Regulatory T Cells in Allogeneic Transplantation

同种异体移植中的调节性 T 细胞

• 批准号: 7855234
• 负责人: Robert S Negrin
• 金额: $ 118.43万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7855234
• 关键词: Acute Myelocytic Leukemia; Address; Alloantigen; Allogenic; Animal Model; Area; Autoimmune Diseases; Award; Biological; Biological Process; Biological Testing; CD34 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular system; Cell Separation; Cell Therapy; Cell Transplantation; Cells; Clinic; Clinical; Clinical Data; Clinical Medicine; Clinical Trials; Common Lymphoid Progenitor; Data; Development; Disease; Dose; Effectiveness; Frequencies; Funding; Goals; Graft-Versus-Tumor Induction; Grant; Granzyme; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Homologous Transplantation; Human; Immune; Infusion procedures; Laboratories; Lung; Mediating; Memory; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Occupations; Operative Surgical Procedures; Opportunistic Infections; Organ; Patients; Phase; Phase III Clinical Trials; Population; Pre-Clinical Model; Reagent; Recovery; Relapse; Request for Applications; Research Personnel; Risk; Role; Science; Solid; Speed; Staging; Stem cells; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Translating; Translational Research; Translations; Transplantation; Validation; Work; base; clinical application; cytotoxic; graft vs host disease; improved; insight; killings; mortality; neoplastic cell; new technology; novel; older patient; outcome forecast; patient population; perforin; pre-clinical; prevent; programs; public health relevance; reconstitution; response; scale up; success; tool; transplantation typing; treatment strategy

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.

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疗法的主要例子。在了解动物模型中特定细胞群的作用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，包括合适匹配的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 第一阶段提案中，我们将尝试转化我们实验室和其他实验室的新见解，这些见解已经证明了关键细胞群的潜在功能作用，可能对细胞疗法在临床上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可靠临床前数据的其他细胞疗法。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来有效分离有时罕见的细胞群。该提案寻求支持实施 Treg 临床试验，其中包括放大、验证和 IND 提交在内的开发工作已经完成。由于临床需求未得到满足，并且认为这种临床环境将允许快速评估 Treg 功能，因此该试验将在接受半相合移植的患者中进行。此外，该提案将建立一个翻译小组来评估其他三种潜在的细胞群，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的研究人员进行了研究，目的是带来一种或可能其中两项提案将进入开发、验证和 IND 提交阶段。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。 公共卫生相关性：将聘请临床试验项目经理来监督多中心 III 期临床试验的运作。对于患有急性髓性白血病的老年患者，该试验试图确定同种异体造血细胞移植是否可以改善该患者群体通常出现的不良预后。到目前为止，初步研究已经证明这种特定类型的移植取得了良好的结果。