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，主要发生在育龄期的年轻女性。活动性SLE的治疗仍不充分，副作用显著。即使是最积极的治疗，其反应率也不超过50%。因此，迫切需要更有效和更安全的治疗选择。间充质干细胞（MSCs）是已知具有显著免疫抑制特性的基质细胞。来自SLE患者的动物模型和非对照试验的证据支持同种异体间充质干细胞输注在降低SLE疾病活动性方面的有效性，并且副作用非常少。MSCs具有相对的免疫特权，因为它们不表达II类抗原或表面激活标记，如CD80/86，因此可以在不交叉匹配或不需要对受体进行骨髓消融的情况下给予。到目前为止，还没有发表或正在进行的对照试验，将MSC治疗与SLE的标准治疗进行比较。我们建议开展一项II期多中心安慰剂对照试验，评估同种异体间充质干细胞治疗成人中度至重度活动性SLE的疗效和安全性。间充质干细胞将从健康的供体脐带中提取，并将测试3剂间充质干细胞。每个参与试验的地点都有良好的生产规范（GMP）质量清洁细胞设施，以确保MSCs在注入研究参与者之前的质量和安全性。我们提出的试验的主要目的是验证这样一种假设，即在对活动性SLE进行标准治疗时，接受MSC输注的患者比接受安慰剂输注的患者反应更好。主要终点将是24周时的临床反应，通过使用经过验证的sle专用仪器减少疾病活动性和将皮质类固醇剂量减少到d10mg /天的泼尼松或同等药物来测量。其他终点将包括MSC剂量比较、组间不良事件、类固醇保留效应、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志物的变化。R34计划拨款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MSCs对活动期SLE患者的多中心试验。

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.