The Use of Venezuelan Equine Encephalitis Encoding the Her-2/neu Tumor Associated Antigen for the Prevention and Treatment of Breast Cancer
Annual summary 15 Apr 2000-14 Apr 2003
NORTH CAROLINA UNIV AT CHAPEL HILL
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Our project has focused developing a vaccination protocol using Venezuelan Equine Encephalitis VEE replicons VRP encoding the Her-2neu tumor associated antigen to mediate anti tumor immunity in Her-2neu transgenic Tg mice. Initial work demonstrated that vaccination with the VRP encoding full-length Her2neu elicited robust Her2neu-specific cytotoxic T lymphocyte CTL reactivity in the non-Tg parental strain FVBn of mice Fig. 1. However, no significant Her2neu-specific CTL reactivity was detected in cultures prepared from the FVBneu Tg mice Fig. 1. The results demonstrated that an element of self tolerance to Her2neu exists in the transgenic mice. We postulated that due to the size of the cDNA encoding full length Her2neu greater than 4 kb, levels of in vivo expression were not sufficient to elicit a CD8 T cell response in FVBneu Tg mice. Accordingly, a VRP encoding the extracellular and transmembrane domains VRP-ECTMD spanning approximately 2 kb was established. More recently, a VRP encoding the intracellular domain VRP-ICD has also been generated. Notably, a comparable frequency of IL-2 and IFNy secreting T cells following stimulation with Her2neu expressing NT2.5 tumor cells was detected in cultures prepared from either FVBn or FVBIneu Tg mice Fig. 2. These results demonstrated that vaccination with VRP-ECTMD could elicit significant Her2neu-specific T cell reactivity despite tolerance to the neo-self antigen.
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