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Efficiency of CAR-T Therapy for Treatment of Solid Tumor in Clinical Trials: A Meta-Analysis. ​

文献信息 ​

DOI10.1155/2019/3425291
PMID30886654
期刊Disease markers
JCR 分区Q2
发表年份2019
被引次数66
关键词CAR-T细胞治疗, 实体肿瘤, meta分析, 治疗效果, 神经母细胞瘤
文献类型Journal Article, Meta-Analysis
ISSN0278-0240
页码3425291
期号2019()
作者Bin Hou, Yao Tang, Wenhan Li, Qingnuo Zeng, Dongmin Chang

一句话小结 ​

本研究通过荟萃分析22项研究，探讨了嵌合抗原受体T细胞（CAR-T）疗法在262名实体肿瘤患者中的反应率，结果显示总体反应率仅为9%，其中神经母细胞瘤效果最佳，而胃肠道恶性肿瘤几乎无效；尽管结果不理想，研究者仍对CAR-T疗法的未来前景抱有希望，期待通过结构修改提升疗效。

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CAR-T细胞治疗 · 实体肿瘤 · meta分析 · 治疗效果 · 神经母细胞瘤

摘要 ​

背景
嵌合抗原受体T细胞（CAR-T）疗法在血液肿瘤中取得了前所未有的成功，但其在实体肿瘤治疗中的作用仍不明确。

方法
两名独立评审者对截至2018年6月1日的电子数据库进行了全面检索。我们纳入了关注CAR-T细胞疗法与实体肿瘤患者反应率和生存时间关联的研究。

结果
我们的荟萃分析纳入了22项研究，共262名患者。CAR-T细胞疗法的总体合并反应率为9%（95%置信区间（CI）：4-16%）。亚组分析显示，CAR-T疗法在神经母细胞瘤中发挥了最佳治疗效果，而在胃肠道恶性肿瘤中几乎没有效果。此外，不同的治疗策略（T细胞输注前的淋巴清除、转染方法、细胞培养时长、CAR-T细胞的持久性、转染效率、总细胞剂量和IL-2的给药）对治疗效果没有显著影响。只有T细胞培养时长与更好的临床预后相关。

结论
尽管CAR-T细胞疗法在实体肿瘤中的反应并不令人满意，但研究人员仍对其未来的疗效持乐观态度，并期待通过更多结构修改来改善其效果。

英文摘要 ​

BACKGROUND Chimeric antigen receptor T (CAR-T) cell therapy has achieved unprecedented success among hematologic tumors, but its role in treating solid tumors is still unclear.

METHODS A comprehensive search of electronic databases up to June 1, 2018, was carried out by two independent reviewers. We included studies which focused on the association between CAR-T cell therapy and patient response rate and survival time in solid tumors.

RESULTS 22 studies with 262 patients were included in our meta-analysis. The overall pooled response rate of CAR-T cell therapy was 9% (95% confidence interval (CI): 4-16%). Subgroup analysis (analyses) demonstrated that CAR-T therapy could perform its best therapeutic effect on neuroblastoma, while barely works among gastrointestinal malignancies. Moreover, the treatment efficacy was not significantly impacted by different treatment strategies (lymphodepletion before T cell infusion, transfection method, cell culture duration, persistence of CAR-T cells, transfection efficacy, total cell dose, and administration of IL-2). Only T cell culture duration was associated with better clinical prognosis.

CONCLUSIONS Although CAR-T cell therapy did not have satisfactory responses in solid tumors, researchers were still holding an optimistic attitude towards its future efficacy with more modifications of its structure.

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主要研究问题 ​

  1. 在对固体肿瘤的CAR-T疗法中，除了神经母细胞瘤，是否有其他类型的肿瘤显示出较好的治疗反应？
  2. 针对不同的治疗策略，CAR-T疗法在固体肿瘤中的潜在改进方向有哪些？
  3. 在临床试验中，如何评估CAR-T细胞疗法对患者生存时间的影响？
  4. 目前对CAR-T细胞疗法在固体肿瘤中的应用存在哪些主要挑战，未来的研究方向是什么？
  5. 在CAR-T细胞的转染方法和细胞培养持续时间方面，如何优化以提高固体肿瘤患者的治疗效果？

核心洞察 ​

研究背景和目的 ​

嵌合抗原受体T细胞（CAR-T）疗法在血液肿瘤治疗中取得了显著成功，但其在固体肿瘤中的应用效果尚不明确。本研究旨在通过系统性回顾和荟萃分析，评估CAR-T疗法在固体肿瘤中的治疗效果，探讨影响疗效的因素。

主要方法/材料/实验设计 ​

本研究采用了荟萃分析方法，包含以下步骤：

Mermaid diagram
  1. 数据来源：通过PubMed、Embase和ASCO等数据库进行文献检索，关键词包括“CAR-T疗法”、“嵌合抗原受体T细胞”、“固体肿瘤”和“预后”。
  2. 纳入标准：纳入关注CAR-T疗法与患者反应率及生存时间的临床研究，排除血液肿瘤、动物实验和非英文文献。
  3. 数据提取：由两名独立评审员提取患者性别、年龄、肿瘤类型、基因转导方法、T细胞培养时间等数据，主要终点为治疗反应率。
  4. 统计分析：使用R软件进行统计分析，采用随机效应模型计算整体反应率，并进行亚组分析。

关键结果和发现 ​

  1. 纳入研究：共纳入22项研究，涉及262名患者。
  2. 整体反应率：CAR-T疗法在固体肿瘤中的整体反应率为9%（95% CI：4%-16%）。
  3. 亚组分析：
    • 神经母细胞瘤反应率最高，达到33%。
    • 胃肠道恶性肿瘤的治疗效果较差。
    • T细胞培养时间与临床预后相关，培养时间超过14天的患者生存期更长（723天 vs 451天）。

主要结论/意义/创新性 ​

尽管CAR-T疗法在固体肿瘤中的反应率不理想，但研究结果表明其在某些类型肿瘤（如神经母细胞瘤）中仍有潜在的治疗效果。未来通过对CAR-T细胞结构的改进及与其他治疗手段的结合，可能提高其在固体肿瘤中的疗效。

研究局限性和未来方向 ​

  1. 局限性：

    • 目前缺乏大规模的临床数据，主要数据集中在反应率和短期生存率上。
    • 不同研究对不良事件的评估标准不一，导致结果不准确。

  2. 未来方向：

    • 需要进行更大规模的临床试验以验证CAR-T疗法在固体肿瘤中的长期效果和安全性。
    • 探索与免疫检查点抑制剂联合使用的可能性，以克服肿瘤微环境对T细胞功能的抑制。

通过这些努力，CAR-T疗法有望在固体肿瘤的治疗中取得更好的临床效果。

参考文献 ​

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引用本文的文献 ​

  1. CAR-T with License to Kill Solid Tumors in Search of a Winning Strategy. - Benedetto Sacchetti;Andrea Botticelli;Luca Pierelli;Marianna Nuti;Maurizio Alimandi - International journal of molecular sciences (2019)
  2. Chimeric Antigen Receptor-T Cells for Targeting Solid Tumors: Current Challenges and Existing Strategies. - Lorraine Springuel;Caroline Lonez;Bertrand Alexandre;Eric Van Cutsem;Jean-Pascal H Machiels;Marc Van Den Eynde;Hans Prenen;Alain Hendlisz;Leila Shaza;Javier Carrasco;Jean-Luc Canon;Mateusz Opyrchal;Kunle Odunsi;Sylvie Rottey;David E Gilham;Anne Flament;Frédéric F Lehmann - BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy (2019)
  3. Engineering T cells for immunotherapy of primary human hepatocellular carcinoma. - Leidy D Caraballo Galva;Lun Cai;Yanxia Shao;Yukai He - Journal of genetics and genomics = Yi chuan xue bao (2020)
  4. Getting CD19 Into Shape: Expression of Natively Folded "Difficult-to- Express" CD19 for Staining and Stimulation of CAR-T Cells. - Elisabeth Lobner;Anna Wachernig;Venugopal Gudipati;Patrick Mayrhofer;Benjamin Salzer;Manfred Lehner;Johannes B Huppa;Renate Kunert - Frontiers in bioengineering and biotechnology (2020)
  5. Comparison of Clinically Relevant Oncolytic Virus Platforms for Enhancing T Cell Therapy of Solid Tumors. - Victor Cervera-Carrascon;Dafne C A Quixabeira;Riikka Havunen;Joao M Santos;Emma Kutvonen;James H A Clubb;Mikko Siurala;Camilla Heiniö;Sadia Zafar;Teija Koivula;Dave Lumen;Marjo Vaha;Arturo Garcia-Horsman;Anu J Airaksinen;Suvi Sorsa;Marjukka Anttila;Veijo Hukkanen;Anna Kanerva;Akseli Hemminki - Molecular therapy oncolytics (2020)
  6. Adoptive immunotherapies in neuro-oncology: classification, recent advances, and translational challenges. - Sabino Luzzi;Alice Giotta Lucifero;Ilaria Brambilla;Mariasole Magistrali;Mario Mosconi;Salvatore Savasta;Thomas Foiadelli - Acta bio-medica : Atenei Parmensis (2020)
  7. CAR T Cell Therapy in Pancreaticobiliary Cancers: a Focused Review of Clinical Data. - Muhammad Yasir Anwar;Grant R Williams;Ravi K Paluri - Journal of gastrointestinal cancer (2021)
  8. Intravital Imaging of Adoptive T-Cell Morphology, Mobility and Trafficking Following Immune Checkpoint Inhibition in a Mouse Melanoma Model. - Doreen Lau;Fabien Garçon;Anita Chandra;Laura M Lechermann;Luigi Aloj;Edwin R Chilvers;Pippa G Corrie;Klaus Okkenhaug;Ferdia A Gallagher - Frontiers in immunology (2020)
  9. Detection of response to tumor microenvironment-targeted cellular immunotherapy using nano-radiomics. - Laxman Devkota;Zbigniew Starosolski;Charlotte H Rivas;Igor Stupin;Ananth Annapragada;Ketan B Ghaghada;Robin Parihar - Science advances (2020)
  10. Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells. - Rapeepat Sangsuwan;Bhasirie Thuamsang;Noah Pacifici;Riley Allen;Hyunsoo Han;Svetlana Miakicheva;Jamal S Lewis - Cellular and molecular bioengineering (2020)

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