Characterization of Morreton virus as an oncolytic virotherapy platform for liver cancers

Abstract

Morreton virus (MORV) is a novel oncolytic Vesiculovirus, genetically distinct from vesicular stomatitis virus (VSV). we report that MORV induced potent cytopathic effects in a panel of cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) cell lines. In addition, high intranasal doses of MORV were not associated with significant adverse effects and were well tolerated in mice bearing liver tumor xenografts and syngeneic liver cancers. Furthermore, single intratumoral treatments with MORV (1 x 10 7 TCID 50 ) triggered a robust antitumor immune response leading to substantial tumor regression and disease control in a syngeneic CCA model, using 10-fold lower dose compared to VSV (1 x 10 8 TCID 50 ). In addition, MORV and VSV both induced prominent tumor growth delay in immunodeficient mice bearing Hep3B hepatocellular carcinoma (HCC) but not in mice bearing HuCCT-1 CCA xenografts. Our findings indicate that wild-type MORV is safe and can induce potent tumor regression in HCC and CCA animal models without adverse events via immune-mediated and immune-independent mechanisms. Further development and clinical translation of MORV as virotherapy for liver cancers are warranted.

Multi-modal Efficacy of a Chimeric Vesiculovirus Expressing the Morreton Glycoprotein in Sarcoma

“…Short term (3 days) and long term (~7 weeks) toxicity was evaluated as previously described. 9 Overall, all doses were well tolerated. In the long-term observation group, only one mouse experienced a drop in body weight (<20% reduction) at the highest dosage of VMG before recovering (Supp.Fig.5).…”

“…To assess whether infection with VMG is associated with neurotoxicity in laboratory mice as shown for VSV, we intranasally administered VMG at four different doses (10 7 , 10 8 , 10 9 , or 10 10 TCID 50 in 10 microliters total volume) to immunocompetent mice. Short term (3 days) and long term (~7 weeks) toxicity was evaluated as previously described.…”

“…We and other groups have explored the use of attenuated or alternative vesiculoviruses such as Morreton virus (MorV) in the treatment of cancer. 8,9 We have previously demonstrated that MorV exhibits a lack of neurotoxicity and hepatotoxicity in contrast to the concerns associated with VSV. 9 In addition, we have shown that intratumoral injection of MorV elicited a cytotoxic T-cell response resulting in a prominent tumor regression at a 10-fold lower dose than VSV in a syngeneic cholangiocarcinoma model.…”

“…8,9 We have previously demonstrated that MorV exhibits a lack of neurotoxicity and hepatotoxicity in contrast to the concerns associated with VSV. 9 In addition, we have shown that intratumoral injection of MorV elicited a cytotoxic T-cell response resulting in a prominent tumor regression at a 10-fold lower dose than VSV in a syngeneic cholangiocarcinoma model. In the current study, we examined the potential for use of a chimeric vesiculovirus in sarcoma, using the genetic backbone of VSV expressing the glycoprotein of MorV (VMG).…”

“…With this approach, we hope to leverage the existing data derived from clinical studies on VSV-based vectors in combination with the pre-clinical safety profile of MorV with the ultimate goal to translate VMG into the clinic. 9…”