IFN Expressing Oncolytic Adenovirus as a Tool to Improve Pancreatic Cancer Therapy

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is the 3rd cause of cancer related death in the US. Aside from surgery, which is not applicable to 80% of patients, there is no highly effective therapy to treat the disease. Due to late diagnosis and advanced disease, PDAC patients live 3–6 months post‐diagnosis and 5‐year survival is 6%. Despite this discouraging scenario, clinical trials testing use of adjuvant therapy combined with IFN‐α (IFN), 5‐FU, CDDP, and radiation improved the 2‐year survival of patients by 20–41%, and the 5‐year survival by 35%. While efficacious, IFN‐therapy drawbacks included high IFN systemic toxicity, increasing patient drop‐out from trials, and low levels of the cytokine in tumors, reducing chemo‐radio sensitization of IFN in tumors. Aiming to perfect this promising therapy, we studied the use of IFN‐expressing oncolytic adenovirus (OAd) vectors in combination with chemoradiation mimicking the aforementioned IFN‐chemoradiation based clinical trials. As IFN can stimulate tumor specific immune response, we first evaluated the effect of a hamster IFN expressing vector (OAd‐hamIFN) in a syngeneic immunocompetent hamster model of PDAC. To analyse the interaction of OAd with chemotherapy and radiation without the interference of the immune system, we later accessed the effect of a human IFN‐expressing vector (OAd‐IFN) in immunodeficient mice bearing human PDAC xenografts. In both studies, OAd vectors included 5/3 fiber modification to enhance infectivity in PDAC cells, over expressed Adenovirus Death Protein (ADP) to potentiate cell oncolysis, and expressed IFN in a replication dependent manner. As PDAC cells upregulate Cox‐2, we used the Cox‐2 promoter in the OAd‐IFN to restrict viral replication to human PDAC cells. Data showed that combinations of 5‐FU, radiation, and 5‐FU + radiation with either OAd‐hamIFN in hamster PDAC cells, or OAd‐IFN in human PDAC cells resulted in highly synergistic and cytotoxic combinations in vitro. Studies in immunocompetent hamsters showed that use of OAd‐hamIFN in combination with therapeutics used in IFN‐therapy improved treatment efficacy, and that use of the virus mimicking the IFN‐therapy was the most efficacious treatment. When analyzing effect of OAd‐IFN in combination with 5‐FU + CDDP in human PDAC cells, combinations were shown to be antagonistic and weakly cytotoxic. However, addition of radiation to treatment (OAd‐IFN + (5‐FU + CDDP) + radiation) overruled chemotherapy antagonism, resulting in highly synergistic and extremely potent treatments in vitro and in mice bearing PDAC xenografts. As radiation was shown to abolish antagonism of chemotherapy to virus in vivo, we tested different radiation protocols in combination with virus. We concluded that the best radiation protocol comprised of infecting tumors before irradiation. In summary, our data strongly supported inclusion of an IFN expressing OAd in treatments mimicking IFN‐therapy. As this therapy is one of the few showing an impact in patient survival, improvement of therapy with the virus might finally result in an potent treatment against PDAC.Support or Funding InformationNIH/NCIP50CA101955, NIH/NCIR01CA094084This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.