Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms

The use of oncolytic viruses in cancer therapy presents numerous unanswered questions. In this research, we evaluated the potential of mpJX-594, a replication-competent vaccinia virus designed as a mouse model of JX-594 and administered through intravenous injection, to target the blood vessels within tumors, stimulate immune responses leading to tumor cell death beyond the immediate sites of viral infection, and inhibit tumor invasion and the spread of metastasis.

These effects were investigated in RIP-Tag2 transgenic mice, a model system in which pancreatic neuroendocrine tumors develop spontaneously and progress in a manner similar to human disease. Our observations indicated that mpJX-594 initially infected the endothelial cells lining the tumor blood vessels. This initial infection led to a process of vascular pruning, effectively reducing the tumor’s blood supply, and caused prolonged leakage from these vessels within the tumors, but not in the blood vessels of normal organs.

Similar effects on tumor vasculature were also seen in U87 glioma tumors. Subsequently, the viral infection spread from the vascular cells to the tumor cells themselves. Notably, the extent of tumor cell death observed was significantly greater than the area directly infected by the virus. We found that this widespread tumor cell killing at five days post-infection was prevented when CD8+ T lymphocytes, a type of immune cell crucial for killing infected cells, were depleted.

Furthermore, this widespread killing did not depend on the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) by the virus, as variants of mpJX-594 that expressed human GM-CSF, mouse GM-CSF, or no GM-CSF at all, induced comparable levels of tumor cell death. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were enhanced when administered concurrently with or sequentially after sunitinib, a drug that inhibits multiple receptor tyrosine kinases.

These amplified effects were not replicated by selectively inhibiting only VEGFR2, a key receptor involved in blood vessel formation, despite achieving a similar degree of vascular pruning. However, the combination of mpJX-594 and sunitinib was associated with a suppression of regulatory T cells, a type of immune cell that can suppress antitumor immunity, and a greater infiltration of activated CD8+ T cells into the tumors.

Taken together, our findings demonstrate that mpJX-594 targets the blood vessels of tumors, subsequently spreads to tumor cells, and induces a widespread tumor cell killing that is dependent on CD8+ T cells in both primary tumors and metastatic sites. Importantly, GSK’963 these beneficial effects can be further amplified by the coadministration of sunitinib.

Significance: These results reveal several previously unrecognized characteristics of the antitumor properties of oncolytic vaccinia viruses, all of which can be potentiated by the multitargeted kinase inhibitor sunitinib. Cancer Research; 78(4); 922-37. ©2017 AACR.