小柯机器人

四川大学You Lu等研究人员报道了CRISPR编辑的T细胞在难治性非小细胞肺癌患者中的安全性和可行性。2020年4月27日，《自然—医学》在线发表了这一成果。

研究人员报道了由CRISPR–Cas9编辑PD-1后的T细胞在晚期非小细胞肺癌患者中进行的首次人类I期临床试验结果（ClinicalTrials.gov NCT02793856）。主要终点是安全性和可行性，次要终点是功效。探索性目标包括跟踪编辑的T细胞。所有预定的终点均符合。研究人员使用电转Cas9和单向导RNA质粒来离体生产了PD-1编辑的T细胞。

共有22例患者入选； 17人有足够的编辑T细胞用来回输，而12人能够接受治疗。所有与治疗相关的不良事件均为1/2级。输注后在外周血中可检测到编辑过的T细胞。中位无进展生存期为7.7周（95％置信区间为6.9至8.5周），中位总生存期为42.6周（95％置信区间为10.3至74.9周）。通过下一代测序，在18个候选位点，脱靶事件的中位突变频率为0.05％（范围为0-0.25％）。

研究人员认为，CRISPR-Cas9基因编辑的T细胞的临床应用基本上是安全可行的。未来的试验应使用更好的基因编辑方法来提高治疗效果。

据介绍，CRISPR-Cas9编辑免疫检查点基因可以提高T细胞疗法的疗效，但是首要的任务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

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex