Development of a novel lymphocyte engineering approach for treatment of vitiligo

开发治疗白癜风的新型淋巴细胞工程方法

• 批准号: 10640098
• 负责人: Xiaoyang Wu
• 金额: $ 18.04万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640098
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Adult; Affect; Aftercare; Antigen Presentation; Antigens; Appearance; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Autologous; B-Lymphocytes; Biology; CD8-Positive T-Lymphocytes; Cell Line; Cell Therapy; Cell Transplantation; Cells; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Consensus; DNA; Dermatologist; Development; Disease; Dopachrome isomerase; Effector Cell; Engineering; Future; Hematologic Neoplasms; Immune; Immune Tolerance; Immunization; Immunosuppressive Agents; In Vitro; Inflammatory; Infusion procedures; Janus kinase; Knock-in; Lesion; Life; Light; Lymphocyte; MHC Class I Genes; Malignant Neoplasms; Melanoma Cell; Modeling; Mus; Myofibroblast; Natural Killer Cells; Oral; Pathogenesis; Patients; Pemphigus Vulgaris; Pharmacologic Substance; Phenotype; Phototherapy; Play; Population; Prevalence; Process; Property; Quality of life; Recurrent disease; Regulatory T-Lymphocyte; Relapse; Research; Signal Transduction; Skin; Social Interaction; T-Cell Receptor; T-Lymphocyte; Terminal Disease; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; United States; Vitiligo; autoreactive T cell; beta-2 Microglobulin; chimeric antigen receptor; chimeric antigen receptor T cells; coronary fibrosis; cytokine; cytokine release syndrome; cytotoxicity; design; disabling disease; engineered NK cell; experience; gene therapy; genome editing; gp100 Antigen; human disease; in vivo; melanocyte; melanoma; novel; overexpression; psychologic; response; self esteem; skin disorder; success; therapeutically effective

Project Summary: Vitiligo is a common skin depigmentation disorder with an estimated prevalence of 1~4% of the population worldwide. Vitiligo is phenotypically characterized by non-scaly, white macules with distinct sharp margins distributed unilaterally on the patients’ skin, caused by systematic destruction of skin melanocytes. It has a significant impact on the patients’ life both biologically and psychologically. Although multiple mechanisms may jointly contribute to the development of vitiligo, there is a growing consensus that autoimmune response plays a key role in this process. Mounting evidence suggest that self-reactive CD8+ T cells are both necessary and sufficient for destruction of functional melanocytes in vitiligo lesions. The treatment of vitiligo remains one of the most difficult challenges for dermatologists. Approximately 40% of patients have relapse of the disease within the first year after the treatment. Cell and gene therapy provide a promising therapeutic approach for a variety of otherwise terminal or disabling diseases. Adoptive transfer of engineered lymphocytes, such as chimeric antigen receptor (CAR) T cells has shown tremendous success in treatment of hematologic malignancies. CAR T cells have been engineered to target activated myofibroblasts for cardiac fibrosis and autoantibody-producing B cells for potential treatment of pemphigus vulgaris. However, treatment with CAR T is associated with severe and sometimes lethal increases in systemic cytokine toxicity. In this regard, natural killer (NK) cells are powerful innate immune effectors cells. NK cells do not attack healthy self-tissues, nor do they induce the inflammatory cytokine storm as T cells, enabling their potential application as a safer adoptive cell therapy for many human diseases beyond cancer. The objective of this exploratory proposal will be to examine the intriguing possibility of CAR NK cell engineering for treatment of vitiligo. Specifically, we plan to test a β2-microglobulin-based CAR design in conjunction with exogenous expression of different melanocyte antigens in engineered NK cells. We posit that overexpression of the self- antigen with a fusion of degron signal domain can lead to efficient antigen presentation through the engineered MHC I complex containing CAR- β2-microglobulin, which can lead to recognition and destruction of self-reactive CD8+ T cells. Our study will define a novel paradigm for vitiligo treatment and lay the essential groundwork for treatment of other autoimmune disease involving self-reactive T cells with CAR-NK platform.

项目概要： 白癜风是一种常见的皮肤色素脱失性疾病，估计患病率为 1%~4% 全世界。白癜风的表型特征是边缘明显锐利的非鳞状白色斑疹 由于皮肤黑素细胞的系统性破坏而导致单侧分布在患者皮肤上。它有一个 对患者的生理和心理生活产生重大影响。尽管多种机制可能 共同促进白癜风的发展，越来越多的共识认为自身免疫反应在白癜风中发挥着重要作用 在此过程中发挥关键作用。越来越多的证据表明，自身反应性 CD8+ T 细胞既是必要的，也是 足以破坏白癜风病变中的功能性黑素细胞。 白癜风的治疗仍然是皮肤科医生面临的最困难的挑战之一。大约 40%的患者在治疗后的第一年内疾病复发。细胞和基因治疗 为多种其他晚期或致残疾病提供了一种有前景的治疗方法。收养 嵌合抗原受体 (CAR) T 细胞等工程化淋巴细胞的转移已显示出巨大的潜力 血液系统恶性肿瘤的治疗取得了成功。 CAR T 细胞已被设计用于靶向激活 用于心脏纤维化的肌成纤维细胞和用于潜在治疗天疱疮的产生自身抗体的 B 细胞 寻常的。然而，CAR T 治疗会导致全身性细胞毒性严重增加，有时甚至致命。 细胞因子毒性。在这方面，自然杀伤（NK）细胞是强大的先天免疫效应细胞。 NK 细胞有 不会攻击健康的自身组织，也不会像 T 细胞那样诱发炎症细胞因子风暴，从而使其能够 作为一种更安全的过继细胞疗法的潜在应用，可用于治疗癌症以外的许多人类疾病。的目标 这项探索性提案将检验 CAR NK 细胞工程治疗以下疾病的有趣可能性： 白癜风。具体来说，我们计划结合外源性测试基于 β2-微球蛋白的 CAR 设计 工程化 NK 细胞中不同黑素细胞抗原的表达。我们认为过度表达自我 具有降解决定子信号结构域融合的抗原可以通过工程设计导致有效的抗原呈递 含有CAR-β2-微球蛋白的MHC I复合体，可导致自身反应性识别和破坏 CD8+ T 细胞。我们的研究将为白癜风治疗定义一种新的范式，并为白癜风治疗奠定必要的基础。 利用 CAR-NK 平台治疗涉及自身反应性 T 细胞的其他自身免疫性疾病。