MicroRNA Modification of Coxsackievirus B3 Decreases Its Toxicity, while Retaining Oncolytic Potency against Lung Cancer

Abstract

We recently discovered that coxsackievirus B3 (CVB3) is a potent oncolytic virus against <i>KRAS</i> mutant lung adenocarcinoma. Nevertheless, the evident toxicity restricts the use of wild-type (WT)-CVB3 for cancer therapy. The current study aims to engineer the CVB3 to decrease its toxicity and to extend our previous research to determine its safety and efficacy in treating <i>TP53</i>/<i>RB1</i> mutant small-cell lung cancer (SCLC). A microRNA-modified CVB3 (miR-CVB3) was generated via inserting multiple copies of tumor-suppressive miR-145/miR-143 target sequences into the viral genome. <i>In vitro</i> experiments revealed that miR-CVB3 retained the ability to infect and lyse <i>KRAS</i> mutant lung adenocarcinoma and <i>TP53</i>/<i>RB1-</i>mutant SCLC cells, but with a markedly reduced cytotoxicity toward cardiomyocytes. <i>In vivo</i> study using a <i>TP53</i>/<i>RB1-</i>mutant SCLC xenograft model demonstrated that a single dose of miR-CVB3 via systemic administration resulted in a significant tumor regression. Most strikingly, mice treated with miR-CVB3 exhibited greatly attenuated cardiotoxicities and decreased viral titers compared to WT-CVB3-treated mice. Collectively, we generated a recombinant CVB3 that is powerful in destroying both <i>KRAS</i> mutant lung adenocarcinoma and <i>TP53</i>/<i>RB1-</i>mutant SCLC, with a negligible toxicity toward normal tissues. Future investigation is needed to address the issue of genome instability of miR-CVB3, which was observed in ~40% of mice after a prolonged treatment.