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T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. ​

文献信息 ​

DOI10.1016/S0140-6736(14)61403-3
PMID25319501
期刊Lancet (London, England)
发表年份2015
被引次数1622
关键词CD19嵌合抗原受体, 急性淋巴细胞白血病, 儿童与年轻成年人, 剂量递增试验, 细胞治疗
文献类型Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't
ISSN0140-6736
页码517-528
期号385(9967)
作者Daniel W Lee, James N Kochenderfer, Maryalice Stetler-Stevenson, Yongzhi K Cui, Cindy Delbrook, Steven A Feldman, Terry J Fry, Rimas Orentas, Marianna Sabatino, Nirali N Shah, Seth M Steinberg, Dave Stroncek, Nick Tschernia, Constance Yuan, Hua Zhang, Ling Zhang, Steven A Rosenberg, Alan S Wayne, Crystal L Mackall

一句话小结 ​

本研究评估了针对CD19的嵌合抗原受体（CAR）修饰的T细胞治疗难治性B细胞恶性肿瘤的可行性和安全性，结果显示该治疗在儿童和年轻成人中是可行的且具有较强的抗白血病活性，所有毒性均为可逆。研究为CD19-CAR T细胞在化疗耐药患者中的应用提供了重要证据，具有显著的临床意义。

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CD19嵌合抗原受体 · 急性淋巴细胞白血病 · 儿童与年轻成年人 · 剂量递增试验 · 细胞治疗

摘要 ​

背景 针对CD19的嵌合抗原受体（CAR）修饰的T细胞在急性和慢性淋巴细胞白血病及B细胞淋巴瘤患者的病例系列中显示出活性，但对连续入组患者的可行性、毒性和反应率，尤其是在采用一致的治疗方案并基于意向治疗原则进行评估的情况下，尚未有相关报道。我们的目标是定义对CD19-CAR T细胞治疗的难治性B细胞恶性肿瘤的儿童和年轻成人的可行性、毒性、最大耐受剂量、反应率以及反应的生物学相关性。

方法 本项I期剂量递增试验连续招募了1至30岁之间的复发或难治性急性淋巴母细胞白血病或非霍奇金淋巴瘤的儿童和年轻成人。自体T细胞通过为期11天的制造过程进行工程改造，以表达一个包含抗CD19单链可变片段、TCR zeta和CD28信号域的CD19-CAR。所有患者在接受单次CD19-CAR T细胞输注前均接受了氟达拉滨和环磷酰胺治疗。采用标准的3 + 3设计确定最大耐受剂量，患者接受的剂量为每千克体重1 × 10^6 CAR转导T细胞（剂量1）、每千克体重3 × 10^6 CAR转导T细胞（剂量2），或在未能生成足够数量的细胞以满足指定剂量时接受全部CAR T细胞产品。剂量递增阶段后，扩展队列在最大耐受剂量下接受治疗。本试验已在ClinicalTrials.gov注册，注册号为NCT01593696。

发现 在2012年7月2日至2014年6月20日期间，共有21名患者（包括8名曾接受异基因造血干细胞移植的患者）入组并接受了CD19-CAR T细胞的输注。其中19名患者接受了规定剂量的CD19-CAR T细胞，而由于两名患者无法生成指定剂量浓度的细胞（可行性为90%）。所有入组患者均接受了反应评估。最大耐受剂量被定义为每千克体重1 × 10^6 CD19-CAR T细胞。所有毒性均为完全可逆，最严重的毒性为4级细胞因子释放综合症，发生在21名患者中的3名（14%）（95% CI 3.0-36.3）。最常见的非血液学3级不良事件包括发热（21名患者中的9名[43%]）、低钾血症（21名患者中的9名[43%]）、发热伴中性粒细胞减少（21名患者中的8名[38%]）和细胞因子释放综合症（21名患者中的3名[14%]）。

解释 针对CD19的CAR T细胞治疗在化疗耐药的儿童和年轻成人急性前体淋巴母细胞白血病患者中是可行的、安全的，并能介导强效的抗白血病活性。所有毒性均为可逆，并未出现长期B细胞无增生现象。

资助 国家卫生研究院内部资金和圣巴尔德里克基金会。

英文摘要 ​

BACKGROUND Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells.

METHODS This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696.

FINDINGS Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients).

INTERPRETATION CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur.

FUNDING National Institutes of Health Intramural funds and St Baldrick's Foundation.

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主要研究问题 ​

  1. CD19-CAR T细胞治疗在儿童和年轻成人中的疗效与成人患者相比有何不同？
  2. 在CD19-CAR T细胞治疗过程中，如何评估和管理细胞因子释放综合症的风险？
  3. 该研究中采用的最大耐受剂量与其他相关研究的结果有何比较？
  4. CD19-CAR T细胞治疗后，患者的长期生存率和复发率的跟踪结果如何？
  5. 针对不同年龄段的患者，CD19-CAR T细胞的制造过程是否存在差异？

核心洞察 ​

研究背景和目的 ​

CD19嵌合抗原受体（CAR）T细胞治疗已在急性淋巴细胞白血病（ALL）及B细胞淋巴瘤患者中显示出活性，但缺乏在连续招募患者中采用一致方案的可行性、毒性和反应率的系统评估。本研究旨在定义CD19-CAR T细胞在治疗难治性B细胞恶性肿瘤的可行性、毒性、最大耐受剂量、反应率及生物学相关性。

主要方法/材料/实验设计 ​

本研究为开放标签的1期剂量递增试验，招募1至30岁间的儿童和年轻成年人，诊断为复发或难治性急性淋巴细胞白血病或非霍奇金淋巴瘤。自体T细胞通过11天的制造过程被改造为表达CD19-CAR。所有患者在接受CD19-CAR T细胞单次输注前，均接受氟达拉滨和环磷酰胺的预处理。使用3+3设计确定最大耐受剂量。患者被分为不同剂量组（1×10⁶或3×10⁶ CAR转导T细胞/kg），并在剂量递增阶段后，对最大耐受剂量进行扩展队列治疗。

Mermaid diagram

关键结果和发现 ​

  • 研究共招募21名患者，19名患者接受了规定剂量的CD19-CAR T细胞输注，90%的可行性。
  • 最大耐受剂量为1×10⁶ CAR T细胞/kg。
  • 66.7%的患者（14/21）达到了完全反应，20名ALL患者中60%（12/20）达到了最小残留病（MRD）阴性完全反应。
  • 主要毒性为可逆的细胞因子释放综合症（CRS），发生率为14%（3/21），大多数不良事件为3级（如发热、低钾血症等）。

主要结论/意义/创新性 ​

CD19-CAR T细胞治疗在儿童和年轻成年人难治性B-ALL患者中是可行的，且具有良好的抗白血病活性。所有毒性均为可逆，且没有发生长期的B细胞再生障碍。该研究首次展示了CD19-CAR T细胞能够清除中枢神经系统的白血病，表明其在难治性疾病治疗中的潜力。

研究局限性和未来方向 ​

  • 本研究的样本量较小，未来需要更大规模的临床试验来验证结果。
  • 由于大多数患者进入缓解后接受了造血干细胞移植（HSCT），因此未能评估CD19-CAR T细胞治疗的长期疗效。
  • 研究表明CD19抗原的丢失可能是CD19-CAR治疗失败的原因之一，未来可以探索双价CAR策略以解决抗原逃逸问题。

参考文献 ​

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引用本文的文献 ​

  1. Immune-based therapies for childhood cancer. - Crystal L Mackall;Melinda S Merchant;Terry J Fry - Nature reviews. Clinical oncology (2014)
  2. T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. - Cor H J Lamers;Sabine van Steenbergen-Langeveld;Mandy van Brakel;Corrien M Groot-van Ruijven;Pascal M M L van Elzakker;Brigitte van Krimpen;Stefan Sleijfer;Reno Debets - Human gene therapy methods (2014)
  3. Challenges to chimeric antigen receptor (CAR)-T cell therapy for cancer. - Michael S Magee;Adam E Snook - Discovery medicine.. (2014)
  4. Advances in T-cell therapy for ALL. - Stephan A Grupp - Best practice & research. Clinical haematology (2014)
  5. Modern immunotherapy of adult B-lineage acute lymphoblastic leukemia with monoclonal antibodies and chimeric antigen receptor modified T cells. - Elena Maino;Anna Maria Scattolin;Piera Viero;Rosaria Sancetta;Anna Pascarella;Michele Vespignani;Renato Bassan - Mediterranean journal of hematology and infectious diseases (2015)
  6. Designing chimeric antigen receptors to effectively and safely target tumors. - Michael C Jensen;Stanley R Riddell - Current opinion in immunology (2015)
  7. Using gene therapy to manipulate the immune system in the fight against B-cell leukemias. - Diana C G Bouhassira;Joshua J Thompson;Marco L Davila - Expert opinion on biological therapy (2015)
  8. Improving access to novel agents for childhood leukemia. - Weili Sun;Paul S Gaynon;Richard Sposto;Alan S Wayne - Cancer (2015)
  9. Thymic expression of a T-cell receptor targeting a tumor-associated antigen coexpressed in the thymus induces T-ALL. - Yongzhi Cui;Masahiro Onozawa;Haven R Garber;Leigh Samsel;Ziyao Wang;J Philip McCoy;Sandra Burkett;Xiaolin Wu;Peter D Aplan;Crystal L Mackall - Blood (2015)
  10. Chimeric antigen receptors and bispecific antibodies to retarget T cells in pediatric oncology. - Maya Suzuki;Kevin J Curran;Nai-Kong V Cheung - Pediatric blood & cancer (2015)

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