CRISPR-engineered T cells in patients with refractory cancer
CRISPR-engineered T cells in patients with refractory cancer
复制标题
DOI：
10.1126/science.aba7365
复制
发表时间：
2020-02-28
期刊：
影响因子：
56.9
通讯作者：
June, Carl H.
中科院分区：
文献类型：
--
作者：
Stadtmauer, Edward A.;Fraietta, Joseph A.;June, Carl H.
CRISPR-Cas9基因编辑提供了一个强大的工具来增强人类T细胞对抗癌症的天然能力。我们报告了一项首次人体i期临床试验，以测试多重CRISPR-Cas9编辑在三名难治性癌症患者中设计T细胞的安全性和可行性。在T细胞中删除编码内源性T细胞受体（TCR）链的两个基因，即TCR α (TRAC)和TCR β (TRBC)，以减少TCR错配，并增强合成的癌症特异性TCR转基因（NY-ESO-1）的表达。去除编码程序性细胞死亡蛋白1 （PD-1; PDCD1）的第三个基因，以提高抗肿瘤免疫。将工程T细胞过继转移到患者体内，在所有三个基因组位点上都进行了编辑，从而实现了持久的植入。虽然检测到染色体易位，但频率随着时间的推移而降低。修饰后的T细胞持续了长达9个月，这表明在这些条件下免疫原性最小，并证明了CRISPR基因编辑用于癌症免疫治疗的可行性。
CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCR alpha (TRAC) and TCR beta (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.