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: 10926261
• 负责人: Christopher Kanakry
• 金额: $ 230.18万
• 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/10926261
• 关键词: Acceleration; Acute Graft Versus Host Disease; Allogeneic Bone Marrow Transplantation; Antigens; Bone Marrow Transplantation; Cell Therapy; Clinical; Clinical Research; Clinical Trials; Communities; Cyclophosphamide; Development; Dose; Engineering; Engraftment; Enrollment; Ensure; Funding; Goals; HLA Antigens; Hematologic Neoplasms; Hematology; Hematopoietic; Human; Immune; Immunologics; Institution; Laboratories; Laboratory Research; Major Histocompatibility Complex; Mixed Lymphocyte Culture Test; Modeling; Modification; Mus; Non-Malignant; Outcome; Patient-Focused Outcomes; Patients; Phase; Prevention; Process; Protocols documentation; Publishing; Recovery; Relapse; Risk Reduction; Siblings; Study models; T-Lymphocyte; Time; Toxic effect; Translating; Translations; Transplant-Related Disorder; Transplantation; Work; clinical efficacy; clinical translation; cohort; conditioning; graft vs host disease; improved; improved outcome; interest; mouse model; novel strategies; pharmacokinetic model; post-transplant; prevent; standard of care; 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 accompanying this trial are funded by an R01. We have three other clinical trials that are accruing that are stemming from the work performed in the laboratory, with two of these studies being multi-institutional to accelerate the development and execution of these studies and draw on the interest in this work within the broader transplant community. 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 6 years on a way of integrating engineered antigen-specific cellular therapies safely and effectively with haplo BMT using PTCy in our murine models, whcih was published in 2023. We are now developing a protocol to clinically translate this approach and expect within the next 12 months to have this clinical study open.

在过去的几年中，我们一直在使用小鼠移植模型来剖析 PTCy 功效的机制，并发现这些机制与该领域先前的教条有很大不同。我们正在积极开展多个项目，以更好地定义新的机制模型，这将为新方法或修改的合理转化提供信息，以改善患者的治疗结果。事实上，在这些研究过程中，我们已经确定 PTCy 的最佳剂量是中间剂量而不是非常高的剂量。我们现已完成 I/II 期研究的主要队列的入组，该研究表明，减少 PTCy 剂量可以很好地预防急性 GVHD，同时可以降低早期移植相关的毒性，并改善造血和免疫恢复和功能。伴随本试验的药代动力学模型研究由 R01 资助。我们正在进行另外三项临床试验，这些试验源于实验室进行的工作，其中两项研究是多机构的，以加速这些研究的开发和执行，并吸引更广泛的移植界对这项工作的兴趣。我们这些临床研究和正在进行的实验室研究的目标是，以我们不断发展的理解为基础，探索如何在临床上改进这种 BMT 方法，以实现进一步减少移植物抗宿主病、确保在最少条件下可靠植入、并作为其他疗法减少复发的平台。我们还在探索 PTCy 对混合淋巴细胞培养物中人类 T 细胞的影响，目的是提高我们对 PTCy 免疫学影响的理解，从而改善临床结果。最后，我们在过去 6 年里一直致力于在我们的小鼠模型中使用 PTCy 安全有效地将工程化抗原特异性细胞疗法与单倍体 BMT 相结合，该方法于 2023 年发表。我们现在正在开发一项协议来临床转化这种方法，并预计在未来 12 个月内开放这项临床研究。

项目成果

Characterization of Hepatic Dysfunction in Subjects Diagnosed With Chronic GVHD by NIH Consensus Criteria.

• DOI: 10.1016/j.jtct.2022.07.017
• 发表时间: 2022-11
• 期刊: TRANSPLANTATION AND CELLULAR THERAPY
• 影响因子: 3.2
• 作者: Yang, Alexander H.;Han, Ma Ai Thanda;Samala, Niharika;Rizvi, Bisharah S.;Marchalik, Rachel;Etzion, Ohad;Wright, Elizabeth C.;Cao, Liang;Hakim, Frances T.;Jones, Elizabeth;Kapuria, Devika;Hickstein, Dennis D.;Fowler, Daniel;Kanakry, Jennifer A.;Kanakry, Christopher G.;Kleiner, David E.;Koh, Christopher;Pavletic, Steven Z.;Heller, Theo
• 通讯作者: Heller, Theo

Haploidentical vs matched unrelated donors for patients with ALL: donor age matters more than donor type.

• DOI: 10.1182/bloodadvances.2022009240
• 发表时间: 2023-04-25
• 期刊: Blood advances
• 影响因子: 7.5

Abnormal liver tests are not sufficient for diagnosis of hepatic graft-versus-host disease in critically ill patients.

• DOI: 10.1002/hep4.1965
• 发表时间: 2022-08
• 期刊: HEPATOLOGY COMMUNICATIONS
• 影响因子: 5.1
• 作者: Yang, Alexander H.;Han, Mai Ai Thanda;Samala, Niharika;Rizvi, Bisharah S.;Marchalik, Rachel;Etzion, Ohad;Wright, Elizabeth C.;Patel, Ruchi;Khan, Vinshi;Kapuria, Devika;Venkat, Vikramaditya Samala;Kleiner, David E.;Koh, Christopher;Kanakry, Jennifer A.;Kanakry, Christopher G.;Pavletic, Steven;Williams, Kirsten M.;Heller, Theo
• 通讯作者: Heller, Theo

Optimized Timing of Post-Transplantation Cyclophosphamide in MHC-Haploidentical Murine Hematopoietic Cell Transplantation.

在MHC-Haploidentical鼠造血细胞移植中移植后环磷酰胺的优化时间。

• DOI: 10.1016/j.bbmt.2019.09.030
• 发表时间: 2020-02
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: Wachsmuth LP;Patterson MT;Eckhaus MA;Venzon DJ;Kanakry CG
• 通讯作者: Kanakry CG

Correction to: An adapted European LeukemiaNet genetic risk stratification for acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplant. A CIBMTR analysis.

更正：针对接受同种异体造血细胞移植的急性髓系白血病患者进行的欧洲 LeukemiaNet 遗传风险分层。

• DOI: 10.1038/s41409-022-01625-6
• 发表时间: 2022
• 期刊: Bone marrow transplantation
• 影响因子: 4.8
• 作者: JimenezJimenez,AntonioM;DeLima,Marcos;Komanduri,KrishnaV;Wang,TrentP;Zhang,Mei-Jie;Chen,Karen;Abdel-Azim,Hisham;Abid,MuhammadBilal;Aljurf,Mahmoud;Alkhateeb,Hassan;Assal,Amer;Bacher,Ulrike;Baron,Frédéric;Battiwalla,Minoo;B
• 通讯作者: B