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文献精选 > 近年高分"CAR-T疗法"研究（IF≥30，近5年）

Strategies to overcome tumour relapse caused by antigen escape after CAR T therapy. ​

文献信息 ​

DOI10.1186/s12943-025-02334-6
PMID40289115
期刊Molecular cancer
影响因子33.9
JCR 分区Q1
发表年份2025
被引次数3
关键词抗原丢失/下调, 抗原/表位扩散, 嵌合抗原受体, 肿瘤异质性
文献类型Journal Article, Review
ISSN1476-4598
页码126
期号24(1)
作者Yufei Lu, Fu Zhao

一句话小结 ​

本综述探讨了嵌合抗原受体（CAR）T细胞疗法在治疗固体肿瘤中的局限性，特别是肿瘤抗原的异质性和获得性抗性导致的免疫逃逸问题。研究提出了通过增强CAR T细胞与宿主免疫细胞的相互作用以及引发内源性抗肿瘤免疫反应的临床转化策略，以克服抗原逃逸，从而改善固体肿瘤的治疗效果。

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抗原丢失/下调 · 抗原/表位扩散 · 嵌合抗原受体 · 肿瘤异质性

摘要 ​

嵌合抗原受体（CAR）T细胞疗法已彻底改变了B细胞和浆细胞恶性肿瘤的治疗，并且对固体肿瘤的多个有前景的靶点正在积极探索。尽管在血液肿瘤中取得了初步的治疗成功，但仍有相当一部分患者出现复发，这突显了在推进CAR T细胞疗法方面进一步创新的必要性。肿瘤抗原的异质性和获得性肿瘤抗性导致的抗原逃逸（抗原丧失/下调）已成为导致免疫逃逸和CAR T细胞抗性的关键因素，尤其是在对固体肿瘤的治疗中，目前仅取得有限的成功。在本综述中，我们讨论了CAR T细胞疗法中肿瘤复发的机制以及正在开发的有前景的策略，以克服多种抗性机制，从而减少抗原逃逸变体的增殖。具体而言，我们强调设计临床转化策略的重要性，以增强CAR T细胞与宿主免疫细胞之间的相互作用，通过抗原/表位扩散引发内源性抗肿瘤免疫反应，这为解决在固体肿瘤中使用单克隆T细胞疗法时针对肿瘤抗原异质性所面临的局限性提供了真正的解决方案。

英文摘要 ​

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B cell and plasma cell malignancies, and numerous promising targets against solid tumours are being explored. Despite their initial therapeutic success in hematological cancers, relapse occurs in a significant fraction of patients, highlighting the need for further innovations in advancing CAR T cell therapy. Tumour antigen heterogeneity and acquired tumour resistance leading to antigen escape (antigen loss/downregulation) have emerged as a crucial factor contributing to immune escape and CAR T cell resistance, particularly in the case of solid tumours with only limited success achieved to date. In this review, we discuss mechanisms of tumour relapse in CAR T cell therapy and the promising strategies that are under development to overcome multiple resistance mechanisms, thereby reducing outgrowth of antigen escape variants. Specifically, we emphasize the importance of designing clinical translational strategies to enhance CAR T cell crosstalk with host immune cells, eliciting endogenous antitumour immune responses through antigen/epitope spreading, which offers a genuine solution to the limitations of targeting tumour antigen heterogeneity in solid tumours with monospecific T cell therapies.

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主要研究问题 ​

  1. 在CAR T细胞疗法中，如何评估和监测肿瘤抗原的异质性以优化治疗策略？
  2. 针对肿瘤抗原逃逸的机制，有哪些新兴的免疫治疗方法可以与CAR T细胞疗法结合使用？
  3. 除了增强CAR T细胞与宿主免疫细胞的相互作用，还有哪些其他策略可以提高对抗肿瘤复发的效果？
  4. 如何利用抗原/表位扩散的概念来设计新的CAR T细胞治疗方案，以应对肿瘤抗原的丧失或下调？
  5. 在临床转化策略中，如何评估不同组合疗法的有效性，以应对肿瘤复发和抗原逃逸的问题？

核心洞察 ​

研究背景和目的 ​

CAR T细胞疗法在治疗B细胞和浆细胞恶性肿瘤方面取得了显著成功，但在固体肿瘤中仍面临抗原逃逸导致的肿瘤复发问题。本文旨在探讨肿瘤复发的机制及克服抗原逃逸的策略，以增强CAR T细胞疗法的有效性。

主要方法/材料/实验设计 ​

本文采用文献综述的方法，分析了抗原逃逸的机制及其对CAR T细胞疗法的影响，重点讨论了多种策略以应对这一挑战。主要策略包括：

  1. 提高靶抗原表达：
    • 药理调节（如γ-分泌酶抑制剂）
    • 表观遗传调节（如DNA甲基转移酶抑制剂）
  2. 增强CAR T细胞对低抗原密度的识别：
    • 联合使用嵌合共刺激受体（CCR）
    • 优化CAR设计
  3. 双靶向和多靶向CAR T细胞：
    • 采用串联CAR或双价CAR
    • 开发三靶向CAR T细胞
  4. 诱导表位/抗原扩散：
    • 通过抗原呈递细胞（APC）促进宿主抗肿瘤免疫反应
Mermaid diagram

关键结果和发现 ​

  1. 抗原逃逸机制：抗原逃逸通过抗原下调或丧失，导致CAR T细胞无法有效识别肿瘤细胞。研究显示，许多患者在CAR T治疗后出现了抗原逃逸现象。
  2. 策略有效性：药理和表观遗传调节可以显著提高靶抗原的表达水平，从而增强CAR T细胞的抗肿瘤活性。此外，联合使用CCR和优化CAR设计的策略已显示出在低抗原密度下的有效性。

主要结论/意义/创新性 ​

本文强调了通过增强宿主免疫反应来克服CAR T细胞疗法中抗原逃逸的必要性。多种新兴策略，如联合免疫检查点抑制剂、细胞因子、疫苗增强和放疗等，显示出增强CAR T细胞疗法在固体肿瘤中的应用潜力。这些创新方法可能为提高治疗效果、降低肿瘤复发风险提供新的解决方案。

研究局限性和未来方向 ​

尽管本研究提供了多种策略，但仍需进一步的临床试验以验证这些方法的有效性和安全性。此外，抗原逃逸的机制复杂，未来的研究应关注如何更好地预测和应对抗原逃逸，尤其是在不同肿瘤类型和患者背景下的应用。

部分内容
研究背景CAR T细胞疗法在固体肿瘤中的抗原逃逸问题
主要方法文献综述，分析抗原逃逸机制和应对策略
关键发现抗原逃逸的多种机制及克服策略的有效性
主要结论强调宿主免疫反应的重要性，提出多种创新策略
研究局限性需要更多临床验证，关注机制复杂性

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引用本文的文献 ​

  1. Targets for CAR Therapy in Multiple Myeloma. - Olga A Bezborodova;Galina V Trunova;Elena R Nemtsova;Varvara A Khokhlova;Julia B Venediktova;Natalia B Morozova;Maria S Vorontsova;Anna D Plyutinskaya;Elena P Zharova;Peter V Shegai;Andrey D Kaprin - International journal of molecular sciences (2025)
  2. Tracing the development of CAR-T cell design: from concept to next-generation platforms. - Ahdab A Alsaieedi;Kawther A Zaher - Frontiers in immunology (2025)
  3. Advancing CAR T-Cell Therapy in Solid Tumors: Current Landscape and Future Directions. - Saeed Rafii;Deborah Mukherji;Ashok Sebastian Komaranchath;Charbel Khalil;Faryal Iqbal;Siddig Ibrahim Abdelwahab;Amin Abyad;Ahmad Y Abuhelwa;Lakshmikanth Gandikota;Humaid O Al-Shamsi - Cancers (2025)

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