Novel Group C Oncolytic Adenoviruses Carrying a miRNA Inhibitor Demonstrate Enhanced Oncolytic Activity In Vitro and In Vivo

Abstract

Abstract Oncolytic adenoviruses (OAd) represent an attractive treatment option for cancer. Clinical efficacy of commonly utilized human adenovirus type 5 (Ad5)-based oncolytic viruses is limited by variable expression levels of the coxsackie- and adenovirus receptor (CAR) in tumor cells and high prevalence of neutralizing antibodies against human Ad5. However, previous studies have highlighted alternative human Ad types as promising candidates for oncolytic therapy. In this study, we generated novel OAds based on Ad1, -2, -5, and -6 derived from species C Ads. These OAds contain a 24-bp deletion in the early gene E1A for tumor selective replication and express the RNAi inhibitor P19. We examined these OAds for in vitro anticancer activity on various cancer cell lines derived from lung, colon, gynecologic, bone, and pancreatic carcinoma. In most surveyed cell lines, OAds based on Ad1, -2, and -6 demonstrated higher cell lysis capability compared with Ad5, suggesting enhanced oncolytic potential. Moreover, enhanced oncolytic activity was associated with P19 expression in a cell type–dependent manner. We further explored a A549 tumor xenograft mouse model to compare the novel OAds directly with Ad5 and H101, an oncolytic adenovirus used in clinical trials. These P19-containing OAds based on Ad1, -2, and -6 showed significantly decelerated tumor progression compared with H101, indicating better antitumor potency in vivo. Our studies provide a novel path for OAd development based on alternative Ad types with improved effectiveness by RNA interference suppression.