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)是目前在临床医学中使用的基于细胞的疗法的主要例子。在动物模型中对特定细胞群体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其他一些重要领域。然而，包括合适配型供者的可获得性和移植物抗宿主病(GVHD)风险在内的关键限制限制了这一潜在治疗策略的有效性和应用。在这个GO之旅第一阶段的提案中，我们将尝试翻译来自我们的实验室和其他已经证明了关键细胞群的潜在功能作用的新见解，这些作用可能对细胞疗法的成功和在临床上的应用产生重大影响。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，并试图开发至少一种具有强大临床前数据的其他细胞疗法。这些治疗策略的成功应用的核心是在临床规模上使用高速细胞分选有效地分离有时罕见的细胞群体。该提案寻求支持，以实施Treg的临床试验，其中包括扩大规模、验证和IND提交的开发已经完成。这项试验将在接受单倍体相合移植的患者中进行，原因是临床需求未得到满足，并认为这种临床设置将允许快速评估Treg功能。此外，该提案将建立一个翻译团队，以评估其他三个潜在的细胞群体，包括纯化的造血干细胞、共同淋巴祖细胞和效应记忆CD8 T细胞，这些细胞都已由该计划内的研究人员进行研究，目标是将其中一个或两个提案提交开发、验证和IND提交。该提案将推进关键科学，开发新技术，并为新细胞疗法的重要开发和实施提供关键工作。 与公共卫生相关：将聘请一名临床试验项目经理来监督一项多中心第三阶段临床试验的运作。对于老年急性髓系白血病患者，这项试验试图确定异基因造血细胞移植是否可以改善这种患者群体中常见的不良预后。到目前为止，初步研究表明，这种特殊类型的移植取得了良好的效果。

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.