Many hematologic cancers that are incurable by conventional chemotherapy may be cured by myeloablative chemoradiotherapy followed by allogeneic bone marrow transplantation, or alloBMT. AlloBMT can be associated with a potent, immunologically mediated graft-versus-tumor (GVT) effect, which can reduce the risk of relapse. Even among patients who relapse, donor lymphocyte infusions (DLI) can induce sustained remissions of disease. Unfortunately, most patients with hematological malignancies that can be cured by alloBMT do not undergo the procedure. This is because the risks of conditioning regimen toxicity and allogeneic graft-versus-host disease (GVHD) exceed the potential benefit of alloBMT for all but young, otherwise healthy patients with HLA-identical donors. Recently, suitable patients have been treated with non-myeloablative alloBMT (NM-alloBMT). This approach seeks to minimize toxicity by using primarily immunosuppressive conditioning to obtain a state of mixed chimerism. DLI is then given to convert mixed to full donor chimerism, thereby eliminating the patient?s cancer. By reducing toxicity substantially, NM-alloBMT may extend the benefits of adoptive immunotherapy of cancer to older or more debilitated patients. The goal of this project is to optimize the strategies of NM-alloBMT and DLI. In particular, we seek to 1) characterize the cellular and molecular parameters governing susceptibility to GVT/GVL following DLI; 2) develop non-myeloablative conditioning regimens that are sufficient to permit stable engraftment of HLA-nonidentical stem cells; and 3) enhance the efficacy of DLI in the prevention or treatment of relapsed malignancy following alloBMT.
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