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

Velia Penza; Justin W Maroun; Rebecca A Nace; Autumn J Schulze; Stephen J Russell

doi:10.1016/j.omto.2022.11.006

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

Mol Ther Oncolytics. 2022 Dec 2:28:15-30. doi: 10.1016/j.omto.2022.11.006. eCollection 2023 Mar 16.

Authors

Velia Penza^{1

2}, Justin W Maroun^{3

2}, Rebecca A Nace², Autumn J Schulze², Stephen J Russell^{3

2

4}

Affiliations

¹ Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55902, USA.
² Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA.
³ Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN 55902, USA.
⁴ Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Abstract

Mengovirus is an oncolytic picornavirus whose broad host range allows for testing in immunocompetent cancer models. Two pathogenicity-ablating approaches, polycytidine (polyC) tract truncation and microRNA (miRNA) targets insertion, eliminated the risk of encephalomyocarditis. To investigate whether a polyC truncated, miRNA-detargeted oncolytic Mengovirus might be boosted, we partially or fully rebuilt the polyC tract into the 5' noncoding region (NCR) of polyC-deleted (MC₀) oncolytic constructs (NC) carrying miRNA target (miRT) insertions to eliminate cardiac/muscular (miR-133b and miR-208a) and neuronal (miR-124) tropisms. PolyC-reconstituted viruses (MC₂₄-NC and MC₃₇-NC) replicated in vitro and showed the expected tropism restrictions, but reduced cytotoxicity and miRT deletions were frequently observed. In the MPC-11 immune competent mouse plasmacytoma model, both intratumoral and systemic administration of MC₀-NC led to faster tumor responses than MC₂₄-NC or MC₃₇-NC, with combined durable complete response rates of 75%, 0.5%, and 30%, respectively. Secondary viremia was higher following MC₀-NC versus MC₂₄-NC or MC₃₇-NC therapy. Sequence analysis of virus progeny from treated mice revealed a high prevalence of miRT sequences loss among MC₂₄- and MC₃₇- viral genomes, but not in MC₀-NC. Overall, MC₀-NC was capable of stably retaining miRT sites and provided a more effective treatment and is therefore our lead Mengovirus candidate for clinical translation.

Keywords: Mengovirus; microRNA; microRNA detargeting; multiple myeloma; oncolytic virotherapy; oncolytic virus; picornavirus; polyC tract.