MicroRNA-detargeting proves more effective than leader gene deletion for improving safety of oncolytic Mengovirus in a nude mouse model.

ABSTRACT

A dual microRNA-detargeted oncolytic Mengovirus, vMC24NC, proved highly effective against a murine plasmacytoma in an immunocompetent syngeneic mouse model; however, there remains the concern of escape mutant development and the potential for toxicity in severely immunocompromised cancer patients when it is used as an oncolytic virus. Therefore, we sought to compare the safety and efficacy profiles of an attenuated Mengovirus containing a virulence gene deletion versus vMC24NC in an immunodeficient xenograft mouse model of human glioblastoma. A Mengovirus construct, vMC24ΔL, wherein the gene coding for the leader protein, a virulence factor, was deleted, was used for comparison. The vMC24ΔL induced significant levels of toxicity following treatment of subcutaneous human glioblastoma (U87-MG) xenografts as well as when injected intracranially in athymic nude mice, reducing the overall survival. The in vivo toxicity of vMC24ΔL was associated with viral replication in nervous and cardiac tissue. In contrast, microRNA-detargeted vMC24NC demonstrated excellent efficacy against U87-MG subcutaneous xenografts and improved overall survival significantly compared to that of control mice without toxicity. These results reinforce microRNA-detargeting as an effective strategy for ameliorating unwanted toxicities of oncolytic picornaviruses and substantiate vMC24NC as an ideal candidate for clinical development against certain cancers in both immunocompetent and immunodeficient hosts.