Improved Antitumor Effect of Adenovirus-Mediated Interferon Therapy in Combination with Chemoradiotherapy in a Syngeneic Immunocompetent Hamster Model

Abstract

Pancreatic cancer is one of the deadliest diseases without a cure. Approximately 85-90% of newly diagnosed patients will present inoperable disease due to an advanced stage of the cancer or metastases. The median survival length of these patients is about 6 months. Even with well-established chemotherapy (5-FU), 95% of the patients will not be alive within five years. Although interferon- α (IFN) emerged as a promising treatment strategy in recent clinical studies, excess toxicity and insufficient level of IFN in tumor site remain as serious concerns. Hence, we designed a novel adenovirus as a vehicle system to deliver high dosage of IFN to only the pancreatic cancer cells, leaving the normal tissues unharmed. We hypothesize that our novel adenovirus expressing IFN (Ad-IFN) in combination with either 5-FU or radiotherapy would significantly enhance anticancer effect of existing IFN-based treatments while reducing toxicity. In vitro assays in human and hamster pancreatic cancer cells revealed that combination of Ad-IFN with either 5-FU or radiation killed cancer cells better than either of the single treatments. Successfully establishing a fully syngeneic pancreatic cancer model in immunocompetent hamsters, we treated them with a single dose of Ad-IFN followed by radiation. Ad-IFN combined with radiotherapy showed remarkable decrease in tumor volume and was significantly superior to single treatments. At day 42, the tumors in the combination group nearly disappeared. Thus, we have the first report of the improved combination effect of Ad-IFN with radiotherapy and 5-FU. Such a strategy may change the paradigm of pancreatic cancer treatment.