Vesicular stomatitis virus expressing tumor suppressor p53 is a highly attenuated, potent oncolytic agent

Area of Science:

• Oncolytic virotherapy
• Immunology
• Molecular biology

Background:

• Vesicular stomatitis virus (VSV) is a rhabdovirus with oncolytic potential, selectively targeting cancer cells.
• The tumor suppressor p53 possesses antitumor properties, potentially by modulating host immune responses.
• Genetic modification of VSV offers a route to enhance its therapeutic efficacy.

Purpose of the Study:

• To investigate the oncolytic efficacy of VSV engineered to express murine p53 (mp53).
• To assess the impact of viral M gene function on VSV-p53 oncolytic activity and in vivo performance.
• To evaluate the therapeutic potential of VSV-p53 in immunocompetent animal models of cancer.

Main Methods:

• Construction of recombinant VSVs expressing mp53, with variations in the viral M gene to modulate host mRNA export.
• In vitro assessment of VSV-p53's ability to lyse transformed versus normal cells.
• In vivo evaluation of VSV-ΔM-mp53 in immunocompetent mice with metastatic mammary adenocarcinoma, including immune response analysis.

Main Results:

• VSV-mp53 and VSV-M(mut)-mp53 expressed functional p53 and demonstrated selective lysis of transformed cells.
• VSV-ΔM-mp53 showed significant attenuation in vivo, attributed to p53-induced activation of innate immune genes like type I interferon.
• Treatment with VSV-ΔM-mp53 led to increased survival in tumor-bearing mice, associated with enhanced CD49b+ NK and CD8+ T cell responses.

Conclusions:

• VSV engineered to express p53 retains oncolytic activity and exhibits enhanced therapeutic potential.
• The p53-mediated activation of innate immunity by VSV-ΔM-mp53 contributes to its in vivo efficacy.
• VSV-p53 represents a viable strategy for developing novel oncolytic therapeutics and vaccines against cancer.