Cell-based Therapy in RA: Proof of Concept

本申请提出了一种在血清阳性患者中进行的双盲安慰剂对照的I期细胞疗法临床试验， 新发RA患者（诊断后2年内），尽管进行了充分的试验，但疾病活动性仍很高， 甲氨蝶呤，一种改善疾病的抗风湿药物（DMARD）。审判将在CWRU进行， 两个临床性能研究中心[MetroHealth医疗中心（MHMC）和大学医院Case Medical 中心]。使用间充质干细胞（MSC）的基于细胞的治疗具有很大的前景。MSC似乎是 周细胞准备感知和修复外源性或内源性威胁引起的损伤，即 “炎症的守护者”这些细胞回到炎症和/或损伤部位，并促进修复， 选择性地减少炎症。 这项临床试验的驱动假设是，MSC将在恢复免疫方面具有治疗价值。 宽容MSC有可能通过重置免疫系统来延迟或中止完全成熟的RA的发作， 诱导免疫耐受并抑制观察到的适应性免疫机制的扩增， 使关节发炎永久化。多种RA疗法可用，但没有特异性修复自身免疫; 相反，大多数干扰自身免疫和保护性宿主免疫。大多数受影响者需要终身 治疗，使RA患者容易受到超出RA本身的感染和恶性肿瘤的影响。 本研究将重点关注静脉输注成人骨髓来源的同种异体间充质干细胞的安全性， 正常供体并离体扩增。患者将被随机分配至MSC或安慰剂组，并接受单药治疗。 输注MSC，同时继续伴随甲氨蝶呤，但MSC输注后立即输注的间隔除外 输注（以免损伤输注的MSC）。三个MSC剂量递增水平和研究将在 执行。监管机构可接受每月1例受试者的入组计划。剂量 已经制定了升级规则和提前停止规则。患者报告的结局（传统和 PROMIS）将被收集。此外，我们还与MHMC的健康差异中心合作， 进行焦点小组讨论，以了解RA患者对潜在和适当时机的看法， MSC作为RA治疗。已提交IRB申请，IND申请将在 审查本申请。 假设安全性，本研究之后将进行II期随机安慰剂对照试验， 有把握检测I期研究中验证的主要临床和转化终点。而 I期概念验证项目的主要终点是安全性，本研究将使用敏感的方法， 检测MSC在新发RA患者中的免疫效应，其中12周的甲氨蝶呤治疗 导致不完全缓解（DAS 28-CRP ≥ 4.4）。检测耐受性的免疫学措施包括 使用PI中开发的新型功能生物标志物测量THBG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MSC的安全性，选择两种剂量 用于后续II期试验，并确定哪些生物标志物应用于该试验。

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.