The long-term objective of this project is to develop a novel active immunotherapy approach to inhibit tumor angiogenesis. Angiogenesis, the formation of capillaries from preexisting blood vessels, is required for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and its receptor Flk-1/KDR have been shown to play a critical role in tumor angiogenesis. Several laboratories including our own have shown that blocking the VEGF pathway is a useful therapeutic strategy for inhibiting angiogenesis and tumor growth. In this proposal, we propose to test the hypothesis that an active immunotherapy approach targeting the Flk-1 receptor can inhibit tumor angiogenesis and tumor growth. The specific aims of this proposal are (1) To test whether immunization with dendritic cells pulsed with Flk-1 antigen will induce an immune response against the Flk-1 receptor; (2) To test whether this immunization approach can inhibit angiogenesis in vivo and tumor growth and metastasis in a mouse model; and (3) Test whether active immunization against Flk-1 has an adverse effect on normal mouse vasculature and normal physiological angiogenesis. The first aim will provide evidence that a humoral or/and cellular immune response can be elicited against the Flk-1 receptor by breaking immune tolerance to the self-antigen. The second aim is designed to provide proof of concept that targeting the Flk-1 receptor by active immunization will inhibit angiogenesis and tumor growth. The results of Aim 3 will provide important information and the basis for further toxicology studies in primates with a candidate VEGF receptor vaccine. Overall, this proposal will provide the basis for development of a novel therapeutic approach that could eventually lead to treatment of human cancers. PROPOSED COMMERCIAL APPLICATIONS: There are potential commercial opportunities for this type of therapy if proof of principle is established. The overall market for a successful anti- angiogenesis therapy that inhibits tumor growth will potentially be very large, since it likely will include many human carcinomas.
Thesaurus Terms: active immunization, angiogenesis, growth factor receptor, neoplasm /cancer blood supply, neoplasm /cancer immunotherapy, vascular endothelial growth factor angiogenesis inhibitor, cellular immunity, dendritic cell, humoral immunity laboratory mouse
