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文献精选 > 近年高分"CAR-T疗法"研究（IF≥30，近5年）

The journey of CAR-T therapy in hematological malignancies. ​

文献信息 ​

DOI10.1186/s12943-022-01663-0
PMID36209106
期刊Molecular cancer
影响因子33.9
JCR 分区Q1
发表年份2022
被引次数93
关键词CAR-T细胞疗法, 组合疗法, 药物产品, 血液恶性肿瘤, 靶向疗法
文献类型Journal Article, Review
ISSN1476-4598
页码194
期号21(1)
作者Junru Lu, Guan Jiang

一句话小结 ​

CAR-T疗法显著改变了血液恶性肿瘤的治疗，许多患者实现了持久的完全缓解，但复发问题仍需解决，因此研究者们探索新策略和技术进展以克服耐药性。本文综述了CAR-T细胞疗法的开发过程、不同产品的疗效差异及其与其他治疗的结合效果，为未来研究提供了重要参考。

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CAR-T细胞疗法 · 组合疗法 · 药物产品 · 血液恶性肿瘤 · 靶向疗法

摘要 ​

嵌合抗原受体T细胞（CAR-T）疗法彻底改变了血液恶性肿瘤的治疗模式，使多条治疗方案无效的患者实现了持久的完全缓解（CR）和相对较高的客观反应率（ORR）。迄今为止，许多CAR-T产品，如Kymriah、Yescarta和Tecartus，已经开发并取得了前所未有的成果。然而，一些患者可能在此后复发，这引发了对新策略的深入研究，以克服耐药性和复发机制。显著的技术进展，如纳米抗体和CRISPR-Cas9，也在不断推进，以确保CAR-T细胞疗法充分发挥其医疗潜力。在本综述中，我们概述了CAR-T细胞疗法的开发和制造过程的基本原则，总结了不同产品在疗效上的相似性和差异以及它们相应的临床结果，并讨论了CAR-T免疫疗法与其他药物治疗的临床效果结合的情况。

英文摘要 ​

Chimeric antigen receptor T (CAR-T) cells therapy has revolutionized the treatment paradigms for hematological malignancies, with multi-line therapy-refractory patients achieving durable complete remissions (CR) and relatively high objective response rate (ORR). So far, many CAR-T products, such as Kymriah, Yescarta and Tecartus, have been developed and got the unprecedented results. However, some patients may relapse afterwards, driving intense investigations into promoting the development of novel strategies to overcome resistance and mechanisms of relapse. Notable technical progress, such as nanobodies and CRISPR-Case9, has also taken place to ensure CAR-T cell therapy fully satisfies its medical potential. In this review, we outline the basic principles for the development and manufacturing processes of CAR-T cell therapy, summarize the similarities and differences in efficacy of different products as well as their corresponding clinical results, and discuss CAR-T immunotherapy combined with other clinical effects of drug therapy.

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主要研究问题 ​

  1. CAR-T细胞疗法在不同类型的血液恶性肿瘤中效果如何？各类肿瘤的治疗反应是否存在显著差异？
  2. 针对CAR-T疗法复发的机制，当前有哪些新的研究进展和潜在解决方案？
  3. 在CAR-T细胞疗法的生产过程中，技术进步（如纳米抗体和CRISPR-Cas9）是如何影响疗效和安全性的？
  4. 不同CAR-T产品（如Kymriah、Yescarta和Tecartus）在临床试验中的具体表现和效果比较如何？
  5. CAR-T免疫疗法与其他药物治疗联合使用时，临床效果和安全性表现如何？有哪些成功案例？

核心洞察 ​

研究背景和目的 ​

CAR-T细胞疗法（嵌合抗原受体T细胞疗法）已在血液恶性肿瘤的治疗中取得了革命性的进展，特别是在多种治疗无效的患者中实现了持久的完全缓解。尽管已有多种CAR-T产品（如Kymriah、Yescarta和Tecartus）获得批准并显示出显著疗效，但部分患者在治疗后可能会复发。因此，研究的主要目的是总结CAR-T细胞疗法的发展历程、机制、不同产品的疗效差异及其与其他治疗方法的联合应用。

主要方法/材料/实验设计 ​

研究采用文献综述的方法，系统总结了CAR-T细胞的基本原理、制造过程、临床效果及其安全性问题。CAR-T细胞的设计和发展历程分为五代，技术路线图如下：

Mermaid diagram

关键结果和发现 ​

  1. CAR-T细胞机制：CAR-T细胞通过识别肿瘤相关抗原（TAA）激活T细胞，从而引发细胞毒性反应。常见的TAA包括CD19、BCMA等。
  2. 疗效比较：不同CAR-T产品在治疗血液恶性肿瘤的疗效存在显著差异。例如，Kymriah在治疗B-ALL和大B细胞淋巴瘤中表现出52%的客观反应率（ORR）和40%的完全缓解率（CR），而Yescarta的ORR高达83%。
  3. 副作用：主要不良反应包括细胞因子释放综合症（CRS）和免疫效应细胞相关神经毒性综合症（ICANS），其发生率因产品而异。

主要结论/意义/创新性 ​

CAR-T细胞疗法为血液恶性肿瘤患者提供了一种新的治疗选择，特别是在传统疗法无效的情况下。然而，治疗的高成本、复杂的制造过程和潜在的毒性反应仍然是其临床应用的主要挑战。研究强调了持续改进CAR-T细胞的制造技术（如MASTER技术）和联合治疗策略（如与免疫检查点抑制剂联合使用）的重要性。

研究局限性和未来方向 ​

尽管CAR-T细胞疗法取得了显著进展，但仍存在一些局限性：

  • 复发机制：肿瘤细胞的抗原丧失和T细胞的功能耗竭是导致复发的主要原因。
  • 制造成本：CAR-T细胞的个性化生产需要高昂的费用和时间。

未来的研究方向包括：

  • 开发更高效的CAR设计以提高疗效。
  • 探索基因编辑技术（如CRISPR/Cas9）在CAR-T细胞制造中的应用，以提高安全性和有效性。
  • 加强对联合疗法的研究，以克服CAR-T细胞疗法的耐药性问题。

参考文献 ​

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引用本文的文献 ​

  1. Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors. - Qiuqiang Chen;Lingeng Lu;Wenxue Ma - Cancers (2022)
  2. Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review. - Stephen Jolles;Sergio Giralt;Tessa Kerre;Hillard M Lazarus;S Shahzad Mustafa;Roberto Ria;Donald C Vinh - Frontiers in oncology (2023)
  3. Emerging roles of the gut microbiota in cancer immunotherapy. - Zhuangzhuang Shi;Hongwen Li;Wenting Song;Zhiyuan Zhou;Zhaoming Li;Mingzhi Zhang - Frontiers in immunology (2023)
  4. Oncolytic virus-based suicide gene therapy for cancer treatment: a perspective of the clinical trials conducted at Henry Ford Health. - Shivani Thoidingjam;Sushmitha Sriramulu;Svend Freytag;Stephen L Brown;Jae Ho Kim;Indrin J Chetty;Farzan Siddiqui;Benjamin Movsas;Shyam Nyati - Translational medicine communications (2023)
  5. Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies. - Shengkang Huang;Xinyu Wang;Yu Wang;Yajing Wang;Chenglong Fang;Yazhuo Wang;Sifei Chen;Runkai Chen;Tao Lei;Yuchen Zhang;Xinjie Xu;Yuhua Li - Molecular cancer (2023)
  6. Thermoresponsive Polypeptide Fused L-Asparaginase with Mitigated Immunogenicity and Enhanced Efficacy in Treating Hematologic Malignancies. - Sanke Zhang;Yuanzi Sun;Longshuai Zhang;Fan Zhang;Weiping Gao - Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2023)
  7. Regeneration of T cells from human-induced pluripotent stem cells for CAR-T cell medicated immunotherapy. - Yanyan Chen;Pufeng Huang;Mengda Niu;Chuanhuizi Tian;Tingting Zhang;Zhiping Peng - Frontiers in bioengineering and biotechnology (2023)
  8. Revealing the impact of CD70 expression on the manufacture and functions of CAR-70 T-cells based on single-cell transcriptomics. - Jiali Cheng;Yuyan Zhao;Hui Hu;Ling Tang;Yuhao Zeng;Xinyue Deng;Shengnan Ding;An-Yuan Guo;Qing Li;Xiaojian Zhu - Cancer immunology, immunotherapy : CII (2023)
  9. Recent advances and future perspectives of CAR-T cell therapy in head and neck cancer. - Chunmei Hu;Min Liu;Yutao Li;Yi Zhao;Amit Sharma;Haotian Liu;Ingo G H Schmidt-Wolf - Frontiers in immunology (2023)
  10. PGE2-EP2/EP4 signaling elicits mesoCAR T cell immunosuppression in pancreatic cancer. - Behnia Akbari;Tahereh Soltantoyeh;Zahra Shahosseini;Farhad Jadidi-Niaragh;Jamshid Hadjati;Christine E Brown;Hamid Reza Mirzaei - Frontiers in immunology (2023)

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