Biology & Transplantation of the Human Stem Cell

生物学

• 批准号: 8725940
• 负责人: John E. Wagner
• 金额: $ 206.48万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725940
• 关键词: Acute Graft Versus Host Disease; Acute leukemia; Address; Adoptive Transfer; Adult; Allogenic; Animals; Back; Biological; Biology; Blood; Blood Cells; Cell Therapy; Cell Transplants; Cell model; Cell physiology; Child; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Conduct Clinical Trials; Cyclic GMP; Data; Development; Disease; Dose; Effector Cell; Engraftment; Environment; Ethnic Origin; Funding; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Human Biology; Immune; Immune System Diseases; Immunologic Monitoring; Immunologics; Immunosuppressive Agents; In Vitro; In complete remission; Infection; Infusion procedures; Instruction; Interleukin-15; Interleukin-2; Laboratories; Lead; Malignant - descriptor; Mediating; Metabolic Diseases; Methodology; Modeling; Modification; Mus; Myeloid Leukemia; Myeloid Progenitor Cells; Natural Killer Cells; Organ Transplantation; Patients; Pluripotent Stem Cells; Positioning Attribute; Principal Investigator; Race; Recovery; Recurrence; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Research Personnel; Role; Safety; Series; Solid; Source; Stem cells; Stimulus; T-Lymphocyte; Testing; Thymic epithelial cell; Translating; Transplantation; Tumor Burden; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; base; design; effective therapy; efficacy testing; graft vs host disease; hematopoietic cell transplantation; human stem cells; immune function; improved; leukemia; mortality; pre-clinical; prevent; progenitor; programs; receptor; reconstitution; repaired; research study; restoration; stem; tumor

DESCRIPTION (provided by applicant): The theme of this program has not changed in 15 years: Understanding the biology of human hematopoietic stem cells (HSC) and their progeny will result in improved hematopoietic cell-based therapy for a variety of lethal malignant diseases. In the current funding period we have established "double umbilical cord blood" (DUCB) transplantation as an effective treatment which may transform the practice of hematopoietic cell transplantation (HCT) because it vastly increases the pool of patients to whom transplant can be offered. We will now approach three important issues in the DUCB transplant setting-graft versus host disease (GVHD), delayed immune reconstitution with resultant late infection, and refractory or relapsed leukemia. John Wagner MD and his co-investigator Bruce Blazar MD have generated preclinical data demonstrating the suppressive effect of UCB-derived regulatory T cells (Treg) on GVHD and performed "first-in-human" UCB Treg safety and dose-finding trials. In Project 1, Dr Wagner proposes a series of clinical trials testing the efficacy of UCB Treg to prevent and to treat acute GVHD including add-back of UCB Tregs and effector T cells (Teffs) in calibrated doses, and development of "off-the-shelf UCB Treg products. Dr Blazar has characterized UCB-derived progenitor T cells (Tprogs), and in Project 2 proposes basic studies exploring their role in restoration of thymic epithelial cell (TEC) function as well as inducible pluripotent stem cell (iPS) models to replace TEC. Findings from these studies will be translated in clinical trials conducted in Project 1 assessing the safety and efficacy of UCB Tprog therapy to reconstitute immune function following transplant and to reduce late, intracellular infections. Finally, in studies supported by this program, Jeffrey Miller MD has confirmed the marked anti-leukemia effects of allogeneic natural killer (NK) cells. In Project 3 he proposes pre-clinical and clinical studies of haplo-identical NK cell adoptive therapy used in combination with DUCB transplant to provide both immediate tumor reduction and long-term anti-leukemia effects in patients with refractory or relapse acute leukemia. These interactive projects are supported by administrative and biostatistical cores (A and B), as well as Core C, providing cGMP cell processing and immune monitoring and Core D, providing animals, environment and expertise to support human adoptive transfer experiments. This long-standing and highly collaborative program project is well positioned to examine these intertwined immunologic and clinical issues and to develop improved cell-based therapies for a variety of lethal hematologic malignancies. RELEVANCE (See instructions): The cumulative results of our current and proposed programmatic studies will be to increase the availability, safety and efficacy of hematopoietic cell transplant and cell-based therapies to treat otherwise lethal hematopoietic malignancies. Findings from the proposed studies can also be used to treat other potentially fatal cancers, hematopoietic, immune, metabolic and infectious disorders, and to address current barriers to solid organ transplant in children and adults world-wide.

描述（由申请人提供）：该程序的主题在15年内没有改变：了解人类造血干细胞（HSC）的生物学及其后代将改善基于造血细胞的疗法治疗多种致命性恶性疾病。在当前的资金期间，我们建立了“双脐带血”（DUCB）移植作为一种有效的治疗方法，可以改变造血细胞移植（HCT）的实践，因为它大大增加了可以提供移植的患者库。现在，我们将在DUCB移植设置 - 植血与宿主疾病（GVHD），延迟免疫重构导致后期感染以及难治性或复发性白血病中处理三个重要问题。约翰·瓦格纳（John Wagner）MD及其共同投资者布鲁斯·布拉萨尔（Bruce Blazar）MD产生了临床前数据，证明了UCB衍生的调节性T细胞（TREG）对GVHD的抑制作用，并进行了“首先是人类” UCB Treg Safety和剂量解决试验。 In Project 1, Dr Wagner proposes a series of clinical trials testing the efficacy of UCB Treg to prevent and to treat acute GVHD including add-back of UCB Tregs and effector T cells (Teffs) in calibrated doses, and development of "off-the-shelf UCB Treg products. Dr Blazar has characterized UCB-derived progenitor T cells (Tprogs), and in Project 2 proposes basic studies exploring它们在胸部上皮细胞（TEC）功能以及可诱导的多能干细胞（IPS）模型中的作用将在项目1中进行的临床试验中进行翻译。 MD证实了在项目3中的同种异体自然杀伤（NK）细胞的明显抗白血病作用。生物统计核心（A和B）以及核心C，提供CGMP细胞处理和免疫监测和核心D，提供动物，环境和专业知识，以支持人类的收养转移实验。 相关性（请参阅说明）：我们当前和拟议的程序研究的累积结果将是增加造血细胞移植和基于细胞的疗法的可用性，安全性和功效，以治疗其他致命的造血恶性肿瘤。拟议研究的发现也可用于治疗其他潜在的致命癌症，造血，免疫，代谢和传染病，并解决全球儿童和成人的当前固体器官移植障碍。