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Adenovirus-Mediated Interferon Therapy Sensitized Chemotherapy and Radiation for Pancreatic Cancer In Vitro and In Vivo Models
Joohee Han1, Yoshiaki Miura1, Leonard Armstrong1, Ryan M. Ryan M Shanley2, Xianghua Luo2, Eric H. Jensen1, Edward W. Greeno3, Selwyn M. Vickers1, Masato Yamamoto1, Julia Davydova*1
1Surgery, University of Minnesota, Minneapolis, MN; 2Division of Biostatistics, University of Minnesota, Minneapolis, MN; 3Medicine - Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
Interferon-α (IFNα) in conjunction with chemoradiotherapy has emerged as a promising treatment for pancreatic adenocarcinoma. However, despite encouraging survival results (e.g. a 5-year survival rate of 55% in a phase II trial by the Virginia Mason study group evaluating adjuvant chemotherapy, immunotherapy and external-beam radiation for resected PDAC), utilization of this regimen has been impeded by systemic toxicity of IFNα.
To circumvent these problems, we engineered a novel infectivity-enhanced oncolytic adenoviral vectors for high-level targeted IFNα expression (Ad-IFN). We hypothesized that a new therapeutic modality combining an Ad-IFN with chemoradiation would overcome the major drawbacks of IFN-based regimens. The adenovirus-mediated tumor-selective expression of IFN will eliminate systemic toxicity of cytokine, while massive IFNα expression via replication-competent vector will yield an extended response. In this study, we combined this vector with chemo- and radiotherapy and analyzed its therapeutic ability in vitro and in vivo models.
The in vitro assays revealed that combination of Ad-IFN with chemotherapeutics (5-FU, gemcitabine, cisplatin) and X-ray radiation killed human and hamster pancreatic cancer cells significantly better than either of the single treatments. Furthermore, we established pancreatic tumors in immunocompetent hamsters and discovered that combination of Ad-IFN with either 5FU or radiation (8 Gy and 20 Gy were tested) resulted in remarkable tumor shrinkage and was significantly superior to radiation and 5-FU alone or both of these combined. The triple-therapy (Ad-IFN+X-ray+5-FU) outperformed all treatment groups. The evaluation of the survival rate also showed statistically significant improvement in groups treated with dual (Ad-IFN+X-ray) and triple (Ad-IFN+X-ray+5-FU) therapies versus conventional approaches (radiation or/and 5FU).
Our results support the impact of Ad-mediated IFNα to sensitize chemotherapy and radiation for pancreatic cancer. This strategy may expand clinical use of the robust and promising IFN-based multimodal therapy to meet the pressing continued need for PDAC treatment.
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