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文献精选 > 高引权威"CAR-T疗法"文献

Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. ​

文献信息 ​

DOI10.1056/NEJMoa1103849
PMID21830940
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2011
被引次数1904
关键词嵌合抗原受体, 慢性淋巴细胞白血病, 自体细胞治疗, 免疫应答
文献类型Case Reports, Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码725-33
期号365(8)
作者David L Porter, Bruce L Levine, Michael Kalos, Adam Bagg, Carl H June

一句话小结 ​

本研究开发了一种针对CD19的嵌合抗原受体T细胞治疗，成功应用于一名难治性慢性淋巴细胞白血病患者，患者在低剂量细胞输注后实现了超过1000倍的细胞扩增和完全缓解，且毒性反应可控。该研究为慢性淋巴细胞白血病的免疫治疗提供了新的思路，显示了嵌合抗原受体T细胞在肿瘤治疗中的潜力。

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嵌合抗原受体 · 慢性淋巴细胞白血病 · 自体细胞治疗 · 免疫应答

摘要 ​

我们设计了一种表达针对B细胞抗原CD19特异性的嵌合抗原受体的慢病毒载体，并结合了CD137（在T细胞中的共刺激受体[4-1BB]）和CD3-zeta（T细胞抗原受体的信号转导组分）信号域。将低剂量（约1.5×10^5个细胞每千克体重）的自体嵌合抗原受体修饰的T细胞再输注给一名难治性慢性淋巴细胞白血病（CLL）患者后，其在体内扩增至超过初始植入水平的1000倍，且肿瘤溶解综合症的发展延迟，并完全缓解。除了肿瘤溶解综合症外，唯一与嵌合抗原受体T细胞相关的3/4级毒性反应是淋巴细胞减少症。经过工程改造的细胞在血液和骨髓中高水平持续存在6个月，并继续表达嵌合抗原受体。在骨髓中检测到特异性免疫反应，伴随正常B细胞和表达CD19的白血病细胞的减少。治疗后10个月，缓解仍在持续。低丙种球蛋白血症是预期的慢性毒性反应。

英文摘要 ​

We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.

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主要研究问题 ​

  1. 在慢性淋巴细胞白血病的治疗中，其他类型的靶向疗法与嵌合抗原受体T细胞疗法相比有哪些优缺点？
  2. 嵌合抗原受体T细胞在不同患者群体中的疗效和安全性是否存在显著差异？
  3. 针对CD19抗原的嵌合抗原受体T细胞疗法在治疗其他类型的血液恶性肿瘤中是否也显示出有效性？
  4. 除了肿瘤溶解综合症，嵌合抗原受体T细胞治疗可能导致的其他长期副作用有哪些？
  5. 如何优化嵌合抗原受体T细胞的设计以提高其在慢性淋巴细胞白血病患者中的治疗效果？

核心洞察 ​

研究背景和目的 ​

慢性淋巴细胞白血病（CLL）是一种常见的血液恶性肿瘤，治疗难度大，特别是对难治性病例。近年来，嵌合抗原受体（CAR）T细胞疗法在血液肿瘤的治疗中展现出良好的前景。本研究旨在评估一种新型CAR T细胞疗法的安全性和有效性，该疗法针对B细胞抗原CD19，并结合了共刺激受体CD137和信号转导成分CD3-zeta。

主要方法/材料/实验设计 ​

本研究采用了慢病毒载体构建表达针对CD19的嵌合抗原受体的T细胞。具体实验设计如下：

Mermaid diagram
  1. 慢病毒载体构建：构建表达针对CD19的CAR，并结合CD137和CD3-zeta。
  2. CAR T细胞的培养与扩增：从患者中提取T细胞，进行基因改造和扩增。
  3. 患者招募与治疗：选择难治性CLL患者进行治疗。
  4. CAR T细胞输注：以每公斤体重约1.5×10^5细胞的低剂量输注。
  5. 监测治疗反应与不良反应：定期评估患者的免疫反应和不良反应。
  6. 评估免疫反应与肿瘤负荷：检测骨髓中的免疫反应及正常B细胞和白血病细胞的变化。

关键结果和发现 ​

  • 细胞扩增：输注后的CAR T细胞在体内扩增超过1000倍。
  • 治疗反应：患者在治疗后实现完全缓解，肿瘤溶解综合征的发生延迟。
  • 不良反应：主要的不良反应为淋巴细胞减少症和预期的低丙种球蛋白血症。
  • 持久性：工程化细胞在血液和骨髓中持续存在高水平，持续时间达到6个月。
  • 免疫反应：在骨髓中检测到特异性免疫反应，伴随正常B细胞和CD19阳性白血病细胞的丧失。

主要结论/意义/创新性 ​

本研究表明，针对CD19的CAR T细胞治疗在难治性CLL患者中具有良好的安全性和有效性。治疗后患者可实现长期的完全缓解，并且工程化T细胞表现出持久的免疫活性。这一疗法为CLL的治疗提供了新的选择，显示出CAR T细胞疗法在血液恶性肿瘤中的潜力。

研究局限性和未来方向 ​

  • 局限性：样本量较小，研究时间相对较短，需在更大规模的临床试验中验证结果。
  • 未来方向：进一步探索不同剂量和治疗方案的安全性与有效性，评估长期疗效和不良反应，并研究其他靶点的CAR T细胞治疗对CLL的影响。

参考文献 ​

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引用本文的文献 ​

  1. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. - Michael Kalos;Bruce L Levine;David L Porter;Sharyn Katz;Stephan A Grupp;Adam Bagg;Carl H June - Science translational medicine (2011)
  2. Treatment of advanced leukemia in mice with mRNA engineered T cells. - David M Barrett;Yangbing Zhao;Xiaojun Liu;Shuguang Jiang;Carmine Carpenito;Michael Kalos;Richard G Carroll;Carl H June;Stephan A Grupp - Human gene therapy (2011)
  3. Biomarkers in T cell therapy clinical trials. - Michael Kalos - Journal of translational medicine (2011)
  4. Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants. - Karen M Kaluza;Jill M Thompson;Timothy J Kottke;Heather C Flynn Gilmer;Darlene L Knutson;Richard G Vile - International journal of cancer (2012)
  5. Evaluation of current cancer immunotherapy: hemato-oncology. - Christopher S Hourigan;Hyam I Levitsky - Cancer journal (Sudbury, Mass.) (2011)
  6. Gene therapies advance towards finish line. - Asher Mullard - Nature reviews. Drug discovery (2011)
  7. Engineered T-cell therapy shows efficacy in blood cancer. - Simon Frantz - Nature biotechnology (2011)
  8. Science gone translational: the OX40 agonist story. - Andrew D Weinberg;Nicholas P Morris;Magdalena Kovacsovics-Bankowski;Walter J Urba;Brendan D Curti - Immunological reviews (2011)
  9. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. - Padmanee Sharma;Klaus Wagner;Jedd D Wolchok;James P Allison - Nature reviews. Cancer (2011)
  10. Comparison of mRNA and lentiviral based transfection of natural killer cells with chimeric antigen receptors recognizing lymphoid antigens. - Laurent Boissel;Monica Betancur;Weiquan Lu;Winfried S Wels;Teresa Marino;Richard A Van Etten;Hans Klingemann - Leukemia & lymphoma (2012)

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