This Program Project Grant application seeks support for clinical and experimental studies concerning the major obstacles to successful allogeneic and autologous bone marrow transplantation for hematologic malignancies. These relevant problems include recurrence of the underlying disease, graft-versus host disease and infections with cytomegalovirus and fungus. The program consists of two clinical and seven experimental projects that are supported by three cores. The two clinical projects deal with attempts to eradicate leukemias and lymphomas and prospectively evaluate drug or drug combinations intended to prevent serious transplant-related complications such as acute or chronic GVHD, as well as pharmacologic and immunologic methods to prevent cytomegalovirus disease. In addition, we will introduce radioimmunotherapy utilizing antibodies to leukemia and lymphoma antigens in the preparatory regimen of patients undergoing allogeneic or autologous marrow transplantation for leukemia and myelodysplasia. It is also the intention to use molecular methods to inhibit the Philadelphia chromosome in ALL and to use new methods of gene transduction to study hematopoiesis and lymphopoiesis and to evaluate the source of relapse in patients undergoing autologous marrow transplantation for lymphoma. The two clinical projects serve as a resource for the experimental projects of the program. The seven experimental projects address the following biologically important transplantation related problems and topics: 1) Biological aspects of cytomegalovirus; 2) Acquisition of immunity to cytomegalovirus; 3) Genetic immunization; 4) Development of heavy metal labeled monoclonal antibodies for use in marrow transplantation to treat minimal residual disease; 5) Efficient transduction of hematopoietic stem cells and tumor cells; and 6) Development of ribozymes for the inhibition of malignant cells; These projects attempt to bring innovative concepts to clinical use in the treatment of patients with malignant hematologic disorders. The 8 interrelated projects of this application are supported by three cores, one for biostatistics, one for cytogenetics, and one for administration and coordination of research in this Program Project.
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