Charles W Macaulay;Mohammad Shahrokh Esfahani;Mari N Olsen;James Hamilton;Hitomi Hosoya;Mark Hamilton;Jay Y Spiegel;John H Baird;Takeshi Sugio;Mia Carleton;Alexander F M Craig;Sheren F Younes;Bita Sahaf;Natasha D Sheybani;Joseph G Schroers-Martin;Chih Long Liu;Jean S Oak;Michael C Jin;Sara Beygi;Andreas Hüttmann;Christine Hanoun;Ulrich Dührsen;Jason R Westin;Michael S Khodadoust;Yasodha Natkunam;Robbie G Majzner;Crystal L Mackall;Maximilian Diehn;David B Miklos;Ash A Alizadeh - Cancer cell (2023)
  2. Advancing CAR T cell therapy through the use of multidimensional omics data. - Jingwen Yang;Yamei Chen;Ying Jing;Michael R Green;Leng Han - Nature reviews. Clinical oncology (2023)
  3. Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia: a systematic review and meta-analysis. - Magdi Elsallab;Moataz Ellithi;Susanne Hempel;Hisham Abdel-Azim;Mohamed Abou-El-Enein - Cancer gene therapy (2023)
  4. Multiomics STEP up in correlative analysis of response to CAR T cells. - Mark B Leick;Marcela V Maus - Nature reviews. Clinical oncology (2023)
  5. CAR immune cells: design principles, resistance and the next generation. - Louai Labanieh;Crystal L Mackall - Nature (2023)
  6. Chimeric Antigen Receptor T-Cell Therapy and Hematopoiesis. - Bryanna Reinhardt;Patrick Lee;Joshua P Sasine - Cells (2023)
  7. Non-viral TRAC-knocked-in CD19KICAR-T and gp350KICAR-T cells tested against Burkitt lymphomas with type 1 or 2 EBV infection: In vivo cellular dynamics and potency. - Tobias Braun;Alina Pruene;Milita Darguzyte;Alexander F Vom Stein;Phuong-Hien Nguyen;Dimitrios L Wagner;Jonas Kath;Alicia Roig-Merino;Michael Heuser;Lucas L Riehm;Andreas Schneider;Sabine Awerkiew;Steven R Talbot;André Bleich;Constanca Figueiredo;Martin Bornhäuser;Renata Stripecke - Frontiers in immunology (2023)
  8. Dynamics and specificities of T cells in cancer immunotherapy. - Giacomo Oliveira;Catherine J Wu - Nature reviews. Cancer (2023)
  9. Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma. - Kai Rejeski;Michael D Jain;Eric L Smith - Transplantation and cellular therapy (2023)
  10. Editorial: Screening and verification of new targets for CAR-T immunotherapy in cancer. - Yang Su;Chen Yuan;Ming Shi - Frontiers in immunology (2023)

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