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CAR T Cell Therapy for Neuroblastoma. ​

文献信息 ​

DOI10.3389/fimmu.2018.02380
PMID30459759
期刊Frontiers in immunology
影响因子5.9
JCR 分区Q1
发表年份2018
被引次数89
关键词CAR T细胞, 过继性T细胞疗法, 临床试验, 免疫疗法, 神经母细胞瘤
文献类型Journal Article, Research Support, Non-U.S. Gov't, Review
ISSN1664-3224
页码2380
期号9()
作者Rebecca M Richards, Elena Sotillo, Robbie G Majzner

一句话小结 ​

高风险神经母细胞瘤患者的预后较差，尽管已有抗GD2单克隆抗体治疗，五年生存率仍约为50%。本综述总结了针对神经母细胞瘤的CAR T细胞治疗的临床试验进展，探讨了其疗效障碍及潜在改善策略，旨在推动这一领域的研究和应用。

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CAR T细胞 · 过继性T细胞疗法 · 临床试验 · 免疫疗法 · 神经母细胞瘤

摘要 ​

高风险神经母细胞瘤患者的预后较差，幸存者往往因治疗而留下严重的长期后遗症。即使在标准的前端治疗方案中整合了抗GD2单克隆抗体治疗，五年总体生存率仍仅约为50%。抗GD2治疗的成功证明了免疫疗法在神经母细胞瘤中的有效性。嵌合抗原受体（CAR）T细胞的采纳性转移有可能在这一成功基础上进一步发展。在早期临床试验中，针对神经母细胞瘤的CAR T细胞治疗已被证明是安全且可行的，但仍存在显著的疗效障碍。这些障碍包括T细胞持久性和效力的缺乏、靶标识别的困难以及免疫抑制的肿瘤微环境。随着CAR T细胞工程的最新进展，许多问题正在实验室中得到解决。在本综述中，我们总结了已完成或正在进行的神经母细胞瘤CAR T细胞治疗的临床试验，讨论了这些试验得出的结论和未解问题，并考虑了改善神经母细胞瘤患者CAR T细胞治疗的潜在策略。

英文摘要 ​

Patients with high risk neuroblastoma have a poor prognosis and survivors are often left with debilitating long term sequelae from treatment. Even after integration of anti-GD2 monoclonal antibody therapy into standard, upftont protocols, 5-year overall survival rates are only about 50%. The success of anti-GD2 therapy has proven that immunotherapy can be effective in neuroblastoma. Adoptive transfer of chimeric antigen receptor (CAR) T cells has the potential to build on this success. In early phase clinical trials, CAR T cell therapy for neuroblastoma has proven safe and feasible, but significant barriers to efficacy remain. These include lack of T cell persistence and potency, difficulty in target identification, and an immunosuppressive tumor microenvironment. With recent advances in CAR T cell engineering, many of these issues are being addressed in the laboratory. In this review, we summarize the clinical trials that have been completed or are underway for CAR T cell therapy in neuroblastoma, discuss the conclusions and open questions derived from these trials, and consider potential strategies to improve CAR T cell therapy for patients with neuroblastoma.

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主要研究问题 ​

  1. CAR T细胞治疗在神经母细胞瘤中的潜在优势与现有治疗方案相比有哪些？
  2. 针对神经母细胞瘤的CAR T细胞治疗在临床试验中遇到的主要挑战是什么？
  3. 如何改善CAR T细胞的持久性和效力以提高神经母细胞瘤患者的治疗效果？
  4. 在神经母细胞瘤的CAR T细胞治疗中，肿瘤微环境的免疫抑制作用如何影响治疗结果？
  5. 目前有哪些新兴的CAR T细胞工程技术被用于提高神经母细胞瘤的治疗效果？

核心洞察 ​

研究背景和目的 ​

神经母细胞瘤是一种源于神经嵴细胞的儿童肿瘤，常在10岁之前被诊断。高风险神经母细胞瘤患者的预后较差，尽管在标准治疗中加入了抗-GD2单克隆抗体，五年生存率仍仅约50%。因此，开发新的治疗方法以改善生存率和减少治疗后遗症至关重要。本文旨在总结CAR T细胞治疗神经母细胞瘤的临床试验进展，探讨当前的挑战及未来的研究方向。

主要方法/材料/实验设计 ​

本研究通过回顾现有文献和临床试验数据，分析了CAR T细胞治疗神经母细胞瘤的临床应用。主要的研究方法包括：

  • CAR T细胞的设计与制造，包括对不同靶点的选择（如GD2和L1-CAM）。
  • 临床试验的设计，分为I期和II期试验，评估疗效和安全性。
  • 对比不同CAR T细胞的信号传导域（如CD3ζ、4-1BB等）对治疗效果的影响。

以下是研究的技术路线图：

Mermaid diagram

关键结果和发现 ​

  1. GD2靶点：GD2是神经母细胞瘤中最常见的靶点，多个临床试验显示，针对GD2的CAR T细胞治疗在部分患者中产生了客观反应，但整体疗效有限。
  2. L1-CAM靶点：L1-CAM同样在神经母细胞瘤中表达，相关CAR T细胞治疗显示出一定的安全性，但临床反应不显著。
  3. T细胞持久性：T细胞的持久性是影响治疗效果的关键因素，许多试验表明，T细胞在体内的存活时间与治疗反应密切相关。
  4. 免疫抑制微环境：神经母细胞瘤的免疫抑制微环境对CAR T细胞的效能构成了显著挑战。

主要结论/意义/创新性 ​

CAR T细胞治疗神经母细胞瘤的研究显示出安全性和一定的疗效，特别是在高风险患者中。然而，T细胞的持久性不足、靶点选择困难以及免疫抑制微环境的存在，仍然是限制其广泛应用的主要障碍。未来的研究应集中在改进CAR设计、增强T细胞持久性以及克服肿瘤微环境的抑制作用上。

研究局限性和未来方向 ​

  • 局限性：当前临床试验的样本量较小，且多为早期试验，缺乏长期随访数据。
  • 未来方向：
    • 进一步优化CAR T细胞的设计，例如结合多种信号传导域以增强细胞活性。
    • 探索新的靶点及其在神经母细胞瘤中的应用。
    • 研究如何克服肿瘤微环境的抑制作用，例如通过联合使用免疫检查点抑制剂或其他免疫疗法。

通过以上措施，有望提高CAR T细胞治疗神经母细胞瘤的效果，改善患者的预后。

参考文献 ​

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引用本文的文献 ​

  1. Prediction of PD-L1 Expression in Neuroblastoma via Computational Modeling. - Salvo Danilo Lombardo;Mario Presti;Katia Mangano;Maria Cristina Petralia;Maria Sofia Basile;Massimo Libra;Saverio Candido;Paolo Fagone;Emanuela Mazzon;Ferdinando Nicoletti;Alessia Bramanti - Brain sciences (2019)
  2. Overexpression of Macrophage Migration Inhibitory Factor and Its Homologue D-Dopachrome Tautomerase as Negative Prognostic Factor in Neuroblastoma. - Eugenio Cavalli;Emanuela Mazzon;Santa Mammana;Maria Sofia Basile;Salvo Danilo Lombardo;Katia Mangano;Placido Bramanti;Ferdinando Nicoletti;Paolo Fagone;Maria Cristina Petralia - Brain sciences (2019)
  3. EGFR-specific CAR-T cells trigger cell lysis in EGFR-positive TNBC. - Yan Liu;Yehui Zhou;Kuo-Hsiang Huang;Ying Li;Xujie Fang;Li An;Feifei Wang;Qingfei Chen;Yunchao Zhang;Aihua Shi;Shuang Yu;Jingzhong Zhang - Aging (2019)
  4. Recent advances in tumor associated carbohydrate antigen based chimeric antigen receptor T cells and bispecific antibodies for anti-cancer immunotherapy. - Zahra Rashidijahanabad;Xuefei Huang - Seminars in immunology (2020)
  5. "UniCAR"-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells. - Nicola Mitwasi;Anja Feldmann;Claudia Arndt;Stefanie Koristka;Nicole Berndt;Justyna Jureczek;Liliana R Loureiro;Ralf Bergmann;Domokos Máthé;Nikolett Hegedüs;Tibor Kovács;Congcong Zhang;Pranav Oberoi;Elke Jäger;Barbara Seliger;Claudia Rössig;Achim Temme;Jiri Eitler;Torsten Tonn;Marc Schmitz;Jessica C Hassel;Dirk Jäger;Winfried S Wels;Michael Bachmann - Scientific reports (2020)
  6. Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors. - Ombretta Melaiu;Valeria Lucarini;Loredana Cifaldi;Doriana Fruci - Frontiers in immunology (2019)
  7. Targets and Antibody Formats for Immunotherapy of Neuroblastoma. - Jeong A Park;Nai-Kong V Cheung - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2020)
  8. Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma. - Lihong Wang-Bishop;Mohamed Wehbe;Daniel Shae;Jamaal James;Benjamin C Hacker;Kyle Garland;Plamen P Chistov;Marjan Rafat;Justin M Balko;John T Wilson - Journal for immunotherapy of cancer (2020)
  9. Chimeric cytokine receptor enhancing PSMA-CAR-T cell-mediated prostate cancer regression. - Shao Weimin;Asimujiang Abula;Ding Qianghong;Wang Wenguang - Cancer biology & therapy (2020)
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