The endothelial layer is a barrier through which circulating oncolytic viruses and virus-infected cell carriers must cross to access tumor cells. We propose that addition of vascular binding motifs on the surfaces of oncolytic measles viruses (or virus-infected cell carriers) allows them to recognize and bind to unique antigenic markers on the lumenal surface of endothelial cells that line the tumor neovasculature, thereby enhancing their localization/arrest at the tumor site. Using the versatile measles virus display platform, we have generated dual tropic measles viruses (vascular binding and tumor tropic) and demonstrated that after intravascular administration, measles viruses displaying a??3 integrin binding motifs, but not parental virus, can interact with the lumenal surface of endothelial cells in the neovessels. The bound viruses can extravasate through fenestrations between endothelial cells, transcytose through or infect the endothelial cell to cross the endothelial barrier and infect underlying tumor cells. We are now poised to test the hypotheses that 1) chimeric MV with added vascular binding motifs (and cell carriers infected with these viruses) will have enhanced localization at sites of tumor growth and 2) such dual tropic vascular binding MV (and virus-infected cell carriers) will have enhanced anti-tumor efficacy compared to parental viruses that cannot interact with tumor neovessels.
Systemically administered therapeutic viruses and virus loaded cell carriers do not always arrive at the tumor site. This grant seeks to improve the tumor localization of measles viruses and virus infected cell carriers by adding vascular binding motifs on their surfaces to enhance their attachment/arrest at tumor neovessels and tumor sites.
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