Simultaneous editing of TCR, HLA-I/II and HLA-E resulted in enhanced universal CAR-T resistance to allo-rejection

作者：Wuling Li, Xiuxiu Zhu, Yanmin Xu, Jun Chen, Hongtao Zhang, Zhi Yang, Yanan Qi, Juan Hong, Yunyan Li, Guixue Wang, Junjie Shen, Cheng Qian · 发表于：Frontiers in Immunology · 年份：2022 · DOI：10.3389/fimmu.2022.1052717 · 被引用次数：43 · 研究领域：CAR-T cell therapy research、Virus-based gene therapy research、Immune Cell Function and Interaction

Introduction The major challenge for universal chimeric antigen receptor T cell (UCAR-T) therapy is the inability to persist for a long time in patients leading to inferior efficacy clinically. The objective of this study was to design a novel UCAR-T cell that could avoid the occurrence of allo-rejection and provide effective resistance to allogeneic Natural Killer (NK) cell rejection, together with the validation of its safety and efficacy ex vivo and in vivo . Methods We prepared T-cell receptor (TCR), Human leukocyte antigen (HLA)-I/II triple-edited (TUCAR-T) cells and evaluated the anti-tumor efficacy ex vivo and in vivo. We measured the resistance of exogenous HLA-E expressing TUCAR-T (ETUCAR-T) to NK rejection by using an enhanced NK. Furthermore, we established the safety and efficacy of this regimen by treating Nalm6 tumor-bearing mice with a repeated high-dose infusion of ETUCAR-T. Moreover, we analyzed the effects of individual gene deficiency CAR-T on treated mice and the changes in the transcriptional profiles of different gene-edited T cells via RNA-Seq. Results Data showed that HLA-II editing didn’t impair the anti-tumor efficacy of TUCAR-T ex vivo and in vivo and we found for the first time that HLA-II deficiency could facilitate the persistence of CAR-T. Contrastively, as the most commonly eliminated target in UCAR-T, TCR deficiency was found to be a key disadvantageous factor for the shorter-term anti-tumor efficacy in vivo . Our study demonstrated ETUCAR-T c...