Circular mRNA-based TCR-T offers a safe and effective therapeutic strategy for treatment of cytomegalovirus infection

作者：Lianghua Shen, Jiali Yang, Chijian Zuo, Jian Xu, Ling Ma, Qiaomei He, Xiao Zhou, Xiaodan Ding, Lixiang Wei, Suqin Jiang, Luanluan Ma, B Y Zhang, Yuqin Yang, Baoxia Dong, Liping Wan, Xueying Ding, Ming Zhu, Zhenhua Sun, Pengran Wang, Xianmin Song, Yan Zhang · 发表于：Molecular Therapy · 年份：2023 · DOI：10.1016/j.ymthe.2023.11.017 · 被引用次数：33 · 研究领域：CAR-T cell therapy research、RNA Interference and Gene Delivery、Virus-based gene therapy research

Circular mRNA (cmRNA) is particular useful due to its high resistance to degradation by exonucleases, resulting in greater stability and protein expression compared to linear mRNA. T cell receptor (TCR)-engineered T cells (TCR-T) represent a promising means of treating viral infections and cancer. This study aimed to evaluate the feasibility and efficacy of cmRNA in antigen-specific-TCR discovery and TCR-T therapy. Using human cytomegalovirus (CMV) pp65 antigen as a model, we found that the expansion of pp65-responsive T cells was induced more effectively by monocyte-derived dendritic cells transfected with pp65-encoding cmRNA compared with linear mRNA. Subsequently, we developed cmRNA-transduced pp65-TCR-T (cm-pp65-TCR-T) that specifically targets the CMV-pp65 epitope. Our results showed that pp65-TCR could be expressed on primary T cells for more than 7 days. Moreover, both in vitro killing and in vivo CDX models demonstrated that cm-pp65-TCR-T cells specifically and persistently kill pp65-and HLA-expressing tumor cells, significantly prolonging the survival of mice. Collectively, our results demonstrated that cmRNA can be used as a more effective technical approach for antigen-specific TCR isolation and identification, and cm-pp65-TCR-T may provide a safe, non-viral, non-integrated therapeutic approach for controlling CMV infection, particularly in patients who have undergone allogeneic hematopoietic stem cell transplantation.