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

项目概要： 嵌合抗原受体T（CART）细胞已经通过遗传学改变了癌症治疗模式。 将患者自身的T细胞工程化以特异性地杀死表达靶抗原的细胞，例如针对B的CD 19 细胞恶性肿瘤CART细胞增殖和记忆CART细胞的形成导致完全B细胞 消耗和持久缓解其他难治性B细胞癌。我们重新设计了CART技术， 利用自身抗原作为嵌合自身抗体的细胞外结构域的自身免疫性疾病治疗 受体（CAAR），与细胞质T细胞受体共刺激和激活结构域连接。CAAR直接T 通过靶向自身抗原特异性B细胞的B细胞受体（表面结合的 一种自身抗体，其特异性与B细胞一旦被激活成熟为 浆母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， 寻常天疱疮（PV），一种由抗上皮细胞抗体引起的潜在致命性水疱性疾病， 粘附蛋白桥粒芯糖蛋白3（DSG 3）。如果针对自身免疫的CAAR被证明与针对B细胞的汽车一样有效， 对于癌症，CAAR T细胞可以代表导致自身免疫性疾病治愈的一次性治疗。 一项开放标签、剂量递增、首次人体I期试验，旨在确定 已经启动了粘膜显性寻常型天疱疮中的DSG 3 CAAR T细胞疗法（DSG 3-CAART）。 DSG 3-CAART是第一个进入临床试验的用于自身免疫性疾病的精确细胞免疫疗法， 这提供了一个独特的机会来确定这种新的治疗方法的免疫调节作用 在人类身上。DSG 3-CAART旨在特异性消除DSG 3反应性记忆B细胞， PV中产生自身抗体的浆母细胞。抗DSG 3记忆B细胞的消耗可以去除一个关键 DSG 3-CAART持续可能是DSG 3特异性T细胞活化的驱动因素，并且DSG 3-CAART持续可能诱导整体T细胞活化的变化。 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和T细胞区室。该提案将评估DSG 3-CAART将重置免疫系统的假设。 通过消耗DSG 3反应性B细胞和使病理性T细胞亚群正常化， 导致安全和持久的疾病缓解。

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.