The overall objectives of this project are to understand the mechanisms that control the effectiveness of T cell responses to tumors and to develop methods for eliciting protective responses to tumors using nonliving vaccines. The objective of Aim 1 is to understand how immune surveillance of tumors is regulated and to manipulate this process to achieve more effective tumor immunotherapy. The investigators hypothesize and have preliminary supporting data that cell death (such as occurs in rapidly dividing tumors and viral infections) generates a signal that stimulates immune surveillance and the generation of CTL responses. The goals of this Aim are to test this hypothesis, determine its underlying mechanisms and exploit this phenomenon to elicit more effective responses with the tumor vaccines developed in Aim 2. The goal of aim 2 is to develop protein-based vaccines that will induce immunity to tumors in cancer bearing animals. The investigators' experimental approach is based on their discovery that proteins conjugated to phagocytic substrates are targeted into the class I and II pathways of dendritic cells and can elicit both CD4 and CD8 T cell immunity. Since this approach has already been effective in protecting animals against challenge with tumors, there is a strong rationale to develop it to treat established tumors. They will systemically explore in different tumor systems how this kind of immunogen can be used most effectively as an immunotherapy. The optimal antigen constructs, adjuvants and dosing schedules will be determined. In parallel they will elucidate the underlying mechanisms by which this therapy leads to immunity or tumor progression and use this information to further optimize the approach. The goal of Aim 3 is to investigate how negative regulatory signals limit immune responses and whether blocking these signals can enhance the efficacy of the tumor vaccines developed in Aim 1. The investigators' studies will focus on negative co-stimulation signals mediated by CTLA4 and apoptotic signals delivered by FAS and TNF. They will determine whether blocking these signals with mAbs or mutations leads to stronger and/or more long-lasting immune responses to immunizations. In addition they will examine whether these manipulations lead to more effective immunotherapy due to stronger responses or by preventing tumors from evading immune responses.
