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, vMC 24 NC, 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 vMC 24 NC in an immunodeficient xenograft mouse model of human glioblastoma. A Mengovirus construct, vMC 24 ΔL, wherein the gene coding for the leader protein, a virulence factor, was deleted, was used for comparison. The vMC 24 ΔL 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 vMC 24 ΔL was associated with viral replication in nervous and cardiac tissue. In contrast, microRNA-detargeted vMC 24 NC 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 vMC 24 NC as an ideal candidate for clinical development against certain cancers in both immunocompetent and immunodeficient hosts.

Polycytidine tract deletion from microRNA-detargeted oncolytic Mengovirus optimizes the therapeutic index in a murine multiple myeloma model

“… 6 MC 24 -NC was previously reported to be a safe and relatively potent oncolytic virus, with varying efficacy depending on the tumor model. 6 , 7 , 8 For the purpose of the current study we generated two additional vectors carrying either a full deletion of the polyC tract (MC 0 -NC) or a long polyC tract (MC 37 -NC) with the sequence C 26 UC 10 ( Figure 2 A). The use of Mengovirus with a wild-type polyC length (C 44 UC 10 ) raises several safety concerns because of its zoonotic potential.…”

“… 3 , 4 , 5 Mengovirus MC 24 -NC, an attenuated and microRNA (miRNA)-detargeted picornavirus, was previously shown to be a safe and efficacious OV in a murine multiple myeloma model. 6 However, a consistently curative therapy with complete and durable response across multiple tumor models was not achieved, 7 , 8 which suggested that the virus may have been over-attenuated and that the therapeutic outcome might be improved if certain attenuating mutations were reversed.…”

Immunology Meets Bioengineering: Improving the Effectiveness of Glioblastoma Immunotherapy

“…vMC 24 NC was generated by the insertion of neuron- and cardiac/muscle-specific miRNA targets into the viral genome. The in vivo analysis of the syngeneic murine plasmacytoma model showed excellent therapeutic efficacy without significant virus-mediated toxicity [ 126 ]. Combining OVs and miRNAs showed reduced toxicity and enhanced potency in preclinical models.…”