These project addresses the overall hypothesis that a specific T cell response of sufficient magnitude directed against tumor associated antigens (TAA) expressed by breast cancers progression and metastasis. It has been recently shown that HER2/neu directed immunotherapy could have clinical benefits in patients with breast cancer. Although early attempts to target HER2/neu have focused on generating CD8+ T cell responses, we have begun to focus on augmenting HER2/neu specific class II restricted CD4+ T cell responses. We have recently used Flt3L mobilized and protein loaded dendritic cells (DC) to augment T helper cell responses against recall antigens and induce T helper cell responses against naive antigens in patients with metastatic cancer. We found that a single immunization with recall antigen (tetanus toxoid = TT) loaded DC lead to a significant circulating T helper response, whereas multiple immunizations with Keyhole Limpet Hemocyanin (KLH) loaded DC were required to generate a detectable circulating T helper response. Using these Flt3L mobilized DC based vaccination strategies, we propose to study the ability of HER2/neu protein loaded DC to induce ER2/neu specific T helper cell responses in patients with HER2/neu overexpressing breast cancer, determining the impact of repeated immunizations on inducing high frequency CD4+ T helper cell responses. We then propose to optimize HER2/neu loading strategies into DC by generating recombinant HER2/neu expressing adenoviral vectors to modify DC. Finally, we will perform a clinical trail immunizing patients with HER2/neu modified DC. This project proposes to extend our previous work with class I peptide pulsed DC based immunotherapy, leading to sequential clinical trials to optimize the generation HER2/neu specific CD8+ cytotoxic and CD4+ T helper cell responses. These clinical trials, focusing on optimizing CD4+ T helper responses to HER2/neu, will form the background to rationally choose HER2/neu specific vaccination strategies in trials designed to demonstrate a clinical benefit of HER2/neu directed immunotherapy.
