Treatment of Pancreatic Cancer With an Oncolytic Adenovirus Expressing Interleukin-12 in Syrian Hamsters

Abstract

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.

Gene therapy of liver cancer: an update

“…Replicating vectors are suited for approaches that require intense expression of trangenes for a short period of time, such as GDEPT and certain immunotherapies. OVs expressing the pro-drug converting enzymes CD [135], cytochrome p450 [136] and TK, pro-apoptotic genes such as TRAIL [137,138], cytokines such as IFN [139,140], IL-12 [141], IL-24 [142] and GM-CSF [143,144] , or antiangionic genes such as endostatin [145] have demonstrated better performance than the previous "disarmed" versions. A VSV engineered to express IFN-alpha has completed the pre-clinical testing and is ready to be tested in HCC patients [146].…”

Recombinant viral vaccines for cancer

“…Less toxic than nonreplicating AdIL-12 due to specific tumour expression and decreased systemic exposure of cytokine. [74] Review Trends in Molecular Medicine September 2012, Vol. 18,No.…”

Oncolytic virotherapy for pancreatic cancer

“…This armed CRAd, expressing IL12, a cytokine that can stimulate innate and adaptive immunity against tumours, was significantly more effective than a control virus expressing luciferase in a Syrian hamster model of pancreatic cancer (Ref. 68). …”