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More effective systemic therapy is clearly needed for pancreatic adenocarcinoma. Interferon alpha (IFNα) is promising in multimodality therapy, but has a short half-life and strong side effects. We hypothesize that by expressing IFNα locally in the tumor environment using a replicating tumor-specific adenovirus, systemic side effects can be greatly minimized while allowing for focused tumor delivery and a powerful treatment effect. We generated a novel adenovirus using several strategies to enhance efficacy while reducing toxicity. The COX2 promoter is used to drive viral replication due to its known overexpression in pancreatic tumor cells, while simultaneously avoiding replication toxicity to normal organs such as liver. Our design uses capsid fiber modification for optimal infectivity, and adenoviral death protein for enhanced apoptosis and viral spread. Most importantly, localized IFNα expression will allow focused tumor treatment and limited systemic toxicity. Previously, we have described a virus targeting human pancreatic cancer with such modifications, but available in vivo models do not allow an assessment of immune response. For this reason we have designed a structurally analogous viral vector for use in immunocompetent hamsters, a system which allows human adenoviral replication and an assessment of the contribution of IFNα on antitumor effect. Qualitative assessment of effect was done with crystal violet staining at serial time points. Quantitative cell viability was assessed colorimetrically using a commercially-available kit. COX2 promoter function was assessed in cell lines by a luciferase gene reporter assay with known COX2-positive and negative controls. IFNα expression levels were quantitiated by ELISA from cell culture supernatant. In vivo, hamsters were injected on each flank with 4x10^6 HP1 hamster pancreatic tumor cells, then intratumorally with our novel virus or controls lacking various of its design features at 3x10^10 viral particles/50μl or with PBS when tumors were 10-15mm in size. In vitro a robust effect on hamster pancreatic cancer cell lines is seen. Analysis of COX2 expression in pancreatic cancer cell lines shows that hamster cell lines under investigation are COX2-positive. In vivo experiments show a strong suppression of tumor growth from the new virus (Fig 1). In summary, a new cancer-targeting oncolytic adenovirus was successfully designed to selectively replicate in cancer cells with a powerful antitumor effect. There is no loss of potency compared to viruses with unrestricted ability to replicate. By expressing IFNα locally in the tumor environment, toxicity from systemic delivery seen in current therapy should be avoided.