Treatment of pancreatic cancer with an oncolytic adenovirus expressing interleukin-12 in Syrian hamsters
Sergia Bortolanza (1), Maria Bunuales (1), Itziar Otano (1), Gloria Gonzalez-Aseguinolaza (1), Carlos Ortiz-de-Solorzano (2), Daniel Perez (2), Jesus Prieto (1,3) and Ruben Hernandez-Alcoceba (1)
(1)Division of Hepatology and Gene Therapy, University of Navarra, Pamplona, Spain
(2) Morphology and Imaging Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
(3) CIBERehd, University Clinic, University of Navarra, Pamplona, Spain
Pancreatic cancer is an aggressive malignancy resistant to most conventional and experimental therapies, including conditionally replicative adenoviruses (CRAds). The incorporation of immunostimulatory genes such as interleukin-12 (IL-12) in these viruses may overcome some of their limitations, but evaluation of such vectors requires suitable preclinical models.
We describe a CRAd in which replication is dependent on hypoxia-inducible factor (HIF) activity and alterations of the pRB pathway in cancer cells.
Transgenes (luciferase or IL-12) were incorporated into E3 region of the virus using a selective 6.7K/gp19K deletion. A novel permissive model of pancreatic cancer developed in immunocompetent Syrian hamsters was used for in vivo analysis. We show that, in contrast with nonreplicating adenoviruses (NR-Ad), active viral production and enhanced transgene expression took place in vivo. A single intratumor inoculation of the CRAd expressing IL-12 (Ad-DHscIL12) achieved a potent antitumor effect, whereas higher doses of replication-competent adenoviruses carrying luciferase did not. Compared to a standard NR-Ad expressing IL-12, Ad-DHscIL12 was less toxic in hamsters, with more selective tumor expression and shorter systemic exposure to the cytokine.
We conclude that the expression of IL-12 in the context of a hypoxia-inducible oncolytic adenovirus is effective against pancreatic cancer in a relevant animal model.
CITATION Mol Ther. 2009 Apr;17(4):614-22