CLINICAL TRIAL: PHASE I/II TRIAL USING CYCLOPHOSPHAMIDE AND LOW-DOSE IL-2 TO IND

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肌萎缩侧索硬化症是一种进行性神经系统疾病，通常是致命的，随着大脑和脊髓的运动神经元死亡，会导致肌肉越来越虚弱和萎缩。这种渐进性的恶化最终会导致呼吸肌无力导致呼吸衰竭。ALS的病因尚不清楚，但最近的证据表明，免疫系统在ALS的发病机制中起着重要作用。在ALS的突变SOD1小鼠模型中，我们已经记录到T细胞，主要是T reg细胞的相对耗竭，与疾病进展加速和存活率下降有关。将T-reg细胞移植到这些小鼠体内可以减缓疾病进展，并显著延长存活期。我们的初步人类ALS研究表明，下降较快的患者比进展缓慢的患者拥有更少的T reg细胞。这项研究的目标是增加ALS患者的Treg细胞数量。这项研究将与细胞和基因治疗主席马尔科姆·布伦纳博士合作进行。布伦纳博士已经进行了大量研究，使用IL-2来增加患者S自己的T细胞群。患者将接受单剂量环磷酰胺静脉注射，然后注射IL-2，每周3次，持续12周，以用Treg细胞重新填充免疫系统。每个受试者将被跟踪一年，以评估他们的免疫反应和疾病的进展。这种疗法已经成功地用于最小化移植物抗宿主反应，是FDA批准的干细胞移植后人类转移性黑色素瘤和肾癌的治疗方法。虽然我们的目标是减缓疾病进展和延长生存期，但没有证据表明这种方法一定会减缓疾病进展。然而，目前还没有针对ALS患者的有效治疗方法；至少，我们将加强对免疫系统在疾病发病机制中潜在作用的了解。 肌萎缩侧索硬化症(ALS)患者在使用环磷酰胺后加用小剂量IL2将延缓ALS患者的疾病进展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ALS is a progressive neurological disease which is usually fatal, causing increasing weakness and wasting of the muscles as the motor neurons of the brain and spinal cord die. This progressive deterioration eventually leads to respiratory failure due to respiratory muscle weakness. The cause of ALS is not known but recent evidence suggests that the immune system plays a significant role in the pathogenesis of ALS. In the mutant SOD1 mouse model of ALS we have documented a relative depletion of T cells, primarily T reg cells, associated with an accelerated disease progression and decreased survival. Transplantation into these mice with T reg cells slows disease progression and significantly prolongs survival. Our preliminary human ALS studies have indicated that patients that decline more rapidly have fewer T reg cells than slow progressors. The goal of this study is to increase the Treg cell population in ALS patients. The study will be conducted in collaboration with Dr. Malcolm Brenner, Chair of Cell and Gene Therapy. Dr. Brenner has carried out numerous studies using IL-2 to increase a patient''s own population of T reg cells. Patients will be given a single dose of intravenous cyclophosphamide followed by administration of IL-2, given 3 times a week for 12 weeks to repopulate the immune system with Treg cells. Each subject will be followed for one year to assess their immune response and progression of disease. This therapy has been successfully employed in minimizing graft-versus-host reactions and is an FDA-approved treatment for metastatic melanoma and kidney cancer in humans following stem cell transplantation. Although our goal is to slow disease progression and prolong survival, there is no evidence to indicate that this approach will definitely slow disease progression. However, there is presently no effective therapy for patients with ALS; and at the very least, we will enhance our understanding of the potential role of the immune system in disease pathogenesis. The use of cyclophosphamide followed by a low dose IL2 administration in patients with amyotrophic lateral sclerosis (ALS) will delay disease progression for patients diagnosed with ALS.