This program project was initiated 22 years ago as a comprehensive effort to study the biology of bone marrow transplantation (BMT) as treatment for human disease. Over that period of time, BMT has proven to be effective therapy, and even the treatment of choice, for a variety of malignant diseases. However, BMT has failed to reach its full therapeutic potential for a number of reasons, including graft-versus-host disease (GVHD), immunodeficiency, infections, preparative regimen toxicities, and inability to completely eradicate tumor. Major advances, particularly in the area of supportive care, have decreased the magnitude of all these problems. Clinical progress in preventing tumor recurrence has generally lagged behind the advances in BMT supportive care. Tumor recurrence remains the major cause for failure of autologous BMT, accounting for nearly 90% of the failures, and is also the major cause of failure of allogeneic BMT for many malignancies. Modifications of cytotoxic preparative regimens have not made a major impact on the outcome of BMT. Cytotoxic preparative regimens for BMT are at or near non-hematologic dose-limiting toxicity; this hinders a further increase in the intensity of, or the addition of new cytotoxic agents to, these preparative regimens. Further, the tumor remaining after the high-dose BMT preparative regimen likely represents an extremely drug-resistant population of cells. Other approaches for improving the antitumor activity of BMT are therefore needed. The overall goal of this proposal is to study such approaches, primarily biologic in nature, in the laboratory and to translate promising strategies into the clinic. These approaches include: 1) the immunologic graft-versus-tumor effect associated with allogeneic BMT; 2) methods to augment cyclosporine (CsA)- induced induced """"""""autologous GVHD""""""""; 3) specific and non-specific adoptive immunotherapy; 4) tumor vaccines, specifically in the setting of autologous BMT; 5) therapy to induce terminal differentiation of malignant progenitors, and 6) modulation of the cell cycle to overcome cellular blocks to apoptosis.
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