Multifactor mRNA Mediated T Cell Reprogramming for Systemic Lupus Erythematosus

多因子 mRNA 介导的 T 细胞重编程治疗系统性红斑狼疮

• 批准号: 9244298
• 负责人: Samuel G Katz
• 金额: $ 29.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244298
• 关键词: Adoptive Immunotherapy; Alpha Cell; American; Antibodies; Apoptosis; Apoptotic; Area; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Automobile Driving; B lymphoid malignancy; B-Lymphocytes; BCL1 Oncogene; BLR1 gene; CD19 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Survival; Cell Therapy; Cell physiology; Cells; Clinical; Clone Cells; Code; Cytotoxic T-Lymphocytes; DNA; Development; Disease; Disease remission; Effector Cell; Electroporation; Event; Exhibits; FDA approved; Flare; Future; Genes; Goals; Grant; Growth; Helper-Inducer T-Lymphocyte; Home environment; Immune; Immune Tolerance; Immunotherapy; Individual; Insertional Mutagenesis; Interleukin-17; Interleukin-2; Lead; Location; Lupus; Lymphocyte; Mediating; Messenger RNA; Metabolic; Methods; Morbidity - disease rate; Multiple Myeloma; Mus; Nature; Pathogenesis; Pathogenicity; Patients; Penetration; Pharmaceutical Preparations; Plasma Cell Neoplasm; Population; Production; Proteins; Relapse; Resistance; Safety; Scheme; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; United States National Institutes of Health; Work; autoreactive B cell; bcl-xlong protein; belimumab; cellular targeting; chemokine receptor; chimeric antigen receptor; cytokine; cytotoxic; cytotoxicity; flexibility; improved; improved functioning; in vivo; killings; lupus-like; mortality; new technology; novel; novel strategies; novel therapeutics; response; rituximab; success; systemic autoimmune disease; systemic intervention; targeted treatment; therapeutic target; tositumomab; uptake

PROJECT SUMMARY Systemic Lupus Erythematosus (SLE) is a severe systemic autoimmune disease that leads to substantial morbidity and mortality in approximately 1 to 2 million Americans. A critical step in the pathogenesis of SLE is a breakdown in immune tolerance, which leads to a T-cell dependent and B-cell mediated disease. The resulting abundant pathogenic autoantibodies produced from the autoreactive B cells are a defining hallmark of SLE. The abrogation of disease in SLE-prone mice deficient in B cells, validates them as a viable therapeutic target. Indeed, several different B-cell directed therapies have been successful at attenuating progression including the anti-CD20 antibody Rituximab, and the anti-BAFF (BLyS) antibody belimumab – the first FDA approved drug for SLE in decades. Despite these exciting developments, the limited clinical response in only half of the treated patients, calls for further exploration of the extent and efficacy of B cell depletion. Overall the goal of this application is to optimize a B-cell targeted therapeutic intervention for SLE using CAR-T cells. Adoptive immunotherapy with genetically modified T cells expressing Chimeric Antigen Receptors (CARs) has shown remarkable therapeutic success in killing select cell populations. In particular, CARs that recognize CD19 have displayed impressive efficacy toward previously unresponsive B cell malignancies, and even plasma cell neoplasms. Here, we propose to employ our multiplexed mRNA-mediated T cell reprogramming technology to transiently eradicate aberrant, CD19-positive B cells. In comparison to antibodies, cellular immunotherapy has the advantages of active tissue penetration and no requirement for FcR-mediated uptake, which is blocked in SLE. In comparison to DNA reprogramming of T cells, an mRNA approach will permit a transient B cell depletion that can be deployed to match the relapsing-remitting nature of SLE. We will test the hypothesis that our mRNA approach will improve the functionality of the damaged SLE T cells by introducing mRNAs, coding multiple beneficial proteins in a single rapid step. Aim 1 will correct the propensity of SLE T cells to undergo apoptosis by reprogramming with a combination of mRNAs encoding an anti-apoptotic protein in addition to the CD19 CAR. Aim 2 will improve SLE T cell metabolic stability with an mRNA encoding a growth stimulatory cytokine that is diminished in SLE in addition to the CD19 CAR. Aim 3 will reprogram SLE T cells with the CD19 CAR and a chemokine receptor that will direct the CAR T cells to B cell rich areas. We will test these individual factors with complementary studies in early and established murine SLE as well as in lymphocytes from patients with SLE. Success of a CAR-T approach in SLE would be novel for autoimmune disease therapy and would lead to many potential opportunities for therapeutic exploration.

项目概要 系统性红斑狼疮 (SLE) 是一种严重的系统性自身免疫性疾病，可导致严重的 大约有 1 至 200 万美国人发病和死亡。 SLE发病机制中的一个关键步骤是 免疫耐受性崩溃，导致 T 细胞依赖性和 B 细胞介导的疾病。这 自身反应性 B 细胞产生丰富的致病性自身抗体是 系统性红斑狼疮。在缺乏 B 细胞的易患 SLE 的小鼠中消除疾病，验证了它们作为一种可行的治疗方法 目标。事实上，几种不同的 B 细胞定向疗法已成功减缓进展 包括抗 CD20 抗体 Rituximab 和抗 BAFF (BLyS) 抗体 belimumab – 第一个 FDA 几十年来批准治疗系统性红斑狼疮的药物。尽管取得了这些令人兴奋的进展，但临床反应有限 一半接受治疗的患者呼吁进一步探索 B 细胞耗竭的程度和功效。全面的 该应用的目标是使用 CAR-T 细胞优化 SLE 的 B 细胞靶向治疗干预。 使用表达嵌合抗原受体 (CAR) 的转基因 T 细胞进行过继免疫疗法 在杀死选定的细胞群方面显示出显着的治疗成功。特别是，认可的 CAR CD19 对以前无反应的 B 细胞恶性肿瘤显示出令人印象深刻的功效，甚至 浆细胞肿瘤。在这里，我们建议采用多重 mRNA 介导的 T 细胞重编程 技术暂时消除异常的 CD19 阳性 B 细胞。与抗体相比，细胞 免疫疗法具有主动组织渗透且无需FcR介导的摄取的优点， 这在 SLE 中被阻止。与 T 细胞的 DNA 重编程相比，mRNA 方法将允许 短暂的 B 细胞耗竭可用于匹配 SLE 的复发缓解性质。我们将测试 假设我们的 mRNA 方法将通过引入 mRNA，通过一个快速步骤编码多种有益蛋白质。目标 1 将纠正 SLE T 倾向 细胞通过编码抗凋亡蛋白的 mRNA 组合进行重编程而发生凋亡 除了CD19 CAR。目标 2 将通过编码 a 的 mRNA 提高 SLE T 细胞代谢稳定性 除了 CD19 CAR 之外，生长刺激细胞因子在 SLE 中也会减少。目标 3 将重新编程 SLE 带有 CD19 CAR 和趋化因子受体的 T 细胞将引导 CAR T 细胞到达 B 细胞丰富的区域。我们 将通过对早期和已建立的小鼠 SLE 以及在 来自 SLE 患者的淋巴细胞。 CAR-T 方法在 SLE 中的成功对于自身免疫性疾病来说是新颖的 疾病治疗，并将带来许多潜在的治疗探索机会。