Bronchiolitis Obliterans: Discovery and Therapy

闭塞性细支气管炎：发现和治疗

• 批准号: 10698177
• 负责人: Corey S Cutler
• 金额: $ 66.35万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698177
• 关键词: Actins; Address; Affect; Aftercare; Air; Air Movements; Allogenic; Antigen Targeting; Antigens; Biological Markers; Bronchioles; Bronchiolitis Obliterans; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cell Communication; Cells; Chronic; Clinical Trials; Coculture Techniques; Data; Disease; Enrollment; Epithelial Cells; Epithelium; Epitopes; Fibroblasts; Fibrosis; Functional disorder; Generations; Genetic Transcription; Helper-Inducer T-Lymphocyte; Human; Image; Immune; Immune Targeting; Immune Tolerance; Immunity; Immunogenomics; Immunologics; Immunosuppressive Agents; Infiltration; Link; Lung; Lung Transplantation; Lung diseases; Maps; Measures; Molecular; Monitor; Mus; Organoids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Policies; Polymers; Population; Prediction of Response to Therapy; Principal Investigator; Process; Pulmonary Fibrosis; Pulmonary function tests; Refractory; Regulatory T-Lymphocyte; Resolution; Role; STAT3 gene; Sampling; Signal Transduction; Specificity; Specimen; Stat5 protein; Steroids; Structure of germinal center of lymph node; Suspensions; Syndrome; T cell receptor repertoire sequencing; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; United States National Institutes of Health; Writing; X-Ray Computed Tomography; airway epithelium; antigen-specific T cells; cell injury; cellular targeting; cohort; hematopoietic cell transplantation; idiopathic pulmonary fibrosis; imaging biomarker; imaging modality; improved; in vitro Model; inhibitor; innovation; mouse model; novel; pharmacologic; phase II trial; polymerization; predicting response; progenitor; programs; regenerative; response; tool; transcriptome; transcriptome sequencing; transcriptomics; transplant survivor; treatment response

Project Summary – Project 3 Bronchiolitis Obliterans Syndrome (BOS) is a progressive, irreversible, and often fatal lung disease that occurs following allogeneic hematopoietic cell transplantation (HCT). BOS occurs in approximately 5-10% of HCT survivors and is the pulmonary manifestation of chronic graft-vs.-host disease (cGVHD). Approximately 10-15% of cGVHD patients develop BOS, and less than 15% of BOS patients survive 5 years. The primary immunologic focus of attack in BOS is the small airway, leading to pathologic fibrosis. BOS has no cure, and treatment options are limited. Little is known about the pathophysiology of BOS. Innovations in lung organoid culture and immunogenomics offers a means to pinpoint the cellular and antigenic targets of BOS, and our murine model of BOS has proven invaluable in identifying promising therapeutics for this disease. Given these advances, in this Project, we hypothesize that we can reverse BOS with a promising pharmacologic agent that addresses dysregulated immunity and reduces fibrosis while fundamentally improving our understanding of the pathophysiology of BOS by using in vitro models to identify the cellular and antigenic targets of immunologic attack in BOS. We will test these hypotheses by performing a clinical trial of the novel agent, KD025, in subjects with BOS. KD025 is a ROCK2 inhibitor whose mechanism of action was initially deciphered and tested by our group. This agent has shown promising activity in cGVHD therapy and in idiopathic pulmonary fibrosis. A phase II trial will determine the BOS response rate, measured by NIH cGVHD Response Criteria, in a cohort of subjects with new onset and steroid-refractory BOS, following a 24-week course of KD025. In this trial we will also test whether CT-scan based parametric response mapping can act an imaging biomarker in BOS. Using samples from subjects being treated on the KD025 trial, we will establish an airway organoid (AO) platform to study mechanisms and therapeutic avenues for BOS. Using AO, we will study cellular injury and cell-cell interactions in BOS, and we will test whether AO can serve as treatment response indicators to therapeutic drugs. The precise role of lung-infiltrating CD4+ T cells in the pathobiology of BOS is unknown; using cutting edge immunogenomics, we will identify the antigenic determinants of immune attack in BOS and interrogate the transcriptional programs in BOS using single-cell TCR sequencing and RNA-seq analysis.

项目概要-项目3 闭塞性细支气管炎综合征（BOS）是一种进行性、不可逆且通常致命的肺部疾病， 异基因造血细胞移植（HCT）后。BOS发生在约5-10%的HCT中 存活者，是慢性移植物vs.宿主疾病（cGVHD）。约10-15% 的cGVHD患者发展为BOS，并且少于15%的BOS患者存活5年。主要免疫学 BOS的发病中心是小气道，导致病理性纤维化。BOS无法治愈，治疗方案 是有限的。对BOS的病理生理学知之甚少。肺类器官培养的创新， 免疫基因组学提供了一种方法来确定BOS的细胞和抗原靶点，我们的小鼠模型， BOS已被证明在确定这种疾病的有希望的治疗方法方面是非常宝贵的。鉴于这些进步，在这 项目，我们假设，我们可以扭转BOS与一个有前途的药物，解决 免疫失调，减少纤维化，同时从根本上提高我们对 BOS的病理生理学，通过使用体外模型来识别免疫学的细胞和抗原靶点， 在BOS的攻击。 我们将通过在BOS受试者中进行新药KD 025的临床试验来验证这些假设。 KD 025是一种ROCK 2抑制剂，其作用机制最初由我们的团队破译和测试。这 该试剂在cGVHD治疗和特发性肺纤维化中显示出有希望的活性。第二阶段试验将 确定BOS反应率，通过NIH cGVHD反应标准测量，在一个新的受试者队列中， 在24周的KD 025疗程后，发生类固醇难治性BOS。在这次试验中，我们还将测试 基于CT扫描的参数反应图可以作为BOS的成像生物标志物。 我们将使用来自KD 025试验中接受治疗的受试者的样本，建立气道类器官（AO）平台 研究BOS的机制和治疗途径。利用AO，我们将研究细胞损伤和细胞-细胞 我们将测试AO是否可以作为治疗反应指标， 毒品肺浸润性CD 4 + T细胞在BOS病理学中的确切作用尚不清楚;使用切割 边缘免疫基因组学，我们将确定在BOS免疫攻击的抗原决定簇，并询问 使用单细胞TCR测序和RNA-seq分析在BOS中进行转录程序。