美国宾夕法尼亚大学Carl H. June、Edward A. Stadtmauer近日取得一项新成果。他们探究了CRISPR-编辑的T细胞在难治性癌症患者中的应用。该项研究成果在线发表在2020年2月6日的《科学》上。

研究人员报告了一项首次在人类中进行的I期临床试验，在3名难治性癌症患者中测试CRISPR-Cas9多重编辑改造T细胞的安全性和可行性。在T细胞中删除了两个用以编码内源性T细胞受体（TCR）链的基因TCRα（TRAC）和TCRβ（TRBC），以减少TCR错配并增强合成的癌症特异性TCR转基因的表达（NY-ESO- 1）。去除编码PD-1（PDCD1）的第三个基因，以提高抗肿瘤免疫力。将工程化的T细胞过继转移到患者体内以维持其持久移植，并在所有三个基因组位点进行编辑。尽管受试者体内检测到染色体易位，但其错配频率随时间降低。修饰的T细胞可持续存在长达9个月，这表明在这些条件下其免疫原性极低。该研究证明了CRISPR基因编辑技术用于癌症免疫疗法的可行性。

研究人员表示，CRISPR-Cas9基因编辑技术是增强人类T细胞抵抗癌症的能力的强大工具。

附：英文原文

Title: CRISPR-engineered T cells in patients with refractory cancer

Author: Edward A. Stadtmauer, Joseph A. Fraietta, Megan M. Davis, Adam D. Cohen, Kristy L. Weber, Eric Lancaster, Patricia A. Mangan, Irina Kulikovskaya, Minnal Gupta, Fang Chen, Lifeng Tian, Vanessa E. Gonzalez, Jun Xu, In-young Jung, J. Joseph Melenhorst, Gabriela Plesa, Joanne Shea, Tina Matlawski, Amanda Cervini, Avery L. Gaymon, Stephanie Desjardins, Anne Lamontagne, January Salas-Mckee, Andrew Fesnak, Donald L. Siegel, Bruce L. Levine, Julie K. Jadlowsky, Regina M. Young, Anne Chew, Wei-Ting Hwang, Elizabeth O. Hexner, Beatriz M. Carreno, Christopher L. Nobles, Frederic D. Bushman, Kevin R. Parker, Yanyan Qi, Ansuman T. Satpathy, Howard Y. Chang, Yangbing Zhao, Simon F. Lacey, Carl H. June

Issue&Volume: 2020/02/06

Abstract: AbstractCRISPR-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 I 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, TCRα (TRAC) and TCRβ (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 PD-1 (PDCD1), was performed to improve anti-tumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Though 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.

DOI: 10.1126/science.aba7365

Source: https://science.sciencemag.org/content/early/2020/02/05/science.aba7365