Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies

项目总结/摘要 这个NCI多样性补充申请概述了研究和职业发展计划， Stephen Persaud，医学博士，博士，谁是准备作为一个学术物理学家科学家的职业生涯。佩尔绍德博士 完成了医学博士学位2015年在华盛顿大学医学院获得免疫学博士学位， 2018年在Barnes-Jewish医院完成了临床病理学的住院医师实习， 科学家培训计划。在他的住院医生选修时间，他开始了他的博士后研究在实验室， John DiPersio，医学博士，博士，华盛顿医学系肿瘤科主任 大学医学院。DiPersio博士是异基因造血干细胞移植专家 （allo-HSCT），正常和恶性造血，以及细胞免疫治疗，并具有出色的跟踪 培养成功的医学科学家的记录。科学资源和环境的提供 DiPersio实验室和华盛顿大学医学院，结合指导，教育， 本文所述的培训计划，将推动博士Persaud的职业生涯向前发展，提高他的成长， 独立的研究项目和他对校外资金的竞争力。 拟议研究的长期目标是优化毒性最小、基于抗体的 HSCT预处理方案治疗急性髓细胞白血病（AML）。在Persaud博士的带领下， DiPersio实验室发表的第一项研究表明，CD 45或cKit靶向抗体-药物缀合物（ADC） 联合Janus激酶1/2（JAK 1/2）抑制剂使小鼠中完全MHC错配的HSCT成为可能， 骨髓供体嵌合率≥ 99%。值得注意的是，与照射条件处理不同，基于ADC的条件处理不 促进移植物抗宿主病（GvHD）。最后，JAK 1/2抑制剂加CD 45-ADC平衡GvHD， 延迟供体淋巴细胞输注淋巴瘤模型中的GvL活性，有直接ADC介导的证据 抗肿瘤功效通过实现同种异体移植和GvL效应，同时减轻GvHD和全身性免疫缺陷， 毒性，我们的新方案提供了理想的混合活动，为立即移植后时期， AML的治疗。我们将以这一工作为基础，有两个具体目标。在目标1中，我们将开发和 表征完全清髓性CD 45和cKit ADC，并评价其抗白血病疗效和对 GvHD和GvL应答。在目标2中，我们将开发无毒性有效载荷、基于抗体的调理方法 通过结合抗cKit和抗CD 47靶向与JAK 1/2抑制，我们假设这将 同时进行allo-HSCT条件化和清除白血病细胞。总的来说，这些研究将适应 基于抗体的调节策略，用于治疗恶性血液病，实现 最大的抗白血病益处，对宿主的损伤最小。

Project Summary/Abstract This NCI Diversity Supplement application outlines the research and career development plans for Stephen Persaud, M.D., Ph.D, who is preparing for a career as an academic physician-scientist. Dr. Persaud completed his M.D. and PhD in immunology in 2015 at Washington University School of Medicine, then completed his residency in Clinical Pathology in 2018 at Barnes-Jewish Hospital as part of the Physician Scientist Training Program. During his residency elective time, he began his postdoctoral research in the lab of John DiPersio, M.D., Ph.D, Chief of the Oncology Division in the Department of Medicine at Washington University School of Medicine. Dr. DiPersio is an expert in allogeneic hematopoietic stem cell transplantation (allo-HSCT), normal and malignant hematopoiesis, and cellular immunotherapy, and has an outstanding track record of training successful physician-scientists. The scientific resources and environment provided by the DiPersio lab and Washington University School of Medicine, combined with the mentoring, educational, and training plans described herein, will propel Dr. Persaud’s career forward by enhancing the growth of his independent research program and his competitiveness for extramural funding. The long-term goal of the proposed research is to optimize minimally toxic, antibody-based HSCT conditioning regimens for the therapy of acute myeloid leukemia (AML). Led by Dr. Persaud, the DiPersio lab published the first study showing that CD45- or cKit-targeted antibody-drug conjugates (ADCs) combined with Janus kinase 1/2 (JAK1/2) inhibitors enabled fully MHC-mismatched HSCT in mice, with myeloid donor chimerism ≥99%. Notably, unlike conditioning with irradiation, ADC-based conditioning did not promote graft-versus-host disease (GvHD). Finally, JAK1/2 inhibitors plus CD45-ADC balanced GvHD with GvL activity in a delayed donor lymphocyte infusion lymphoma model, with evidence of direct ADC-mediated antitumor efficacy. By enabling allogeneic engraftment and GvL effects while mitigating GvHD and systemic toxicities, our novel regimen provides the ideal blend of activities for the immediate post-transplant period in the treatment of AML. We will build on this body of work with two Specific Aims. In Aim 1, we will develop and characterize fully myeloablative CD45 and cKit ADCs and evaluate their antileukemic efficacy and impact on GvHD and GvL responses. In Aim 2, we will develop toxic payload-free, antibody-based conditioning methods by combining anti-cKit and anti-CD47 targeting with JAK1/2 inhibition, which we hypothesize will simultaneously condition for allo-HSCT and eliminate leukemia cells. Collectively, these studies will adapt antibody-based conditioning strategies for the purpose of treating hematologic malignancies, achieving maximal antileukemia benefit with minimal injury to the host.