The applicant's hypothesis is that a polynucleotide immunization strategy can induce cellular and humoral immunity to human tumor-associated antigens with resultant eradication of limited numbers of tumor cells in animals or patients with low tumor burden breast cancer. The applicant proposes to test this hypothesis in the context of two tumor-associated antigens, CEA and HER2/neu. The applicant has already demonstrated that immunization with plasmid DNA encoding human CEA can elicit CEA-specific humoral and cellular immune responses with resultant protection against subsequent challenge with syngeneic, CEA-expressing tumor cells. The applicant now proposes to address the main issue relevant to successful translation of CEA polynucleotide immunization to clinical breast cancer trials, the ability to break tolerance to CEA in mice transgenic for human CEA. The primary issue with regard to use of HER2/neu as the target antigen for polynucleotide immunization is which molecular construct will elicit HER2/neu-specific immune responses and antitumor effects while minimizing the risk of cellular transformation. The applicant proposes to evaluate plasmid DNA encoding portions of the HER2/neu cDNA as well as replicative and non-replicative RNA encoding HER2/neu for the purpose of polynucleotide immunization. Those constructs capable of eliciting potent HER2/neu specific immune responses will be evaluated regarding their ability to prevent or reverse the growth of spontaneous mammary adenocarcinomas overexpressing neu in mice transgenic for activated neu. The most promising reagents identified in preclinical animals models will be translated to phase I trials.
|Hampton, T A; Conry, R M; Khazaeli, M B et al. (2000) SEREX analysis for tumor antigen identification in a mouse model of adenocarcinoma. Cancer Gene Ther 7:446-55|
|Conry, R M; White, S A; Fultz, P N et al. (1998) Polynucleotide immunization of nonhuman primates against carcinoembryonic antigen. Clin Cancer Res 4:2903-12|