) The broad, long-term objectives and specific aims are to reduce the relapse rate following BMT for breast cancer. The primary limitation to treating persons with metastatic breast cancer with myeloablative therapy and autologous stem cell transplantation is post- transplant relapse. The central hypothesis of this project is that transplantation of patients with allogeneic stem cells after myeloablative therapy will induce a graft-vs.-tumor response resulting in a reduction in the relapse rate. Two complementary strategies will be pursued in order to test this hypothesis. First, persons with metastatic breast cancer will be transplanted with HLA matched sibling donor PBSCs. This strategy will be evaluated in a pivotal multi-institutional clinical study designed to statistically determine the net benefit of allogeneic BMT compared to similar historical patients treated with autologous BMT. Patients will be enrolled in this trial who have extensive refractory disease or bone marrow involvement with breast cancer, precluding an autologous transplant. In order to evaluate efficacy, toxicity, engraftment, GVHD, disease free, and overall survival will be made. This first approach will measure the clinical outcome. The second strategy will rely on in vitro measurements. These in vitro studies will define the kinetics of immune reconstitution in transplant recipients. These measurements will consist of general, antigen specific, alloreactive, and tumor antigen specific immune responses to define the dynamics of immune reconstitution following allogeneic transplantation in this patient population, and to determine whether a GVT effect has occurred. Specifically, autologous tumor cell or autologous tumor derived RNA transfected into a target cell will be used as targets. The goal of this last aim will be to detect donor derived cells that can recognize these tumor targets and lyse these target cells. The overall goal of these two strategies (clinical and laboratory) is to define the benefit of allogeneic stem cell transplantation for women with extensive metastatic breast cancer. The lessons learned from these trials will set the stage for future studies aimed at decreasing relapse and improving long-term survival.
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