University of Pennsylvania Clinical Autoimmunity Center of Excellence

宾夕法尼亚大学临床自身免疫卓越中心

基本信息

批准号：
9918249
负责人：
AMIT BAR-OR
金额：
$ 7.89万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918249
关键词：
Address Antigen Targeting Antigens Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving B-Lymphocyte Subsets B-Lymphocytes Biological Biological Markers Blood Brain Cellular immunotherapy Chronic Clinical Clinical Research Clinical Trials Clone Cells Communication Communication Programs Development Disease Disease remission Dose Engineered Gene Epigenetic Process Fellowship Fostering Functional disorder Funding Future Future Generations Goals Grant Review Human Immune Immune Tolerance Individual Infection Inflammatory Infrastructure Institution Insulin-Dependent Diabetes Mellitus Islet Cell Knowledge Lead Life Magnetic Resonance Imaging Maintenance Mediating Mentors MicroRNAs Mucous Membrane Multiple Sclerosis Myelogenous Pancreas Pancreatic Injury Patients Pemphigus Vulgaris Pennsylvania Peripheral Phase Phenotype Physicians Placebos Population Randomized Randomized Clinical Trials Research Risk Safety Scientist T-Lymphocyte T-Lymphocyte Subsets Time Tissue imaging Tissues Translational Research Travel Treatment Protocols Universities Withdrawal Work anti-CD20 base career career development clinical care commensal microbes effective therapy first-in-human innovation insight multiple sclerosis patient next generation novel novel therapeutics open label patient subsets potential biomarker predictive marker programs prospective randomized trial secondary lymphoid organ standard of care transcriptome transcriptome sequencing transcriptomics translational research program translational study treatment effect treatment strategy

项目摘要

The overall goals of the University of Pennsylvania Clinical Autoimmunity Center of Excellence (Penn ACE) are 1) to perform cutting-edge clinical and translational research to advance our understanding of human autoimmunity through Clinical and Collaborative Projects, 2) to encourage the next generation of physician- scientists to pursue clinical and translational research in autoimmunity through Scientific Communications and Mentoring and Enrichment Programs overseen by an Administrative Core, and 3) to provide the financial and regulatory guidance and infrastructure to support collaborative scientific interactions within and between academic institutions nationwide through an ACE Funds Management Core. The clinical and translational research program of the Penn ACE centers around the theme of “B cells as drivers of autoimmunity”, focusing on three debilitating and potentially life-threatening autoimmune diseases (pemphigus vulgaris (PV), multiple sclerosis (MS), and type 1 diabetes (T1D)) for which prospective randomized clinical trials of anti-CD20-mediated B cell depletion have demonstrated significant clinical benefit. Thus, B cells are key drivers of autoimmunity in these conditions, but risk of serious and potentially fatal infections compromises the utility of chronic B cell depletion as a long-term treatment strategy. Each of the proposed Clinical and Collaborative Projects, as well as the Administrative Core, addresses a key question or barrier to progress in the field. The Primary Clinical Project will execute a phase 1b open-label dose escalation study to evaluate the safety, tolerability, and potential efficacy of a novel gene-engineered cellular immunotherapy known as DSG3-CAART to achieve targeted, antigen-specific B cell depletion and lasting disease remission in PV. The Alternate Clinical Project will utilize a prospective randomized trial of ocrelizumab withdrawal in MS to evaluate whether B cell depletion can be safely withdrawn in MS patients without compromising efficacy and will identify potential biomarkers that predict long-term tolerance induction. A Collaborative Project will perform deep phenotyping, immune repertoire analysis, and target antigen discovery for expanded B cell clones in the pancreas, secondary lymphoid organs, and blood of patients with T1D, which may not only identify novel therapeutic strategies for T1D, but also establish a framework for how similar experimental approaches can be used to elucidate the pathophysiology and targets of B cells in a broad range of other autoimmune diseases. Finally, an Administrative Core will implement a scientific communications and mentoring program to foster collaborative research within and beyond the Penn ACE and encourage future generations of physician-scientists to pursue careers in autoimmune disease clinical care and research.

宾夕法尼亚大学临床自身免疫卓越中心（Penn ACE）是1）进行尖端的临床和转化研究，以增进我们对人类的理解通过临床和合作项目，2) 鼓励下一代医生- 科学家通过科学通讯和技术进行自身免疫的临床和转化研究由行政核心监督的指导和丰富计划，以及 3) 提供财务和支持内部和之间协作科学互动的监管指导和基础设施通过 ACE 基金管理核心覆盖全国的学术机构。 Penn ACE 的临床和转化研究项目围绕“B 细胞作为自身免疫的驱动因素”，重点关注三种使人衰弱且可能危及生命的自身免疫性疾病（寻常型天疱疮 (PV)、多发性硬化症 (MS) 和 1 型糖尿病 (T1D)）抗 CD20 介导的 B 细胞耗竭的随机临床试验已证明具有显着的临床益处。因此，在这些情况下，B 细胞是自身免疫的关键驱动因素，但存在严重且可能致命的风险感染会损害慢性 B 细胞耗竭作为长期治疗策略的效用。拟议的临床和合作项目以及行政核心解决了一个关键问题或该领域进展的障碍。主要临床项目将执行 1b 期开放标签剂量递增。研究评估新型基因工程细胞的安全性、耐受性和潜在功效称为 DSG3-CAART 的免疫疗法，可实现靶向、抗原特异性 B 细胞消除和持久 PV 疾病缓解。替代临床项目将利用 ocrelizumab 的前瞻性随机试验。在多发性硬化症患者中停药，以评估多发性硬化症患者的 B 细胞消除是否可以安全地停药，而无需影响疗效，并将识别预测长期耐受诱导的潜在生物标志物。合作项目将进行深度表型分析、免疫组库分析和靶抗原发现用于 T1D 患者胰腺、次级淋巴器官和血液中扩增的 B 细胞克隆，不仅可以确定 T1D 的新治疗策略，还可以建立一个框架来说明如何相似实验方法可用于阐明广泛范围内 B 细胞的病理生理学和靶标最后，行政核心将实施科学沟通和治疗。指导计划，以促进宾夕法尼亚大学 ACE 内部和外部的合作研究，并鼓励未来一代又一代的医师科学家致力于自身免疫性疾病临床护理和研究的职业生涯。