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Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. ​

文献信息 ​

DOI10.1126/scitranslmed.3008226
PMID24553386
期刊Science translational medicine
影响因子14.6
JCR 分区Q1
发表年份2014
被引次数1351
关键词CAR T细胞疗法, B细胞急性淋巴细胞白血病, 细胞因子释放综合症
文献类型Journal Article, Research Support, Non-U.S. Gov't
ISSN1946-6234
页码224ra25
期号6(224)
作者Marco L Davila, Isabelle Riviere, Xiuyan Wang, Shirley Bartido, Jae Park, Kevin Curran, Stephen S Chung, Jolanta Stefanski, Oriana Borquez-Ojeda, Malgorzata Olszewska, Jinrong Qu, Teresa Wasielewska, Qing He, Mitsu Fink, Himaly Shinglot, Maher Youssif, Mark Satter, Yongzeng Wang, James Hosey, Hilda Quintanilla, Elizabeth Halton, Yvette Bernal, Diana C G Bouhassira, Maria E Arcila, Mithat Gonen, Gail J Roboz, Peter Maslak, Dan Douer, Mark G Frattini, Sergio Giralt, Michel Sadelain, Renier Brentjens

一句话小结 ​

本研究报告了16例复发或难治性B细胞急性淋巴细胞白血病患者接受19-28z CAR T细胞治疗的结果，发现88%的患者达到了完全缓解，并且该疗法在高危的费城染色体阳性患者中同样有效。此外，研究还定义了严重细胞因子释放综合征的诊断标准，并指出血清C反应蛋白可作为CRS严重程度的可靠指标，为进一步多中心研究和患者管理提供了重要依据。

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CAR T细胞疗法 · B细胞急性淋巴细胞白血病 · 细胞因子释放综合症

摘要 ​

我们报告了16例复发或难治性B细胞急性淋巴细胞白血病（B-ALL）患者，这些患者接受了表达针对CD19抗原的19-28z嵌合抗原受体（CAR）的自体T细胞治疗。总体完全缓解率为88%，这使我们能够将大多数患者转至标准的异基因造血干细胞移植（allo-SCT）治疗。这种疗法在费城染色体阳性（Ph(+)）疾病的高危患者中与在先前接受allo-SCT后复发的患者中同样有效。通过对T细胞输注后前21天的临床数据和血清细胞因子水平进行系统分析，我们定义了严重细胞因子释放综合征（sCRS）的诊断标准，旨在更好地识别需要使用皮质类固醇或白细胞介素-6受体阻断剂进行治疗干预的患者亚组。此外，我们发现血清C反应蛋白作为一种容易获取的实验室检测，可以作为CRS严重程度的可靠指示指标。综上所述，我们的数据为开展多中心二期研究以进一步评估19-28z CAR T细胞在B-ALL中的疗效提供了有力支持，并为目前考虑使用CAR T细胞治疗的中心提供了患者管理的路线图。

英文摘要 ​

We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome-positive (Ph(+)) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.

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主要研究问题 ​

  1. 19-28z CAR T细胞疗法在不同年龄段的B细胞急性淋巴细胞白血病患者中的疗效是否存在差异？
  2. 在使用19-28z CAR T细胞疗法后，患者的长期生存率与短期生存率的比较结果如何？
  3. 针对19-28z CAR T细胞治疗引起的严重细胞因子释放综合征，是否有新的管理策略或药物正在开发中？
  4. 目前在19-28z CAR T细胞疗法的临床试验中，是否有观察到其他潜在的毒性反应？
  5. 在B细胞急性淋巴细胞白血病的治疗中，如何优化19-28z CAR T细胞疗法与其他疗法的联合使用以提高疗效？

核心洞察 ​

研究背景和目的 ​

本研究旨在评估19-28z CAR T细胞治疗在复发或难治性B细胞急性淋巴细胞白血病（B-ALL）患者中的疗效及毒性管理。CAR T细胞疗法是一种新兴的肿瘤免疫治疗方法，已显示出在多种血液肿瘤中的潜力，但相关的细胞因子释放综合征（CRS）和其他毒性反应仍需进一步研究。

主要方法/材料/实验设计 ​

本研究为一项单中心的1期临床试验，涉及16名复发或难治性B-ALL患者。所有患者接受了自体T细胞的采集和19-28z CAR T细胞的转导，随后进行条件性化疗，最后进行CAR T细胞的输注。研究采用以下流程设计：

Mermaid diagram

关键结果和发现 ​

  • 疗效：在16名患者中，总体完全反应率为88%。大多数患者在CAR T细胞输注后成功过渡到标准的异基因造血干细胞移植（allo-SCT）。
  • CRS管理：通过对临床数据和血清细胞因子水平的系统分析，定义了重度CRS（sCRS）的诊断标准，并发现C反应蛋白（CRP）可以作为sCRS严重程度的可靠指标。
  • 细胞持久性：大多数患者在输注后1至2周内观察到CAR T细胞的高峰，但在2至3个月后数量显著下降。

主要结论/意义/创新性 ​

本研究表明19-28z CAR T细胞在复发或难治性B-ALL患者中具有显著的疗效，并提供了一套系统的毒性管理方案，特别是对CRS的早期识别和干预。这为多中心的2期临床试验奠定了基础，进一步验证CAR T细胞治疗的安全性和有效性。

研究局限性和未来方向 ​

  • 局限性：本研究为单中心试验，样本量较小，结果的普遍适用性需要在更大规模的多中心试验中验证。
  • 未来方向：未来研究将集中在进一步优化CRS的管理策略，评估不同毒性管理方法的效果，并探索19-28z CAR T细胞的长期疗效及其在其他类型血液肿瘤中的应用潜力。
研究要点具体内容
研究设计单中心1期临床试验
参与患者数量16名复发或难治性B-ALL患者
完全反应率88%
CRS管理策略定义sCRS标准，CRP作为指标
未来研究方向多中心2期试验，优化CRS管理策略

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  2. How do we prepare ourselves for a new paradigm of medicine to advance the treatment of pediatric acute lymphoblastic leukemia? - Kyung Duk Park - Blood research (2014)
  3. Nature Biotechnology's academic spinouts of 2013. - Aaron Bouchie;Malorye Allison;Sarah Webb;Laura DeFrancesco - Nature biotechnology (2014)
  4. Gene therapy: charting a future course--summary of a National Institutes of Health Workshop, April 12, 2013. - Marina O'Reilly;Howard J Federoff;Yuman Fong;Donald B Kohn;Amy P Patterson;Nabil Ahmed;Aravind Asokan;Shannon E Boye;Ronald G Crystal;Satiro De Oliveira;Linda Gargiulo;Scott Q Harper;Yasuhiro Ikeda;Robert Jambou;Maureen Montgomery;Lawrence Prograis;Eugene Rosenthal;Daniel H Sterman;Luk H Vandenberghe;Laurie Zoloth;Mehrdad Abedi;Jennifer Adair;Prasad S Adusumilli;William F Goins;Jhanelle Gray;Paul Monahan;Leslie Popplewell;Miguel Sena-Esteves;Bakhos Tannous;Thomas Weber;William Wierda;Rashmi Gopal-Srivastava;Cheryl L McDonald;Daniel Rosenblum;Jacqueline Corrigan-Curay - Human gene therapy (2014)
  5. Antibody therapy for pediatric leukemia. - Aditi Vedi;David S Ziegler - Frontiers in oncology (2014)
  6. Current concepts in the diagnosis and management of cytokine release syndrome. - Daniel W Lee;Rebecca Gardner;David L Porter;Chrystal U Louis;Nabil Ahmed;Michael Jensen;Stephan A Grupp;Crystal L Mackall - Blood (2014)
  7. Progress and prospects for engineered T cell therapies. - Waseem Qasim;Adrian J Thrasher - British journal of haematology (2014)
  8. Engineered T cells for cancer therapy. - Carl H June;Marcela V Maus;Gabriela Plesa;Laura A Johnson;Yangbing Zhao;Bruce L Levine;Stephan A Grupp;David L Porter - Cancer immunology, immunotherapy : CII (2014)
  9. CAR-T cell therapy seeks strategies to harness cytokine storm. - Laura DeFrancesco - Nature biotechnology (2014)
  10. Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. - Lehn K Weaver;Edward M Behrens - Current opinion in rheumatology (2014)

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