Vesicular Stomatitis Virus-Based Oncolytic Virotherapy: Recent Progress and Emerging Trends

Vesicular Stomatitis virus (VSV) is a prototype Rhabdovirus which is characterised by rapid cytoplasmic replication and robust cell lysis but is normally non pathogenic in humans. It has shown a prominent oncolytic virus Potential. VSV uses low density lipoprotein receptors for entry and its tumor selectivity relies mainly on widespread type I interferon (IFN) signaling defects in cancer cells other than tumor-restricted cell binding. Recently, engineering strategies have focused on limiting wildtype M protein mediated neurotoxicity and off target replication. Selectivity and safety has been enhanced by use of chimeric envelope swapping, attenuation via different mutations and insertions of IFN transgenes, and microRNA mediated suppression in normal tissues. To overcome resistance in IFN competent tumors, VSV has been combined with JAK/STAT inhibitors (such as ruxolitinib), epigenetic modulators (targeting SIRT1, CHD1, MAP3K7), and metabolic reprogramming agents. Direct oncolysis has been also amplified by giving vectors pro-apoptotic/PANoptotic drugs or tumor suppressors and also using  radiation and chemotherapeutics. To evade rapid immune/complement clearance during delivery, cellular carriers like naïve T cells, MSCs are being used. Related vesiculoviruses like Maraba, Morreton, and Jurona viruses are also being studied due to their complement resistance, distinct receptor usage, and reduced neurovirulence.
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