The Use of Her2/Neu-Specific Genetic Vaccines for the Prevention and Treatment of Breast Cancer
Final rept. 1 Jul 1998-30 Jun 2002
NORTH CAROLINA UNIV AT CHAPEL HILL
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We are investigating the feasibility of using HER2neu encoding genetic vaccines to induce potent CD4 and CD8 T cell reactivity for the prevention and treatment of breast cancer. Two strategies of genetic vaccination, each with distinct advantages will be assessed. The first strategy entails the use of alphavirus Venezuelan equine encephalitis virus VEE-replicons which selectively infect dendritic cells in vivo. Dendritic cells are characterized by a highly potent capacity to activate naive T cells. Our second strategy is to employ a plasmid DNA pDNA vaccine encoding HER2neu. pDNA vaccination has been shown to be effective in eliciting persistent T cell reactivity in various experimental model systems. VEE-replicon and pDNA vaccines encoding cytokines such as IL-12 and IL-18 will be used to enhance anti-HER2neu-specific CD4 Th1 cell and CD8 CTL activity. To directly assess the efficacy of our approach to prevent tumor cell growth andor eradicate established tumors, mice transgenic for a rat HER2neu gene will be employed. These mice develop mammary tumors and pulmonary metastatic lesions. Furthermore, we will use mice transgenic for HLA-A2.1 to investigate CD8 CTL responses to HER2neu-specific peptide epitopes which have been proposed as targets for immunotherapy in a clinical setting.
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