Madeleine Lepard, McMaster University

Madeleine Lepard (1), Maria Davola (1), Olga Cormier (1), Susan Collins (1), Amy Gillgrass (2) and Karen Mossman (1) – (1) Department of Medicine, Centre for Discovery in Cancer Research, McMaster University, Hamilton ON Canada, and (2) Department of Microbiology and Immunology, Dalhousie University, Halifax NS Canada.

Fighting & Responding

Pancreatic ductal adenocarcinoma (PDAC) is a prevalent and aggressive form of pancreatic cancer. Prognosis is often poor due to its resistance to available therapies. Bovine herpesvirus type 1 (BHV-1) is an oncolytic virus with robust immunostimulatory anti-tumour activity that targets a wide range of human PDAC cells, thus demonstrating promise as a potential virotherapy. Syngeneic mouse models have demonstrated that BHV-1 activates and recruits CD8 T cells into the tumour, however these models prevent us from studying human tumours due to xenoreactivity. Humanized mouse models engrafted with human stem cells develop a functional human immune system, so they are ideal for investigating immune responses against human tumours. The addition of HLA-class-I match reduces tumour xenoreactivity and improves the activity of CD8 T cells. Here, we compared two HLA-class-I-matched humanized PDAC models engrafted with either cord blood-derived (hu-CB) or mobilised peripheral blood-derived (hu-mPB) stem cells. While the number of human leukocytes in the blood did not differ before 16 weeks post-engraftment, after that time the number of human leukocytes, especially CD4 T cells, was significantly higher in hu-CB-mice. By 24 weeks post-engraftment, hu-mPB-mice had almost entirely lost human immune reconstitution while hu-CB-mice's levels continued to rise. Th1 cytokine responses and CD8 cytotoxicity were also greater in hu-CB-mice. When tumours were treated with BHV-1, 71% of hu-CB-mice showed complete tumour regression, whereas hu-mPB-mice showed reduction in tumour size but failed to achieve total regression. While both models have merit, hu-CB-mice are likely a better model for investigating the immunostimulatory ability of BHV-1.