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Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. ​

文献信息 ​

DOI10.1056/NEJMoa1709919
PMID29385376
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2018
被引次数1405
关键词CD19 CAR疗法, 急性淋巴细胞白血病, 细胞因子释放综合症, 生存率, 缓解
文献类型Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码449-459
期号378(5)
作者Jae H Park, Isabelle Rivière, Mithat Gonen, Xiuyan Wang, Brigitte Sénéchal, Kevin J Curran, Craig Sauter, Yongzeng Wang, Bianca Santomasso, Elena Mead, Mikhail Roshal, Peter Maslak, Marco Davila, Renier J Brentjens, Michel Sadelain

一句话小结 ​

本研究评估了针对CD19的19-28z CAR T细胞在复发性B细胞急性淋巴细胞白血病患者中的安全性和疗效，结果显示接受治疗的患者中83%达到了完全缓解，且中位总生存期为12.9个月，低疾病负担患者的生存期显著延长。该研究为CAR T细胞治疗在此类疾病中的应用提供了重要的临床依据，尤其是在患者疾病负担较低的情况下。

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CD19 CAR疗法 · 急性淋巴细胞白血病 · 细胞因子释放综合症 · 生存率 · 缓解

摘要 ​

背景
特异性针对CD19的嵌合抗原受体（CAR）T细胞在复发性B细胞急性淋巴细胞白血病（ALL）患者中诱导了高比例的初始反应，并在部分患者中实现了长期缓解。

方法
我们在纪念斯隆凯特琳癌症中心（MSKCC）进行了一项I期试验，涉及接受表达19-28z CAR的自体T细胞输注的复发性B细胞ALL成年患者。我们评估了安全性和长期结果，并分析了这些结果与人口、临床和疾病特征之间的关联。

结果
共有53名成年人接受了在MSKCC制造的19-28z CAR T细胞。输注后，53名患者中有14名（26%；95%置信区间[CI]，15到40）出现严重细胞因子释放综合症；1名患者死亡。观察到83%的患者达到完全缓解。在中位随访29个月（范围1到65个月）时，中位无事件生存期为6.1个月（95% CI，5.0到11.5），中位总生存期为12.9个月（95% CI，8.7到23.4）。在治疗前疾病负担较低（<5%骨髓母细胞）的患者，其缓解持续时间和生存期显著延长，中位无事件生存期为10.6个月（95% CI，5.9到未达到），中位总生存期为20.1个月（95% CI，8.7到未达到）。而疾病负担较高（≥5%骨髓母细胞或外髓疾病）的患者则出现更高的细胞因子释放综合症和神经毒性事件的发生率，且长期生存期较低于疾病负担较低的患者。

结论
在整个队列中，中位总生存期为12.9个月。在疾病负担较低的患者中，中位总生存期为20.1个月，并且在19-28z CAR T细胞输注后，细胞因子释放综合症和神经毒性事件的发生率显著低于疾病负担较高的患者。（研究由联邦癌症研究基金会及其他机构资助；临床试验注册号，NCT01044069）。

英文摘要 ​

BACKGROUND CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients.

METHODS We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics.

RESULTS A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden.

CONCLUSIONS In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).

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主要研究问题 ​

  1. CD19 CAR T细胞治疗对不同年龄段患者的长期疗效有何差异？
  2. 在急性淋巴细胞白血病患者中，如何评估低疾病负担对治疗结果的影响？
  3. 其他类型的CAR T细胞治疗在治疗复发性B细胞急性淋巴细胞白血病方面的效果如何？
  4. 针对高疾病负担患者，是否有针对性的管理策略来减少细胞因子释放综合症的发生？
  5. 长期随访中，患者的生活质量如何受到CD19 CAR T细胞治疗的影响？

核心洞察 ​

研究背景和目的 ​

急性淋巴细胞白血病（ALL）患者的预后较差，尤其是在复发后。标准化疗的完全缓解率较低，且生存期短。近年来，针对CD19的嵌合抗原受体（CAR）T细胞疗法显示出较高的初始反应率和部分患者的长期缓解。本研究旨在评估19-28z CAR T细胞在复发性B细胞ALL患者中的安全性和长期效果。

主要方法/材料/实验设计 ​

本研究为一项I期临床试验，招募了53名接受19-28z CAR T细胞输注的复发性B细胞ALL成人患者。研究设计如下：

Mermaid diagram
  • 患者选择：所有患者均为复发或难治性B细胞ALL，具有明确的临床特征。
  • 疗效评估：通过骨髓评估和流式细胞术检测最小残留病（MRD）。
  • 安全性评估：使用MSKCC标准对细胞因子释放综合症进行分级。

关键结果和发现 ​

  • 治疗反应：83%的患者（44/53）达到了完全缓解（CR），其中67%（32/48）在缓解后无最小残留病。
  • 生存分析：中位事件无生存期为6.1个月，中位总生存期为12.9个月。低疾病负担患者（<5%骨髓芽细胞）中位总生存期为20.1个月。
  • 不良反应：85%的患者出现细胞因子释放综合症，其中26%为重度。神经毒性发生率为59%（高疾病负担组）。

主要结论/意义/创新性 ​

本研究表明，19-28z CAR T细胞在复发性B细胞ALL患者中具有显著的抗肿瘤效果，尤其在低疾病负担患者中，显示出更好的生存率和较低的毒性。研究还强调了预处理疾病负担作为长期生存的预测因子，提示高效的CAR T细胞扩增与肿瘤负担的比率可能是影响长期生存的关键。

研究局限性和未来方向 ​

  • 局限性：本研究为单中心I期试验，样本量较小，可能限制了结果的普遍性和统计学意义。
  • 未来方向：建议进行多中心、大规模的II期和III期试验，以进一步验证19-28z CAR T细胞的疗效及其与疾病负担的关系。此外，应探索优化治疗方案以减少不良反应并提高患者生存率。

参考文献 ​

  1. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. - Renier J Brentjens;Jean-Baptiste Latouche;Elmer Santos;Francesc Marti;Michael C Gong;Clay Lyddane;Philip D King;Steven Larson;Mark Weiss;Isabelle Rivière;Michel Sadelain - Nature medicine (2003)
  2. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. - Adele K Fielding;Susan M Richards;Rajesh Chopra;Hillard M Lazarus;Mark R Litzow;Georgina Buck;I Jill Durrant;Selina M Luger;David I Marks;Ian M Franklin;Andrew K McMillan;Martin S Tallman;Jacob M Rowe;Anthony H Goldstone; ; - Blood (2007)
  3. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. - E Tavernier;J-M Boiron;F Huguet;K Bradstock;N Vey;T Kovacsovics;A Delannoy;N Fegueux;P Fenaux;A Stamatoullas;O Tournilhac;A Buzyn;O Reman;C Charrin;C Boucheix;J Gabert;V Lhéritier;J-P Vernant;H Dombret;X Thomas; ; ; - Leukemia (2007)
  4. Outcome of adults with acute lymphocytic leukemia after second salvage therapy. - Susan O'Brien;Deborah Thomas;Farhad Ravandi;Stefan Faderl;Jorge Cortes;Gautum Borthakur;Sherry Pierce;Guillermo Garcia-Manero;Hagop M Kantarjian - Cancer (2008)
  5. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. - Daniel Hollyman;Jolanta Stefanski;Mark Przybylowski;Shirley Bartido;Oriana Borquez-Ojeda;Clare Taylor;Raymond Yeh;Vanessa Capacio;Malgorzata Olszewska;James Hosey;Michel Sadelain;Renier J Brentjens;Isabelle Rivière - Journal of immunotherapy (Hagerstown, Md. : 1997) (2009)
  6. Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. - Hagop M Kantarjian;Deborah Thomas;Farhad Ravandi;Stefan Faderl;Elias Jabbour;Guillermo Garcia-Manero;Sherry Pierce;Jianquin Shan;Jorge Cortes;Susan O'Brien - Cancer (2010)
  7. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. - Max S Topp;Peter Kufer;Nicola Gökbuget;Mariele Goebeler;Matthias Klinger;Svenja Neumann;Heinz-A Horst;Thorsten Raff;Andreas Viardot;Mathias Schmid;Matthias Stelljes;Markus Schaich;Evelyn Degenhard;Rudolf Köhne-Volland;Monika Brüggemann;Oliver Ottmann;Heike Pfeifer;Thomas Burmeister;Dirk Nagorsen;Margit Schmidt;Ralf Lutterbuese;Carsten Reinhardt;Patrick A Baeuerle;Michael Kneba;Hermann Einsele;Gert Riethmüller;Dieter Hoelzer;Gerhard Zugmaier;Ralf C Bargou - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2011)
  8. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. - Renier J Brentjens;Isabelle Rivière;Jae H Park;Marco L Davila;Xiuyan Wang;Jolanta Stefanski;Clare Taylor;Raymond Yeh;Shirley Bartido;Oriana Borquez-Ojeda;Malgorzata Olszewska;Yvette Bernal;Hollie Pegram;Mark Przybylowski;Daniel Hollyman;Yelena Usachenko;Domenick Pirraglia;James Hosey;Elmer Santos;Elizabeth Halton;Peter Maslak;David Scheinberg;Joseph Jurcic;Mark Heaney;Glenn Heller;Mark Frattini;Michel Sadelain - Blood (2011)
  9. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. - Nicola Gökbuget;Daniel Stanze;Joachim Beck;Helmut Diedrich;Heinz-August Horst;Andreas Hüttmann;Guido Kobbe;Karl-Anton Kreuzer;Lothar Leimer;Albrecht Reichle;Markus Schaich;Stefan Schwartz;Hubert Serve;Michael Starck;Matthias Stelljes;Reingard Stuhlmann;Andreas Viardot;Knut Wendelin;Mathias Freund;Dieter Hoelzer; - Blood (2012)
  10. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. - Renier J Brentjens;Marco L Davila;Isabelle Riviere;Jae Park;Xiuyan Wang;Lindsay G Cowell;Shirley Bartido;Jolanta Stefanski;Clare Taylor;Malgorzata Olszewska;Oriana Borquez-Ojeda;Jinrong Qu;Teresa Wasielewska;Qing He;Yvette Bernal;Ivelise V Rijo;Cyrus Hedvat;Rachel Kobos;Kevin Curran;Peter Steinherz;Joseph Jurcic;Todd Rosenblat;Peter Maslak;Mark Frattini;Michel Sadelain - Science translational medicine (2013)

引用本文的文献 ​

  1. Posttransplant chimeric antigen receptor therapy. - Melody Smith;Johannes Zakrzewski;Scott James;Michel Sadelain - Blood (2018)
  2. Immunotherapy: CAR T cell therapy efficacious against B-ALL across age groups. - Peter Sidaway - Nature reviews. Clinical oncology (2018)
  3. Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. - Karlo Perica;Kevin J Curran;Renier J Brentjens;Sergio A Giralt - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2018)
  4. CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing? - Brooke L Prinzing;Stephen M Gottschalk;Giedre Krenciute - Expert review of anticancer therapy (2018)
  5. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies. - Li-Na Zhang;Yongping Song;Delong Liu - Journal of hematology & oncology (2018)
  6. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. - Jordan Gauthier;Cameron J Turtle - Current research in translational medicine (2018)
  7. Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. - Eric L Smith;Mette Staehr;Reed Masakayan;Ishan J Tatake;Terence J Purdon;Xiuyan Wang;Pei Wang;Hong Liu;Yiyang Xu;Sarah C Garrett-Thomson;Steven C Almo;Isabelle Riviere;Cheng Liu;Renier J Brentjens - Molecular therapy : the journal of the American Society of Gene Therapy (2018)
  8. Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis. - Leslie S Kean - Blood (2018)
  9. Natural killer cells as a therapeutic tool for infectious diseases - current status and future perspectives. - Stanislaw Schmidt;Lars Tramsen;Bushra Rais;Evelyn Ullrich;Thomas Lehrnbecher - Oncotarget (2018)
  10. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. - Theodoros Giavridis;Sjoukje J C van der Stegen;Justin Eyquem;Mohamad Hamieh;Alessandra Piersigilli;Michel Sadelain - Nature medicine (2018)

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