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

  • J Exp Med. 2025 Nov 3;222(11):e20241851. doi: 10.1084/jem.20241851.
Fan Xing  1  2 ,  Xuemei Wang  3 ,  Zeying Li  1 ,  Liangying Zheng  1 ,  Zuda Huang  2 ,  Jieqing Guo  1 ,  Zhihui Xi  1 ,  Huolun Feng  4 ,  Baijin Xia  1 ,  Yingtong Lin  3 ,  Fei Yu  1 ,  Jie Chen  5 ,  Hui Zhang  3
Affiliations
  • 1. Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University , Guangzhou, China.
  • 2. School of Pharmaceutical Sciences, Southern Medical University , Guangzhou, China.
  • 3. Department of Pathogen Biology and Biosecurity, Key Laboratory of Tropical Disease Control of Ministry of Education, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 4. Department of Gastrointestinal Surgery Department of General Surgery Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • 5. Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
PMID: 40938370 DOI: 10.1084/jem.20241851
Abstract

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.

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