Preclinical safety evaluation of hepatic arterial infusion of oncolytic poxvirus

Euna Cho,1,2,* Eun Jin Ryu,2,3,* Fen Jiang,2,4 Ung Bae Jeon,3 Mong Cho,1,2 Cy Hyun Kim,1 Miyoung Kim,1 Nam Deuk Kim,5 Tae-Ho Hwang1,2 1Department of Pharmacology and Medical Research Center (MRC), Pusan National University School of Medicine, Yangsan, Korea; 2Department of Research and Development, Bionoxx Inc, Seongnam-si, Korea; 3Department of Radiology, Pusan National University Yangsan Hospital, Yangsan, Korea; 4School of Pharmaceutical Science (Shenzhen), Sun Yat-sen University, Guangzhou, China; 5Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, Korea *These authors contributed equally to this work Purpose: Oncolytic poxvirus has shown promise in treating various solid tumors, such as liver cancer, and administration of oncolytic poxvirus via the hepatic artery may provide more survival benefits than other routes of administration. However, there is a lack of safety information to guide the application of hepatic arterial infusion (HAI) of oncolytic poxvirus in human studies. To investigate the acute and chronic toxicity of HAI administration of oncolytic poxvirus in animals and provide safety information for future human studies. Methods: VVtk-, a vaccinia poxvirus with inactivated thymidine kinase gene, was administered via HAI to rabbits with normal liver function under angiography (1×108 or 1×109 pfu), and rats with N-nitrosomorpholine-induced precancerous liver cirrhosis under open surgery (1×108 pfu). Body weights and survival were monitored and blood samples were collected for hematological and biochemical tests. Distribution of A56 (a specific marker for poxvirus infection) in rabbit organs was evaluated using immunofluorescence assays. Results: HAI of high doses of VVtk- did not cause any acute or chronic changes in body weight, survival or in biochemical, hematological tests in the 2 animal models, and none of the changes showed dose dependency (in rabbit study), or were influenced by liver cirrhosis (in rat study). A56 was not detected in any of the major rabbit organs. Conclusion: HAI may provide a safe alternative route of oncolytic poxvirus administration for human studies. Keywords: oncolytic virus, transhepatic angiography, hepatocellular carcinoma, liver cirrhosis