DNA vaccines designed to inhibit tumor growth by suppression of angiogenesis

The development of new blood vessels, i.e. angiogenesis, is a rate-limiting step in the development of tumors since tumor growth is generally limited to 1-2 mm3 in the absence of a blood supply. Thus, the inhibition of tumor growth by attacking the tumor's vascular supply offers a primary target for antiangiogenic intervention by DNA-based vaccines. Here, we describe two novel orally delivered DNA vaccines which suppress tumor angiogenesis and induce a robust cell-mediated immune response that provides for long-lived protection against melanoma, colon, breast and non-small-cell lung carcinoma in mouse model systems. These vaccines, which are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs, are directed against such targets as vascular endothelial growth factor receptor 2 (FLK-1) and transcription factor Fos-related antigen 1 (Fra-1). Both vaccines break peripheral T cell tolerance against these self-antigens and induce a robust T cell-mediated immune response leading to suppression of tumor angiogenesis and resulting in effective suppression of tumor growth and metastases. Such research efforts may open up new possibilities for the rational design of future DNA vaccines effective for the prevention and treatment of cancer.