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.

项目摘要/摘要 确定间充质干细胞（MSC）及其作用机理的临床有效性 治疗难治性狼疮非常重要。我们和其他人报告了可再现的改进 狼疮的鼠模型在健康小鼠或人类的同种异体MSC输注后。输注MSC， 源自骨髓或脐带，在100多个治疗难治性狼疮患者中已导致 在65-75％的接受治疗的人中，临床益处为积极。但是，狼疮中MSC的安慰剂对照试验具有 没有进行确定表明MSC比标准护理更有效。一个明确的结果 从迄今为止的多次MSC试验中，几乎没有严重的不良事件可以安全地给予它们。这 临床前数据，不受控制的试验和安全性概况为对照试验创造了一项授权，以测试 MSC作为狼疮的治疗性的功效。该试验至关重要的是定义MSC的机械研究 影响疾病。狼疮和类风湿关节炎的先前研究报告说，循环中的Treg细胞增加， MSC后，患者的Th17细胞减少，TFH细胞降低，激活B和浆细胞较少 输液。这些细胞效应发生的机制尚不清楚。我们发现狼疮患者 糖蛋白A的循环水平降低了重复（GARP）/TGF复合物。 MSC Express GARP，GARP是TGF生物活性的主要确定，并且具有重要的增强 对Treg编号和功能的影响。我们假设同种异体MSC输注以及护理标准将 与单独的护理标准相比，在治疗患有活性疾病的狼疮患者方面，事实证明，有效得多。我们 进一步假设MSC在狼疮中的影响通过调节和致病性T和B的调节而发生 通过上调GARP表达的细胞，从而提高了TGF生物活性并增加了Treg 数字和活动。为了检验这些假设，我们的具体目的是： 1。确定在两剂量升级双重升级中间充质干细胞疗法的安全性和效率 盲目的安慰剂对照多中心试验作为中度至重度的狼疮患者的治疗 与持续的护理标准相比，疾病活动对护理疗法的反应无反应。 2。机械定义狼疮患者中MSC如何调节调节性和致病性T和B细胞 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，这些中心都熟练，成功和经验 进行狼疮试验。如果我们确认MSC治疗与报道的有效性一样，则MSC输注可能 成为狼疮的替代疗法。详细的机械分析将为您提供新的洞察力 狼疮中的复杂细胞基质和影响MSC对这些细胞相互作用具有。有一个定义 FDA途径用于许可细胞疗法，允许将这种疗法（如果有效）转化为诊所。