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

临床试验：使用环磷酰胺和低剂量 IL-2 进行 IND 的 I/II 期试验

• 批准号: 8166775
• 负责人: Stanley H. Appel
• 金额: $ 0.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166775
• 关键词: Amyotrophic Lateral Sclerosis; Brain; Cells; Clinical Trials; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Cyclophosphamide; Deterioration; Diagnosis; Disease; Disease Progression; Dose; FDA approved; Funding; Goals; Grant; Human; IL2 gene; Immune response; Immune system; Institution; Interleukin-2; Intravenous; Metastatic Melanoma; Motor Neurons; Mus; Muscle; Muscle Weakness; Pathogenesis; Patients; Phase; Play; Population; Regulatory T-Lymphocyte; Relative (related person); Renal carcinoma; Research; Research Personnel; Resources; Respiratory Failure; Respiratory Muscles; Role; Source; Spinal Cord; Stem cell transplant; T-Cell Depletion; Time; Transplantation; United States National Institutes of Health; effective therapy; gene therapy; graft vs host reaction; mouse model; mutant; nervous system disorder; wasting

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 ALS 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，导致肌肉日益虚弱和萎缩。这种逐渐恶化最终导致由于呼吸肌无力而导致呼吸衰竭。 ALS 的病因尚不清楚，但最近的证据表明免疫系统在 ALS 的发病机制中发挥着重要作用。在 ALS 突变 SOD1 小鼠模型中，我们记录了 T 细胞（主要是 T reg 细胞）的相对消耗，与疾病进展加速和生存率降低相关。将 T reg 细胞移植到这些小鼠体内可以减缓疾病进展并显着延长生存期。我们的初步人类 ALS 研究表明，病情恶化较快的患者比进展缓慢的患者的 T reg 细胞更少。这项研究的目标是增加 ALS 患者的 Treg 细胞数量。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。患者将接受单剂静脉注射环磷酰胺，然后注射 IL-2，每周注射 3 次，持续 12 周，以使免疫系统重新充满 Treg 细胞。每个受试者将被跟踪一年，以评估他们的免疫反应和疾病进展。该疗法已成功用于最大程度地减少移植物抗宿主反应，并且是 FDA 批准的用于干细胞移植后人类转移性黑色素瘤和肾癌的治疗方法。 尽管我们的目标是减缓疾病进展并延长生存期，但没有证据表明这种方法肯定会减缓疾病进展。然而，目前对于ALS患者尚无有效的治疗方法；至少，我们将加深对免疫系统在疾病发病机制中潜在作用的理解。 在肌萎缩性脊髓侧索硬化症 (ALS) 患者中使用环磷酰胺后给予低剂量 IL2 将延缓诊断为 ALS 的患者的疾病进展。