Specific loading of oncolytic VSV on CAR enhances CAR-T cell signaling and antitumor activity

作者：Fan Xing, Xuemei Wang, Zeying Li, Liangying Zheng, Zuda Huang, Jieqing Guo, Zhihui Xi, Huolun Feng, Baijin Xia, Yingtong Lin, Fei Yu, Jie Chen, Hui Zhang · 发表于：The Journal of Experimental Medicine · 年份：2025 · DOI：10.1084/jem.20241851 · 被引用次数：7 · 研究领域：Virus-based gene therapy research、CAR-T cell therapy research、Viral Infectious Diseases and Gene Expression in Insects

Oncolytic viruses (OVs) have been shown to increase the efficacy of chimeric antigen receptor (CAR) T cells in treating solid tumors. However, their combined effect has been limited by the unbalanced distribution of two agents in tumor tissue and viral infection-mediated CAR-T cell exhaustion. Here, we designed a CAR moiety by inserting the CR2 and CR3 domains (CR2/3-CAR) of low-density lipoprotein receptor, which is the viral receptor of oncolytic vesicular stomatitis virus (VSV) mutant (VSVΔ51), enabling specific loading of VSVΔ51 onto CAR-T cells. The anchored VSVΔ51 could be released from CAR-T cells and efficiently delivered to tumor tissue. Further investigation revealed that the cross-connection between viral envelope proteins and CR2/3-CAR moieties facilitated forming antigen-free CAR clusters and antigen-induced CAR synapse, triggered CAR signaling transduction, and directly pre-activated the CAR-T cells. Consequently, this approach potently enhanced the proliferation, metabolic fitness, and immunological activities of CAR-T cells, and subsequently enhanced the OV/CAR-T synergetic cytotoxicity, revealing an effective strategy for treating solid tumors.