ALLOGENIC BONE MARROW TRANSPLANTATION

产品说明：（申请人的描述）广泛的、长期的目的和具体的目标是降低乳腺癌BMT后的复发率。用清髓性疗法和自体干细胞移植治疗患有转移性乳腺癌的人的主要限制是移植后复发。 该项目的中心假设是，在清髓治疗后移植异基因干细胞的患者将诱导移植物抗-肿瘤反应导致复发率降低。 为了检验这一假设，将采取两种互补的战略。 首先，患有转移性乳腺癌的人将被移植HLA匹配的同胞供体PBSC。 该策略将在一项关键性多机构临床研究中进行评价，该研究旨在统计学上确定同种异体BMT与接受自体BMT治疗的类似历史患者相比的净获益。 本试验将招募患有广泛难治性疾病或骨髓受累乳腺癌的患者，排除自体移植。 为了评价疗效，将进行毒性、植入、GVHD、无病和总生存期。 第一种方法将测量临床结果。 第二种策略将依赖于体外测量。 这些体外研究将确定移植受体中免疫重建的动力学。 这些测量将包括一般、抗原特异性、同种异体反应性和肿瘤抗原特异性免疫应答，以确定该患者人群中同种异体移植后免疫重建的动力学，并确定是否发生GVT效应。 具体地，将自体肿瘤细胞或转染到靶细胞中的自体肿瘤来源的RNA用作靶标。 这最后一个目标的目标将是检测能够识别这些肿瘤靶点并裂解这些靶细胞的供体衍生细胞。 这两种策略（临床和实验室）的总体目标是确定异基因干细胞移植对广泛转移性乳腺癌妇女的益处。 从这些试验中吸取的经验教训将为旨在减少复发和改善长期生存的未来研究奠定基础。

DESCRIPTION: (Applicant's Description) 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.