Novel Chimeric Immuno-Oncolytic Virus CF33-hNIS-antiPDL1 for the Treatment of Pancreatic Cancer
Yanghee Woo, Zhifang Zhang, Annie Yang, Shyambabu Chaurasiya, Anthony K. Park, Jianming Lü, Sang‐In Kim, Susanne G. Warner, Daniel D. Von Hoff, Yuman Fong
Abstract
BACKGROUND: Peritoneal carcinomatosis (PC) from pancreatic ductal adenocarcinoma (PDAC) is fatal. Our preclinical study presents an effective treatment against PDAC PC using a novel oncolytic viral agent, CF33-hNIS-antiPDL1. STUDY DESIGN: CF33-hNIS-antiPDL1 is a genetically engineered chimeric orthopoxvirus, CF33, armed with the human Sodium Iodide Symporter (hNIS) and anti-PD-L1 antibody (anti-PD-L1). The in vitro cytotoxic ability of this virus against 5 PDAC cell lines was tested at various doses (multiplicity of infection [MOI] = 0.01, 0.1, 1, 10). Production and blockade function of virus-encoded anti-PD-L1 antibody were verified using immunoblot, immunoprecipitation, and PD-1/PD-L1 bioassay. In vivo mouse models of PC, with or without subcutaneous (SC) tumors, created by injecting AsPC-1-ffluc cells into nude mice, were treated with PBS or a single dose (1×105 plaque-forming units) of either intraperitoneal (IP) or IV injection of CF33-hNIS-antiPDL1. Mice with PC tumors were treated on days 0, 2, or 14 after tumor implantation. RESULTS: CF33-hNIS-antiPDL1 killed PDAC cells in a dose-dependent manner, achieving >90% cell killing by day 8. Cells infected with CF33-hNIS-antiPDL1 produced bioactive anti-PD-L1 antibody, which blocked PD-1/PD-L1 interaction. In vivo, a single dose of virus reduced tumor burden and prolonged survival of treated mice. It was observed that IP administration of CF33-hNIS-antiPDL1 was more effective than IV administration. CONCLUSIONS: CF33-hNIS-antiPDL1 virus is effective in infecting and killing human PDACs and producing functional anti-PD-L1 antibody. Intraperitoneal delivery of CF33-hNIS-antiPDL1 effectively reduces peritoneal tumor burden and improves survival after only 1 dose and is superior to IV delivery.