The goal of this clinical and laboratory based research program is to improve the outcome of bone marrow transplantation for hematologic malignancies using matched and mismatched normal marrow stem cell donors. In particular the work focuses on ways to improve the quality and speed of immunological recovery after the transplant. This involves preventing the unwanted graft-versus-host disease (GVHD) effect of donor lymphocytes and amplifying beneficial immune responses to viruses and to the patient's leukemia - the so-called graft-versus-leukemia (GVL) effect. Fifty bone marrow transplants from closely matched donors have been carried out in a phase 1 study to determine the effect of delayed donor lymphocyte add-back to T cell depleted marrow transplants for leukemia and multiple myeloma. The results indicate that it is feasible to restore donor immunity separately from bone marrow function. They restore donor immunity separately from bone marrow function. They provide the clinical basis for adding back donor T cells with reduced capacity to cause GVHD but with conserved responsiveness to leukemia and viral agents. The laboratory-based research has three major aspects: (1) Perfecting a selective immunodepletion technique to provide donor immune cells deprived of GVHD reactivity. (2) Characterizing interactions of T lymphocytes with leukemia cells in order to define the effector lymphocytes involved in GVL reactions. (3) Identifying antigens presented by leukemia cells which elicit leukemia-specific T cell responses. These studies are precursors to adoptive immunotherapy for leukemia in man using T cells exhibiting specific and enhanced antileukemia reactivity.
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