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

项目总结/摘要 确定间充质干细胞（MSC）的临床有效性及其在肿瘤治疗中的作用机制。 治疗难治性狼疮是非常重要的。我们和其他人已经报告了可重复的改善， 来自健康小鼠或人的同种异体MSC输注后的狼疮鼠模型。MSC的输注， 在100多名难治性狼疮患者中， 在65-75%的治疗患者中有积极的临床获益。然而，一项在狼疮患者中进行的MSC安慰剂对照试验表明， 尚未进行以明确显示MSC比标准护理更有效。一个明确的结果 迄今为止，从多项MSC试验中得出的结论是，它们可以安全地给予，几乎没有严重的不良事件。的 临床前数据、非对照试验和安全性特征要求进行对照试验， MSC作为狼疮治疗剂的功效。这项试验的关键是机制研究，以确定如何MSC 影响疾病。先前在狼疮和类风湿性关节炎中的研究报告了循环Treg细胞增加， MSC后患者中Th 17细胞减少，TFH细胞减少，活化的B和浆细胞减少 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重复占优势（GARP）/TGF β复合物的循环水平降低。MSCs 表达GARP，GARP是TGF β 1生物活性的主要决定因素，也具有重要的增强作用。 影响Treg数量和功能。我们假设同种异体MSC输注，加上标准治疗， 证明在治疗活动性疾病的狼疮患者中比单独的标准护理显著更有效。我们 进一步假设MSC在狼疮中的作用是通过调节调节性和致病性T和B而发生的 细胞通过上调GARP表达，导致TGF β生物活性增强和Treg增加 数字和活动。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个剂量递增的双剂量中的安全性和有效性， 一项治疗中重度狼疮患者的盲法安慰剂对照多中心试验 与正在进行的标准治疗相比，对标准治疗无反应的疾病活动。 2.阐明狼疮患者骨髓间充质干细胞如何调节调节性和致病性T和B细胞的机制 以及GARP介导的TFG生物活性在这一过程中的作用。 拟议的试验将在六个学术中心进行，这些中心都是熟练的，成功的和经验丰富的， 进行狼疮试验如果我们证实MSC治疗与报道的一样有效，那么MSC输注可能 成为狼疮的替代疗法详细的机理分析将提供新的见解， 狼疮中复杂的细胞基质以及MSC对这些细胞相互作用的影响。存在定义的 FDA许可细胞疗法的途径，允许这种疗法（如果有效）转化为临床。

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.