Bronchiolitis Obliterans: Discovery and Therapy

闭塞性细支气管炎：发现和治疗

• 批准号: 10493801
• 负责人: Corey S Cutler
• 金额: $ 67.36万
• 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/10493801
• 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; Epithelial Cells; 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; Measures; Molecular; Monitor; Mus; Organoids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Policies; 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; X-Ray Computed Tomography; airway epithelium; antigen-specific T cells; base; cell injury; cellular targeting; cohort; hematopoietic cell transplantation; idiopathic pulmonary fibrosis; imaging biomarker; imaging modality; improved; in vitro Model; inhibitor; innovation; mouse model; novel; 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.

项目总结 – 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) 后约 5-10% 的 HCT 发生 BOS。 幸存者，是慢性移植物抗宿主病 (cGVHD) 的肺部表现，约占 10-15%。 的 cGVHD 患者出现 BOS，并且只有不到 15% 的 BOS 患者能存活 5 年。 BOS的攻击焦点是小气道，导致BOS病理性纤维化尚无治愈方法和治疗方案。 对于 BOS 的病理生理学和肺类器官培养的创新知之甚少。 免疫基因组学提供了一种精确定位 BOS 的细胞和抗原靶点的方法，以及我们的小鼠模型 鉴于这些进展，BOS 已被证明在识别这种疾病的有前途的治疗方法方面具有无价的价值。 项目中，我们认为我们可以用一种有前途的药物来逆转 BOS，该药物可以解决 免疫失调并减少纤维化，同时从根本上提高我们对免疫系统的理解 通过使用体外模型来识别免疫学的细胞和抗原靶点，了解 BOS 的病理生理学 攻击BOS。 我们将通过在患有 BOS 的受试者中进行新型药物 KD025 的临床试验来检验这些假设。 KD025是一种ROCK2抑制剂，其作用机制最初由我们课题组破译和测试。 该药物在 cGVHD 治疗和特发性肺纤维化的 II 期试验中显示出有希望的活性。 确定 BOS 反应率，通过 NIH cGVHD 反应标准测量，在一组患有新疾病的受试者中 在 KD025 24 周疗程后，我们还将测试是否会出现发作和类固醇难治性 BOS。 基于 CT 扫描的参数响应图可以充当 BOS 中的成像生物标志物。 使用 KD025 试验中接受治疗的受试者样本，我们将建立一个气道类器官 (AO) 平台 为了研究 BOS 的机制和治疗途径，我们将使用 AO 研究细胞损伤和细胞间的关系。 BOS 中的相互作用，我们将测试 AO 是否可以作为治疗反应指标 肺浸润 CD4+ T 细胞在 BOS 病理学中的确切作用尚不清楚； 边缘免疫基因组学，我们将鉴定 BOS 中免疫攻击的抗原决定因素并询问 使用单细胞 TCR 测序和 RNA-seq 分析的 BOS 转录程序。