Cell-based Therapy in RA: Proof of Concept

这项申请提出了一项针对血清阳性患者的双盲安慰剂对照I期细胞治疗临床试验， 新发的RA患者(在确诊后2年内)，尽管进行了适当的试验，但疾病活跃度较高 甲氨蝶呤，一种疾病修饰性抗风湿药物(DMARD)。审判将在CWRU进行， 两个临床表现站点[MetroHealth医疗中心(MHMC)和大学医院病例医疗 中心]。使用间充质干细胞(MSCs)进行基于细胞的治疗前景广阔。骨髓间充质干细胞似乎 周细胞，准备感知和修复由外源性或内源性威胁引起的损伤，即 “炎症的卫士”。这些细胞是炎症和/或损伤部位的家园，并促进修复 有选择地减少炎症。 这项临床试验的驱动假设是，骨髓间充质干细胞在恢复免疫方面将具有治疗价值。 宽容。MSCs有可能通过重置免疫系统来延缓或中止全面爆发的RA的发病， 诱导免疫耐受并抑制观察到的适应性免疫机制的放大 使关节持续发炎。有多种RA疗法可用，但没有一种是专门修复自身免疫的； 相反，大多数病毒同时干扰自身免疫和保护性宿主免疫。受影响最大的人需要终生 治疗，使类风湿性关节炎患者更容易受到感染和恶性疾病的影响，这超出了类风湿关节炎本身的范围。 本研究将重点研究成人骨髓来源的同种异体MSCs静脉注射的安全性。 一个正常的捐赠者和扩大的体外。患者将被随机分配到MSCs或安慰剂，并接受单一的 骨髓间充质干细胞输注同时应用甲氨蝶呤，但在紧接MSC后的间歇期除外 输液(以免损伤输注的MSCs)。三个MSC剂量升级水平和研究将是 已执行。每月一科的招生时间表是监管机构可以接受的。剂量 已经制定了上报规则和提前停止规则。患者报告的结果(遗留和 PROMIS)将被收集。此外，我们还与MHMC的健康差距中心合作， 组织焦点小组，了解RA患者对潜在的和适当的治疗时机的看法 骨髓间充质干细胞作为类风湿关节炎治疗。IRB申请已经提交，IND提交将在 审核此应用程序。 假定安全，这项研究之后将进行第二阶段随机安慰剂对照试验。 有能力检测在第一阶段调查中验证的主要临床和转换终端。而当 第一阶段概念验证计划的主要终点是安全性，本研究将使用敏感的方法 检测甲氨蝶呤治疗12周后新发RA患者的MSC免疫效应 结果为不完全应答(DAS28-CRP4.4)。检测耐受性的免疫措施将包括 用PI‘s开发的一种新的功能生物标记物测量Treg的数量和功能 实验室。在研究结束时，我们应该能够证明在RA中输注MSCs的安全性，选择两种剂量 用于后续的第二阶段试验，并确定应该使用哪些生物标记物。

This application proposes a double blind placebo-controlled Phase I cell therapy clinical trial in sero-positive, new-onset RA patients (within 2 years of diagnosis) who have high disease activity despite an adequate trial of a methotrexate, a Disease Modifying Anti-Rheumatic Drug (DMARD). The trial will take place at CWRU with two clinical performanace sites [MetroHealth Medical Center (MHMC) and University Hospitals Case Medical Center]. Cell based therapy using mesenchymal stem cells (MSCs) holds great promise. MSCs appear to be pericytes, poised to sense and repair damage arising from exogenous or endogenous threats, i.e. the “guardians of inflammation”. These cells home to sites of inflammation and/or injury and facilitate repair while selectively reducing inflammation. The driving hypothesis for this clinical trial is that MSCs will have therapeutic value in restoring immune tolerance. MSCs have potential to delay or abort onset of full blown RA by resetting the immune system, inducing immune tolerance and dampening the observed amplification of adaptive immune mechanisms that perpetuate joint inflammation. Multiple RA therapies are available but none specifically repair autoimmunity; rather most interfere with both autoimmunity and protective host immunity. Most affected require lifelong therapy, rendering RA patients susceptible to infection and malignancy beyond that which RA itself confers. This study will focus on the safety of IV delivery of adult, bone marrow-derived allogeneic MSCs collected from a normal donor and expanded ex vivo. Patients will be randomized to MSCs or placeo and treated with a single infusion of MSCs while remaining on concomitant methotrexate except in the interval immediately after MSC infusion (so as not to damage the infused MSCs). Three MSC dose-escalation levels and studies will be performed. The enrollment schedule of one subject per month is acceptable to regulatory agencies. Dose escalation rules and early stopping rules have been developed. Patient reported outcomes (legacy and PROMIS) will be collected. In addition, we have engaged the Center for Health Disparities at MHMC in conducting focus groups to understand what RA patients think about the potential and appropriate timing for MSCs as RA therapy. An IRB application has been submitted and an IND submission will be completed prior to review of this application. Presuming safety, this study will be followed by a Phase II randomized placebo-controlled trial adequately powered to detect primary clinical and translational endpoints validated in the Phase I investigation. While the primary endpoint for the Phase I proof of concept program is safety, this study will use sensitive approaches to detect MSC immunologic effects in new onset RA patients in whom 12 weeks of methotrexate therapy has resulted in incomplete response (DAS28-CRP ≥ 4.4 ). Immunologic measures to detect tolerance will include measuement of number and function of Tregs using a novel functional biomarker developed in the PI's laboratory. At study end, we should be able to demonstrate safety of infusing MSCs in RA, pick two dosages for a successor Phase II trial, and identify which biomarkers should be used that trial.