Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies

项目摘要/摘要 这份NCI多样性补充申请概述了以下项目的研究和职业发展计划 斯蒂芬·佩尔绍德，医学博士，博士，他正在为学术内科科学家的职业生涯做准备。佩尔绍德博士 2015年在华盛顿大学医学院完成免疫学医学博士学位，然后 2018年在巴恩斯犹太医院完成临床病理学实习，成为医生的一部分 科学家培训计划。在他的实习选修期间，他开始了他的博士后研究 John DiPersio，医学博士，华盛顿医学部肿瘤科主任 大学医学院。迪佩西奥博士是异基因造血干细胞移植方面的专家 (allo-HSCT)，正常和恶性造血，细胞免疫治疗，并有突出的跟踪 培养成功的内科科学家的记录。世界银行提供的科学资源和环境 DiPersio实验室和华盛顿大学医学院，结合指导、教育和 这里描述的培训计划将通过促进佩尔绍德博士的成长来推动他的职业生涯向前发展 独立研究计划和他对外部资金的竞争力。 这项拟议研究的长期目标是优化毒性最小的、基于抗体的 HSCT预适应方案治疗急性髓系白血病(AML)在佩尔绍德博士的领导下， DiPersio实验室发表的第一项研究表明，CD45或cKit靶向的抗体药物结合物(ADCs) 与Janus Kinase 1/2(JAK1/2)抑制剂联合使用可使小鼠完全MHC不相合的HSCT， 髓系供者嵌合体≥99%。值得注意的是，与辐射条件作用不同，基于ADC的条件作用不是 促进移植物抗宿主病(GvHD)。最后，JAK1/2抑制剂加CD45-ADC平衡GvHD与 供者淋巴细胞输注延迟淋巴瘤模型中的GVL活性：直接ADC介导的证据 抗肿瘤功效。通过启用同种异体移植和GVL效应，同时减轻GvHD和全身 毒副作用，我们的新方案为移植后即刻提供了理想的活动组合 急性髓系白血病的治疗。我们将以这一机构的工作为基础，以两个具体目标为基础。在目标1中，我们将发展和 完全清髓性CD45和cKit ADC的特征及其抗白血病疗效和影响 GVHD和GVL反应。在目标2中，我们将开发无毒性、基于抗体的调节方法。 通过将抗cKit和抗CD47靶向与JAK1/2抑制结合起来，我们假设 同时进行allo-HSCT，清除白血病细胞。总体而言，这些研究将适应 基于抗体的调节策略用于治疗血液系统恶性肿瘤，实现 最大的抗白血病益处，对宿主的伤害最小。

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.