Improving haploidentical stem cell engraftment in sickle cell disease using autologous mesenchymal stromal cells

项目摘要/摘要 这份K23申请为儿科医生伊丽莎白·斯滕格博士提出了一项研究和职业发展计划 埃默里大学专门研究血液和骨髓移植的血液学家/肿瘤学家，是一名年轻的 研究人员在面向患者的临床和转化性研究方面奠定了她的职业生涯。K23的支持 该奖项将使斯滕格博士发展成为一名在造血细胞方面拥有专业知识的独立研究员 移植(HCT)用于包括镰状细胞病(SCD)在内的非恶性疾病，并用于细胞 减少HCT免疫介导的并发症的治疗，包括移植物排斥反应和移植物抗宿主病。 寄主疾病。为了实现这些长期目标，斯滕格博士制定了以下短期目标 要通过此K23计划完成：1)获得进行I/II期临床所需的技能 试验，特别是使用细胞疗法；2)发展HCT治疗SCD的临床专业知识，特别是 不相关和不匹配的捐赠者；3)获得临床研究监管方面的培训 申请并保持IND学位；以及4)获得临床试验方法学方面的高级培训和经验 和生物统计学。斯滕格博士组建了一个指导团队，将由Jacques Galipeau博士和 Lakshmanan Krishnamurti博士，作为一名KL2学者，他一直成功地共同指导Stenger博士。作为共同的- 初级导师，他们各自在使用新型免疫疗法进行翻译研究方面的专长(包括 细胞疗法)和SCD的HCT临床研究是斯滕格博士建议的一个重要优势。这个 指导团队将通过辛西娅·韦特莫尔博士的参与而得到加强，她作为该中心的主任 临床和转化性研究以及开发治疗学在进行I/II阶段方面具有专业知识 临床试验，以及格雷戈里·吉布森博士，他是美国国立卫生研究院综合遗传学中心的主任 佐治亚理工学院在基因组分析和生物信息学方面拥有专业知识。 SCD影响着大约10万美国人和全球数百万人，尽管 羟基脲和慢性输血等医学治疗的进展，SCD患者有 严重的发病率和早期死亡率。HCT是治疗SCD的唯一有效的治疗方法，具有良好的疗效 配对的亲缘供者移植的结果。不幸的是，不能为大多数病人提供治愈方法。 因为大多数人缺乏匹配的亲属或非亲属捐赠者。单倍体相合的家庭成员是有吸引力的 供者选择，但移植排斥反应仍然是成功的重要障碍。受体T淋巴细胞发挥关键作用 在移植物排斥反应中的作用，强调了新的T淋巴细胞导向疗法的必要性。间充质基质 细胞(MSCs)是一种罕见的多潜能细胞，存在于正常骨髓中，是一种有吸引力的细胞基础。 免疫治疗由于其在造血和免疫调节方面的双重功能。临床前研究 已经证明MSCs可以促进HSC的植入，早期临床试验已经确定了安全性 以及可能的疗效。尽管MSCs被描述为免疫缺陷，但研究表明，捐赠者 来源和冷冻保存会影响MSC的功能，这可能是疗效差异的原因 在临床前研究和临床研究之间。斯滕格博士进行的研究表明，骨髓间充质干细胞可以 成功地从SCD患者的骨髓中扩增，并部署了表型和 功能特性符合国际细胞治疗学会的指南。 拟议的研究计划寻求使用新鲜的自体骨髓间充质干细胞进行第一次临床试验 提高单倍体相合移植后重度SCD患者的植入率。目标1，在 I期临床试验的限制，将确定输注不断增加的剂量的安全性和耐受性 此设置中的自体MSCs。目标2将通过以下两种方式评估MSC产品的潜在疗效 除了基于实验室的研究终端之外的标准临床植入终端，包括新型 使用RNAseq.AIM 3将通过对MSC的体外检测来评估MSC产物的效力 免疫调节和造血支持。完成这些研究目标将为 随后的第二阶段临床试验以及提供MSC剂量计划和基于实验室的 功效终点。 要求为斯滕格博士的研究计划和职业发展提供4年的K23支持 使她成为一名独立的临床医生兼科学家的关键。斯滕格博士之前的临床和研究 在非恶性疾病的血细胞移植和临床前细胞治疗研究方面的培训是一个重要的优势。 对这项提议。斯滕格博士将从广泛的研究环境和临床护理中受益 埃默里大学的基础设施，该大学拥有全国最大的SCD项目之一， 治疗性移植已经完成，其中许多是通过临床试验进行的。这是除了在 临床试验方法学和生物信息学，将使斯滕格博士实现她领导的长期目标 研究努力扩大根治性血细胞移植对非恶性疾病的使用，包括SCD，通过使用 新的免疫疗法。

PROJECT SUMMARY/ABSTRACT This K23 application proposes a research and career development plan for Dr. Elizabeth Stenger, a pediatric hematologist/oncologist specializing in blood and marrow transplantation at Emory University, who is a young investigator establishing her career in patient-oriented clinical and translational research. The support of a K23 award would allow Dr. Stenger to develop into an independent investigator with expertise in hematopoietic cell transplantation (HCT) for non-malignant diseases, including sickle cell disease (SCD), and in the use of cellular therapy to decrease the immune-mediated complications of HCT, including graft rejection and graft-versus- host disease. To achieve these long-term goals, Dr. Stenger has formulated the following short-term objectives to be accomplished through this K23 proposal: 1) to acquire the skills needed to conduct phase I/II clinical trials, specifically using cellular therapies; 2) to develop clinical expertise in HCT for SCD, particularly with unrelated and mismatched donors; 3) to acquire training in regulatory aspects of clinical research needed to apply for and maintain an IND; and 4) to gain advanced training and experience in clinical trial methodology and biostatistics. Dr. Stenger has assembled a mentoring team that will be led by Dr. Jacques Galipeau and Dr. Lakshmanan Krishnamurti, who have been successfully co-mentoring Dr. Stenger as a KL2 scholar. As co- primary mentors, their respective expertise in translational research using novel immunotherapeutics (including cell therapy) and in clinical research in HCT for SCD is a significant strength to Dr. Stenger's proposal. The mentoring team will be enhanced by the involvement of Dr. Cynthia Wetmore, who as Director of the Center for Clinical and Translational Research and of Developmental Therapeutics has expertise in conducting phase I/II clinical trials, and by Dr. Gregory Gibson, who as the Director of the Center for Integrative Genetics at the Georgia Institute of Technology has expertise in genomic assays and bioinformatics. SCD affects approximately 100,000 Americans and millions of individuals worldwide, and despite advances in medical treatment such as hydroxyurea and chronic transfusion, individuals with SCD have significant morbidity and early mortality. HCT is the only available curative therapy for SCD, with excellent outcomes following matched related donor transplant. Unfortunately, a cure cannot be offered to most patients as the majority lack a matched related or unrelated donor. Haploidentical family members are an attractive donor option, but graft rejection remains a significant barrier to success. Recipient T lymphocytes play a critical role in graft rejection, highlighting the need for novel T lymphocyte directed therapies. Mesenchymal stromal cells (MSCs) are rare, multipotent cells present in normal bone marrow that are an attractive cell-based immunotherapeutic due to their dual function in hematopoiesis and immunomodulation. Pre-clinical studies have demonstrated that MSCs can promote HSC engraftment, and early clinical trials have established safety and possible efficacy. Although MSCs have been described as immunoprivileged, studies suggest that donor source and cryopreservation impact MSC function, and these may account for differences in efficacy seen between pre-clinical and clinical studies. Dr. Stenger has conducted studies to show that MSCs can be expanded successfully from the bone marrow of individuals with SCD and that they deploy phenotypical and functional properties consistent with guidelines by the International Society for Cellular Therapy. The proposed research plan seeks to perform the first clinical trial using fresh, autologous MSCs to enhance engraftment in patients with severe SCD following haploidentical transplant. Aim 1, within the confines of a phase I clinical trial, will determine the safety and tolerability of infusing escalating doses of autologous MSCs in this setting. Aim 2 will evaluate the potential efficacy of the MSC product through both standard clinical engraftment endpoints in addition to laboratory-based research endpoints, including novel studies using RNASeq. Aim 3 will evaluate the potency of the MSC product, both by in vitro assays of MSC immunomodulation and support of hematopoiesis. Completion of these research aims will establish support for the subsequent phase II clinical trial as well as provide the MSC dosing schedule and laboratory-based efficacy endpoints. The requested 4 years of K23 support for Dr. Stenger's research plan and career development will be critical in establishing her as an independent clinician-scientist. Dr. Stenger's previous clinical and research training in HCT for non-malignant diseases and in pre-clinical cellular therapy studies are a significant strength to this proposal. Dr. Stenger will benefit from the extensive research environment and clinical care infrastructure at Emory University, which has one of the largest SCD programs in the country and where >50 curative transplants have been performed, many through clinical trials. This, in addition to formal training in clinical trials methodology and bioinformatics, will allow Dr. Stenger to reach her long-term goal of leading research efforts to expand the use of curative HCT for non-malignant diseases, including SCD, through the use of novel immunotherapeutics.