Deciphering the efficacy of posttransplant cyclophosphamide in haplo transplant

解读移植后环磷酰胺在单倍体移植中的功效

• 批准号: 10014754
• 负责人: Christopher Kanakry
• 金额: $ 108.13万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10014754
• 关键词: Allogeneic Bone Marrow Transplantation; Antigens; Bone Marrow Transplantation; Clinical; Clinical Research; Clinical Trials; Cyclophosphamide; Engraftment; Ensure; Goals; HLA Antigens; Human; Immunologics; Major Histocompatibility Complex; Mixed Lymphocyte Culture Test; Modeling; Outcome; Patient-Focused Outcomes; Patients; Prevention; Relapse; Siblings; T-Lymphocyte; Translating; Transplantation; United States National Institutes of Health; Weight; clinical efficacy; clinical translation; conditioning; graft vs host disease; improved; improved outcome; mouse model; post-transplant; prevent; transplant model

We developed an MHC-haploidentical allogeneic bone marrow transplantation model that parallels human treatment and is being used to decipher the immunologic impact of post-transplantation cyclophosphamide (PTCy). We are studying the impact of this therapy on clinical endpoints (survival, graft-versus-host disease, weight); accompanying these studies is a detailed characterization of the immunologic and histopathologic changes associated with this approach. We have found that the mechanisms thought to underlie GVHD prevention by PTCy were not responsible for GVHD prevention by PTCy, but instead have provided the basis for a new mechanistic model which we are working on elaborating and more fully developing. Once the mechanisms by which PTCy prevents GVHD are fully understood, we will use this understanding as a basis to explore how to refine this BMT approach clinically towards the clinical goals of further reducing graft-versus-host disease, ensuring reliable engraftment with minimal conditioning, and serving as a platform for other therapies to reduce relapse. Some of these findings are already beginning to be translated clinically with the opening of a new clinical trial this month at the NIH Clinical Center which seeks to optimize the exposure of PTCy clinically. We also are exploring the impact of PTCy on human T cells in mixed lymphocyte cultures with the goal of improving our understanding of the immunologic impact of PTCy in order to improve clinical outcomes. Lastly, we have been working over the past two years on a way of integrating antigen-specific cellular therapy safely and effectively with haplo BMT using PTCy in our murine models. We are now exploring the clinical translation of this approach and expect by the end of the next fiscal year to have a clinical study open to translate that approach..

我们开发了一种与人类治疗平行的MHC-半相合异基因骨髓移植模型，并用于解读移植后环磷酰胺（PTCy）的免疫学影响。我们正在研究这种疗法对临床终点（生存率、移植物抗宿主病、体重）的影响;伴随这些研究的是与这种方法相关的免疫学和组织病理学变化的详细特征。我们已经发现，被认为是PTCy预防GVHD的基础的机制并不负责PTCy预防GVHD，而是为我们正在详细阐述和更充分开发的新机制模型提供了基础。一旦PTCy预防GVHD的机制被完全理解，我们将以这一理解为基础，探索如何在临床上完善这种BMT方法，以实现进一步减少移植物抗宿主病的临床目标，确保在最小条件下可靠的植入，并作为其他疗法的平台，以减少复发。其中一些发现已经开始在临床上转化，本月在NIH临床中心开始了一项新的临床试验，旨在优化PTCy的临床暴露。我们还在探索PTCy对混合淋巴细胞培养物中人T细胞的影响，目的是提高我们对PTCy免疫影响的理解，以改善临床结局。最后，在过去的两年中，我们一直致力于在我们的鼠模型中使用PTCy安全有效地将抗原特异性细胞疗法与单倍BMT整合。我们现在正在探索这种方法的临床转化，预计到下一个财政年度结束时，将有一项临床研究开放，以转化这种方法。