University of California, San Francisco, USA
Oncolytic viruses are promising new treatments for cancer. We examined the anti-tumor effects of a replication-competent, oncolytic vaccinia virus mpJX-594 (mouse-prototype JX-594, a mouse-adapted version of Pexa-Vec) administered intravenously to RIP-Tag2 transgenic mice that spontaneously develop pancreatic neuroendocrine tumors. We found that mpJX-594 infected the endothelial cells of tumor blood vessels within hours of iv injection, before spreading to tumor cells. Endothelial cell infection by mpJX-594 was followed by leakiness and pruning of the tumor blood vessels. Non-tumor vasculature was not infected or detectably altered. Subsequently, the virus infected focal regions of tumor cells in the neuroendocrine tumors. Despite the sites of tumor infection being focal, infiltration by activated CD8 T-lymphocytes and apoptosis of tumor cells were widespread within tumors, and were followed by reduction in tumor size, invasion, and metastasis. The magnitude of mpJX-594 infection and anti-tumor actions were increased when the oncolytic virus was administered with the multi-targeted receptor tyrosine kinase inhibitor sunitinib. Together, these findings revealed that intravenous injection of oncolytic virus mpJX-594 results initially in selective infection of tumor blood vessels followed by focal regions of tumor cell infection and widespread CD8 T-cell influx and cell killing in tumors. Anti-tumor actions of mpJX-594 were stronger when the virus was given together with sunitinib. Even though the oncolytic viral infection of tumor cells was focal, the widespread influx of activated CD8 T-cells and tumor-cell apoptosis contributed to reduced tumor burden, invasion, and metastasis.
Dr. Donald McDonald is a Professor in the Department of Anatomy, UCSF. Research in the McDonald Anatomy Lab is examining the cellular mechanisms of angiogenesis, vascular remodeling, and lymphangiogenesis in mouse models of cancer, chronic inflammation, and obesity. Using in-vivo cell-biological approaches to determine how abnormalities of blood vessels and lymphatics contribute to disease pathophysiology are studied. Current interests include developing approaches for preventing, stopping, or reversing disease-related changes in blood vessels and lymphatics and learning the consequences of these actions. Related interests include the regulation of endothelial barrier function, downstream effects of altered plasma leakage and cellular trafficking, and control mechanisms of tissue fluid and cell clearance by lymphatics.
The overall goal is to advance the understanding and development of strategies that can stop or reverse angiogenesis and lymphangiogenesis and to characterize the downstream benefits and consequences in cancer, inflammatory disease, and obesity.