학술논문
Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer
Document Type
Article
Author
Lu, You; Xue, Jianxin; Deng, Tao; Zhou, Xiaojuan; Yu, Kun; Deng, Lei; Huang, Meijuan; Yi, Xin; Liang, Maozhi; Wang, Yu; Shen, Haige; Tong, Ruizhan; Wang, Wenbo; Li, Li; Song, Jin; Li, Jing; Su, Xiaoxing; Ding, Zhenyu; Gong, Youling; Zhu, Jiang; Wang, Yongsheng; Zou, Bingwen; Zhang, Yan; Li, Yanying; Zhou, Lin; Liu, Yongmei; Yu, Min; Wang, Yuqi; Zhang, Xuanwei; Yin, Limei; Xia, Xuefeng; Zeng, Yong; Zhou, Qiao; Ying, Binwu; Chen, Chong; Wei, Yuquan; Li, Weimin; Mok, Tony
Source
Nature Medicine; May 2020, Vol. 26 Issue: 5 p732-740, 9p
Subject
Language
ISSN
10788956; 1546170X
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 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3–74.9 weeks). 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.