Cellular Immunotherapy to Combat Fibrosis and Inflammation in Systemic Sclerosis

细胞免疫疗法对抗系统性硬化症中的纤维化和炎症

• 批准号: 10731572
• 负责人: Patricia A. Pioli
• 金额: $ 24.52万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731572
• 关键词: Affect; Autoantibodies; Autoimmune Diseases; Automobile Driving; Biological Assay; Bleomycin; Blood Vessels; CAR T cell therapy; Case Fatality Rates; Cell Therapy; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cellular immunotherapy; Chronic; Clinical Pathology; Collagen; Data; Defect; Deposition; Dermal; Development; Diagnosis; Disease; Disease Progression; Dose; Dropout; Engineering; Extracellular Matrix; Fibroblasts; Fibrosis; Foundations; Gene Expression; Gene Expression Profiling; Generations; Genes; Genomics; Heterogeneity; Immune System Diseases; Immunotherapeutic agent; Immunotherapy; Impairment; Inflammation; Innate Immune Response; Innate Immune System; Laboratories; Lung; Macrophage; Maintenance; Malignant Neoplasms; Measures; Methodology; Modeling; Molecular; Monitor; Myelogenous; Nature; Organ; Pathogenesis; Pathology; Pathway Analysis; Patients; Process; Production; Pulmonary Fibrosis; Qualifying; Quality of life; Receptor Gene; Research; Role; Skin; Standardization; Systemic Scleroderma; T-Lymphocyte; Technology; Testing; Therapeutic; Thick; Tissues; Treatment Efficacy; Vascular Diseases; Work; body system; cell type; chimeric antigen receptor; chimeric antigen receptor T cells; cohort; combat; design; efficacy evaluation; genome-wide; in vivo; inflammatory marker; insight; manufacture; mortality; mouse model; novel; novel therapeutic intervention; pre-clinical; preclinical study; response; skin fibrosis; success; systemic autoimmune disease; targeted treatment; therapeutic target; therapy development

Systemic sclerosis (SSc) is an autoimmune disease that affects multiple organ systems and is characterized by chronic inflammation, vasculopathy, and fibrosis. The standardized mortality ratio for SSc has not changed significantly in the past 40 years, and one in three patients dies within 10 years of diagnosis. The scientific premise of our proposal is that pro-fibrotic macrophages (MØs) are key drivers of SSc. Our hypothesis is that targeting activated MØs in SSc will provide a novel and effective approach to treat the disease, and that the elimination of these MØs will result in decreased fibrosis. We have designed a novel therapeutic approach to eliminate pro-fibrotic MØs using chimeric antigen receptor (CAR) T cells, and localized anti-CD206 CAR T cell treatment reduces dermal thickness and gene expression associated with disease progression in a bleomycin (BLM) mouse model of skin fibrosis. Given the systemic nature of SSc and the mortality associated with internal organ involvement, we propose to determine the efficacy of systemic administration of anti-CD206 CAR T cells for the treatment of pulmonary and dermal fibrosis. Specific Aim 1: Determine if elimination of profibrotic MØs by CAR T cell immunotherapy reduces skin and lung fibrosis. Depletion of the myeloid subsets targeted by CD206-CAR T cell immunotherapy and their impact on skin and lung fibrosis are unknown. We will use CITE-seq to identify MØ subsets in skin and lung pre and post- CAR T cell treatment and will measure collagen deposition, markers of inflammation, and tissue thickness. Specific Aim 2: Determine anti-CD206 CAR T cell persistence in vivo using a systemic model of fibrosis. Successful treatment of SSc will depend on CAR T persistence and maintenance of effector function. To monitor anti-CD206 CAR T cells in preclinical in vivo studies, we will develop and validate a quantitative PCR assay to measure copy number of the anti-CD206 CAR gene.

系统性硬化症（SSc）是一种影响多个器官系统的自身免疫性疾病，其特征是 慢性炎症、血管病变和纤维化。 SSc 的标准化死亡率没有改变 过去 40 年来，这种情况显着增加，三分之一的患者在诊断后 10 年内死亡。科学的 我们建议的前提是促纤维化巨噬细胞 (MØs) 是 SSc 的关键驱动因素。我们的假设是 针对 SSc 中激活的 MØ 将为治疗该疾病提供一种新颖且有效的方法，并且 消除这些 MØ 将导致纤维化减少。我们设计了一种新颖的治疗方法 使用嵌合抗原受体 (CAR) T 细胞和局部抗 CD206 CAR T 细胞消除促纤维化 MØ 博来霉素治疗可减少真皮厚度和与疾病进展相关的基因表达 (BLM) 皮肤纤维化小鼠模型。鉴于 SSc 的系统性以及与内部相关的死亡率 器官受累，我们建议确定抗 CD206 CAR T 细胞全身给药的功效 用于治疗肺纤维化和皮肤纤维化。 具体目标 1：确定通过 CAR T 细胞免疫疗法消除促纤维化 MØ 是否会减少皮肤和肺部的损伤 纤维化。 CD206-CAR T 细胞免疫疗法靶向的骨髓亚群的耗竭及其对 皮肤和肺纤维化尚不清楚。我们将使用 CITE-seq 来识别治疗前和治疗后皮肤和肺部的 MØ 子集 CAR T 细胞治疗将测量胶原蛋白沉积、炎症标志物和组织厚度。 具体目标 2：使用纤维化系统模型确定抗 CD206 CAR T 细胞在体内的持久性。 SSc 的成功治疗将取决于 CAR T 的持久性和效应功能的维持。监控 抗 CD206 CAR T 细胞在临床前体内研究中，我们将开发并验证定量 PCR 检测 测量抗 CD206 CAR 基因的拷贝数。