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; 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.

项目摘要 - 项目3 支气管炎闭塞综合征（BOS）是一种进行性，不可逆且经常发生致命的肺部疾病 遵循同种异体造血细胞移植（HCT）。 BOS发生在大约5-10％的HCT中 幸存者，是慢性移植-Vs.-host疾病（CGVHD）的肺部表现。约10-15％ CGVHD患者患有BOS，不到15％的BOS患者存活了5年。主要免疫学 BOS攻击的重点是小气道，导致病理纤维化。 BOS无法治愈和治疗选择 有限。关于BOS的病理生理学知之甚少。肺器官培养和 免疫原性提供了一种方法来查明BOS的细胞和抗原靶标，而我们的鼠模型的模型 BOS在识别该疾病的有希望的治疗方面已证明是无价的。鉴于这些进步，在这方面 项目，我们假设我们可以用有前途的药物来逆转BOS 免疫力失调并降低纤维化，同时从根本上提高我们对 通过使用体外模型来鉴定免疫学的细胞和抗原靶标，BOS的病理生理学 在BOS中攻击。 我们将通过对BOS受试者进行新型药物KD025的临床试验来检验这些假设。 KD025是一种Rock2抑制剂，其作用机理最初是由我们小组决定和测试的。这 代理在CGVHD疗法和特发性肺纤维化中表现出了有希望的活性。 II期审判将 通过NIH CGVHD响应标准确定BOS响应率 在KD025的24周课程之后，发作和类固醇难治性BOS。在此试验中，我们还将测试是否 基于CT扫描的参数响应映射可以在BOS中发挥成像生物标志物。 使用在KD025试验中处理的受试者的样本 研究BOS的机制和治疗途径。使用AO，我们将研究细胞损伤和细胞细胞 BOS中的相互作用，我们将测试AO是否可以用作治疗的治疗反应指标 毒品。肺浸润CD4+ T细胞在BOS病理生物学中的确切作用尚不清楚。使用切割 边缘免疫原性，我们将确定BOS中免疫攻击的抗原决定剂，并审问 使用单细胞TCR测序和RNA-seq分析中BOS中的转录程序。