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.

项目摘要/摘要 该K23申请为小儿Elizabeth Stenger博士提出了一项研究和职业发展计划 血液学家/肿瘤学家专门研究埃默里大学的血液和骨髓移植 研究人员在以患者为导向的临床和翻译研究中确立了她的职业生涯。 K23的支持 奖项将使Stenger博士能够发展成为具有造血细胞专业知识的独立研究者 非恶性疾病的移植（HCT），包括镰状细胞疾病（SCD），并在使用细胞中 治疗以减少HCT的免疫介导并发症，包括移植物排斥和移植物 - 宿主病。为了实现这些长期目标，Stenger博士提出了以下短期目标 通过此K23提案完成：1）获取进行I/II阶段临床所需的技能 试验，专门使用细胞疗法； 2）在SCD中开发HCT的临床专业知识，尤其是 无关和不匹配的捐助者； 3）在需要的临床研究的监管方面获得培训 申请并维持IND； 4）获得临床试验方法的高级培训和经验 和生物统计学。 Stenger博士组建了一个指导团队，该团队将由Jacques Galipeau博士和 Lakshmanan Krishnamurti博士一直成功地担任Stenger博士担任KL2学者。作为共同 主要导师，他们在转化研究方面的专业知识，使用新颖的免疫治疗药（包括 细胞疗法）和HCT的SCD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）博士的参与将增强指导团队，后者担任中心主任 临床和转化研究以及发育疗法在进行I/II期方面具有专业知识 临床试验和格雷戈里·吉布森（Gregory Gibson）博士，他是综合遗传学中心主任 佐治亚理工学院在基因组测定和生物信息学方面具有专业知识。 SCD在全球范围内影响大约100,000美国人和数百万个人，尽管 羟基脲和慢性输血等医疗方面的进步，患有SCD的人有 大量发病率和早期死亡率。 HCT是SCD唯一可用的治疗疗法，具有出色的 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 由于大多数人缺乏相关或无关的捐助者。单倍型家庭成员很有吸引力 捐助者的选择，但移植拒绝仍然是成功的重大障碍。受体T淋巴细胞起着关键 在移植排斥中的作用，突出了对新型T淋巴细胞定向疗法的需求。间充质基质 细胞（MSC）是罕见的，多能细胞存在于正常骨髓中，这是一个有吸引力的基于细胞的细胞 免疫疗法由于其在造血和免疫调节中的双重功能而引起的。临床前研究 已经证明MSC可以促进HSC植入，并且早期的临床试验已建立安全性 并可能的功效。尽管MSC已被描述为免疫动物，但研究表明供体 来源和冷冻保存影响MSC功能，这些功能可能解释了疗效的差异 在临床前和临床研究之间。 Stenger博士已经进行了研究，以表明MSC可以是 从SCD的个体的骨髓成功扩展，并部署表型和 与国际细胞疗法学会的指南一致的功能性能。 拟议的研究计划旨在使用新鲜的自体MSC进行第一次临床试验 在单倍性移植后，会增强患有严重SCD患者的植入。目标1，在 I期临床试验的局限性将确定注入不断升级剂量的安全性和耐受性 在这种情况下自体MSC。 AIM 2将通过两者都评估MSC产品的潜在功效 除了基于实验室的研究终点之外，标准的临床植入端点包括新颖 使用RNASEQ的研究。 AIM 3将通过MSC的体外测定评估MSC产品的效力 免疫调节和造血的支持。这些研究目标的完成将为 随后的II期临床试验以及提供MSC给药时间表和基于实验室的临床试验 功效终点。 要求的4年K23支持Stenger博士的研究计划和职业发展将是 建立她为独立的临床医生科学家至关重要。 Stenger博士以前的临床和研究 在HCT培训非恶性疾病和临床前细胞疗法研究中的培训是重要的强度 对此提议。 Stenger博士将受益于广泛的研究环境和临床护理 埃默里大学（Emory University）的基础设施，该大学拥有该国最大的SCD计划之一，其中> 50 已经进行了治疗移植，许多通过临床试验进行了。除此之外 临床试验方法和生物信息学，将使Stenger博士能够达到领导的长期目标 通过使用的研究工作，以扩大治疗性HCT在包括SCD在内的非恶性疾病的使用 新颖的免疫治疗药。