A Phase II Controlled Trial of Allogeneic Mesenchymal Stem Cells for the Treatment of Refractory Lupus

同种异体间充质干细胞治疗难治性狼疮的 II 期对照试验

• 批准号: 10356843
• 负责人: Gary S Gilkeson
• 金额: $ 70.78万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-19 至 2023-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356843
• 关键词: Academia; Aftercare; Allogenic; Alternative Therapies; Autoimmune; Autoimmunity; Autologous; B-Cell Activation; B-Lymphocytes; Bone Marrow; Cell Therapy; Cells; Clinic; Clinical; Clinical Trials; Clinical effectiveness; Complex; Cyclophosphamide; Cytoskeleton; Data; Dental; Development; Disease; Dose; Double-Blind Method; Effectiveness; FDA approved; Fatty acid glycerol esters; Female of child bearing age; Human; Immune; Immune Targeting; Immunologic Factors; Immunologics; In Vitro; Individual; Industry; Inflammatory Response; Infusion procedures; LRRC32 gene; Laboratories; Licensing; Lupus; Lupus Nephritis; MHC Class II Genes; Mediating; Mesenchymal Stem Cells; Multicenter Trials; Mus; Pathogenicity; Pathway interactions; Patients; Pharmacotherapy; Phase; Placebo Control; Placebos; Plasma Cells; Prednisone; Process; Property; Recurrence; Refractory; Regulatory T-Lymphocyte; Reporting; Reproducibility; Research; Research Personnel; Rheumatoid Arthritis; Role; Safety; Serious Adverse Event; Serum; Source; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Translating; Translations; Umbilical cord structure; Uncontrolled Study; Up-Regulation; Wound healing therapy; base; cohort; effective therapy; efficacy testing; experience; immunological intervention; innovation; insight; mouse model; novel; novel therapeutics; placebo controlled trial; pre-clinical; preclinical study; preconditioning; predictive marker; receptor; response; side effect; standard of care; stem cell therapy; young woman

PROJECT SUMMARY/ABSTRACT Determining the clinical effectiveness of mesenchymal stem cells (MSCs) and their mechanism of action in treating refractory lupus is of significant importance. We and others have reported reproducible improvement in murine models of lupus following allogeneic MSC infusions from healthy mice or humans. Infusion of MSCs, derived from bone marrow or umbilical cords, in more than 100 treatment-refractory lupus patients has resulted in positive clinical benefit in 65-75% of those treated. However, a placebo-controlled trial of MSCs in lupus has not been performed to show definitively that MSCs are more effective than standard of care. One clear result from multiple trials of MSCs to date is that they can be given safely with almost no serious adverse events. The preclinical data, the uncontrolled trials and the safety profile create a mandate for a controlled trial to test the efficacy of MSCs as a therapeutic for lupus. Critical to this trial are mechanistic studies to define how MSCs impact disease. Prior studies in lupus and rheumatoid arthritis reported increased circulating Treg cells, decreased Th17 cells, decreased TFH cells and fewer activated B and plasma cells in patients after MSC infusion. The mechanism by which these cellular effects occur is unknown. We have found that lupus patients have decreased circulating levels of glycoprotein A repetitions predominant (GARP)/TGF complexes. MSCs express GARP, and GARP is a major determinant of TGF bioactivity and also has important enhancing effects on Treg number and function. We hypothesize that allogeneic MSC infusion, plus standard of care, will prove significantly more effective in treating lupus patients with active disease than standard of care alone. We further hypothesize that effects of MSCs in lupus occur via modulation of regulatory and pathogenic T and B cells through upregulation of GARP expression, resulting in enhanced TGF bioactivity and increased Treg numbers and activity. To test these hypotheses, our specific aims are to: 1. Determine the safety and efficacy of mesenchymal stem cell therapy in a two-dose escalation double- blind placebo-controlled multi-center trial as a treatment for lupus patients with moderate to severe disease activity unresponsive to standard of care therapy compared to ongoing standard of care. 2. Define mechanistically how MSCs modulate regulatory and pathogenic T and B cells in lupus patients and the role of GARP-mediated TFG bioactivity in this process. The proposed trial will be performed in six academic centers that are all skilled, successful and experienced in performing lupus trials. If we confirm that MSC therapy is as effective as reported, then MSC infusions may become an alternative therapy for lupus. The detailed mechanistic analysis will provide novel insight into the complex cellular matrix in lupus and the impact MSCs have on these cellular interactions. There is a defined FDA pathway for licensing cellular therapies allowing this therapy, if effective, to be translated to the clinic.

项目概要/摘要 确定间充质干细胞 (MSC) 的临床有效性及其作用机制 我们和其他人报告了治疗难治性狼疮的可重复性改善。 来自健康小鼠或人类的同种异体 MSC 输注后的狼疮小鼠模型。 源自骨髓或脐带，在 100 多名难治性狼疮患者中产生了结果 然而，一项 MSCs 治疗狼疮的安慰剂对照试验显示，65-75% 的治疗者具有积极的临床获益。 尚未明确表明 MSC 比标准护理更有效。 迄今为止的多项 MSC 试验表明，它们可以安全给药，几乎不会发生严重不良事件。 临床前数据、非对照试验和安全性概况要求进行对照试验来测试 间充质干细胞作为狼疮治疗的功效对该试验至关重要的是确定间充质干细胞如何发挥作用的机制研究。 先前对狼疮和类风湿性关节炎的研究报告了循环 Treg 细胞的增加， MSC 治疗后患者的 Th17 细胞减少，TFH 细胞减少，活化的 B 细胞和浆细胞减少 我们发现狼疮患者发生这些细胞效应的机制尚不清楚。 糖蛋白 A 重复为主 (GARP)/TGF MSC 复合物的循环水平降低。 表达 GARP，GARP 是 TGF 生物活性的主要决定因素，也具有增强重要作用 我们发现同种异体 MSC 输注加上标准护理将会对 Treg 数量和功能产生影响。 事实证明，治疗患有活动性疾病的狼疮患者比单独使用标准护理更有效。 此外，间充质干细胞对狼疮的影响是通过调节调节性和致病性 T 和 B 来实现的 通过上调 GARP 表达，增强 TGF 生物活性并增加 Treg 细胞 为了检验这些假设，我们的具体目标是： 1. 确定间充质干细胞治疗在两次剂量递增双剂量中的安全性和有效性 用于治疗中度至重度狼疮患者的盲法安慰剂对照多中心试验 与持续标准护理相比，疾病活动对标准护理治疗无反应。 2. 从机制上定义 MSC 如何调节狼疮患者的调节性和致病性 T 细胞和 B 细胞 以及 GARP 介导的 TFG 生物活性在此过程中的作用。 拟议的试验将在六个学术中心进行，这些中心在以下领域均拥有熟练、成功和经验丰富的技能。 如果我们确认 MSC 治疗与报道的一样有效，那么 MSC 输注可能会进行。 成为狼疮的替代疗法。详细的机制分析将为我们提供新的见解。 狼疮中复杂的细胞基质以及间充质干细胞对这些细胞相互作用的影响是明确的。 FDA 批准细胞疗法的途径允许这种疗法如果有效的话可以转化为临床。