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: 10702608
• 负责人: Christopher Kanakry
• 金额: $ 184.55万
• 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/10702608
• 关键词: Acute Graft Versus Host Disease; Allogeneic Bone Marrow Transplantation; Antigens; Bone Marrow Transplantation; Cell Therapy; Clinical; Clinical Research; Clinical Trials; Cyclophosphamide; Dose; Engineering; Engraftment; Enrollment; Ensure; Funding; Goals; HLA Antigens; Hematologic Neoplasms; Hematology; Hematopoietic; Human; Immune; Immunologics; Institutional Review Boards; Laboratories; Laboratory Research; Major Histocompatibility Complex; Mixed Lymphocyte Culture Test; Modeling; Modification; Mus; Non-Malignant; Outcome; Patient-Focused Outcomes; Patients; Phase; Prevention; Protocols documentation; Recovery of Function; Relapse; Risk; Siblings; Study models; T-Lymphocyte; Toxic effect; Translating; Translations; Transplant-Related Disorder; Transplantation; Work; clinical efficacy; clinical translation; cohort; conditioning; graft vs host disease; improved; improved outcome; mouse model; novel strategies; pharmacokinetic model; post-transplant; prevent; stem; transplant model

Over the past several years, we have been using our murine transplant models to dissect the mechanisms underlying the efficacy of PTCy and have found that these diverge widely from the prior dogma in the field. We are actively working across several projects to better define a new mechanistic model, which will inform rational translation of new approaches or modifications to improve outcomes for patients. Indeed, in the course of these studies, we have determined that the optimal dose of PTCy is an intermediate dose rather than a very high dose. We have now completed enrollment of the primary cohort of a phase I/II study that has shown that reduced dosing PTCy allows for excellent prevention of acute GVHD while allowing lower early transplant-associated toxicity and better hematopoietic and immune recovery and function. Pharmacokinetic modeling studies by Jeannine McCune accompanying this trial are funded by an R01. We have three other clinical trials that are accruing or will begin accruing soon that are stemming from the work performed in the laboratory. Our goals with these clinical studies and ongoing laboratory research are to use our developing 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. 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 5 years on a way of integrating engineered antigen-specific cellular therapies safely and effectively with haplo BMT using PTCy in our murine models. We are now developing a protocol to clinically translate this approach and expect within the next 12-18 months to have this clinical study open.

在过去的几年里，我们一直在使用我们的小鼠移植模型来剖析PTCy疗效的机制，并发现这些机制与该领域先前的教条存在很大差异。我们正在积极开展多个项目，以更好地定义一个新的机制模型，这将为新方法的合理翻译或修改提供信息，以改善患者的预后。事实上，在这些研究过程中，我们已经确定PTCy的最佳剂量是中等剂量，而不是非常高的剂量。我们现在已经完成了一项I/II期研究的主要队列登记，该研究表明，减少PTCy剂量可以很好地预防急性GVHD，同时降低早期移植相关毒性，改善造血和免疫恢复和功能。Jeannine McCune的药代动力学模型研究是由R01资助的。我们还有另外三个临床试验正在进行或即将开始进行这些试验都是在实验室进行的。我们的这些临床研究和正在进行的实验室研究的目标是利用我们不断发展的认识作为基础，探索如何在临床上改进这种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地植入，并作为其他治疗减少复发的平台。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5年里，我们一直致力于在我们的小鼠模型中使用PTCy安全有效地将工程抗原特异性细胞疗法与单倍体BMT结合起来。我们现在正在开发一种方案，用于临床转化这种方法，并期望在未来12-18个月内开展这项临床研究。