Although adoptive immunotherapy and tumor-specific vaccines can cure cancer in animal models, the application of immunotherapy to the treatment of human malignancy hinges on the identification of human tumor antigens to which specific immunity can be elicited. The goal of this proposal is to develop and apply a system for effectively immunizing human T cells to tumor antigens, in vitro. Such a method will provide a way to test the immunogenicity of potential tumor antigens, as well as a means of generating antigen specific T cells. In vitro immunization has the potential to be directly applied to vaccine design and may speed the realization of specific adoptive immunotherapy of cancer. Autologous bone marrow-derived dendritic cells will be used as antigen presenting cells, and purified CD4+ and CD8+ T cells will be used as responders to generate or augment T cell immunity to human tumor antigens, in vitro. HER-2/neu, a non-mutated self protein that is overexpressed in breast cancer, will be used as the prototype antigen, but the aim is to apply this system to investigations of the immunogenicity of other potential tumor antigens.
The specific aims are l) to generate HER-2/neu-specific CD4+ T cells using in vitro priming with dendritic cells in (a) normal individuals and (b) individuals with HER-2/neu positive breast cancers; 2) to determine the culture conditions for preferentially priming Th1 versus Th2 CD4+ T cells in vitro; and 3) to develop in vitro priming with dendritic cells to generate HER-2/neu-specific CD8+ cytotoxic T cells from (a) normal individuals and (b) individuals with HER-2/neu positive breast cancers.
