Matrix metalloproteinase-guided targeting of vesicular stomatitis virus to tumors following systemic administration

The lack of tumor-specific targeting by oncolytic viruses (OVs) restricts their therapeutic potential. Here, we report a "cap-linker" strategy to modify the vesicular stomatitis virus (VSV) glycoprotein (G protein, VSV-G^IN). The modified VSV (Pro-VSV^IN) loses its ability to infect cells until present in the tumor microenvironment, where the linker is cleaved by tumor-enriched matrix metalloproteinases (MMPs). When Pro-VSV^IN is armed with a single-chain IL-12 (Pro-VSV^IN-IL-12) and systemically injected into MC38 tumor-bearing mice, Pro-VSV^IN-IL-12 eradicates established tumors while avoiding systemic toxicity, and elicits long-term anti-tumor immune memory. Systemic administration of Pro-VSV^IN-IL-12 also markedly inhibits the growth of metastatic cancers in the lung. The efficacy of Pro-VSV^IN-IL-12 was further improved when combined with PD-1 checkpoint blockade. Compared to WT VSV^IN that carries IL-12, intravenously injected Pro-VSV^IN-IL-12 leads to strong Th1 immunity, near abolishment of regulatory T cells, and potent CD8⁺ T cell activation and clonal expansion in tumors. This preclinical work demonstrates a new tumor-specific targeting strategy of VSV for enhanced immunotherapy safety with superior efficacy.