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

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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 IFNbased 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 IFNexpressing 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.

Original languageEnglish (US)
Pages (from-to)18041-18052
Number of pages12
JournalOncotarget
Volume9
Issue number26
DOIs
StatePublished - Apr 1 2018

Bibliographical note

Funding Information:
We appreciate Dr. Eiji Ucida (Nippon Medical School, Tokyo, Japan) for providing PGHAm cells, and Dr. Aoki (National Cancer Center Research Institute, Tokyo, Japan) for allowing us to use the hamster and human IFN-alpha coding plasmids. We thank Jessica Ryvlin for her help performing the in vitro combination treatments and Keith Wirth for his help editing the manuscript. This study was supported by NIH NCI R01CA174861 (PI: J. Davydova); NIH NCI P50CA101955 UAB-UMN Pancreatic Cancer SPORE (PI: D. Buchsbaum), NIH NCI R01CA196215, R01CA168448 (PI: M. Yamamoto), Cancer Biology Training Grant, University of Minnesota (NIH T32 CA009138, PI: Carol Lange), and NIH NCI P30CA77598 utilizing the Masonic Cancer Center, University of Minnesota shared resources

Publisher Copyright:
© 2018 Salzwedel et al.

Keywords

  • Chemoradiation
  • Combination therapy
  • Interferon
  • Oncolytic adenovirus
  • Pancreatic cancer

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