Biology & Transplantation of the Human Stem Cell

描述（由申请人提供）：该计划的主题在15年内没有改变：了解人类造血干细胞（HSC）及其后代的生物学将导致改善造血细胞为基础的治疗各种致命的恶性疾病。在目前的资助期内，我们已将“双脐带血”移植确立为一种有效的治疗方法，这种方法可能会改变造血细胞移植的做法，因为它大大增加了可接受移植的患者人数。我们现在将探讨DUCB移植中的三个重要问题-移植物抗宿主病（GVHD）、延迟免疫重建导致的晚期感染和难治性或复发性白血病。John瓦格纳医学博士和他的合作研究者布鲁斯Blazar医学博士已经产生了临床前数据，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“首次人体”UCB Treg安全性和剂量探索试验。在项目1中，瓦格纳博士提出了一系列临床试验，测试UCB Treg预防和治疗急性GVHD的功效，包括以校准剂量添加UCB Treg和效应T细胞（Teff），以及开发“现成的UCB Treg产品”。Blazar博士描述了UCB衍生的祖细胞T细胞（Tprogs），并在项目2中提出了探索其在恢复胸腺上皮细胞（TEC）功能中的作用的基础研究，以及替代TEC的诱导性多能干细胞（iPS）模型。这些研究的结果将转化为项目1中进行的临床试验，评估UCB Tprog治疗在移植后重建免疫功能和减少晚期细胞内感染的安全性和有效性。最后，在该项目支持的研究中，Jeffrey米勒医学博士证实了同种异体自然杀伤（NK）细胞的显著抗白血病作用。在项目3中，他提出了与DUCB移植联合使用的单倍体相同NK细胞过继治疗的临床前和临床研究，以在难治性或复发性急性白血病患者中提供立即的肿瘤减少和长期的抗白血病作用。这些互动项目得到了行政和生物统计核心（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过继转移实验）的支持。这个长期存在的高度合作的项目很好地定位于研究这些交织在一起的免疫学和临床问题，并为各种致命的血液恶性肿瘤开发改进的基于细胞的疗法。 相关性（参见说明）：我们目前和拟议的计划性研究的累积结果将增加造血细胞移植和基于细胞的治疗的可用性，安全性和有效性，以治疗其他致命的造血系统恶性肿瘤。拟议研究的结果也可用于治疗其他可能致命的癌症，造血，免疫，代谢和感染性疾病，并解决目前全球儿童和成人实体器官移植的障碍。

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.