Pexa-Vec (JX-594) is an engineered oncolytic vaccinia virus that lacks thymidine kinase and expresses human granulocyte-macrophage colony stimulating factor. In addition to having oncolytic effects on tumor cells and promoting an immune response, Pexa-Vec has been found to cause rapid reduction of tumor blood flow in preclinical models and in clinical trials. The angiogenesis inhibitor sunitinib reduces tumor vascularity and can augment the activity of vesicular stomatitis virus by suppressing two interferon-induced anti-viral host proteins, RNA-dependent protein kinase and ribonuclease L.
We explored the interaction of mpJX-594, a mouse-adapted version of Pexa-Vec, and sunitinib. The mouse-adapted version, mpJX-594, was engineered from Western Reserve strain vaccinia virus by deletion of thymidine kinase and addition of human GM-CSF, yellow fluorescent protein, and luciferase genes. The effects of mpJX-594 or sunitinib given individually on pancreatic neuroendocrine tumors in RIP-Tag2 mice were compared to those of the two agents given together. Treatment with mpJX-594 alone reduced tumor vascularity and induced widespread apoptosis in the tumors. After treatment with sunitinib alone, tumor vascularity was decreased, but apoptosis was much less than after mpJX-594 alone. When mpJX-594 was given together with sunitinib, the amount of viral infection in tumors, assessed by vaccinia immunoreactivity, was much more than after mpJX-594 alone. Vaccinia staining was detected in most of the tumor blood vessels and in large patches of tumor cells. The reduction of tumor vascularity and amount of apoptosis were greater after both agents than after either of them given alone.
To determine whether mpJX-594 increased the efficacy of sunitinib in tumors or vice versa, we examined the effects of sequential administration, where mpJX-594 or sunitinib was given first and then followed 5 days later by the other. In both cases, the reduction in tumor vascularity after sequential treatment was greater than after either agent given alone. When sunitinib was given first, tumor vascularity was less throughout tumors, and the surviving vessels appeared more normal. By comparison, when mpJX-594 was given before sunitinib, the tumor vasculature was greatly reduced in some regions and less so in others, and the remaining blood vessels were abnormal. Apoptotic cells were much more numerous and widespread when mpJX-594 preceded sunitinib than after either agent given alone. In contrast, when sunitinib was given first, tumor apoptosis was greater than after sunitinib alone but not after mpJX-594 alone.
Together these findings indicate that mpJX-594 amplifies the anti-vascular and anti-tumor effects of sunitinib and vice versa in RIP-Tag2 pancreatic neuroendocrine tumors, regardless of the sequence of administration, but the magnitude of the changes differs according to the sequence of administration.
Citation Format: Corry E. McDonald, Barbara Sennino, Brian J. Schriver, John C. Bell, David H. Kirn, Caroline J. Breitbach, Donald M. McDonald. Synergistic actions of oncolytic vaccinia virus and sunitinib on pancreatic neuroendocrine tumors in RIP-Tag2 mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 296. doi:10.1158/1538-7445.AM2015-296