Inducible Regulatory T Cells for the Prevention and Treatment of Acute GVHD

诱导性调节性 T 细胞预防和治疗急性 GVHD

基本信息

批准号：
8536939
负责人：
Margaret L MacMillan
金额：
$ 51.14万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8536939
关键词：
Acute Graft Versus Host Disease Adoptive Transfer Adult Alleles Allogenic Autoimmunity Biological Assay Blood Blood Component Removal Bone Marrow Transplantation CD4 Positive T Lymphocytes CD8B1 gene Cause of Death Cell physiology Cells Clinical Clinical Protocols Clinical Trials Consent Consent Forms Development Disease Dose Frequencies Future Goals Hematopoietic Stem Cell Transplantation Human IL2RA gene Immunology In Vitro Infusion procedures Interleukin-2 Kinetics Leukocytes Life Lymphocyte Measures Methodology Methods Minnesota Modeling Morbidity - disease rate Mus National Heart, Lung, and Blood Institute Opportunistic Infections Patients Phase Phase I Clinical Trials Phenotype Population Positioning Attribute Prevention Procedures Production Prophylactic treatment Reagent Regulatory T-Lymphocyte Relative (related person)Research Personnel Safety Series Siblings Sirolimus T-Lymphocyte Testing Thymus Gland Transplantation Universities active method base blood product clinical application disorder prevention flexibility follow-up graft vs host disease high risk in vivo mortality novel therapeutic intervention patient safety peripheral blood pre-clinical prevent product development scale up transcription factor volunteer

项目摘要

DESCRIPTION (provided by applicant): Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). T regulatory (Tregs) cells are a subset of CD4+ T cells that co-express high levels of the IL-2Ra chain (CD25) and the transcription factor, FoxP3. Adoptive transfer of natural Tregs (nTregs, CD4+CD25brFoxP3+) that arise in the thymus have already been shown to prevent aGVHD and autoimmunity in mice but high ratios of nTreg:donor T cells are required. Clinical application of nTregs has been hampered by low frequency and low proliferative potential of nTregs derived from peripheral blood (PB). In the periphery, a population of non-Treg CD4+ T-cells can be induced to acquire a Treg phenotype and function - these cells are referred to as inducible Tregs (iTregs). Our group was the first to show that human iTregs could be reliably activated in the presence of IL-2, rapamycin and TGFss, leading to a population with stable Foxp3 expression and potent suppressive of aGVHD in a xenogeneic GVHD murine model. Furthermore, we have recently developed a manufacturing procedure using GMP reagents for cell purification, activation and expansion. Importantly, we have already completed scale-up studies and have demonstrated that we can reproducibly culture >109 iTregs from a PB buffy coat and ~240x109 cells from a full apheresis PB product within 2 weeks of culture initiation. With these expansion rates, we expect to achieve an iTreg:donor T cell ratio up to 5:1, remarkably in excess of the targeted minimum of 1:1 ratio for aGVHD prevention, as shown in preclinical murine models. However, it is possible that higher ratios or multiple doses of iTreg may be required in patients with active disease. With the ultimate goal of manufacturing a clinical grade 'off the shelf' 3rd party iTreg product for aGVHD prophylaxis and treatment, we will embark on a series of 'first-in-human' clinical trials to methodically evaluate the safety and potential efficacy of iTregs. Here, we will establish the safety and kinetics of HLA matched, partially matched, and unmatched iTregs for aGVHD prevention. We will perform a series of phase I trials with an extension phase to determine the MTD, safety profile and potential efficacy of fresh and subsequently cryopreserved iTregs. We will first establish the safety of fresh HLA matched iTregs in recipients of HLA matched sibling donor HSCT, followed by a follow-up study using fresh (and later cryopreserved) HLA mismatched iTregs obtained from a haploidentical relative for use in recipients of HLA-matched, unrelated donor HSCT. The successful completion of these first two clinical trials and the subsequent testing of cryopreserved iTregs, will justify the penultimate trial testing banked 'off-the-shelf' iTregs from an HLA mismatched donor. In parallel to the clinical trials, we will optimize the culture conditions for iTreg expanson required to permit multi-dose infusions and establishment of an "off-the-shelf" product. At the completion of these studies, we will have developed a bank of iTregs for immediate 'off-the-shelf' use for the prevention and treatment of aGVHD.

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）后，急性移植物抗宿主病（AGVHD）是发病率和死亡率的主要原因。 T调节（Tregs）细胞是CD4+ T细胞的子集，该细胞共表达高水平的IL-2RA链（CD25）和转录因子Foxp3。胸腺中出现的天然Treg（Ntregs，CD4+CD25Brfoxp3+）的产物转移已经显示出可以防止小鼠的AGVHD和自身免疫性，但需要NTREG的高比例：供体T细胞。 Ntregs的临床应用已受到源自外周血（PB）的NTREG的低频和低增殖潜力的阻碍。在外围，可以诱导非Treg CD4+ T细胞的种群获得Treg表型和功能 - 这些细胞被称为诱导型Treg（ITREGS）。我们的小组是第一个表明在IL-2，雷帕霉素和TGFSS存在下可以可靠地激活人ITREG的人，从而导致人口具有稳定的Foxp3表达，并且在异构GVHD鼠模型中具有稳定的AGVHD抑制作用。此外，我们最近使用GMP试剂开发了一种制造程序，用于细胞纯化，激活和扩展。重要的是，我们已经完成了扩大研究的研究，并证明我们可以从PB Buffy Coat和〜240x109细胞中可重复培养> 109个ITREG，并在培养开始后的2周内从完整的磨牙PB产物中获得了〜240x109的细胞。随着这些膨胀率，我们期望达到ITREG：供体T细胞的比率高达5：1，明显超过了预防AGVHD的目标最小值1：1的比率，如临床前鼠模型所示。但是，在活性疾病患者中可能需要更高的比率或多剂量ITREG。为了制造临床级“货架上的临床等级”第三方ITREG产品的临床级别，用于AGVHD预防和治疗，我们将启动一系列“人类第一”临床试验，以有条不紊地评估ITREGS的安全性和潜在功效。在这里，我们将建立HLA匹配，部分匹配和无与伦比的ITREGS的安全性和动力学，以预防AGVHD。我们将执行一系列I期试验，以确定新鲜和随后冷冻保存的ITREGS的MTD，安全性和潜在功效。我们将首先建立新鲜HLA匹配的ITREGS的安全性，在HLA匹配的兄弟姐妹供体HSCT中，然后进行了后续研究，使用了新的（后来和后来的冷冻保存）HLA不匹配的ITREGS，该ITREG是从HaploIdentical亲戚获得的，可用于HLA匹配的HLA匹配，未匹配的，未匹配的供体HSCT的HSCT。前两个临床试验的成功完成以及随后对冷冻保存的ITREGS的测试将证明倒数第二个试验测试是从HLA不匹配的捐助者中进行的“现成” ITREGS的倒数式试验。与临床试验并行，我们将优化ITREG扩张子的培养条件，以允许多剂量输注和建立“现成”产品。这些研究完成后，我们将开发一批ITREG，以立即“现成”用于预防和治疗AGVHD。