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当前位置: Science » 免疫 » Sci Transl Med:美学者发表CAR-T细胞疗法在临床研究研究进展

Sci Transl Med:美学者发表CAR-T细胞疗法在临床研究研究进展

摘要 : 2016年9月7日,国际顶尖学术期刊《Science》旗下《 Science Translational Medicine》杂志上在线发表了美国西雅图弗雷德哈钦森癌症研究中心Cameron J. Turtle研究员的一篇研究论文,研究对由32位B细胞型非何杰金氏淋巴瘤晚期患者参加的I期临床研究中,用限定的T细胞亚群而非整个T细胞群进行免疫治疗显示出了强力的抗肿瘤活性。

 2016年9月7日,国际顶尖学术期刊《Science》旗下《 Science Translational Medicine》杂志上在线发表了美国西雅图弗雷德哈钦森癌症研究中心Cameron J. Turtle研究员的一篇研究论文,研究对由32位B细胞型非何杰金氏淋巴瘤晚期患者参加的I期临床研究中,用限定的T细胞亚群而非整个T细胞群进行免疫治疗显示出了强力的抗肿瘤活性。

研究结果表明:确定若干关键性变量(如最佳T细胞组合、剂量、治疗前化疗方案)对于嵌合抗原受体(CAR)修饰的T细胞疗法展现其全部潜力至关重要,这种治疗方法对T细胞进行了重新编程,因而具有人工设计的、以肿瘤细胞为标靶的受体。尽管这种治疗正快速地向临床应用方向发展,但CAR-T细胞组成的不一致性成为了重大的障碍。为了精简CAR-T细胞疗法以改善患者的转归,Cameron Turtle和同事用CD4 和 CD8 CAR-T细胞的特定比例加上,或未加固定浓度的氟达拉滨来治疗受试者,这类化疗常常在CAR-T疗法前进行,旨在增进其功效。氟达拉滨组的患者显示出,除了反应率更高外,其CAR-T细胞有了更大的扩展,抗肿瘤时间也更为持久,他们中有50%达到了完全的缓解,而那些没有接受氟达拉滨的患者,其完全缓解率只有8%。尽管氟达拉滨治疗一般与更大的毒性相关,但研究人员能成功地检测血液中的生物标记,后者能指示CAR-T细胞输注后的毒性,从而提供了一种潜在的识别高风险患者的策略,令这些患者得益于早期的干预治疗。所有这些结果为提高CAR-T细胞疗法的整体功效和安全性策略提供了新的线索。

原文链接:

Immunotherapy of non-Hodgkin lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells

原文摘要:

CD19-specific chimeric antigen receptor (CAR)–modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4+/CD8+ ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin’s lymphoma after cyclophosphamide (Cy)–based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had increased CAR-T cell expansion and persistence, and higher response rates [50% complete remission (CR), 72% overall response rate (ORR)] than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR). The CR rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR; n = 11). Cy/Flu minimized the effects of an immune response to the murine single-chain variable fragment component of the CAR, which limited CAR-T cell expansion and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥3 neurotoxicity were observed in 13 and 28% of all patients, respectively. Serum biomarkers, one day after CAR-T cell infusion, correlated with subsequent sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4+/CD8+ ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.

来源: Science Translational Medicine 浏览次数:0

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