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

Huitao Liu; Yuan Chao Xue; Haoyu Deng; Yasir Mohamud; Chen Seng Ng; Axel Chu; Chinten James Lim; William W Lockwood; William W G Jia; Honglin Luo

doi:10.1016/j.omto.2020.01.002

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

Mol Ther Oncolytics. 2020 Jan 21:16:207-218. doi: 10.1016/j.omto.2020.01.002. eCollection 2020 Mar 27.

Authors

Huitao Liu^{1

2}, Yuan Chao Xue^{1

3}, Haoyu Deng^{1

3

4}, Yasir Mohamud^{1

3}, Chen Seng Ng^{1

3}, Axel Chu⁵, Chinten James Lim⁵, William W Lockwood^{3

6}, William W G Jia⁷, Honglin Luo^{1

3

2}

Affiliations

¹ Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.
² Department of Experimental Medicine, University of British Columbia, Vancouver, BC, Canada.
³ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Vascular Surgery, RenJi Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁵ Department of Pediatrics, University of British Columbia, BC Children's Hospital Research Institute, Vancouver, BC, Canada.
⁶ Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
⁷ Department of Surgery, Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada.

Abstract

We recently discovered that coxsackievirus B3 (CVB3) is a potent oncolytic virus against KRAS 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 TP53/RB1 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. In vitro experiments revealed that miR-CVB3 retained the ability to infect and lyse KRAS mutant lung adenocarcinoma and TP53/RB1-mutant SCLC cells, but with a markedly reduced cytotoxicity toward cardiomyocytes. In vivo study using a TP53/RB1-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 KRAS mutant lung adenocarcinoma and TP53/RB1-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.

Keywords: KRAS mutation; TP53/RB1 mutation; cardiotoxicity; coxsackievirus B3; lung adenocarcinoma; miRNA-143; miRNA-145; oncolytic virus; small-cell lung cancer; virotherapy.