ABSTRACT The goal of this project is to enable the clinical translation of systemically delivered Oncolytic Adenoviruses (OAds) for combined diagnostic imaging and curative therapy of Pancreatic Ductal Adenocarcinoma (PDAC), a devastating disease without effective therapies. PDAC has no effective screening methods, and its spread and metastases are difficult to assess. This new generation of OAds expressing Sodium-Iodide Symporter (OAd5/3- NIS vectors) developed in the Davydova lab, induces uptake of radioactive iodine by pancreatic cancer cells, thus facilitating both SPECT/CT imaging and radiotherapy with 131I. We have demonstrated remarkable pre- clinical data to support the applicability of the OAd5/3-NIS platform to facilitate radioiodine-based imaging and treatment of PDAC. However, the clinical translation of intravenously administrated OAds has been stalled by the lack of an animal model that allows OAd replication. Murine tissues do not support replication of human adenovirus, preventing the use of mice to study biodistribution and off target effects of systemically delivered OAds. Moreover, all rodent systems lack Adenovirus type 3 (Ad3) receptors necessary to bind to Ad3-based vectors (including our OAd5/3-NIS). The need for reliable animal models is critical. Less than 5% of anti-cancer treatments that are promising in murine models are successful in human clinical trials. Therefore, to address this urgent need, we are developing a novel translational swine model of PDAC. Pigs have been attractive as an alternative platform for cancer modeling because of their similarity with humans in terms of anatomy, metabolism, tumorigenesis, genetics, immunity, and body size. Furthermore, as we have recently reported, unlike rodent and canine models, pigs permit replication of both Adenovirus type 5 and Adenovirus type 3 vectors on the level similar to that in humans. Validating systemic administration of OAd5/3-NIS in our swine model of pancreatic cancer is the next step before clinical trials. In this work, we will 1) Produce a novel transgenic KrasG12D/+/TP53R167H/+ swine model of PDAC; 2) Monitor and characterize PDAC tumor development; and 3) Conduct the preclinical studies to evaluate the potential of intravenously administrated OAd5/3-NIS to facilitate both radioiodine-based imaging and radiotherapy with 131I in swine PDAC models. Completion of this proposal will enable clinical translation of systemically injected OAd5/3-NIS vectors for treatment and diagnostic imaging of patients with PDAC, including patients with metastatic cancer. Importantly, these studies will generate essential information on biodistribution, clearance, off target effects, and overall therapeutic potential of other OAds in a clinically relevant, adenovirus replication permissive, immunocompetent model. In addition, our novel pig model will overcome many of the disadvantages inherent in rodents, particularly with respect to size, genetics, cancer biology, metabolism, and immunity leading to translation of safer, more effective cancer treatments for patients with PDAC, a dismal disease with no effective treatments available. 1

Project Narrative: The goal of this proposal is to develop a new swine model of pancreatic cancer to enable preclinical testing of systemically delivered oncolytic adenoviruses to detect and treat pancreatic cancer. Successful products from this proposal can be promptly translated to the clinical arena bringing novel therapeutic approaches to the patients with pancreatic cancer including those with unresectable metastatic disease. 1