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Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. ​

文献信息 ​

DOI10.1056/NEJMoa1707447
PMID29226797
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2017
被引次数2838
关键词轴突细胞疗法, 大B细胞淋巴瘤, 细胞因子释放综合症
文献类型Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码2531-2544
期号377(26)
作者Sattva S Neelapu, Frederick L Locke, Nancy L Bartlett, Lazaros J Lekakis, David B Miklos, Caron A Jacobson, Ira Braunschweig, Olalekan O Oluwole, Tanya Siddiqi, Yi Lin, John M Timmerman, Patrick J Stiff, Jonathan W Friedberg, Ian W Flinn, Andre Goy, Brian T Hill, Mitchell R Smith, Abhinav Deol, Umar Farooq, Peter McSweeney, Javier Munoz, Irit Avivi, Januario E Castro, Jason R Westin, Julio C Chavez, Armin Ghobadi, Krishna V Komanduri, Ronald Levy, Eric D Jacobsen, Thomas E Witzig, Patrick Reagan, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, David Chang, Jeff Wiezorek, William Y Go

一句话小结 ​

在一项多中心II期试验中，轴克巴替尼（axi-cel）作为自体抗CD19 CAR T细胞疗法对难治性大B细胞淋巴瘤患者显示出82%的客观反应率和54%的完全反应率，且在中位随访15.4个月时，42%的患者仍保持反应。该研究强调了axi-cel在治疗难治性淋巴瘤中的潜在有效性及其安全性特征，对未来相关治疗策略具有重要意义。

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轴突细胞疗法 · 大B细胞淋巴瘤 · 细胞因子释放综合症

摘要 ​

背景
在一项I期试验中，轴克巴替尼（axi-cel），一种自体抗CD19嵌合抗原受体（CAR）T细胞疗法，在常规治疗失败后的难治性大B细胞淋巴瘤患者中显示出有效性。

方法
在这项多中心II期试验中，我们招募了111名患有弥漫性大B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤或转化性滤泡性淋巴瘤的患者，这些患者在接受推荐的先前治疗后仍然存在难治性疾病。患者在接受低剂量环磷酰胺和氟达拉滨的预处理方案后，接受每公斤体重2×10^6个抗CD19 CAR T细胞的目标剂量。主要终点是客观反应率（计算为完全反应和部分反应的合并率）。次要终点包括整体生存率、安全性和生物标志物评估。

结果
在招募的111名患者中，110名（99%）成功制造了axi-cel，并向101名（91%）患者施用。客观反应率为82%，完全反应率为54%。在中位随访15.4个月时，42%的患者仍然保持反应，其中40%的患者继续保持完全反应。18个月的总生存率为52%。治疗过程中，发生的3级或更高级别的不良事件中，最常见的是中性粒细胞减少症（在78%的患者中）、贫血（在43%）和血小板减少症（在38%）。3级或更高级别的细胞因子释放综合症和神经系统事件分别发生在13%和28%的患者中。在治疗期间，有3名患者死亡。血液中较高的CAR T细胞水平与反应相关。

结论
在这项多中心研究中，接受axi-cel CAR T细胞疗法的难治性大B细胞淋巴瘤患者表现出高水平的持久反应，其安全性特征包括骨髓抑制、细胞因子释放综合症和神经系统事件。（由Kite Pharma和白血病与淋巴瘤学会治疗加速计划资助；ZUMA-1临床试验注册号，NCT02348216。）

英文摘要 ​

BACKGROUND In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.

METHODS In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.

RESULTS Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.

CONCLUSIONS In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).

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主要研究问题 ​

  1. 除了CD19，是否有其他靶点的CAR T细胞疗法正在研究中，特别是针对大B细胞淋巴瘤？
  2. 在接受axi-cel治疗的患者中，哪些生物标志物被发现与治疗反应相关？
  3. 对于那些在axi-cel治疗后未能获得完全缓解的患者，后续的治疗选择有哪些？
  4. 有哪些因素可能影响CAR T细胞疗法的安全性，特别是对于老年患者或合并症患者？
  5. 在其他类型的淋巴瘤中，axi-cel的疗效与安全性是否表现出类似的趋势？

核心洞察 ​

研究背景和目的 ​

本研究旨在评估轴克塔基因西罗细胞（axicabtagene ciloleucel，axi-cel）作为一种自体抗CD19嵌合抗原受体（CAR）T细胞疗法在难治性大B细胞淋巴瘤患者中的疗效和安全性。大B细胞淋巴瘤是治疗难度较大的恶性肿瘤，传统治疗方法的效果有限，因此需要探索新的治疗方案。

主要方法/材料/实验设计 ​

本研究为一项多中心、二期临床试验，共纳入111名患者。患者均为经推荐治疗后仍然难治的弥漫性大B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤或转化性滤泡淋巴瘤患者。所有患者接受了低剂量环磷酰胺和氟达拉滨的预处理方案，随后接受了每千克体重2×10^6个抗CD19 CAR T细胞的静脉输注。主要终点为客观反应率（ORR），包括完全反应和部分反应的合并率；次要终点包括总生存率、安全性及生物标志物评估。

Mermaid diagram

关键结果和发现 ​

  • 111名患者中，110名成功制造了axi-cel，101名接受了治疗。
  • 客观反应率为82%，其中完全反应率为54%。
  • 中位随访时间为15.4个月，42%的患者持续有反应，40%为完全反应。
  • 18个月的总生存率为52%。
  • 常见的3级及以上不良事件包括中性粒细胞减少（78%）、贫血（43%）和血小板减少（38%）。13%和28%的患者出现了3级及以上的细胞因子释放综合征和神经系统事件。
  • 较高的CAR T细胞水平与治疗反应相关。

主要结论/意义/创新性 ​

本研究表明，axi-cel在难治性大B细胞淋巴瘤患者中具有高效且持久的反应，且安全性良好。相较于传统疗法的26%客观反应率，axi-cel显示出显著的临床优势。这为难治性大B细胞淋巴瘤患者提供了一种新的治疗选择，并可能改变该疾病的治疗策略。

研究局限性和未来方向 ​

研究的局限性包括缺乏对分子和细胞遗传特征的详细分析，未来需进一步探索不同生物学特征对CAR T细胞疗法结果的影响。此外，虽然目前结果显示良好，但仍需长期随访以确认疗效的持久性和安全性。未来的研究可以集中在优化CAR构建、制造流程及联合免疫调节剂的策略上，以提高疗效并降低不良反应的发生率。

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引用本文的文献 ​

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  4. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. - Sattva S Neelapu;Sudhakar Tummala;Partow Kebriaei;William Wierda;Frederick L Locke;Yi Lin;Nitin Jain;Naval Daver;Alison M Gulbis;Sherry Adkins;Katayoun Rezvani;Patrick Hwu;Elizabeth J Shpall - Nature reviews. Clinical oncology (2018)
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