Background: Morreton virus (MORV) is an oncolytic Vesiculovirus, genetically distinct from vesicular stomatitis virus (VSV). Aim: To report that MORV induced potent cytopathic effects (CPEs) in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) in vitro models. Approach and Results: In preliminary safety analyses, high intranasal doses (up to 1010 50% tissue culture infectious dose [TCID50]) of MORV were not associated with significant adverse effects in immune competent, non–tumor-bearing mice. MORV was shown to be efficacious in a Hep3B hepatocellular cancer xenograft model but not in a CCA xenograft HuCCT1 model. In an immune competent, syngeneic murine CCA model, single intratumoral treatments with MORV (1 × 107 TCID50) triggered a robust antitumor immune response leading to substantial tumor regression and disease control at a dose 10-fold lower than VSV (1 × 108 TCID50). MORV led to increased CD8+ cytotoxic T cells without compensatory increases in tumor-associated macrophages and granulocytic or monocytic myeloid-derived suppressor cells. Conclusions: Our findings indicate that wild-type MORV is safe and can induce potent tumor regression via immune-mediated and immune-independent mechanisms in HCC and CCA animal models without dose limiting adverse events. These data warrant further development and clinical translation of MORV as an oncolytic virotherapy platform.
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