中國科學家完成基因編輯T細胞的I期臨床安全性試驗
作者：
小柯機器人發布時間：2020/4/29 10:25:07
四川大學You Lu等研究人員報導了CRISPR編輯的T細胞在難治性非小細胞肺癌患者中的安全性和可行性。2020年4月27日，《自然—醫學》在線發表了這一成果。
研究人員報導了由CRISPR–Cas9編輯PD-1後的T細胞在晚期非小細胞肺癌患者中進行的首次人類I期臨床試驗結果（ClinicalTrials.gov NCT02793856）。主要終點是安全性和可行性，次要終點是功效。探索性目標包括跟蹤編輯的T細胞。所有預定的終點均符合。研究人員使用電轉Cas9和單向導RNA質粒來離體生產了PD-1編輯的T細胞。
共有22例患者入選； 17人有足夠的編輯T細胞用來回輸，而12人能夠接受治療。所有與治療相關的不良事件均為1/2級。輸注後在外周血中可檢測到編輯過的T細胞。中位無進展生存期為7.7周（95％置信區間為6.9至8.5周），中位總生存期為42.6周（95％置信區間為10.3至74.9周）。通過下一代測序，在18個候選位點，脫靶事件的中位突變頻率為0.05％（範圍為0-0.25％）。
研究人員認為，CRISPR-Cas9基因編輯的T細胞的臨床應用基本上是安全可行的。未來的試驗應使用更好的基因編輯方法來提高治療效果。
據介紹，CRISPR-Cas9編輯免疫檢查點基因可以提高T細胞療法的療效，但是首要的任務是了解其安全性和可行性。
附：英文原文
Title: Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer
Author: You Lu, Jianxin Xue, Tao Deng, Xiaojuan Zhou, Kun Yu, Lei Deng, Meijuan Huang, Xin Yi, Maozhi Liang, Yu Wang, Haige Shen, Ruizhan Tong, Wenbo Wang, Li Li, Jin Song, Jing Li, Xiaoxing Su, Zhenyu Ding, Youling Gong, Jiang Zhu, Yongsheng Wang, Bingwen Zou, Yan Zhang, Yanying Li, Lin Zhou, Yongmei Liu, Min Yu, Yuqi Wang, Xuanwei Zhang, Limei Yin, Xuefeng Xia, Yong Zeng, Qiao Zhou, Binwu Ying, Chong Chen, Yuquan Wei, Weimin Li, Tony Mok
Issue&Volume: 2020-04-27
Abstract: Clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR–Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7weeks (95% confidence interval, 6.9 to 8.5weeks) and median overall survival was 42.6weeks (95% confidence interval, 10.3–74.9weeks). The median mutation frequency of off-target events was 0.05% (range, 0–0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR–Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.
DOI: 10.1038/s41591-020-0840-5
Source: https://www.nature.com/articles/s41591-020-0840-5