Deciphering the efficacy of posttransplant cyclophosphamide in BMT

解读移植后环磷酰胺在 BMT 中的功效

• 批准号: 10262388
• 负责人: Christopher Kanakry
• 金额: $ 178.03万
• 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/10262388
• 关键词: Allogeneic Bone Marrow Transplantation; Antigens; Bone Marrow Transplantation; Cell Therapy; Clinical; Clinical Research; Clinical Trials; Cyclophosphamide; Engraftment; Ensure; Funding; Goals; HLA Antigens; Human; Immunologics; Major Histocompatibility Complex; Mixed Lymphocyte Culture Test; Modeling; Outcome; Patient-Focused Outcomes; Patients; Prevention; Relapse; Siblings; Study models; T-Lymphocyte; Translating; Transplantation; United States National Institutes of Health; Weight; clinical center; clinical efficacy; clinical translation; conditioning; graft vs host disease; improved; improved outcome; mouse model; pharmacokinetic 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 in July, 2019 at the NIH Clinical Center which seeks to optimize the exposure of PTCy clinically. Pharmacokinetic modeling studies by Jeannine McCune accompanying this trial are funded by an R01. 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 3 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 within the next 6-12 months to have a clinical study open to translate that approach..

我们开发了一种与人类治疗相似的mhc -单倍体同种异体骨髓移植模型，并被用于破译移植后环磷酰胺（PTCy）的免疫影响。我们正在研究这种疗法对临床终点（生存、移植物抗宿主病、体重）的影响；伴随这些研究的是与该方法相关的免疫学和组织病理学变化的详细描述。我们发现，被认为是PTCy预防GVHD的机制并不是PTCy预防GVHD的原因，而是为我们正在努力阐述和更充分发展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，我们将以此为基础，探索如何在临床中完善这种BMT方法，以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移植，并作为其他治疗减少复发的平台。随着2019年7月在美国国立卫生研究院临床中心开展的一项新的临床试验的开始，其中一些发现已经开始在临床上转化，该试验旨在优化PTCy的临床暴露。Jeannine McCune的药代动力学模型研究是由R01资助的。我们也在探索PTCy对混合淋巴细胞培养中人类T细胞的影响，目的是提高我们对PTCy免疫影响的理解，以改善临床结果。最后，在过去的3年里，我们一直致力于在我们的小鼠模型中使用PTCy安全有效地将抗原特异性细胞治疗与单倍体BMT结合起来。我们现在正在探索这种方法的临床翻译，并期望在未来6-12个月内有一项临床研究开放来翻译这种方法。