Mesenchymal Stem Cell Therapy for Active Systemic Lupus Erythematosus

描述(由申请人提供)：系统性红斑狼疮(SLE)是一种毁灭性的疾病，主要发作于育龄的年轻女性。活动期系统性红斑狼疮的治疗仍然不够充分，有显著的不良反应。即使是最激进的疗法，其有效率也被限制在50%。因此，非常需要更有效和更安全的治疗方案。间充质干细胞(MSCs)是已知的具有显著免疫抑制特性的基质细胞。来自动物模型和对SLE患者的非对照试验的证据支持同种异体骨髓间充质干细胞输注在减少SLE疾病活动性方面的有效性，不良反应非常少。MSCs相对免疫优势，因为它们不表达II类抗原或CD80/86等表面激活标记，因此可以在不交叉配型或任何需要骨髓切除的情况下进行移植。到目前为止，还没有已发表的或正在进行的关于系统性红斑狼疮的MSC疗法与标准护理相比的对照试验。我们提出了一项II期多中心安慰剂对照试验，评估同种异体骨髓间充质干细胞治疗中度至重度活动期SLE的有效性和安全性。MSCs将从健康的供者脐带中分离出来，并将对3剂MSCs进行测试。每个参与试验的地点都有一个良好的制造规范(GMP)质量清洁细胞设施，以确保在向研究参与者注入MSCs之前的质量和安全。我们提议的试验的主要目的是检验这样一种假设，即接受MSC输注的患者在加入活动期SLE的标准治疗时将比接受安慰剂输注的患者反应更好。主要终点将是24周后的临床反应，通过使用经过验证的SLE专用仪器减少疾病活动性以及将强的松或同等药物的皮质类固醇剂量减少到D10毫克/天来衡量。其他终点将包括MSC剂量比较、组间不良事件、类固醇节省效应、患者报告的生活质量变化、疲劳、疼痛和抑郁，以及细胞和血清生物标记物的变化。R34规划补助金将允许我们完成方案开发，并在每个地点建立必要的行政和监管结构，以成功实施针对活动期SLE患者的MSCs多中心试验。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a devastating illness striking primarily young women in their reproductive years. Treatments for active SLE remain inadequate with significant adverse effects. Response rates for even the most aggressive therapies are capped at 50%. Thus there is a significant need for more effective and safer therapeutic options. Mesenchymal stem cells (MSCs) are stromal cells known to possess significant immunosuppressive properties. Evidence from animal models and uncontrolled trials in patients with SLE supports the effectiveness of allogeneic MSC infusions in reducing SLE disease activity, with remarkably few adverse effects. MSCs are relatively immune-privileged in that they do not express Class II antigens or surface activating markers such as CD80/86, and therefore can be given without cross-matching or any need for bone marrow ablation of the recipient. To date there are no published or in progress controlled trials of MSC therapy compared to standard of care in SLE. We propose a Phase II multicenter placebo controlled trial evaluating efficacy and safety of allogeneic MSCs for the treatment of adults with moderate to severely active SLE. MSCs will be derived from healthy donor umbilical cords and 3 doses of MSCs will be tested. Each of the participating trial sites has a good manufacturing practice (GMP) quality Clean Cell Facility to ensure the quality and safety of the MSCs prior to infusing into study participants. Our primary aim for the proposed trial is to test the hypothesis that patients receiving the MSC infusion will respond better than patients receiving the placebo infusion when added to standard-of-care therapy for active SLE. The primary endpoint will be clinical response at 24 weeks as measured by reduction in disease activity using validated SLE-specific instruments and reduction in corticosteroid dose to d10 mg/day of prednisone or equivalent. Additional endpoints will include MSC dose comparisons, adverse events between groups, steroid-sparing effects, changes in patient-reported quality of life, fatigue, pain and depression, and changes in cellular and serum biomarkers. The R34 Planning Grant will allow us to complete protocol development and set up the administrative and regulatory structures necessary at each of the sites for successful implementation of a multicenter trial of MSCs for patients with active SLE.