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Intermediate-Size Expanded Access Trial of Autologous Hybrid TREG/Th2 Cell Therapy (RAPA-501) of Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症自体杂交 TREG/Th2 细胞疗法 (RAPA-501) 的中型扩大试验

基本信息

批准号：
10834469
负责人：
Suma Babu
金额：
$ 1120.3万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-25 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10834469
关键词：
Academic Medical Centers Acceleration Address Adverse event Amyotrophic Lateral Sclerosis Anti-Inflammatory Agents Antigens Antiinflammatory Effect Arizona Autologous Berry Biological Blood Component Removal Blood specimen CXCL5 gene Cell Therapy Cells Cellular Assay Cessation of life Characteristics Clinic Clinical Clinical Trials Collaborations Comparison arm Data Science Databases Disease Progression Dose Enrollment Ensure Event FDA approved FOXP3 gene Failure GATA3 gene General Hospitals Geographic Locations Goals Homing Hospitals Hybrids IL16 gene IL8 gene Idaho Immune System Diseases Immunotherapy Inflammasome Inflammation Inflammatory Infusion procedures Interleukin-10 Interleukin-16 Interleukin-4 Interleukin-6 Intervention Intravenous infusion procedures Iowa LOX gene Light Machine Learning Mediating Methods Microglia Morbidity - disease rate Nerve Degeneration Neurodegenerative Disorders Oregon Outcome Oxidative Stress Participant Patients Peripheral Persons Phase Phase II/III Trial Phenotype Placebos Population Prevention Protocols documentation Research Research Personnel Respiratory Failure Riluzole Risk Safety Sampling Serum Signal Transduction Site Symptoms T cell regulation T cell therapy T-Lymphocyte TNF gene Testing Th2 Cells Therapeutic Therapeutic Effect Thymus Gland Time Underserved Population Up-Regulation Vital capacity amyotrophic lateral sclerosis therapy arm cell type chemokine chemotherapy cohort conditioning cytokine design experience high risk high risk population immune checkpoint immune reconstitution improved in vivo manufacture mortality mouse model neurofilament neuroinflammation novel oxidized low density lipoprotein phase I trial phase I/IIa trial phenylmethylpyrazolone prediction algorithm prognostic programmed cell death ligand 1 programmed cell death protein 1 pulmonary function decline remote monitoring safety and feasibility slow potential stem targeted agent treatment effect trend virtual

项目摘要

ALS is a lethal neurodegenerative disease accelerated by neuroinflammation. Current FDA-approved therapies have modest benefits and do not address inflammation. To address this, RAPA Therapeutics, LLC (RAPA) has developed an autologous T cell therapy (RAPA-501) that reduces inflammation, with the goal of reducing ALS morbidity and mortality. RAPA-501 are manufactured ex vivo to attain dual TREG/Th2 anti- inflammatory activity and a T-stem phenotype that permits T cell therapy without conditioning chemotherapy. In an ongoing clinical trial of RAPA-501 in people with ALS (pwALS) (NCT04220190), RAPA-501 cells were found to be safe (no product-related adverse events), biologically active (diverse anti-inflammatory effects in pwALS), and showed early trends toward stabilizing pulmonary function decline. A phase 2/3 expansion cohort was added to the trial to assess whether RAPA-501 is efficacious in standard-risk pwALS. We will extend RAPA-501 therapy to pwALS not eligible for this ongoing phase 2/3 trial or other ALS trials, which nearly universally require that participants have a slow vital capacity (SVC) value of ≥50% of predicted normal. The proposed EAP will enroll pwALS who have SVC values <50%. This population of pwALS is considered “high risk” (~50% chance of respiratory failure or death within 180 days) and thus particularly suitable for experimental immune therapies such as RAPA-501. In addition, the RAPA-501-EAP will not exclude pwALS who have a prolonged time from ALS-related symptoms or low ALSFRS-R scores. Participants will receive four RAPA-501 IV infusions (every 42-days at established safe dose, 80 x 106 cells/infusion). This RAPA-501-EAP will further evaluate the safety of this therapy, expand an understanding of the RAPA-501 therapeutic mechanism of action, and evaluate signals of efficacy in this real-world population of pwALS using standard methods and Origent Data Sciences machine learning ALS prediction algorithms. The RAPA-501 EAP will be led by investigators at Mass General Hospital (MGH; Drs. Berry, Babu, and Paganoni) and sponsored by RAPA, which is responsible for RAPA-501 manufacturing and FDA regulatory filings under existing IND 019480 (Dr. Fowler, Sponsor). Clinical trial site investigators have experience with RAPA-501 therapy (MGH; Hackensack University Medical Center; and Mayo Clinic Arizona) or other cells therapies. Sites are geographically diverse and likely to accrue a significant number of underserved pwALS (U of Iowa; U of Idaho; Providence Hospital, Portland, Oregon; UC-Irvine; Columbia, NYC). In addition, several research collaborations will emanate from the intensive study of the clinically-annotated, valuable research samples obtained from the RAPA-501 EAP.

ALS 是一种由神经炎症加速的致命性神经退行性疾病。目前 FDA 批准疗法的益处有限，并且不能解决炎症。为了解决这个问题，RAPA Therapeutics, LLC (RAPA) 开发了一种可减少炎症的自体 T 细胞疗法 (RAPA-501)，目的是降低 ALS 发病率和死亡率。 RAPA-501 是在体外制造的，以获得双重 TREG/Th2 抗炎症活动和 T 干表型允许 T 细胞治疗而无需预处理化疗。在一项正在进行的 RAPA-501 在 ALS 患者 (pwALS) (NCT04220190) 中的临床试验，发现了 RAPA-501 细胞安全（无与产品相关的不良事件）、生物活性（pwALS 中的多种抗炎作用）、并显示出稳定肺功能下降的早期趋势。添加了 2/3 期扩展队列参加评估 RAPA-501 对标准风险 pwALS 是否有效的试验。我们将把 RAPA-501 疗法扩展到不符合正在进行的 2/3 期试验或其他 ALS 试验资格的 pwALS，几乎普遍要求参与者的慢肺活量 (SVC) 值≥预测值的 50% 普通的。拟议的 EAP 将招募 SVC 值 <50% 的 pwALS。 pwALS 的这一群体是被认为是“高风险”（180 天内呼吸衰竭或死亡的可能性约为 50%），因此特别适合用于实验性免疫疗法，例如 RAPA-501。此外，RAPA-501-EAP 不会排除 pwALS 长期出现 ALS 相关症状或 ALSFRS-R 评分较低的人。参与者将获得四份 RAPA-501 IV 输注（每 42 天一次，按既定安全剂量，80 x 106 个细胞/输注）。这个 RAPA-501-EAP 将进一步评估该疗法的安全性，扩大对RAPA-501治疗机制的了解行动，并使用标准方法和评估在现实世界的 pwALS 人群中的功效信号 Origent Data Sciences 机器学习 ALS 预测算法。 RAPA-501 EAP 将由麻省总医院 (MGH) 的研究人员领导；Berry 博士、Babu 博士和 Paganoni）并由 RAPA 赞助，RAPA 负责 RAPA-501 的制造和 FDA 监管根据现有 IND 019480 提交申请（Fowler 博士，发起人）。临床试验现场研究者有以下经验 RAPA-501 疗法（MGH；哈肯萨克大学医学中心；和亚利桑那州梅奥诊所）或其他细胞疗法。站点地理分布广泛，可能会积累大量服务不足的 pwALS（U 爱荷华州；爱达荷大学；普罗维登斯医院，俄勒冈州波特兰；加州大学欧文分校；哥伦比亚，纽约）。此外，还有几个研究合作将源于对临床注释的有价值研究的深入研究从 RAPA-501 EAP 获得的样品。