Bacille Calmette-Guerin is the treatment of choice for superficial bladder tumors. Prospective randomized clinical trials have shown that the efficacy of intravesical BCG as an adjuvant to surgery is superior to surgery alone or adjuvant chemotherapy. The mechanisms by which BCG mediates antitumor activity are not known. The importance of understanding the mechanisms of action of intravesical BCG could be far-reaching and could provide a basis for better selection of bladder cancer patients for therapy, improve monitoring of patient progress to therapy and could provide a basis for developing immunotherapy protocols for other forms of cancer. Furthermore, a clear understanding of the mechanisms could lead to effective therapy without the need for treating with a viable, potentially infective, bacterium. Data from clinical trials on bladder cancer patients as well as studies on animal tumor models suggest that inhibition of tumor growth is closely associated with BCG-induced modulation of the immune response. The data suggest that intravesical BCG attaches to the bladder wall via a fibronectin bridge. Fibronectin attachment appears to be a requisite first step in the initiation of the immune response to BCG. The subsequent development of a T cell dependent immune response is required for antitumor activity. Neither the responding T cell subset nor the actual tumoricidal mechanism are known. To more clearly understand the effector mechanisms, a mouse bladder tumor model in which tumors are implanted directly into bladders has been adapted for the study of intravesical BCG therapy. Using this model, the immunological responses required for inhibition of bladder tumor growth will be studied. Adoptive transfer of T lymphocyte subsets will be performed to identify the population required for antitumor activity. The antigens recognized will be determined and clones T lymphocyte cultures will be established. Effector function of fractionated spleen T cells and cloned T cell lines will be determined and in vivo antitumor activity of each will be established. Factors influencing the initiation of the immune response will be established including functional analysis of antigen presenting cells and the modulatory effects of fibronectin on the initiation of the response. Other effector functions which may be important to antitumor activity include monokine production, non specific cell-mediated mechanisms and antibody production.
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