Regulatory T Cells in Allogeneic Transplantation

描述（由申请人提供）：细胞疗法在治疗多种疾病方面具有巨大的潜力。目前，造血细胞移植（HCT）是目前临床医学中使用基于细胞的治疗方法的主要例子。在动物模型中对特定细胞群的作用的理解方面取得的许多进展表明，这种治疗模式有可能扩展到许多其他重要领域。然而，包括合适匹配供体的可用性和移植物抗宿主病（GVHD）风险在内的关键限制限制了这种潜在治疗策略的有效性和应用。在这个GO TRIP第一阶段的提案中，我们将尝试翻译来自我们实验室和其他人的新见解，这些见解已经证明了关键细胞群的潜在功能作用，这些作用可能对细胞治疗在临床中的成功和应用产生重大影响。在该提案中，我们将在HCT中进行CD4+CD25+FoxP3+调节性T细胞（Treg）的临床试验，并尝试开发至少一种具有强大临床前数据的其他细胞治疗方法。这些治疗策略成功应用的核心是在临床规模上使用高速细胞分选有效分离有时罕见的细胞群。该提案寻求支持实施Treg的临床试验，其中开发包括扩大规模，验证和IND提交已经完成。由于未满足的临床需求，该试验将在接受单倍体移植的患者中进行，并且认为这种临床环境将允许快速评估Treg功能。此外，该提案将建立一个翻译团队来评估其他三种潜在的细胞群体，包括纯化的造血干细胞、普通淋巴样祖细胞和效应记忆CD8+ T细胞，这些细胞群体都已被项目内的研究人员研究过，目标是将其中一种或两种提案推进开发、验证和IND提交。该提案将推进关键科学，开发新技术，并为新型细胞疗法的重要开发和实施提供关键工作。

DESCRIPTION (provided by applicant): Cellular therapy has enormous potential for the treatment of a broad range of diseases. Currently, hematopoietic cell transplantation (HCT) serves as the major example of the use of cell based therapeutics currently practiced in clinical medicine. Many advances in the understanding of the role of specific cell populations performed in animal models demonstrate the potential for the extension of this mode of therapy into a number of other important areas. However, key limitations including the availability of suitably matched donors and the risk of graft vs. host disease (GVHD) limit the effectiveness and application of this potential treatment strategy. In this GO TRIP stage I proposal we will attempt to translate novel insights from our laboratory and others that have demonstrated the potential functional role of key cell populations that could have a major impact in the success and application of cellular therapeutics in the clinic. In the proposal we will pursue a clinical trial of CD4+CD25+FoxP3+ regulatory T cells (Treg) in HCT and to attempt to develop at least one other cellular therapeutic with strong preclinical data. Central to the successful application of these treatment strategies is the effective isolation of sometimes rare populations of cells using high speed cell sorting on a clinical scale. The proposal seeks support to implement a clinical trial of Treg where development including scale-up, validation and IND submission has already been completed. The trial will be pursued in patients undergoing haploidentical transplantation due to the unmet clinical need and the view that this clinical setting will allow for rapid assessment of Treg function. Further, the proposal will establish a Translation Team to evaluate three other potential cellular populations including purified hematopoietic stem cells, common lymphoid progenitor cells and effector memory CD8+ T cells which have all been studied by investigators within the Program with the goal of bringing one or possibly two of these proposals forward to development, validation and IND submission. The proposal will advance critical science, develop novel technology and provide critical jobs for the important development and implementation of novel cellular therapeutics. PUBLIC HEALTH RELEVANCE: A Clinical Trials Project Manager will be hired to oversee the operations of a multicenter, Phase III clinical trial. For elderly patients with acute myeloid leukemia, this trial is attempting to determine if allogeneic hematopoietic cell transplantation can improve the poor prognoses typically seen in this patient population. Preliminary studies, so far, have demonstrated favorable results with this specific type of transplant.