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Chimeric antigen receptor T cells for sustained remissions in leukemia. ​

文献信息 ​

DOI10.1056/NEJMoa1407222
PMID25317870
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2014
被引次数2888
关键词嵌合抗原受体T细胞, 急性淋巴细胞白血病, 持久缓解
文献类型Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码1507-17
期号371(16)
作者Shannon L Maude, Noelle Frey, Pamela A Shaw, Richard Aplenc, David M Barrett, Nancy J Bunin, Anne Chew, Vanessa E Gonzalez, Zhaohui Zheng, Simon F Lacey, Yolanda D Mahnke, Jan J Melenhorst, Susan R Rheingold, Angela Shen, David T Teachey, Bruce L Levine, Carl H June, David L Porter, Stephan A Grupp

一句话小结 ​

本研究评估了针对CD19的嵌合抗原受体改造T细胞（CTL019）在复发或难治性急性淋巴细胞白血病患者中的疗效，结果显示90%的患者达到了完全缓解，且在干细胞移植失败的患者中也表现出显著的缓解率和持续性，表明该疗法有望改善难治性ALL的治疗效果。该研究为复发性ALL的治疗提供了新的靶向免疫治疗选择，具有重要的临床意义。

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嵌合抗原受体T细胞 · 急性淋巴细胞白血病 · 持久缓解

摘要 ​

背景
复发性急性淋巴细胞白血病（ALL）尽管有强效治疗方案，但仍然难以治愈。靶向CD19的嵌合抗原受体改造T细胞可能克服传统疗法的诸多局限，并在难治性疾病患者中诱导缓解。

方法
我们在复发或难治性ALL患者中，输注了转导有CD19靶向嵌合抗原受体（CTL019）慢病毒载体的自体T细胞，剂量为每千克体重0.76×10^6到20.6×10^6个CTL019细胞。我们监测患者的反应、毒副作用，以及循环CTL019 T细胞的扩增和持久性。

结果
共有30名儿童和成人接受了CTL019治疗。27名患者（90%）达到了完全缓解，包括2名对blinatumomab耐药的患者和15名曾接受过干细胞移植的患者。CTL019细胞在体内增殖，并在有反应的患者的血液、骨髓和脑脊液中可被检测到。持续缓解的6个月事件无生存率为67%（95%置信区间[CI]，51到88），总体生存率为78%（95% CI，65到95）。在6个月时，患者维持CTL019的概率为68%（95% CI，50到92），而患者无复发B细胞无增生的概率为73%（95% CI，57到94）。所有患者均出现了细胞因子释放综合征。27%的患者发展为严重的细胞因子释放综合征，这与输注前的疾病负担较高有关，并且通过抗白介素-6受体抗体托珠单抗得到了有效治疗。

结论
针对CD19的嵌合抗原受体改造T细胞治疗在复发和难治性ALL的治疗中是有效的。即使在干细胞移植失败的患者中，CTL019也与高缓解率相关，并观察到了持续缓解，最长可达24个月。（本研究由诺华及其他机构资助；CART19临床试验注册号，NCT01626495和NCT01029366）。

英文摘要 ​

BACKGROUND Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.

METHODS We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells.

RESULTS A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab.

CONCLUSIONS Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

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主要研究问题 ​

  1. CD19靶向的嵌合抗原受体T细胞疗法在其他类型的白血病中的效果如何？
  2. 在不同年龄段的患者中，CTL019的疗效和安全性是否存在差异？
  3. 目前有哪些策略可以进一步提高CTL019的持久性和疗效？
  4. 对于经历了严重细胞因子释放综合症的患者，有哪些后续管理和监测建议？
  5. CTL019疗法的经济性和成本效益分析在临床实践中是怎样的？

核心洞察 ​

研究背景和目的 ​

急性淋巴细胞白血病（ALL）复发后治疗困难，尽管已有多种激进治疗方法。改造的嵌合抗原受体（CAR）T细胞靶向CD19可能克服传统疗法的局限性，并诱导难治性疾病患者的缓解。

主要方法/材料/实验设计 ​

本研究为一项临床试验，涉及30名复发或难治性ALL患者，采用自体T细胞转导CD19靶向的CAR（CTL019）进行治疗。具体步骤如下：

Mermaid diagram
  • 患者筛选：招募年龄在5至60岁之间的复发或难治性ALL患者。
  • 白细胞分离：通过单采术获得患者的T细胞。
  • T细胞激活与转导：使用带有CD3和CD28抗体的磁珠刺激T细胞，并转导CD19-BB-zeta转基因。
  • 细胞扩增：在体外扩增转导的T细胞。
  • CTL019细胞输注：根据患者体重，输注CTL019细胞。
  • 疗效与毒性监测：监测患者的临床反应和副作用。
  • 随访评估：定期评估疗效、细胞持久性和生存率。

关键结果和发现 ​

  • 30名患者中，有27名（90%）在输注后1个月内达到完全缓解，其中包括对blinatumomab耐药的患者。
  • CTL019细胞在患者体内增殖，且在血液、骨髓和脑脊液中可检测到。
  • 6个月无事件生存率为67%（95%置信区间[CI]，51至88），总体生存率为78%（95% CI，65至95）。
  • 所有患者均出现细胞因子释放综合征，27%的患者出现严重反应，与输注前的疾病负担相关。

主要结论/意义/创新性 ​

CD19靶向的CAR T细胞疗法在治疗复发和难治性ALL中表现出显著的疗效，具有高缓解率和持久缓解的潜力，尤其是对于先前经历过干细胞移植失败的患者。研究结果为未来的治疗策略提供了重要依据。

研究局限性和未来方向 ​

  • 本研究的样本量较小，长期效果和副作用需要在更大规模的试验中验证。
  • 对于细胞因子释放综合征的管理仍需进一步研究，以优化疗法的安全性。
  • 未来研究应关注对CD19阴性克隆的监测，以降低复发风险，并探索其他靶向治疗的潜力。

参考文献 ​

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引用本文的文献 ​

  1. Toward synthetic biology with engineered T cells: a long journey just begun. - Carl H June - Human gene therapy (2014)
  2. Immunotherapy: CAR-modified T cells targeting CD19-curing the incurable. - Lisa Hutchinson - Nature reviews. Clinical oncology (2014)
  3. Immune-based therapies for childhood cancer. - Crystal L Mackall;Melinda S Merchant;Terry J Fry - Nature reviews. Clinical oncology (2014)
  4. Central nervous system involvement in adult acute lymphoblastic leukemia: diagnostic tools, prophylaxis, and therapy. - Maria Ilaria Del Principe;Luca Maurillo;Francesco Buccisano;Giuseppe Sconocchia;Mariagiovanna Cefalo;Giovanna De Santis;Ambra Di Veroli;Concetta Ditto;Daniela Nasso;Massimiliano Postorino;Marco Refrigeri;Cristina Attrotto;Giovanni Del Poeta;Francesco Lo-Coco;Sergio Amadori;Adriano Venditti - Mediterranean journal of hematology and infectious diseases (2014)
  5. 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)
  6. Advances in T-cell therapy for ALL. - Stephan A Grupp - Best practice & research. Clinical haematology (2014)
  7. Developers seek to finetune toxicity of T-cell therapies. - Chris Morrison - Nature biotechnology (2014)
  8. When cancer and immunology meet. - Martin Carroll - Immunological reviews (2015)
  9. 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)
  10. Treatment strategies in patients with AML or high-risk myelodysplastic syndrome relapsed after Allo-SCT. - T Sauer;G Silling;C Groth;F Rosenow;U Krug;D Görlich;G Evers;J Albring;R Besoke;R M Mesters;C Müller-Tidow;T Kessler;T Büchner;W E Berdel;M Stelljes - Bone marrow transplantation (2015)

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