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Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy. ​

文献信息 ​

DOI10.3389/fimmu.2022.879608
PMID36081506
期刊Frontiers in immunology
影响因子5.9
JCR 分区Q1
发表年份2022
被引次数42
关键词CAR-T细胞, 免疫效应细胞相关神经毒性综合征（ICANS）, 嵌合抗原受体T细胞（CAR-T细胞）疗法, 细胞因子释放综合征（CRS）, 免疫效应细胞相关神经毒性综合征（ICANS）
文献类型Journal Article, Review
ISSN1664-3224
页码879608
期号13()
作者Robert C Sterner, Rosalie M Sterner

一句话小结 ​

嵌合抗原受体（CAR）T细胞疗法在血液恶性肿瘤治疗中显示出良好效果，但其相关的免疫效应细胞相关神经毒性综合征（ICANS）限制了其广泛应用。本文探讨了ICANS的机制及其治疗方案，强调了改善CAR-T细胞疗法以提高患者生存率和降低治疗成本的重要性。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

CAR-T细胞 · 免疫效应细胞相关神经毒性综合征（ICANS） · 嵌合抗原受体T细胞（CAR-T细胞）疗法 · 细胞因子释放综合征（CRS） · 免疫效应细胞相关神经毒性综合征（ICANS）

摘要 ​

嵌合抗原受体（CAR）T细胞疗法在某些血液恶性肿瘤的治疗中已成为一种新兴的标准方案。尽管CAR-T细胞在某些血液恶性肿瘤中产生了显著的反应，但与该疗法相关的毒性反应限制了其应用。免疫效应细胞相关神经毒性综合征（ICANS）是一种潜在的危及生命的神经毒性，常见于CAR-T细胞疗法中。本文将讨论ICANS及其治疗、可能的机制以及应对CAR-T细胞疗法这一关键局限性的潜在解决方案。随着CAR-T细胞疗法的发展，改善治疗方法和规避或克服ICANS的策略是必要的，以提高患者的发病率、生存率并降低CAR-T细胞疗法的费用。这种严重且危及生命的副作用需要进一步研究，以更好地理解其机制并开发治疗方案和替代策略。

英文摘要 ​

Chimeric antigen receptor (CAR)-T cell therapy is an emerging staple in the treatment of certain hematological malignancies. While CAR-T cells have produced robust responses in certain hematological malignancies, toxicities associated with the therapy have limited their use. Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) is a potentially life-threatening neurotoxicity that commonly occurs with CAR-T cell therapy. Here we will discuss ICANS, its treatment, possible mechanisms, and potential solutions to this critical limitation of CAR-T cell therapy. As the field of CAR-T cell therapy evolves, improved treatments and methods to circumvent or overcome ICANS are necessary to improve morbidity, mortality, and decrease the cost of CAR-T cell therapy. This serious, life-threatening side effect needs to be studied to better understand its mechanisms and develop treatments and alternative strategies.

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主要研究问题 ​

  1. 在CAR-T细胞治疗中，ICANS的发生率与哪些患者特征或治疗方案相关？
  2. 除了ICANS，CAR-T细胞治疗还可能引发哪些其他类型的神经毒性？
  3. 针对ICANS的现有治疗方案有哪些，它们的有效性和安全性如何？
  4. 在开发新的CAR-T细胞治疗时，如何设计实验以评估ICANS的风险和机制？
  5. ICANS的机制是否与其他免疫相关的不良反应存在共通之处？如果有，这些共通机制是什么？

核心洞察 ​

研究背景和目的 ​

嵌合抗原受体T细胞（CAR-T细胞）疗法是治疗某些血液恶性肿瘤的重要方法。尽管CAR-T细胞在治疗某些血液肿瘤方面取得了显著效果，但与之相关的毒性反应限制了其应用。免疫效应细胞相关神经毒性综合症（ICANS）是一种可能危及生命的神经毒性反应，常见于CAR-T细胞治疗中。本文旨在探讨ICANS的治疗、可能机制及解决方案，以应对CAR-T细胞治疗的这一关键限制。

主要方法/材料/实验设计 ​

研究采用文献综述的方法，分析了ICANS的临床表现、发病机制及其治疗策略。具体流程如下：

Mermaid diagram

关键结果和发现 ​

  • ICANS的发生率在接受CAR-T细胞治疗的患者中为20-70%。
  • ICANS的临床表现包括意识模糊、头痛、注意力缺陷、语言障碍及严重的脑水肿等。
  • ICANS的发病机制尚不明确，但与血脑屏障的破坏、细胞因子的释放及T细胞与髓系细胞的相互作用密切相关。
  • ICANS的治疗主要依赖支持性治疗和皮质类固醇，且目前尚无特定的预防性治疗方法。

主要结论/意义/创新性 ​

ICANS是一种常见且严重的副作用，限制了CAR-T细胞治疗的应用。深入理解ICANS的机制对于开发新的治疗策略至关重要。未来的研究应聚焦于改善CAR-T细胞的设计，以降低其毒性反应，同时探索靶向细胞因子的治疗方法。

研究局限性和未来方向 ​

目前对于ICANS的研究存在动物模型不足、发病机制不清晰等局限性。未来的研究方向应包括：

  • 开发更有效的动物模型以研究ICANS。
  • 进一步探索ICANS的发病机制，特别是细胞因子网络的作用。
  • 设计新型CAR-T细胞，以减少其毒性反应，并评估其在临床中的有效性与安全性。

参考文献 ​

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  1. Neurological Complications of Conventional and Novel Anticancer Treatments. - Paola Alberti;Alessandro Salvalaggio;Andreas A Argyriou;Jordi Bruna;Andrea Visentin;Guido Cavaletti;Chiara Briani - Cancers (2022)
  2. Neoantigen-directed therapeutics in the clinic: where are we? - Lien Lybaert;Kris Thielemans;Steven A Feldman;Sjoerd H van der Burg;Cedric Bogaert;Patrick A Ott - Trends in cancer (2023)
  3. CAR T-cell-associated neurotoxicity in central nervous system hematologic disease: Is it still a concern? - Roser Velasco;Alberto Mussetti;Macarena Villagrán-García;Anna Sureda - Frontiers in neurology (2023)
  4. IRF4 downregulation improves sensitivity and endurance of CAR T cell functional capacities. - Dennis Christoph Harrer;Valerie Bezler;Jordan Hartley;Wolfgang Herr;Hinrich Abken - Frontiers in immunology (2023)
  5. Early and Late Toxicities of Chimeric Antigen Receptor T-Cells. - Rebecca Epperly;Victoria M Giordani;Lekha Mikkilineni;Nirali N Shah - Hematology/oncology clinics of North America (2023)
  6. Toxicity Profile of Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapies in Multiple Myeloma: Pathogenesis, Prevention and Management. - Mariam Markouli;Fauzia Ullah;Serhan Unlu;Najiullah Omar;Nerea Lopetegui-Lia;Marissa Duco;Faiz Anwer;Shahzad Raza;Danai Dima - Current oncology (Toronto, Ont.) (2023)
  7. CAR-T State of the Art and Future Challenges, A Regulatory Perspective. - Lorenzo Giorgioni;Alessandra Ambrosone;Maria Francesca Cometa;Anna Laura Salvati;Armando Magrelli - International journal of molecular sciences (2023)
  8. A Pharmacovigilance Study on the Safety of Axicabtagene Ciloleucel Based on Spontaneous Reports from the EudraVigilance Database. - Concetta Rafaniello;Valerio Liguori;Alessia Zinzi;Mario Gaio;Angela Falco;Luigi Di Costanzo;Francesca Gargano;Valentina Trimarco;Mauro Cataldi;Annalisa Capuano - Biomedicines (2023)
  9. Outcomes of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Large B-Cell Lymphoma (LBCL): A Single-Institution Experience. - Aaron Trando;Anna Ter-Zakarian;Phillip Yeung;Aaron M Goodman;Ayad Hamdan;Michael Hurley;Ah-Reum Jeong;Dimitrios Tzachanis - Cancers (2023)
  10. CD44v6 specific CAR-NK cells for targeted immunotherapy of head and neck squamous cell carcinoma. - Ioana Sonya Ciulean;Joe Fischer;Andrea Quaiser;Christoph Bach;Hinrich Abken;Uta Sandy Tretbar;Stephan Fricke;Ulrike Koehl;Dominik Schmiedel;Thomas Grunwald - Frontiers in immunology (2023)

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