The design of immunotherapy for the treatment of human tumors is dependent on an understanding of the host-tumor interaction, which we feel is best accomplished by studying the immune cells/mechanisms present at the tumor site. Intravesical immunotherapy with BCG for human bladder cancer is arguably the most effective immunotherapeutic modality for cancer today. While it is highly effective, it cures less than 50% of patients and its mechanism of action is not known. The studies described in this application are aimed at determining the role of BCG in mediating host anti-tumor responsiveness. We will examine three putative mechanisms of BCG action by analyzing its effects on the host-anti-tumor response at the bladder site. We will determine if: 1. BCG therapy results in tumor lysis as a result of the generation of a BCG-specific T cell response and a resultant """"""""bystander"""""""" killing or via the presentation of BCG antigens to the responder T cells. 2. BCG induces and/or enhances the generation of tumor-specific T cell response resulting in tumor lysis by directly cytotoxic and/or lymphokine-producing T cells. 3. BCG activated gamma/delta T cells either directly lyse or product lymphokines which lyse the tumor. Using cellular and molecular methods, we will study both the effector T cells as well as the bladder carcinoma cells in order to identify aspects of both populations required for productive anti-tumor interactions. The results of the above studies will be correlated with clinical outcome in order to identify clinically important response criteria. The long term goal of these studies is to identify the cells and mechanisms involved in the anti-tumor response to BCG which can be further manipulated in the design of more effective immunotherapeutic approaches.
