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

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.

Oncolytic Adenoviruses: Strategies for Improved Targeting and Specificity

“…Hemminki et al and others further demonstrated its effectiveness in patients who had failed conventional chemotherapy and radiation [156][157][158][159][160]170,171]. Similar to GMCSF, several other receptors and cytokines such as CD40L [162][163][164] and interferons [165][166][167][172][173][174] have also been evaluated. Yamamoto's group has effectively used interferon expressing OAdVs to target pancreatic cancer in mice models and immunocompetent hamster models [172][173][174].…”

“…Similar to GMCSF, several other receptors and cytokines such as CD40L [162][163][164] and interferons [165][166][167][172][173][174] have also been evaluated. Yamamoto's group has effectively used interferon expressing OAdVs to target pancreatic cancer in mice models and immunocompetent hamster models [172][173][174]. OAdVs have also been developed to express a monoclonal antibody against CTLA4.…”

“…Promoter-based CRAd Lung, prostate, ovarian, pancreatic cancer, adult T cell Leukemia/Lymphoma, glioma, meduloblastoma, sarcomas [69,[209][210][211][212][213][214][215][216][217][218][219][220][221][222] CRAds based on Interaction of essential viral genes withTumor-specific proteins colon, breast, non-small cell lung, head and neck, and pancreatic tumors, cervical carcinoma, glioblastoma, cancers with disturbed Rb pathway [172,[223][224][225][226][227][228] As with genes, several endogenous miRNAs and other lncRNAs can be targeted to enhance the detargeting and retargeting ability of OAdVs [229]. For instance, liver, where most of the OAdV sequestration is observed, overexpresses miRNA122 and miR145.…”

Optimizing Oncolytic Viral Design to Enhance Antitumor Efficacy: Progress and Challenges

“…The rationale for using Type-I IFN as a transgene in oncolytic viruses is that, apart from their antiviral function, they also have antitumor potential due to their role in the maturation of dendritic cells [75] and cytotoxic T cells [76]. An oncolytic adenovirus armed with IFN-α and used in combination with radiation was found to yield a modest increase in antitumor efficacy in murine models of pancreatic cancer [77]. Likewise, some degree of improvement in antitumor efficacy of oncolytic VACV [78], VSV [79], NDV [80] and measles [81] were observed after arming them with IFN-β.…”

Macrophage migration inhibitory factor of Syrian golden hamster has similar structure and function as human MIF and promotes pancreatic tumor growth

“…Hamsters are important animal models for studying various infectious diseases of humans [1][2][3][4][5][6][7][8]. The hamster models of pancreatic and oral cancer have gained importance in their respective fields [9][10][11][12][13][14]. Moreover, these animals have also been instrumental in studying metabolic and/or inflammatory diseases like diabetes and pancreatitis [15,16].…”