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Oncolytic virotherapy has gained enormous attention and is undergoing extensive research, specifically, the Vesicular Stomatitis Virus (VSV). VSV has been shown to provide a potential tool on which many modifications can be introduced to improve its efficacy. Here we report utilizing a modified VSV with a deletion mutation at the 51 amino acid of its matrix protein (VSVΔ51), designed to leverage the innate antiviral immunity of healthy cells through the interferon pathway. We serially passaged VSVΔ51M thirty times in B16F10 and LLC1 cell lines. Plaque purification was performed post-passaging to ensure viral homogeneity. Using an ATP release-based assay, we demonstrated that serial passaging significantly enhanced the oncolytic activity of VSVΔ51M in vitro without increasing its toxicity in normal fibroblasts. Whole-genome sequencing of the resultant viruses detected several mutations in the viral glycoprotein and the large RNA polymerase: VSV-P30-LLC1 (VSV-G gene: N25T; VSV-L gene: S1538F) and VSV-P30-B16F10 (VSV-G gene: K2E, I53V, E369K). Most likely, these mutations are responsible for the enhanced efficacy observed both in vitro and in vivo . In silico studies further supported these findings, revealing an increased affinity of the VSV-P30-B16F10 glycoprotein for the LDLR receptor. Additionally, the therapeutic index of VSV-P30-B16F10 improved in the B16F10 peritoneal tumor model. Our findings suggest that serial passaging of VSVΔ51M generates novel variants with enhanced oncolytic profiles while maintaining oncoselectivity. However, further investigation, in preclinical and clinical settings, is necessary to validate the safety and efficacy of these novel variants.
Albaradie et al. (Fri,) studied this question.