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）：细胞疗法具有巨大的治疗多种疾病的潜力。目前，造血细胞移植（HCT）是目前在临床医学中实践的基于细胞的疗法的主要例子。在了解动物模型中执行的特定细胞群体作用的许多进步都证明了将这种治疗方式扩展到许多其他重要领域的潜力。但是，关键局限性包括适当匹配的捐助者的可用性以及嫁接与宿主疾病（GVHD）的风险限制了这种潜在治疗策略的有效性和应用。在此Go Trip阶段，我们将尝试翻译来自我们实验室的新见解和其他证明关键细胞种群潜在功能作用，这些功能可能会对诊所中细胞疗法的成功和应用产生重大影响。在提案中，我们将在HCT中进行CD4+CD25+FOXP3+调节T细胞（TREG）的临床试验，并尝试使用强有力的临床前数据开发至少一种其他细胞治疗。成功应用这些治疗策略的核心是使用临床规模上的高速细胞分选有时有时罕见的细胞种群。该提案寻求支持，以实施TREG的临床试验，其中包括扩大，验证和IND提交在内的开发已经完成。由于未满足的临床需求以及这种临床环境将允许快速评估Treg功能，因此将在接受单倍体移植的患者中进行该试验。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种群，包括纯化的造血干细胞，常见的淋巴样祖细胞和效应记忆CD8+ T细胞，这些细胞均由研究人员在程序中研究，目的是将这些建议中的一个或可能的两个提案带入开发，验证和验证，验证和提交。该提案将推进批判性科学，发展新技术，并为新颖的细胞治疗剂的重要开发和实施提供关键的工作。 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。对于老年患有急性髓样白血病的老年患者，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人群中通常看到的不良预后。到目前为止，初步研究已经证明了这种特定类型的移植类型的结果。