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

使用自体间充质基质细胞改善镰状细胞病中的单倍相合干细胞植入

• 批准号: 9333428
• 负责人: Elizabeth O Stenger
• 金额: $ 18.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333428
• 关键词: Affect; Allogenic; Alloimmunization; American; Animal Model; Autologous; Bioinformatics; Biological Assay; Biological Products; Biometry; Blood; Blood Platelets; Blood specimen; Bone Marrow; Bone Marrow Transplantation; Cell Therapy; Cell physiology; Cells; Cessation of life; Chimerism; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Country; Cryopreservation; Cyclophosphamide; Data; Development Plans; Developmental Therapeutics Program; Disease; Donor person; Dose; Engraftment; Enrollment; Environment; Erythrocytes; Failure; Family member; First Degree Relative; Freezing; Genetic; Genomics; Goals; Graft Rejection; Guidelines; Heat-Shock Response; Hematopoiesis; Hematopoietic stem cells; Human; Immune; Immune system; Immunotherapeutic agent; Incidence; Individual; Infusion procedures; Institutes; International; Ischemia; Laboratories; Lead; Marrow; Mediating; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mesenchymal; Methodology; Methods; Modality; Morbidity - disease rate; Mothers; Multipotent Stem Cells; Mutation; Non-Malignant; Nucleotides; Oncologist; Outcome; Patients; Pediatric Hematologist; Persons; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Play; Predictive Factor; Production; Property; Regimen; Research; Research Infrastructure; Research Personnel; Research Training; Residual state; Role; Safety; Sampling; Schedule; Scientist; Siblings; Sickle Cell Anemia; Societies; Source; Stem cells; Steroid Resistance; Stromal Cells; Symptoms; T-Lymphocyte; Technology; Testing; Training; Transfusion; Translational Research; Transplantation; Universities; base; beta Globin; burden of illness; career; career development; clinical care; conditioning; curative treatments; design; experience; fetal bovine serum; graft failure; graft vs host disease; hematopoietic cell transplantation; hydroxyurea; immunoregulation; improved; improved outcome; in vitro Assay; in vivo; insight; mortality; multipotent cell; neutrophil; novel; patient oriented; peripheral blood; phase 1 study; pre-clinical; preclinical study; programs; reconstitution; research and development; safety study; skills; success; transcriptome sequencing

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.

项目概要/摘要 此 K23 申请为儿科医师 Elizabeth Stenger 博士提出了一项研究和职业发展计划 埃默里大学专门从事血液和骨髓移植的血液学家/肿瘤学家，是一名年轻的 研究员在以患者为导向的临床和转化研究领域建立了自己的职业生涯。 K23的支持 该奖项将使 Stenger 博士发展成为一名具有造血细胞专业知识的独立研究者 移植（HCT）治疗非恶性疾病，包括镰状细胞病（SCD），以及使用细胞 减少 HCT 免疫介导并发症的治疗，包括移植物排斥和移植物抗 宿主疾病。为了实现这些长期目标，Stenger 博士制定了以下短期目标 通过本 K23 提案要完成的任务： 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的试验； 2) 发展 SCD 的 HCT 临床专业知识，特别是 不相关且不匹配的捐赠者； 3) 获得临床研究监管方面的培训 申请并维持 IND； 4) 获得临床试验方法方面的高级培训和经验 和生物统计学。 Stenger 博士组建了一个指导团队，由 Jacques Galipeau 博士和 Lakshmanan Krishnamurti 博士作为 KL2 学者成功地共同指导 Stenger 博士。作为共同 主要导师，他们各自在使用新型免疫疗法的转化研究方面的专业知识（包括 细胞疗法）以及 SCD 的 HCT 临床研究是 Stenger 博士提议的重要优势。这 辛西娅·韦特莫尔 (Cynthia Wetmore) 博士的参与将加强指导团队，她是该中心主任 临床和转化研究以及发育治疗学拥有进行 I/II 期临床和转化研究的专业知识 临床试验，由格雷戈里·吉布森博士（Gregory Gibson）负责，他是该大学综合遗传学中心主任 佐治亚理工学院拥有基因组分析和生物信息学方面的专业知识。 SCD 影响着大约 100,000 名美国人和全世界数百万人，尽管 随着羟基脲和慢性输血等医学治疗的进步，SCD 患者已 显着的发病率和早期死亡率。 HCT 是 SCD 唯一可用的治疗方法，具有良好的疗效 匹配相关供体移植后的结果。不幸的是，大多数患者无法治愈 因为大多数人缺乏匹配的相关或无关捐赠者。单倍体家族成员是一个有吸引力的 供体选择，但移植排斥仍然是成功的重大障碍。受体T淋巴细胞发挥着关键作用 移植排斥中的作用，强调了对新型 T 淋巴细胞定向疗法的需求。间充质基质 间充质干细胞 (MSC) 是存在于正常骨髓中的稀有多能细胞，是一种有吸引力的细胞基础 由于其造血和免疫调节的双重功能而具有免疫治疗作用。临床前研究 已证明 MSC 可以促进 HSC 植入，早期临床试验已确立安全性 以及可能的功效。尽管 MSC 被描述为免疫豁免的，但研究表明，供体 来源和冷冻保存会影响 MSC 功能，这些可能是所见功效差异的原因 临床前研究和临床研究之间。 Stenger 博士进行的研究表明 MSC 可以 成功地从 SCD 患者的骨髓中扩增出来，并且它们部署了表型和 功能特性符合国际细胞治疗学会的指导方针。 拟议的研究计划旨在使用新鲜的自体 MSC 进行首次临床试验 增强半相合移植后严重 SCD 患者的植入。目标1，在 I 期临床试验的范围将确定输注剂量递增的安全性和耐受性 在这种情况下使用自体 MSC。目标 2 将通过以下两个方面评估 MSC 产品的潜在功效： 除了基于实验室的研究终点之外，还包括标准的临床移植终点，包括新颖的 使用 RNASeq 进行研究。目标 3 将通过 MSC 的体外测定来评估 MSC 产品的效力 免疫调节和造血支持。完成这些研究目标将为以下方面提供支持： 后续II期临床试验以及提供MSC给药方案和基于实验室的 功效终点。 所请求的 4 年 K23 支持 Stenger 博士的研究计划和职业发展将是 对于使她成为一名独立的临床医生科学家至关重要。 Stenger博士之前的临床和研究 针对非恶性疾病的 HCT 和临床前细胞治疗研究的培训是一项重要优势 对此提案。 Stenger 博士将受益于广泛的研究环境和临床护理 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，其中超过 50 已经进行了治愈性移植，其中许多是通过临床试验进行的。这除了正规培训外 临床试验方法和生物信息学，将使 Stenger 博士实现她领导的长期目标 通过使用以下方法，扩大 HCT 治疗非恶性疾病（包括 SCD）的应用的研究工作 的新型免疫疗法。