Blocking Blood Supply to Breast Carcinoma with a DNA Vaccine Encoding VEGF Receptor-2
Annual rept. 15 Mar 2003-14 Mar 2004
SCRIPPS RESEARCH INST LA JOLLA CA
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The major goal of cancer immunology is to induce a tumor protective immune response that could effectively eradicate growth and dissemination of metastases. In our second fiscal year, we demonstrated proof of concept indicating that effective suppression of tumor angiogenesis can be achieved with a DNA vaccine encoding either muring VEGF receptor-2 Flk-1 or Flk-1 minigenes designed to induce CTL-mediated immune responses by targeting proliferation endothelial cells in the tumor vasculature. In fact, CTL-medicated killing of endothelial cells indicated a breaking of peripheral immune tolerance against FLK-1 or fragments of this self-antigen resulting in markedly reduced dissemination of metastases. Angiogenesis in the vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis and with only a slight delay in wound healing. Furthermore, a similar strategy was performed by targeting the transcription factor Fra-1 co-expressing secretory IL-18, in breast cancer model, which was highly effective in suppression or eradicating aggressive metastases by inducing anti-angiogenesis coupled with pronounced activation of T and NK cells. We demonstrated that this combination could not only suppress D2F2 breast cancer growth and metastases, but also induces a long-lived T cell memory.
- Medicine and Medical Research