Immunization with synthetic VEGF peptides in ovarian cancer

Abstract

Objective: To assess the role of active immunotherapy targeting VEGF with a peptide vaccine as a potential treatment for ovarian cancer. Methods: A peptide vaccine targeting antigenic B-cell epitopes of VEGF were identified and linked to a promiscuous T-cell epitope. Elicited antibodies were assessed for their ability to recognize the VEGF protein, inhibit angiogenesis, inhibit the interaction of VEGF with its receptor, and inhibit cancer growth in mice. Results: Following immunization, high-titered elicited antibodies were shown to be specific for the full-length VEGF protein by ELISA and Western blot. Anti-VEGF peptide antibodies inhibited cellular migration, proliferation, invasion, tube formation, and growth of aortic ring cultures. These antibodies inhibited the interaction between VEGF and its receptor (VEGFR2) in a concentration-dependent manner. Confirmation of this mechanism was demonstrated through inhibition of VEGFR2 phosphorylation following culture of human endothelial vein endothelial cells with anti-VEGF peptide antibodies. These antibodies were shown to inhibit ovarian cancer xenograft growth in a nude mouse model following intraperitoneal passive immunization. Active immunization with the VEGF peptide vaccine inhibited VEGF-dependent pancreatic islet cell tumor growth in RIP1-Tag2 transgenic mice and was associated with decreased vasculogenesis in these tumors compared with animals vaccinated with an irrelevant peptide. Active immunization also inhibited growth of tumors from a VEGF overexpressing ovarian cancer cell line, resulting in decreased tumor size and tumor vessel density compared with control mice. Conclusions: Active immunization with VEGF peptides elicits antibodies that inhibit tumor growth by blocking VEGF-dependent angiogenesis. © 2010 Elsevier Inc. All rights reserved.