Biology & Transplantation of the Human Stem Cell

描述（申请人提供）：该项目的主题15年来从未改变：了解人类造血干细胞（HSC）及其后代的生物学特性将改善基于造血细胞的多种致命恶性疾病的治疗。在当前的资助期内，我们已经建立了“双脐带血”（DUCB）移植作为一种有效的治疗方法，它可能会改变造血细胞移植（HCT）的实践，因为它大大增加了可以提供移植的患者数量。我们现在将讨论 DUCB 移植环境中的三个重要问题：移植物抗宿主病 (GVHD)、延迟免疫重建导致的晚期感染以及难治性或复发性白血病。 John Wagner 医学博士和他的共同研究员 Bruce Blazar 医学博士已经生成了临床前数据，证明 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，Wagner 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，包括按校准剂量添加 UCB Treg 和效应 T 细胞 (Teffs)，以及开发“现成的 UCB Treg 产品。Blazar 博士对 UCB 衍生的祖 T 细胞 (Tprogs) 进行了表征，并在项目 2 中提出了探索其在胸腺上皮恢复中作用的基础研究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 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。单倍体 NK 细胞过继疗法与 DUCB 移植相结合，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的临床前和临床研究。这些互动项目得到了管理和生物统计核心（A 和 B）以及核心 C 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、环境和专业知识来支持人类过继转移实验。高度协作的计划项目非常有能力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疗法。 相关性（参见说明）：我们当前和拟议的计划性研究的累积结果将提高造血细胞移植和基于细胞的疗法的可用性、安全性和有效性，以治疗其他致命的造血系统恶性肿瘤。拟议研究的结果还可用于治疗其他潜在致命的癌症、造血、免疫、代谢和感染性疾病，并解决目前全世界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.