LAUSR

Oncolytic adenoviruses (OAds) represent an attractive treatment option for cancer. Clinical efficacy of commonly utilized human Ad 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 Ad type 5. 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-base pair (bp) deletion in the early gene E1A for tumor selective replication and express the RNA interference 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 to 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 to 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 to H101, indicating better anti-tumor potency in vivo. Our studies provide a novel path for OAd development based on alternative Ad types with improved effectiveness by RNA interference suppression.