Pancreatic cancer is the 3rd leading cause of cancer-related death in North America. Most pancreatic ductal adenocarcinoma (PDAC) patients are diagnosed at an advanced stage of the disease, and treatment at these late stages is extremely challenging. Novel therapeutics for the treatment of advanced PDAC are desperately needed. In this project, we plan to develop combination therapy with interferon-expressing oncolytic adenovirus (IFN- OAd) and chemoradiation for locally advanced and unresectable pancreatic cancer (LAPC) including borderline resectable pancreatic cancer (BRPC), which constitute more than 50% of the PDAC patients. Treatment of local disease in these groups will benefit the resectability and prognosis. We have been developing oncolytic adenoviruses (OAds) as cancer therapeutics. OAds are designed to selectively replicate and spread within the tumor, resulting in a strong oncolytic effect mediated by the cytocidal function of the virus leading to immunogenic cell death. OAds can also induce massive and selective expression of a transgene in the target cancer cells where viral replication is taking place. Therefore, OAd system will be exploited to overcome the current obstacles of IFN-based therapy by selectively expressing a massive amount of IFN in the tumor region. In our preliminary experiments, IFN- expressing OAd (IFN-OAd) showed impressive tumor regression in a syngeneic PDAC model in immunocompetent hamsters, and its effect was greatly enhanced when combined with chemoradiation. We have also reported shrinkage induced by IFN-expressing Ad not only in the injected tumor but also in the untreated contralateral tumor caused by the stimulation of systemic immunity. These suggest that this new combination therapy may realize a more effective treatment of locally advanced and metastatic diseases. Toward this goal, we will first analyze the effects of the combination therapy in human PDAC cell lines and the tissue-slice culture system. We then will optimize chemoradiation regimens in order to maximize the effect of the combination therapy with IFN-OAd in an immunocompetent syngeneic hamster model. The immunological effect and toxicity of the combination therapy will also be examined rigorously. Finally, the therapeutic benefit of the novel combination approach of IFN-OAd with chemoradiaion will be analyzed in LAPC models as well as with patient-derived tumor xenografts. This project will establish a therapeutic regimen of the novel IFN-OAd-based chemoradiation in order to commence clinical translation in LAPC and BRPC patients. We have a strong team with a history of success in bringing such therapeutics to patients, andonce implemented, the therapeutic/treatment will provide an excellent opportunity to improve the current devastating clinical outcome of pancreatic cancers.

More than 50% of the pancreatic ductal adenocarcinoma (PDAC) patients have locally advanced and unresectable pancreatic cancer, and the prognosis of these patients is dismal. Interferon (IFN)‐ based chemoradiation therapy showed a clinical benefit for the treatment of PDAC, but still has several obstacles impairing its clinical utility (i.e. systemic toxicity of IFN). By using oncolytic adenovirus that is capable of selective expression of massive IFN in the tumor site, we will develop a less toxic yet more potent IFN therapy for PDAC patients by exploiting the oncolytic adenovirus system for selective and massive expression of IFN in the tumor in combination with chemoradiation.