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Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis.

文献信息

DOI10.1016/j.tmrv.2019.01.005
PMID30948292
期刊Transfusion medicine reviews
影响因子2.5
JCR 分区Q2
发表年份2019
被引次数111
关键词CAR-T细胞疗法, 癌症, 血液系统, 系统评价
文献类型Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't, Systematic Review
ISSN0887-7963
页码98-110
期号33(2)
作者Emma J M Grigor, Dean Fergusson, Natasha Kekre, Joshua Montroy, Harold Atkins, Matthew D Seftel, Mads Daugaard, Justin Presseau, Kednapa Thavorn, Brian Hutton, Robert A Holt, Manoj M Lalu

一句话小结

本研究系统总结了嵌合抗原受体(CAR)T细胞治疗在复发或难治性血液恶性肿瘤和实体肿瘤患者中的疗效和安全性,发现CD19阳性血液恶性肿瘤患者的完全缓解率为54.4%,但实体肿瘤患者的疗效较低,仅为4.1%,同时存在较高的细胞因子释放综合症和神经毒性风险。这些结果为患者和医疗决策提供了重要的参考,帮助评估CAR-T细胞治疗的潜在益处与风险。

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CAR-T细胞疗法 · 癌症 · 血液系统 · 系统评价

摘要

嵌合抗原受体(CAR)T细胞治疗的疗效结果令人鼓舞,但安全性问题使其前景受到一定限制。我们的目标是全面总结CAR-T细胞治疗在复发或难治性血液恶性肿瘤或实体瘤患者中的疗效和安全性。我们检索了MEDLINE、Embase和Cochrane控制试验注册库(创立至2017年11月21日)。纳入了针对恶性肿瘤患者的CAR-T细胞治疗的干预性研究。我们的主要关注结果是完全缓解(定义为无可检测癌症)。两名独立评审者提取了相关数据,评估了偏倚风险,并使用既定方法对证据质量进行了分级。总共有42项血液恶性肿瘤研究和18项实体肿瘤研究符合纳入标准(共913名参与者)。在486名可评估的血液患者中,54.4% [95% CI, 42.5%-65.9%] 在27项CD19 CAR-T细胞治疗研究中经历了完全缓解。在65名可评估的血液患者中,24.4% [95% CI, 9.4%-50.3%] 在七项非CD19 CAR-T细胞治疗研究中经历了完全缓解。55.3% [95% CI, 40.3%-69.4%] 的患者经历了细胞因子释放综合症,37.2% [95% CI, 28.6%-46.8%] 的患者出现了神经毒性。在86名可评估的实体肿瘤患者中,4.1% [95% CI, 1.6%-10.6%] 在八项CAR-T细胞治疗研究中经历了完全缓解。研究的局限性包括研究人群的异质性以及纳入研究的高偏倚风险。目前的结果显示,CAR-T细胞治疗在CD19阳性血液恶性肿瘤患者中具有显著的疗效信号,而在迄今发布的实体肿瘤试验中未见整体信号。这些结果将帮助患者、医生和其他利益相关者了解CAR-T细胞治疗的益处和风险。

英文摘要

Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize the efficacy and safety of CAR-T cell therapy in patients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane Register of Controlled Trials (inception - November 21, 2017). Interventional studies investigating CAR-T cell therapy in patients with malignancies were included. Our primary outcome of interest was complete response (defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients, 54.4% [95% CI, 42.5%-65.9%] experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65 evaluable hematologic patients, 24.4% [95% CI, 9.4%-50.3%] experienced complete response in seven non-CD19 CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% [95% CI, 40.3%-69.4%] of patients and neurotoxicity 37.2% [95% CI, 28.6%-46.8%] of patients with hematologic malignancies. Of 86 evaluable solid tumor patients, 4.1% [95% CI, 1.6%-10.6%] experienced complete response in eight CAR-T cell therapy studies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy.

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主要研究问题

  1. CAR-T疗法在不同类型的血液恶性肿瘤和实体肿瘤中的疗效差异是什么?
  2. 在接受CAR-T疗法的患者中,如何评估和管理细胞因子释放综合症和神经毒性?
  3. 现有的CAR-T疗法研究中,患者的基本特征和合并症如何影响治疗效果?
  4. 除了CD19靶向的CAR-T疗法外,还有哪些新兴的靶点正在研究中?
  5. 在临床实践中,如何平衡CAR-T疗法的潜在收益与其安全风险?

核心洞察

1. 研究背景和目的

随着肿瘤免疫治疗的快速发展,嵌合抗原受体T细胞(CAR-T)疗法作为一种新兴的治疗手段,已显示出对某些类型癌症的显著疗效。然而,该疗法的安全性问题也引起了广泛关注。本研究通过系统评估和荟萃分析,旨在全面总结CAR-T细胞疗法在复发或难治性血液恶性肿瘤及实体瘤患者中的疗效和安全性,以便为患者、医生及相关利益相关者提供可靠的参考。

2. 主要方法和发现

研究从MEDLINE、Embase和Cochrane临床试验注册库中筛选了相关的干预研究,纳入了对CAR-T细胞疗法进行评估的研究。共纳入42项血液恶性肿瘤研究和18项实体瘤研究,总参与者为913人。主要结果为完全缓解率(定义为无可检测癌症)。在486名可评估的血液恶性肿瘤患者中,接受CD19 CAR-T细胞治疗的患者中,有54.4%(95% CI, 42.5%-65.9%)达到了完全缓解;而在7项非CD19 CAR-T细胞治疗的研究中,65名可评估患者中仅有24.4%(95% CI, 9.4%-50.3%)获得完全缓解。在安全性方面,血液恶性肿瘤患者中,55.3%(95% CI, 40.3%-69.4%)出现细胞因子释放综合征,37.2%(95% CI, 28.6%-46.8%)发生神经毒性。对于86名可评估的实体瘤患者,仅有4.1%(95% CI, 1.6%-10.6%)达成完全缓解。

3. 核心结论

本研究结果表明,在CD19阳性的血液恶性肿瘤患者中,CAR-T细胞疗法具有显著的疗效,尤其是在完全缓解率方面表现突出;然而,在当前的实体瘤研究中未显示出整体有效信号。此外,虽然疗效良好,但伴随的安全性风险,如细胞因子释放综合征和神经毒性,仍需引起重视。

4. 研究意义和影响

这项系统评估和荟萃分析为CAR-T细胞疗法的临床应用提供了重要的证据基础,帮助医生在治疗选择时权衡疗效与安全性之间的利弊。研究结果不仅有助于指导临床实践,还为进一步的研究提供方向,尤其是在实体瘤的CAR-T疗法研究中,提示需要更深入的探索和优化。同时,这也为患者及其家庭在治疗决策中提供了重要的信息支持。

引用本文的文献

  1. Integrated cancer tissue engineering models for precision medicine. - Michael E Bregenzer;Eric N Horst;Pooja Mehta;Caymen M Novak;Shreya Raghavan;Catherine S Snyder;Geeta Mehta - PloS one (2019)
  2. Integrative Approaches to Cancer Immunotherapy. - Gregory L Szeto;Stacey D Finley - Trends in cancer (2019)
  3. CAR T-cell product performance in haematological malignancies before and after marketing authorisation. - Magdi Elsallab;Bruce L Levine;Alan S Wayne;Mohamed Abou-El-Enein - The Lancet. Oncology (2020)
  4. Preclinical safety evaluation of chimeric antigen receptor-modified T cells against CD19 in NSG mice. - Hairuo Wen;Zhe Qu;Yujing Yan;Chengfei Pu;Chao Wang;Hua Jiang;Tiantian Hou;Yan Huo - Annals of translational medicine (2019)
  5. Chimeric antigen receptor T-cell therapies: Optimising the dose. - Nathaniel Dasyam;Philip George;Robert Weinkove - British journal of clinical pharmacology (2020)
  6. Biomarkers in individualized management of chimeric antigen receptor T cell therapy. - Mengyi Du;Parameswaran Hari;Yu Hu;Heng Mei - Biomarker research (2020)
  7. The future of cancer immunotherapy: microenvironment-targeting combinations. - Yonina R Murciano-Goroff;Allison Betof Warner;Jedd D Wolchok - Cell research (2020)
  8. Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study. - Bénédicte Lefebvre;Yu Kang;Amanda M Smith;Noelle V Frey;Joseph R Carver;Marielle Scherrer-Crosbie - JACC. CardioOncology (2020)
  9. CAR T Cell Therapy for Pediatric Brain Tumors. - John D Patterson;Jeffrey C Henson;Rebecca O Breese;Kevin J Bielamowicz;Analiz Rodriguez - Frontiers in oncology (2020)
  10. Partnering with patients to get better outcomes with chimeric antigen receptor T-cell therapy: towards engagement of patients in early phase trials. - Madison Foster;Dean A Fergusson;Terry Hawrysh;Justin Presseau;Natasha Kekre;Stuart Schwartz;Gisell Castillo;Sarah Asad;Grace Fox;Harold Atkins;Kednapa Thavorn;Joshua Montroy;Robert A Holt;Zarah Monfaredi;Manoj M Lalu - Research involvement and engagement (2020)

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