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

• 批准号: 8890183
• 负责人: Margaret L MacMillan
• 金额: $ 52.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890183
• 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; 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; phase I trial; pre-clinical; prevent; product development; scale up; transcription factor; volunteer

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（由申请方提供）：急性移植物抗宿主病（aGVHD）是异基因造血干细胞移植（HSCT）后发病和死亡的主要原因。调节性T细胞（TlR）是共表达高水平IL-2 Ra链（CD 25）和转录因子FoxP 3的CD 4 + T细胞亚群。已经显示胸腺中产生的天然T细胞（nT细胞，CD 4 + CD 25 brFoxP 3+）的连续转移可预防小鼠中的aGVHD和自身免疫，但需要高比例的nTreg：供体T细胞。由于外周血来源的nTHBE的低频率和低增殖潜力，阻碍了nTHBE的临床应用。在外周中，非Treg CD 4 + T细胞群体可以被诱导以获得Treg表型和功能-这些细胞被称为诱导型T细胞（iT细胞）。我们的研究组首次表明，在IL-2、雷帕霉素和TGF β的存在下，人iT β可以被可靠地激活，从而在异种GVHD鼠模型中产生具有稳定Foxp 3表达和有效抑制aGVHD的群体。此外，我们最近开发了一种使用GMP试剂进行细胞纯化、活化和扩增的生产程序。重要的是，我们已经完成了规模扩大研究，并证明我们可以在培养开始后2周内从PB血沉棕黄层中可重复地培养>109个iT细胞，从完全单采PB产品中可重复地培养约240 × 109个细胞。如临床前小鼠模型所示，凭借这些扩增率，我们预计iTreg与供体T细胞的比例将达到5：1，显着超过aGVHD预防的目标最低比例1：1。然而，活动性疾病患者可能需要更高比例或多次剂量的iTreg。最终目标是生产用于aGVHD预防和治疗的临床级“现成”第三方iTreg产品，我们将 开展一系列“首次人体”临床试验，以系统地评估iTsalt的安全性和潜在疗效。在这里，我们将建立HLA匹配的，部分匹配的，和不匹配的iTclad预防aGVHD的安全性和动力学。我们将进行一系列I期试验和扩展期试验，以确定新鲜和随后冷冻保存的iTdR的MTD、安全性特征和潜在疗效。我们将首先在HLA匹配的同胞供体HSCT的接受者中确定新鲜HLA匹配的iT细胞的安全性，随后使用从单倍体相合的亲属获得的新鲜（和随后冷冻保存的）HLA不匹配的iT细胞用于HLA匹配的无关供体HSCT的接受者中进行随访研究。这前两项临床试验的成功完成以及随后对冷冻保存的iTclone的测试将证明倒数第二项试验测试来自HLA不匹配供体的库存“现成”iTclone是合理的。在临床试验的同时，我们将优化iTreg expanson的培养条件，以允许多剂量输注和建立“现成”产品。在这些研究完成后，我们将开发出一个iTHBG库，可立即用于预防和治疗aGVHD。