Biology & Transplantation of the Human Stem Cell

描述(申请人提供)：这个项目的主题15年来没有改变：了解人类造血干细胞(HSC)及其后代的生物学将导致改进基于造血细胞的治疗各种致命的恶性疾病。在目前的资助期内，我们已经确定“双脐血”移植是一种有效的治疗方法，它可能会改变造血细胞移植的做法，因为它极大地增加了可以接受移植的患者池。我们现在将探讨DUCB移植环境中的三个重要问题-移植物抗宿主病(GVHD)，延迟免疫重建并导致晚期感染，以及难治性或复发性白血病。John Wagner医学博士和他的合作者Bruce Blazar医学博士已经生成了临床前数据，证明了脐带血来源的调节性T细胞(Treg)对GVHD的抑制作用，并进行了“人类首例”UCB Treg安全性和剂量发现试验。在项目1中，Wagner博士提出了一系列临床试验，以测试UCB Treg预防和治疗急性GVHD的有效性，包括按校准剂量添加UCB Treg和效应器T细胞(TeFs)，以及开发“现成的UCB Treg产品”。Blazar博士已经确定了脐带血来源的祖细胞(Tprogs)的特征，并在项目2中提出了基础研究，探索它们在胸腺上皮细胞(TEC)功能恢复中的作用，以及可诱导的多能干细胞(IPS)模型来取代TEC。这些研究的结果将被转化为项目1中进行的临床试验，评估UCB Tprog疗法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，在该计划支持的研究中，杰弗里·米勒医学博士证实了异基因自然杀伤(NK)细胞具有显著的抗白血病作用。在项目3中，他建议进行半相合NK细胞过继治疗与DUCB移植相结合的临床前和临床研究，为难治性或复发性急性白血病患者提供即时肿瘤减少和长期抗白血病效果。这些互动项目得到行政和生物统计学核心(A和B)以及核心C和核心D的支持，核心C提供cGMP细胞处理和免疫监测，核心D提供动物、环境和专业知识，以支持人类收养移植实验。这个长期和高度合作的项目处于有利地位，可以检查这些相互交织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治疗方法。 相关性(见说明)：我们目前和拟议的程序性研究的累积结果将是增加造血细胞移植和基于细胞的治疗方法的可用性、安全性和有效性，以治疗其他致命的血液系统恶性肿瘤。拟议研究的结果还可用于治疗其他可能致命的癌症、造血、免疫、新陈代谢和感染性疾病，并解决目前世界各地儿童和成年人进行固体器官移植的障碍。

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.