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文献精选 > 近年高分"CAR-T疗法"研究（IF≥30，近5年）

Chimeric antigen receptor T cell therapy for autoimmune disease. ​

文献信息 ​

DOI10.1038/s41577-024-01035-3
PMID38831163
期刊Nature reviews. Immunology
影响因子60.9
JCR 分区Q1
发表年份2024
被引次数24
关键词嵌合抗原受体T细胞疗法, 自身免疫疾病, B细胞, 临床试验, 免疫调节
文献类型Journal Article, Review
ISSN1474-1733
页码830-845
期号24(11)
作者James B Chung, Jennifer N Brudno, Dominic Borie, James N Kochenderfer

一句话小结 ​

本研究探讨了工程化T细胞通过嵌合抗原受体（CAR）靶向B细胞在治疗自身免疫疾病中的潜力，发现针对CD19的CAR T细胞在临床试验中显示出良好效果。研究强调了靶细胞选择、CAR设计及安全性等关键因素，为CAR T细胞在自身免疫领域的安全应用提供了重要指导。

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嵌合抗原受体T细胞疗法 · 自身免疫疾病 · B细胞 · 临床试验 · 免疫调节

摘要 ​

工程化的T细胞通过表达靶向B细胞的嵌合抗原受体（CAR）进行输注，已被证明是治疗B细胞恶性肿瘤的成功方法。这一成功激发了开发CAR T细胞，以选择性地消除或调节导致自身免疫疾病的异常免疫反应。目前，针对B细胞驱动的自身免疫疾病的临床试验中，靶向B细胞蛋白CD19的CAR T细胞显示出了有希望的结果。为了扩展CAR T细胞治疗在自身免疫领域的应用并提高其安全性，正在设计进一步的方法，包括使用嵌合自身抗体受体选择性消除特定自身抗原的B细胞，以及使用工程化的调节性T细胞表达特定抗原的CAR进行靶向免疫调节。在此，我们强调了一些重要考虑因素，如最佳靶细胞群体、CAR构建设计、可接受的毒性以及持久免疫重置的潜力，这些因素将为CAR T细胞治疗自身免疫疾病的安全采用提供指导。

英文摘要 ​

Infusion of T cells engineered to express chimeric antigen receptors (CARs) that target B cells has proven to be a successful treatment for B cell malignancies. This success inspired the development of CAR T cells to selectively deplete or modulate the aberrant immune responses that underlie autoimmune disease. Promising results are emerging from clinical trials of CAR T cells targeting the B cell protein CD19 in patients with B cell-driven autoimmune diseases. Further approaches are being designed to extend the application and improve safety of CAR T cell therapy in the setting of autoimmunity, including the use of chimeric autoantibody receptors to selectively deplete autoantigen-specific B cells and the use of regulatory T cells engineered to express antigen-specific CARs for targeted immune modulation. Here, we highlight important considerations, such as optimal target cell populations, CAR construct design, acceptable toxicities and potential for lasting immune reset, that will inform the eventual safe adoption of CAR T cell therapy for the treatment of autoimmune diseases.

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主要研究问题 ​

  1. 在CAR T细胞治疗自身免疫疾病的过程中，如何选择最佳的靶细胞群体？
  2. 有哪些不同的CAR构建设计可以提高自身免疫疾病治疗的安全性和有效性？
  3. 针对B细胞驱动的自身免疫疾病，CAR T细胞治疗的潜在副作用有哪些，如何进行管理？
  4. 在临床试验中，CAR T细胞治疗的长期效果如何评估，是否存在持久的免疫重置现象？
  5. 除了CD19靶向，是否还有其他靶点正在研究中，以改善CAR T细胞在自身免疫疾病中的应用？

核心洞察 ​

研究背景和目的 ​

近年来，工程化的嵌合抗原受体（CAR）T细胞在治疗B细胞恶性肿瘤方面取得了显著成功。这一成功激发了对CAR T细胞在自身免疫性疾病中的应用研究，旨在选择性去除或调节导致这些疾病的异常免疫反应。本文旨在探讨CAR T细胞在治疗B细胞驱动的自身免疫性疾病中的潜力，并讨论相关的设计和安全性考虑。

主要方法/材料/实验设计 ​

本研究主要采用以下方法来评估CAR T细胞在自身免疫性疾病中的应用：

Mermaid diagram
  1. CAR T细胞工程化：将T细胞转基因，使其表达针对B细胞的CAR。
  2. 靶向B细胞CD19：主要靶点为B细胞表面蛋白CD19。
  3. 临床试验评估：在患者中进行临床试验，观察治疗效果和安全性。
  4. 选择性去除自体抗原特异性B细胞：设计嵌合自体抗体受体（CAAR）以去除异常B细胞。
  5. 调节性T细胞工程化：利用工程化的调节性T细胞进行免疫调节。
  6. 评估免疫调节效果：评估治疗对免疫系统的长期影响。

关键结果和发现 ​

  • 临床试验显示，靶向CD19的CAR T细胞在B细胞驱动的自身免疫性疾病中表现出良好的疗效。
  • 采用嵌合自体抗体受体的策略成功去除了特定的自体抗原特异性B细胞。
  • 工程化调节性T细胞的应用在调节异常免疫反应方面显示出潜力。

主要结论/意义/创新性 ​

CAR T细胞治疗在自身免疫性疾病中展现出良好的应用前景。通过优化CAR构建设计和靶向细胞群体，可以实现对异常免疫反应的有效调节。这项研究为CAR T细胞在自身免疫性疾病中的安全应用提供了重要的理论基础和实践指导，具有重要的临床意义和创新性。

研究局限性和未来方向 ​

  • 局限性：当前研究主要集中在特定类型的自身免疫性疾病，缺乏广泛的适应性验证。安全性和长期效果仍需进一步评估。
  • 未来方向：
    • 扩大临床试验范围，验证不同自身免疫性疾病的适应性。
    • 研究CAR T细胞治疗的长期安全性和潜在副作用。
    • 探索更多的靶向策略和联合治疗方法，以提高治疗效果和安全性。

参考文献 ​

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引用本文的文献 ​

  1. Advances in Juvenile Dermatomyositis: Pathophysiology, Diagnosis, Treatment and Interstitial Lung Diseases-A Narrative Review. - Ichiro Kobayashi - Children (Basel, Switzerland) (2024)
  2. Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome. - Jonathan Wickel;Ulf Schnetzke;Anne Sayer-Klink;Jenny Rinke;Dominic Borie;Diana Dudziak;Andreas Hochhaus;Lukas Heger;Christian Geis - Cell reports. Medicine (2024)
  3. Exploring structure-function relationships in engineered receptor performance using computational structure prediction. - William K Corcoran;Amparo Cosio;Hailey I Edelstein;Joshua N Leonard - bioRxiv : the preprint server for biology (2024)
  4. Chimeric antigen receptor T-cell therapy in autoimmune diseases. - Jie Liu;Yan Zhao;Hai Zhao - Frontiers in immunology (2024)
  5. Targeted degradation of membrane proteins. - Grace Hohman;Michael Shahid;Mohamed Eldeeb - Nature structural & molecular biology (2025)
  6. Past interactions of T cells with antigens shape CAR T cell responses. - Nature immunology (2025)
  7. Why is it so difficult to understand why we don't understand human systemic lupus erythematosus? Contemplating facts, conflicts, and impact of "the causality cascade paradigm". - Ole Petter Rekvig - Frontiers in immunology (2024)
  8. Monitoring the neurological complications of chimeric antigen receptor (CAR) T-cell therapy in patients with sensory and physical impairments and non-native-speaking backgrounds using modified immune effector cell-associated encephalopathy (ICE) scores: a case series. - Christina Kazzi;Ty Simpson;Cassandra Abbott;Miriam Wronski;Nabil Seery;Tracie Huey-Lin Tan;Robb Wesselingh;Katherine Ko;Shu Min Wong;Shafqat Inam;Constantine Tam;Shaun Fleming;Terence J O'Brien;Rubina Alpitsis;Andrew Spencer;Charles Malpas;Mastura Monif - BMJ neurology open (2025)
  9. Defining immune reset: achieving sustained remission in autoimmune diseases. - Tobias Junt;Thomas Calzascia;Elisabetta Traggiai;André Nogueira da Costa;Peter Gergely;Georg Schett;Thomas Dörner;Richard M Siegel - Nature reviews. Immunology (2025)
  10. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. - Xiaofeng Dai;Yuting Fan;Xing Zhao - Signal transduction and targeted therapy (2025)

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