Vesicular stomatitis virus (VSV) as an oncolytic therapeutic agent for cancer

Vesicular stomatitis virus (VSV), an enveloped RNA virus that naturally infects livestock, has emerged as a highly versatile and potent platform for research purposes and, especially, for oncolytic virotherapy. The unique advantages of VSV as an oncolytic platform, including its rapid replication kinetics, strong cytolytic activity, its easily manipulated genome and ability to express foreign transgenes, and the ability to manufacture VSV at high concentrations, make this virus particularly well-suited as an oncolytic virus vector. This chapter provides a comprehensive overview of the biological and therapeutic foundations underlying the development of oncolytic VSV. It begins with the basic virology of VSV, including its genome organization, host range, and its inherent tumor specificity due to its sensitivity to type I interferons, allowing for preferential replication in cells that harbor impairments in antiviral responses, which is a hallmark of cancer. The principles of oncolytic virotherapy are outlined, emphasizing the multiple mechanisms of action, including direct tumor cell lysis and induction of local and systemic antitumor immunity. Examples of genetic engineering strategies to enhance efficacy and improve the translational potential are outlined. Finally, the current state of clinical development, highlighting completed and ongoing clinical trials evaluating recombinant oncolytic VSV vectors in various malignancies is summarized. Together, these basic principles, the extensive preclinical development spanning over 2 decades, and recent clinical advances underscore the promise of VSV as a next-generation oncolytic platform with substantial potential to transform cancer therapy through virus engineering and combinatorial immuno-oncology strategies.