Chimeric VSV-NDV mediates a multimechanistic therapeutic response supported by immune activation in orthotopic hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents a challenging malignancy due to its advanced stage at diagnosis and the underlying tolerogenic environment in the liver. Oncolytic virotherapy can provide a promising therapeutic approach through direct tumor cell lysis and induction of local inflammation, thereby reprogramming the tumor microenvironment. We have developed a novel chimeric oncolytic virus platform, VSV-NDV, based on the vesicular stomatitis virus (VSV) backbone and expressing the fusogenic envelope proteins of Newcastle disease virus (NDV), which offers an excellent safety profile and potent therapeutic effects in several tumor models. We have now performed a comprehensive preclinical evaluation of oncolytic VSV-NDV therapy in HCC and investigated the resulting immune-cell signatures in the liver and tumors. In vitro, we demonstrate a potent oncolytic effect of VSV-NDV in human HCC cell lines and patient-derived organoids, which leads to dendritic cell (DC) activation in co-culture. Using inducible and implantable models of HCC in mice and rats, VSV-NDV demonstrates delayed tumor growth and significant prolongation of survival. We have characterized an early increase in innate immune cells and myeloid cells in the liver and a significant increase in total and effector CD8+T cells on day 7 post-treatment in the liver and tumor of VSV-NDV-treated mice. Furthermore, rVSV-NDV-mediated expression of a high-affinity soluble PD-1 mediates further enhanced therapeutic effects, coinciding with systemic increases in CD8+T cells, and prolongs survival in an aggressive multifocal orthotopic model of HCC. These results support the further development of oncolytic rVSV-NDV vectors as a potentially valuable immunotherapy modality for HCC.

Publication History

Article published online:
20 January 2025