Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer

Abstract

Background The addition of interferon alpha (IFN) to adjuvant chemoradiotherapy regimens resulted in remarkable improvements in survival for pancreatic cancer patients. However, systemic toxicities and insufficient levels of IFN at the tumor sites have limited its widespread adoption in treatment schemes. We have previously developed an IFN-expressing conditionally replicative oncolytic adenovirus and demonstrated its therapeutic effects both in vitro and in vivo. Here, the same vectors were tested in a syngeneic and immunocompetent Syrian hamster model to better understand the roles of adenoviral replication and of IFN’s pleiotropic effects on pancreatic tumor growth suppression. Methods Oncolytic adenoviruses expressing human or hamster IFN were designed and generated. Viral vectors were tested in vitro to determine qualitative and quantitative cell viability, Cox2 promoter activity, and IFN production. For the in vivo studies, subcutaneous hamster pancreatic cancer tumors were treated with one intratumoral dose of virus. Similarly, one intraperitoneal dose of virus was used to prolong survival in a carcinomatosis model. Results All cell lines tested demonstrated Cox2 promoter activity. The oncolytic potential of a replication competent adenovirus expressing the IFN cytokine was clearly demonstrated. These viruses resulted in significant tumor growth suppression and survival increases compared to controls in a hamster model. Conclusions The profound therapeutic potential of an IFN-expressing oncolytic adenovirus for the treatment of pancreatic cancer was demonstrated in a syngeneic Syrian hamster model. These results strongly suggest the potential application of our viruses as part of combination regimens with other therapeutics.

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

“…To improve the infectivity and oncolysis of conventional OAds, the virus was genetically modified to include an Ad5/Ad3 chimeric fiber and overexpress the adenovirus death protein (ADP). In our later studies we have tested another OAd (OAd-hamIFN) in an immunocompetent Syrian hamster model of PDAC [ 22 ]. In contrast to mice, Syrian hamsters support human adenovirus replication [ 23 ] and provide the opportunity to analyze the immunostimulatory effect of IFN-expressing adenoviruses [ 23 – 25 ].…”

The Development of Oncolytic Adenovirus Therapy in the Past and Future - For the Case of Pancreatic Cancer

“…As a result, IFN expressing Ad vectors have been made at high titer[65], and OAd with IFN-α showed efficient replication in pancreatic cancer cells[53,66]. In this way, OAd with IFN-α has a unique benefit for its application to pancreatic cancers.…”

Recent advances in oncolytic adenovirus therapies for cancer

“…An armed Onc.Ad expressing IFNα resulted in significant tumor suppression and survival advantage in a Syrian hamster model of pancreatic cancer compared to replication deficient Ad or a control Onc.Ad, although all of the animals eventually succumbed to the disease. Immune cell infiltration was not evaluated in this model [35]. The transient anti-tumor response may reflect transcriptional silencing of Ad replication and/or elimination of Ad infected cells, which can occur as a result of type I IFN-induced anti-viral responses [36].…”