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

临床试验：使用环磷酰胺和低剂量 IL-2 进行 I/II 期试验

• 批准号: 8356778
• 负责人: Stanley H. Appel
• 金额: $ 3.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356778
• 关键词: Aftercare; Amyotrophic Lateral Sclerosis; Brain; Cell Therapy; Cells; Clinical Research; Clinical Trials; Collaborations; Cyclophosphamide; Deterioration; Diagnosis; Disease; Disease Progression; Dose; FDA approved; Funding; Goals; Grant; Human; IL2 gene; IL2RA gene; Immune response; Immune system; Immunophenotyping; Interleukin-2; Intravenous; Measures; Metastatic Melanoma; Motor Neurons; Mus; Muscle; Muscle Weakness; National Center for Research Resources; Natural Killer Cells; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phase I/II Trial; Play; Population; Principal Investigator; Protocols documentation; Regulatory T-Lymphocyte; Relative (related person); Renal carcinoma; Research; Research Infrastructure; Resources; Respiratory Failure; Respiratory Muscles; Role; Source; Spinal Cord; Stem cell transplant; T-Cell Depletion; Time; Toxic effect; Transplantation; United States National Institutes of Health; cost; cytokine; dosage; effective therapy; gene therapy; graft vs host reaction; mouse model; mutant; nervous system disorder; patient safety; wasting

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT 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. I. HYPOTHESIS 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. II. SPECIFIC AIMS To assess the effects of cyclophosphamide followed by low dose IL-2 administration in patients with amyotrophic lateral sclerosis (ALS) To assess in this group of patients the safety and the toxicity of cyclophosphamide and low-dose IL-2, administered according to the dosage described in this protocol. To investigate the immunomodulatory effects of the combination of cyclophosphamide and low dose IL-2 administered in patients with ALS, by comparing before, during and after treatment: -The immunophenotype of peripheral blood mononuclear cells (PBMCs) -The suppressive activity of CD4+ CD25+ FoxP3+ Tregs -Cytokines secreted by PBMCs -NK cell analysis To measure disease progression before during and after administration of cyclophosphamide and low dose IL-2

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 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。 一、假说 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。 二、具体目标 评价环磷酰胺联合小剂量IL-2治疗肌萎缩侧索硬化症(ALS)的疗效 在这组患者中评估环磷酰胺和小剂量IL-2的安全性和毒性，根据本方案中描述的剂量给予。 目的：观察环磷酰胺联合小剂量白介素2治疗ALS患者的免疫调节作用。 -外周血单个核细胞(PBMCs)免疫表型 -CD4+CD25+FoxP3+树突状细胞的抑制活性 -PBMCs分泌的细胞因子 -NK细胞分析 在使用环磷酰胺和小剂量IL-2之前、期间和之后测量疾病进展