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

摘要 系统性红斑狼疮（SLE）是一种复杂的慢性自身免疫性疾病，目前尚无治愈方法 影响了150万美国人系统性红斑狼疮是一种风湿性疾病，可导致严重的器官损害， 功能障碍，包括终末期肾病。自身反应性B细胞已成为 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细胞活化因子（BAFF）信号传导轴的疗法，包括 贝利木单抗是一种靶向BAFF的单克隆抗体， B细胞相关自身免疫性疾病的严重程度，但这些治疗是不能治愈的。一 最近的研究使用CD 19嵌合抗原受体（CAR）T细胞疗法导致B细胞 5例患者中有4例清除和疾病缓解。这些患者均处于早期阶段 狼疮，但没有反应的人有9年的最长疾病。本研究 表明B细胞清除可以解决SLE疾病进展，但CD 19-CAR治疗 局限于靶向所有的自身反应性B细胞，包括长寿命的浆细胞， 产生自身反应性抗体但不表达CD 19。因此，我们寻求绕过这个问题 在使用基于同种异体BAFF配体的CAR γδ T细胞产物的SLE的新治疗中。 BAFF家族受体BAFFR、TACI和BCMA在B细胞上高度表达， 不同的比例取决于它们的成熟状态，包括浆细胞。我们 假设消除了所有自身反应性B细胞，包括 骨髓，将减少自身抗体的产生，并导致长期缓解。的 使用γδ T细胞允许从单个T细胞大量生产同种异体CAR T细胞 捐助者，降低成本和增加生产过程中的安全监督。我们已经生产 初步数据证实了我们使用非病毒TcBuster DNA转座子系统的能力 以产生具有BAFF-CAR表达的γδ T细胞，并显示这些细胞在 消除表达BAFF受体家族的细胞。为了测试CAR在 在SLE的背景下，我们提出了两个互补的目标，将评估BAFF的表达 受体，并测试这些细胞对患者的活性和选择性。 体外B细胞。最后，我们将测试BAFF-CAR γδ T细胞在减少肿瘤细胞增殖中的功效。 炎症、肾脏疾病和自身抗体的产生。 我们希望通过将该技术推进IND研究来改善SLE的结局。

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.