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

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 抽象的 ALS是一种进行性神经系统疾病，通常是致命的，随着脑部和脊髓的运动神经元死亡，肌肉会增加肌肉的虚弱和浪费。这种进行性恶化最终导致呼吸道肌肉无力导致呼吸衰竭。 ALS的原因尚不清楚，但最近的证据表明，免疫系统在ALS的发病机理中起着重要作用。在ALS的突变体SOD1小鼠模型中，我们记录了T细胞的相对耗竭，主要是与加速疾病进展和生存降低相关的T Reg细胞。带有T Reg细胞的小鼠移植到这些小鼠中减慢疾病的进展并显着延长生存率。我们的初步人类ALS研究表明，与慢速进步者相比，下降的患者的T型细胞更快。这项研究的目的是增加ALS患者的Treg细胞群体。该研究将与细胞和基因治疗主席Malcolm Brenner博士合作进行。 Brenner博士使用IL-2进行了大量研究，以增加患者自身的T Reg细胞群体。将给予患者单剂量的静脉注射环磷有剂，然后给予IL-2，每周3次，持续12周，用Treg细胞重新填充免疫系统。每位受试者将遵循一年来评估其免疫反应和疾病进展。该疗法已成功地用于最大程度地减少移植物抗宿主反应，是一种经过FDA批准的治疗，用于在干细胞移植后针对人类的转移性黑色素瘤和肾癌。 尽管我们的目标是减慢疾病进展并延长生存期，但没有证据表明这种方法肯定会慢慢疾病的进展。但是，目前尚无针对ALS患者的有效疗法。至少，我们将增强对免疫系统在疾病发病机理中潜在作用的理解。 I.假设 在肌萎缩性侧索硬化症患者中使用环磷酰胺，然后使用低剂量IL2给药，这将延迟诊断为ALS患者的疾病进展。 ii。 具体目标 为了评估环磷酰胺，然后施用低剂量IL-2对肌萎缩性侧索硬化症患者（ALS）的影响 在这组患者中评估环磷酰胺和低剂量IL-2的安全性和毒性，根据本方案中描述的剂量进行给药。 通过比较前，期间和治疗后，研究了在ALS患者中施用环磷酰胺和低剂量IL-2组合的免疫调节作用： - 外周血单核细胞的免疫表型（PBMC） - CD4+ CD25+ FOXP3+ Tregs的抑制作用 - pBMC分泌的循环因子 -NK细胞分析 测量在施用环磷酰胺和低剂量IL-2之前和之后的疾病进展