ALLOGENIC BONE MARROW TRANSPLANTATION

描述：(申请者描述)广泛的、长期的目标和具体的目标是降低乳腺癌BMT后的复发率。使用清髓疗法和自体干细胞移植治疗转移性乳腺癌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，从而降低复发率。为了检验这一假设，将采取两种互补的策略。首先，转移性乳腺癌患者将接受人类白细胞抗原相合的同胞捐赠者PBSCs移植。这一策略将在一项关键的多机构临床研究中进行评估，该研究旨在从统计上确定与接受自体骨髓移植治疗的类似历史患者相比，异基因骨髓移植的净效益。患者将参加这项试验，这些患者有广泛的难治性疾病或与乳腺癌有关的骨髓，排除了自体移植。为了评估疗效、毒性、植入率、移植物抗宿主病、无病和总存活率。这第一种方法将衡量临床结果。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者免疫重建的动力学。这些测量将包括一般、抗原特异性、同种异体反应和肿瘤抗原特异性免疫反应，以确定在该患者群体中异基因移植后免疫重建的动态，并确定是否发生了GVT效应。具体地说，将使用导入靶细胞的自体肿瘤细胞或自体肿瘤来源的RNA作为靶标。最后一个目标的目标将是检测能够识别这些肿瘤靶点并溶解这些靶细胞的供体来源细胞。这两种策略(临床和实验室)的总体目标是确定同种异基因干细胞移植对患有广泛转移性乳腺癌的女性的益处。从这些试验中吸取的经验教训将为未来旨在减少复发和改善长期存活率的研究奠定基础。

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.