Long-term outcomes following CAR T cell therapy: what we know so far.
Long-term outcomes following CAR T cell therapy: what we know so far.
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DOI：
10.1038/s41571-023-00754-1
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发表时间：
2023-06
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影响因子：
--
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嵌合抗原受体(CAR)是一种针对T细胞和癌细胞上表达的抗原而设计的工程化融合蛋白。CAR T细胞现在是复发性和/或难治性B细胞淋巴瘤、B细胞急性淋巴细胞性白血病和多发性骨髓瘤患者的既定治疗方法。在写这篇文章的时候，从接受CD19靶向CAR T细胞治疗B细胞恶性肿瘤的首批患者那里已经有了超过十年的随访数据。关于接受B细胞成熟抗原(BCMA)靶向CAR T细胞治疗多发性骨髓瘤的患者的结果的数据更有限，因为这些结构的发展较新。在这篇综述中，我们总结了以CD19或BCMA为靶点的CAR T细胞治疗患者的疗效和毒性的长期随访数据。总体而言，数据表明，以CD19为靶点的CAR T细胞可以诱导B细胞恶性肿瘤患者的长期缓解，通常具有最小的长期毒性，并且可能对部分患者有效。相比之下，BCMA靶向的CAR T细胞诱导的缓解通常更短暂，但通常也只有有限的长期毒性。我们讨论了与长期缓解相关的因素，包括初始反应的深度、预测反应的恶性特征、循环CAR峰值水平以及淋巴清除化疗的作用。我们还讨论了正在进行的旨在提高CAR T细胞治疗后缓解时间的研究策略。嵌合抗原受体(CAR)T细胞显著改善了某些复发和/或难治性血液系统恶性肿瘤患者的预后。由于取得了有希望的短期生存结果，关于安全性和存活率的长期数据正变得越来越重要。在这篇综述中，作者描述了可获得的长期随访数据，这些数据来自测试接受靶向CD19的CAR T细胞的安全性和有效性的早期研究，以及最近关于BCMA靶向CAR T细胞在复发和/或难治性多发性骨髓瘤患者中的数据。在血液系统恶性肿瘤中，使用嵌合抗原受体(CAR)T细胞的适应症正在迅速扩大。CD19靶向CAR T细胞现在被批准用于复发和/或难治性B细胞淋巴瘤和B细胞急性淋巴细胞性白血病，B细胞成熟抗原靶向CAR T细胞被批准用于复发和/或难治性多发性骨髓瘤。长期的随访数据表明，CD19靶向的CAR T细胞很可能对B细胞淋巴瘤的一部分患者有疗效。这些CAR T细胞可能需要与巩固的异基因造血干细胞移植相结合，以使B细胞急性淋巴细胞性白血病患者的长期缓解成为可能。针对B细胞成熟抗原的CAR T细胞可以诱导复发和/或难治性多发性骨髓瘤患者的长期缓解，尽管这些反应中是否有任何一种是治愈的仍不清楚。CAR T细胞治疗后持久缓解的相关因素包括初始反应深、基线肿瘤体积较低、无髓外疾病、循环CAR T细胞峰值水平较高以及接受淋巴清除化疗。CAR T细胞治疗后最显著的长期毒副作用包括红细胞减少和低丙种球蛋白血症。与细胞输注后的急性期相比，CAR T细胞治疗后1个月的严重感染发生率较低。正在进行的研究工作正在试图提高CAR T细胞治疗后反应的持久性，例如，通过改进患者选择、新颖的汽车设计(包括针对多种抗原的设计)以及对制造工艺的修改。
Chimeric antigen receptors (CAR) are engineered fusion proteins designed to target T cells to antigens expressed on cancer cells. CAR T cells are now an established treatment for patients with relapsed and/or refractory B cell lymphomas, B cell acute lymphoblastic leukaemia and multiple myeloma. At the time of this writing, over a decade of follow-up data are available from the initial patients who received CD19-targeted CAR T cells for B cell malignancies. Data on the outcomes of patients who received B cell maturation antigen (BCMA)-targeted CAR T cells for multiple myeloma are more limited owing to the more recent development of these constructs. In this Review, we summarize long-term follow-up data on efficacy and toxicities from patients treated with CAR T cells targeting CD19 or BCMA. Overall, the data demonstrate that CD19-targeted CAR T cells can induce prolonged remissions in patients with B cell malignancies, often with minimal long-term toxicities, and are probably curative for a subset of patients. By contrast, remissions induced by BCMA-targeted CAR T cells are typically more short-lived but also generally have only limited long-term toxicities. We discuss factors associated with long-term remissions, including the depth of initial response, malignancy characteristics predictive of response, peak circulating CAR levels and the role of lymphodepleting chemotherapy. We also discuss ongoing investigational strategies designed to improve the length of remission following CAR T cell therapy. Chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of patients with certain relapsed and/or refractory haematological malignancies. Owing to the promising short-term survival outcomes achieved, long-term data on both safety and survival are becoming increasingly relevant. In this Review, the authors describe the available long-term follow-up data from early studies testing the safety and efficacy of receiving CAR T cells targeting CD19 as well as more recent data on BCMA-targeted CAR T cells in patients with relapsed and/or refractory multiple myeloma. Among haematological malignancies, the indications for use of chimeric antigen receptor (CAR) T cells are rapidly expanding. CD19-targeted CAR T cells are now approved for relapsed and/or refractory B cell lymphoma and B cell acute lymphoblastic leukaemia, and B cell maturation antigen-targeted CAR T cells are approved for relapsed and/or refractory multiple myeloma. Long-term follow-up data indicate that CD19-targeted CAR T cells are likely to be curative for a subset of patients with B cell lymphomas. These CAR T cells might need to be combined with consolidative allogeneic haematopoietic stem cell transplantation to enable long-term remissions for patients with B cell acute lymphoblastic leukaemia. B cell maturation antigen-targeted CAR T cells can induce prolonged remissions in patients with relapsed and/or refractory multiple myeloma, although whether any of these responses are curative remains unclear. Factors associated with durable remission after CAR T cell therapy include a deep initial response, lower baseline tumour volume, an absence of extramedullary disease, higher peak circulating CAR T cell levels and receipt of lymphodepleting chemotherapy. The most prominent long-term toxicities after CAR T cell therapy include cytopenias and hypogammaglobulinaemia. The incidence of severe infections >1 month after CAR T cell therapy is low compared to infections seen in the acute period immediately after cell infusion. Ongoing research efforts are attempting to improve the durability of responses after CAR T cell therapy, for example, through improved patient selection, novel CAR designs, including those targeting multiple antigens, and modifications to the manufacturing process.
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影响因子：
82.9
作者：
Cordoba S;Onuoha S;Thomas S;Pignataro DS;Hough R;Ghorashian S;Vora A;Bonney D;Veys P;Rao K;Lucchini G;Chiesa R;Chu J;Clark L;Fung MM;Smith K;Peticone C;Al-Hajj M;Baldan V;Ferrari M;Srivastava S;Jha R;Arce Vargas F;Duffy K;Day W;Virgo P;Wheeler L;Hancock J;Farzaneh F;Domning S;Zhang Y;Khokhar NZ;Peddareddigari VGR;Wynn R;Pule M;Amrolia PJ
通讯作者：
Amrolia PJ
患者特征对 B 细胞急性淋巴细胞白血病嵌合抗原受体 T 细胞治疗的影响
影响因子：
16.6
作者：
An F;Wang H;Liu Z;Wu F;Zhang J;Tao Q;Li Y;Shen Y;Ruan Y;Zhang Q;Pan Y;Zhu W;Qin H;Wang Y;Fu Y;Feng Z;Zhai Z
通讯作者：
Zhai Z
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：
168.9
作者：
Abramson, Jeremy S.;Palomba, M. Lia;Siddiqi, Tanya
通讯作者：
Siddiqi, Tanya
影响因子：
4.3
作者：
Cordeiro, Ana;Bezerra, Evandro D.;Bar, Merav
通讯作者：
Bar, Merav