Oncotarget

Research Papers:

Combination of interferon-expressing oncolytic adenovirus with chemotherapy and radiation is highly synergistic in hamster model of pancreatic cancer

Amanda O. Salzwedel, Joohee Han, Christopher J. LaRocca, Ryan Shanley, Masato Yamamoto and Julia Davydova _

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Oncotarget. 2018; 9:18041-18052. https://doi.org/10.18632/oncotarget.24710

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Abstract

Amanda O. Salzwedel1, Joohee Han1, Christopher J. LaRocca1, Ryan Shanley2, Masato Yamamoto1,3,4 and Julia Davydova1,4

1Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA

2Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA

3Institute of Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA

4Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA

Correspondence to:

Julia Davydova, email: [email protected]

Masato Yamamoto, email: [email protected]

Keywords: oncolytic adenovirus; pancreatic cancer; interferon; combination therapy; chemoradiation

Received: November 06, 2017     Accepted: March 06, 2018     Published: April 06, 2018

ABSTRACT

Recent clinical trials utilizing Interferon-alpha (IFN) in combination with chemoradiation have demonstrated significant improvements in the survival of patients with pancreatic cancer. However, efficacy was limited by the systemic toxicity of IFN and low intratumoral levels of the cytokine. We sought to address these drawbacks by using an Oncolytic Adenovirus expressing IFN (OAd-hamIFN) in combination with chemotherapy and/or radiation in regimens mimicking the IFN-based therapies used in clinical trials. IFN expressed from OAd-hamIFN potentiated the cytotoxicity of radiation and chemotherapy (5-FU, Gemcitabine, and Cisplatin), and enhanced pancreatic cancer cell death in both in vitro and in vivo experimental settings. Notably, synergism was demonstrated in therapeutic groups that combined the interferon-expressing oncolytic virus with chemotherapy and radiation. In an in vivo immunocompetent hamster model, treatment regimens combining oncolytic virus therapy with 5-FU and radiation demonstrated significant tumor growth inhibition and enhanced survival. This is the first study to report synergism between an IFN-expressing oncolytic adenovirus and chemoradiation-based therapies. When combined with an IFN-expressing OAd, there is a significant enhancement of radiation and especially chemoradiation, which may broaden the application of this new therapeutic approach to the pancreatic cancer patients who cannot tolerate existing chemotherapy regimens.


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