Immunomodulatory effects of desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) in mucosal pemphigus vulgaris

桥粒芯糖蛋白 3 嵌合自身抗体受体 T 细胞 (DSG3-CAART) 对粘膜寻常型天疱疮的免疫调节作用

• 批准号: 10679911
• 负责人: Aimee S Payne
• 金额: $ 42.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679911
• 关键词: Adhesions; Adoptive Transfer; Antibody titer measurement; Antigen Targeting; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; B lymphoid malignancy; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Biological Assay; Blood Component Removal; Bulla; CD19 gene; Cell Compartmentation; Cell Therapy; Cell surface; Cells; Cellular immunotherapy; Clinical; Clinical Trials; Collecting Cell; Cytoplasm; Cytotoxic Chemotherapy; Data; Disease; Disease remission; Dose; Engineering; Enrollment; Enzyme-Linked Immunosorbent Assay; Epithelium; Evaluation; Experimental Models; Extracellular Domain; Flow Cytometry; Gene Expression Profiling; Genetic Engineering; Human; Immune Tolerance; Immune response; Immune system; Immunize; Immunological Models; Immunotherapy; In Vitro; Infection; Infusion procedures; Investigational New Drug Application; Link; Memory; Memory B-Lymphocyte; Molecular; Molecular Profiling; Mucous Membrane; Mus; Pathologic; Pathway interactions; Patients; Pemphigus; Pemphigus Vulgaris; Phenotype; Plasmablast; Pre-Clinical Model; Proteins; Proteome; Proteomics; Refractory; Risk; Safety; Sampling; Serious Adverse Event; Serology; Serum; Specificity; Splenocyte; Surface; T cell therapy; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Therapeutic; Therapy Clinical Trials; Treatment Efficacy; Xenograft Model; biomarker identification; cancer cell; cancer therapy; cell killing; cellular targeting; chimeric antigen receptor; chimeric antigen receptor T cells; chronic autoimmune disease; cohort; cytokine; cytotoxicity; design; desmoglein III; exhaustion; experimental study; first-in-human; human model; immunoregulation; in vitro Model; in vivo; indexing; manufacture; molecular marker; new therapeutic target; novel therapeutic intervention; open label; peripheral blood; phase 1 study; phase I trial; receptor; response; transcriptome; transcriptomics

Project summary: Chimeric antigen receptor T (CART) cells have transformed the cancer therapy paradigm by genetically engineering a patient's own T cells to specifically kill cells expressing the targeted antigen, such as CD19 for B cell malignancies. CART cell proliferation and formation of memory CART cells result in complete B cell depletion and durable remission of otherwise refractory B cell cancers. We re-designed CART technology for autoimmune disease therapy by utilizing an autoantigen as the extracellular domain of a chimeric autoantibody receptor (CAAR), linked to cytoplasmic T cell receptor costimulatory and activation domains. CAARs direct T cell cytotoxicity against autoantigen-specific B cells by targeting their B cell receptor, a surface-bound autoantibody identical in specificity to the autoantibody the B cell will secrete once activated to mature into a plasmablast. We established proof-of-concept for CAAR safety and efficacy in experimental models of pemphigus vulgaris (PV), a potentially fatal blistering disease caused by autoantibodies to the epithelial adhesion protein desmoglein 3 (DSG3). If CAARs for autoimmunity prove to be as effective as CARs for B cell cancers, CAAR T cells could represent a one-time treatment leading to autoimmune disease cure. An open-label, dose-escalation, first-in-human phase 1 trial to determine the safety and tolerability of DSG3 CAAR T cell therapy (DSG3-CAART) in mucosal-dominant pemphigus vulgaris has been initiated. DSG3-CAART is the first precision cellular immunotherapy for autoimmune disease to enter clinical trials, which presents a unique opportunity to define the immunomodulatory effects of this novel therapeutic approach in humans. DSG3-CAART is designed to specifically eliminate DSG3-reactive memory B cells that replenish the autoantibody-producing plasmablasts in PV. Depletion of anti-DSG3 memory B cells could remove a key driver of DSG3-specific T cell activation, and DSG3-CAART persistence may induce changes in global T cell subset composition and/or cytokine milieu, resulting in dual mechanisms for disease remission through both the B and T cell compartments. The proposal will evaluate the hypothesis that DSG3-CAART will reset immune tolerance in PV by depleting DSG3-reactive B cells and normalizing pathologic T cell subsets, potentially leading to safe and lasting disease remission.

项目总结： 嵌合抗原受体T(CART)细胞通过基因工程改变了癌症治疗模式 改造患者自己的T细胞，以特异性地杀伤表达靶向抗原的细胞，如B细胞的CD19 细胞恶性肿瘤。CART细胞的增殖和记忆卡细胞的形成导致完整的B细胞 其他难治性B细胞癌的衰竭和持久缓解。我们重新设计了购物车技术 利用自身抗原作为嵌合自身抗体的胞外区治疗自身免疫性疾病 受体(CAAR)，连接到细胞质T细胞受体的共刺激和激活区域。CAARs Direct T 靶向其表面结合的B细胞受体对自身抗原特异性B细胞的细胞毒作用 自身抗体在特异性上与B细胞一旦被激活成熟后将分泌的自身抗体相同 成浆细胞。我们在实验模型中建立了CAAR安全性和有效性的概念验证 寻常型天疱疮(PV)，一种由上皮性自身抗体引起的潜在致命水疱性疾病 黏附蛋白桥粒芯糖蛋白3(DSG3)。如果用于自身免疫的CAAR被证明与CARS对B细胞同样有效 癌症，CAAR T细胞可以代表一次性治疗导致自身免疫性疾病治愈。 一项开放标签、剂量递增的首例人类1期试验，以确定该药的安全性和耐受性 DSG3 CAAR T细胞疗法(DSG3-CAART)已经开始治疗黏膜优势型寻常型天疱疮。 DSG3-CAART是首个进入临床试验的针对自身免疫性疾病的精确细胞免疫疗法， 这为确定这种新的治疗方法的免疫调节效应提供了一个独特的机会 在人类身上。DSG3-CAART专为消除DSG3反应的记忆B细胞而设计 PV中产生自身抗体的浆母细胞。耗尽抗DSG3记忆B细胞可能会移除一把钥匙 DSG3特异性T细胞活化的驱动因素和DSG3-CAART的持久性可能导致全球T细胞的变化 亚群组成和/或细胞因子环境，导致通过两者缓解疾病的双重机制 B细胞室和T细胞室。该提案将评估DSG3-CAART将重置免疫的假设 可能通过耗尽DSG3反应性B细胞和正常化病理性T细胞亚群来耐受PV 导致安全和持久的疾病缓解。