Allogeneic BAFF Ligand Based CAR T-Cells as a Novel Therapy for Systemic Lupus Erythematous

基于同种异体 BAFF 配体的 CAR T 细胞作为系统性红斑狼疮的新疗法

• 批准号: 10761003
• 负责人: Hunter Ramsdell Gibbons
• 金额: $ 29.98万
• 依托单位: LUMINARY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761003
• 关键词: Ablation; Address; Affect; Allogenic; American; Animal Model; Antibody titer measurement; Anticardiolipin Antibodies; Antigens; Antinuclear Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmunity; B cell therapy; B-Cell Activation; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological; Biological Assay; Biological Markers; Blood; Blood Circulation; Bone Marrow; CAMLG gene; CAR T cell therapy; CD19 gene; Cell Compartmentation; Cell Maturation; Cells; Clinical Trials; Coculture Techniques; Complex; DNA Transposons; Data; Development; Diagnosis; Disease; Disease Progression; Disease remission; Early treatment; End stage renal failure; Engineering; Engraftment; Family; Functional disorder; Histopathology; Human; Immunotherapeutic agent; Immunotherapy; In Vitro; Inflammation; Inflammatory; Interleukin 4 Receptor; Kidney; Kidney Diseases; Ligands; Lung; Lupus; Mature B-Lymphocyte; Membrane; Memory B-Lymphocyte; Monoclonal Antibodies; Mus; Musculoskeletal; Natural Killer Cells; Nephritis; Onset of illness; Organ; Pathology; Patient-Focused Outcomes; Patients; Pilot Projects; Plasma; Plasma Cells; Production; Proteinuria; Pulmonary Inflammation; RNA; Relaxation; Rheumatism; Safety; Severity of illness; Signal Transduction; Source; Spleen; Survival Rate; System; Systemic Lupus Erythematosus; T-Lymphocyte; TNF gene; Technology; Testing; Time; Tissues; Transplantation; anti-dsDNA antibodies; autoimmune pathogenesis; autoreactive B cell; belimumab; cell killing; cell type; chimeric antigen receptor; chimeric antigen receptor T cells; chronic autoimmune disease; clinical application; cost; cost effective; cytokine; efficacy testing; experience; humane endpoint; humanized mouse; improved; improved outcome; in vivo evaluation; innovation; large scale production; manufacture; member; monocyte; mouse model; novel; novel therapeutics; peripheral blood; polarized cell; pre-clinical; receptor; receptor expression; treatment strategy; γδ T cells

Abstract Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease with no cure which affects 1.5 million Americans. SLE is a rheumatic disease which can lead to severe organ dysfunction, including end stage renal disease. Autoreactive B cells have emerged as primary drivers of the disease and the presence of anti-nuclear antibodies is a biomarker for diagnosis. Therapies targeting B cells and the B cell activating factor (BAFF) signaling axis, including belimumab, a monoclonal antibody targeting BAFF, have shown promising results in reducing severity of disease in B cell associated autoimmunity, but these treatments are not curative. A recent studying using CD19 Chimeric antigen receptor (CAR) T cell therapy led to B cell clearance and disease remission in 4 of 5 patients. Each of these patients were in early-stage lupus, but the one who did not respond had the longest-term disease at 9 years. This study indicates B cell clearance can resolve SLE disease progression, but the CD19-CAR treatment was limited in targeting all the autoreactive B cells, including long-lived plasma cells which produce autoreactive antibody but do not express CD19. We thus seek to circumvent this issue in a new treatment for SLE using an allogeneic BAFF-ligand based CAR γδ T cell product. The BAFF family receptors BAFFR, TACI, and BCMA are highly expressed on B cells at different proportions depending on their maturation state including plasma cells. We hypothesize that elimination of all autoreactive B cells, including long-lived plasma cells in the bone marrow, will reduce the production of autoantibodies and lead to long term remission. The use of γδ T cells allows for the mass production of allogeneic CAR T cells from a single T cell donor, reducing cost and increasing safety oversight during manufacturing. We have produced preliminary data that confirms our ability to use the non-viral TcBuster DNA transposon system to generate γδ T cells with BAFF-CAR expression and show that these cells are effective at eliminating cells expressing the BAFF family of receptors. To test the efficacy of the CAR in the context of SLE, we propose two complementary aims that will assess the expression of BAFF receptors in SLE patient B cells and test the activity and selectivity of these cells against patient B cells in vitro. Finally, we will test the efficacy of the BAFF-CAR γδ T cells in reducing inflammation, renal disease, and autoantibody production in a humanized mouse model of SLE. We hope to improve outcomes in SLE by advancing this technology to IND-enabling studies.

抽象的 全身性红斑狼疮（SLE）是一种复杂的慢性自身免疫疾病，无治愈 影响150万美国人。 SLE是一种风湿病，可能导致严重器官 功能障碍，包括末期肾脏疾病。自动反应性B细胞已成为主要 该疾病的驱动因素和抗核抗体的存在是诊断的生物标志物。 靶向B细胞和B细胞激活因子（BAFF）信号轴的疗法，包括 Belimimab是一种靶向BAFF的单克隆抗体，在减少的结果中显示出令人鼓舞的结果 与B细胞相关的自身免疫性中疾病的严重程度，但这些治疗方法无法治愈。一个 最近使用CD19嵌合抗原受体（CAR）T细胞治疗的研究导致B细胞 5例患者中有4例清除和疾病缓解。这些患者中的每一个都处于早期 狼疮，但没有反应的人在9年时疾病最长。这项研究 表明B细胞清除率可以解决SLE疾病的进展，但CD19卡车处理 在靶向所有自动反应性B细胞方面受到限制，包括长寿命的浆细胞 产生自动反应性抗体，但不表达CD19。因此，我们试图绕过这个问题 在使用同种异体BAFF-配体CARγδT细胞产物的SLE治疗中。 BAFF家族接收器BAFFR，TACI和BCMA在B细胞上高度表达 不同的比例取决于其成熟状态，包括浆细胞。我们 假设消除所有自动反应性B细胞，包括长寿命的浆细胞 骨髓将减少自身抗体的产生并导致长期缓解。这 使用γδT细胞可以从单个T细胞中质量产生同种异体CAR T细胞 捐助者，降低成本并增加制造过程中的安全监督。我们已经生产了 初步数据证实了我们使用非病毒TCBUSTER DNA转座系统的能力 用BAFF-CAR表达产生γδT细胞，并表明这些细胞在 消除表达BAFF受体家族的细胞。测试汽车在 SLE的背景，我们提出了两个完整的目标，可以评估BAFF的表达 SLE患者B细胞中的接收器并测试这些细胞对患者的活性和选择性 B细胞体外。最后，我们将测试BAFF-CARγδT细胞的效率 在人源化小鼠模型中，炎症，肾脏疾病和自身抗体产生。 我们希望通过将这项技术推进到索引研究来改善SLE的结果。