MicroRNA Modification of Coxsackievirus B3 Decreases Its Cardiotoxicity, While Retaining Oncolytic Potency Against Lung Cancer

Abstract

Background: We recently discovered that coxsackievirus B3 (CVB3) is a potent oncolytic virus against KRAS-mutant (KRASmut) lung adenocarcinoma. Nevertheless, the evident cardiotoxicity restricts the use of wild-type (WT)-CVB3 for lung cancer therapy. The current study aims to genetically engineer the CVB3 genome to decrease its toxicity towards normal tissues and to extend our previous research to determine the safety and oncolytic efficacy of the modified CVB3 in treating TP53-and/or RB1-mutant small cell lung cancer (TP53mut/RB1mut SCLC). Methods: A microRNA-modified CVB3 (miR-CVB3) was generated via inserting multiple copies of tumor-suppressive miR-145 and miR-143 target sequences into the 5' untranslated region of the viral genome. The safety and effectiveness of the miR-CVB3 were then examined in cultured cells and using a TP53mut/RB1mut SCLC cell-derived xenograft model. Findings: In vitro experiments revealed that miR-CVB3 retained the ability to infect and lyse KRASmut lung adenocarcinoma and TP53mut/RB1mut SCLC cells, but with a markedly reduced cytotoxicity towards cardiomyocytes. In vivo study demonstrated that a single dose of miR-CVB3 via systemic administration resulted in a significant tumor regression. Most strikingly, mice treated with miR-CVB3 all survived the time-course of the experiment with greatly attenuated cardiotoxicities and decreased viral titers as compared to WT-CVB3-treated mice. Interpretation: We generated a recombinant CVB3 that was powerful in destroying both KRASmut lung adenocarcinoma and TP53mut/RB1mut SCLC, with a negligible toxicity towards normal tissues. Fundings: This work was supported by the BC Lung Association, Providence Health Care Research Institute and Vancouver Coastal Health Research Institute Innovation and Translational Research Award. Declaration of Interest: WWGJ is the Chief Scientific Officer at Virogin Biotech Ltd. HL (H Liu) and CSN are partially sponsored by Virogin Biotech Ltd. through MITACS Accelerate Program. No conflicts of interest were disclosed by others. Ethical Approval: The protocol was approved by the University Animal Care Committee (A18-0275).