Treatment of pancreatic cancer with an oncolytic adenovirus expressing interleukin-12 in Syrian hamsters.
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.
Bortolanza
Sergia
S
Division of Hepatology and Gene Therapy, University of Navarra, Pamplona, Spain.
Bunuales
Maria
M
Otano
Itziar
I
Gonzalez-Aseguinolaza
Gloria
G
Ortiz-de-Solorzano
Carlos
C
Perez
Daniel
D
Prieto
Jesus
J
Hernandez-Alcoceba
Ruben
R
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000818:Animals; D006224:Cricetinae; D018664:Interleukin-12 / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000556:secondary; D008647:Mesocricetus; D050130:Oncolytic Virotherapy; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D019076:Transgenes; D014779:Virus Replication
D018664:Interleukin-12