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.

项目摘要： 嵌合抗原受体T（CART）细胞已通过遗传学转化了癌症治疗范例 工程患者自己的T细胞专门杀死表达靶向抗原的细胞，例如B的CD19 细胞恶性肿瘤。卡车细胞的增殖和记忆推车细胞的形成导致完整的B细胞 其他难治性B细胞癌的消耗和持久的缓解。我们重新设计了推车技术 自身免疫性疾病疗法通过利用自身抗原作为嵌合自身抗体的细胞外域 受体（CAAR），与细胞质T细胞受体共刺激和激活结构域有关。 Caars Direct t 针对自身抗原特异性B细胞的细胞细胞毒性通过靶向其B细胞受体（一种表面结合） 自身抗体的特异性与自身抗体相同，B细胞将分泌一旦激活以成熟到A plasmablast。我们在实验模型中建立了CAAR安全性和功效的概念证明 Pemphigus vulgaris（PV），一种由自身抗体引起的潜在致命的起泡疾病 粘附蛋白脱木蛋白3（DSG3）。如果自身免疫性的CAARS证明与B细胞的汽车一样有效 癌症，CAAR T细胞可以代表一种一次性治疗，导致自身免疫性疾病治疗。 开放标签，剂量升级，第一阶段1期试验，以确定的安全性和耐受性 已经开始了粘膜占主导地位的Pemphigus ulgaris中的DSG3 CAAR T细胞疗法（DSG3-CAART）。 DSG3-CAART是进行自身免疫性疾病的第一个精确细胞免疫疗法，进入临床试验， 它提供了一个独特的机会来定义这种新型治疗方法的免疫调节作用 在人类中。 DSG3-CAART旨在专门消除补充DSG3反应性记忆B细胞 PV中产生自身抗体的浆体。抗DSG3存储B细胞的耗竭可以删除键 DSG3特异性T细胞激活和DSG3-CAART持久性的驱动器可能会导致全局T细胞的变化 子集成分和/或细胞因子环境，从而导致双重缓解双重机制 B和T细胞室。该提案将评估DSG3-CAART将重置免疫的假设 通过耗尽DSG3反应B细胞并使病理T细胞亚群降低PV的耐受性，可能有可能 导致安全和持久的疾病缓解。