409. Novel Recombinant Coxsackievirus B3 Infection Elicits Robust Oncolytic Activity Against Human Non-Small Lung Cancer and Triple-Negative Breast Cancer

Oncolytic virotherapy using enteroviruses emerges as a promising anticancer strategy. As therapeutic advantages, enteroviruses immediately induce robust oncolytic activity and do not have oncogenes that may lead to tumorigenesis. We recently showed coxsackievirus B3 wild type (CVB3-WT) infection elicited remarkably oncolytic activity against human non-small cell lung cancer cells (NSCLC). However, CVB3-WT infection caused adverse events of weight loss, pancreatitis, and myocarditis in mice. To overcome these pathogenicity, we engineered CVB3-WT genome for the development of microRNA (miRNA)-regulated oncolytic virus. We focused on two miRNAs (miR-1 and miR-217) expressed mainly normal muscle or pancreas. We successfully genetically constructed a novel recombinant CVB3-miR-1&217T (CVB3-miRT) by inserting 4 tandem target sequences complementary to two miR-1 and two miR-217 into the 3’UTR of CVB3-WT genome. Recently, we investigated whether an infection with CVB3-miRT displays oncolytic activities against NSCLC. We found that CVB3-miRT infection induced potent oncolytic activity comparable to CVB3-WT in human NSCLC in vitro and in vivo. Here, we attempted to explore the oncolysis to triple-negative breast cancer (TNBC) because TNBC are highly aggressive and intractable tumors with dismal prognosis. We performed in vitro crystal violet staining to examine the effect of CVB3-miRT on TNBC. These results showed that CVB3-miRT had potent oncolytic activity against TNBC cell lines in a MOI-dependent manner. Furthermore, consecutive administrations of CVB3-miRT into subcutaneous xenografts of human TNBC pre-established in athymic nude mice significantly suppressed the tumor growth with a prolonged survival rate. The intratumoral CVB3-miRT administrations into human TNBC xenograft tumor mice model displayed dramatically decreased side effects of CVB3-WT-induced pathogenicity. Collectively, we showed that CVB3-miRT infection indicated marked oncolytic activity against human NSCLC and TNBC cells in vitro and in vivo as well as CVB3-WT. This approach could be a promising new therapeutic modality to improve survival in patients suffering from NSCLC and TNBC in advanced stage.