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，无法治愈 这影响了150万美国人。系统性红斑狼疮是一种可导致严重器官损害的风湿性疾病。 功能障碍，包括终末期肾病。自体反应性B细胞已成为主要细胞 疾病的驱动因素和抗核抗体的存在是诊断的生物标记物。 针对B细胞和B细胞激活因子(BAFF)信号轴的治疗，包括 Belimumab是一种针对BAFF的单抗，在减少 B细胞相关自身免疫疾病的严重程度，但这些治疗方法并不能治愈。一个 最近研究使用CD19嵌合抗原受体(CAR)T细胞治疗导致B细胞 5例患者中有4例病情缓解。这些患者都处于早期阶段。 狼疮，但没有反应的人在9年后患上了最长的疾病。本研究 表明B细胞清除可以缓解SLE疾病的进展，但CD19-CAR治疗 仅限于靶向所有自身反应的B细胞，包括长寿的浆细胞 产生自身反应性抗体，但不表达CD19。因此，我们试图绕过这个问题。 在一种新的治疗系统性红斑狼疮的方法中，使用了基于CARγδ配体的同种异体BAFF T细胞产品。 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 假设消除所有自身反应的B细胞，包括长寿的浆细胞 骨髓，会减少自身抗体的产生，导致长期缓解。这个 使用γδT细胞可以从单个T细胞大量生产同种异体CAR T细胞 捐赠者，降低成本，加强生产过程中的安全监督。我们已经制作了 初步数据证实了我们使用非病毒TcBuster DNA转座子系统的能力 产生表达BAFF-CAR的γδT细胞，并显示这些细胞对 清除表达BAFF受体家族的细胞。为了测试这辆车在 在系统性红斑狼疮的背景下，我们提出了两个互补的目标来评估BAFF的表达 SLE患者B细胞表面受体的检测及其抗SLE活性和选择性 B细胞体外培养。最后，我们将测试BAFF-CARγδT细胞在降低 系统性红斑狼疮人源化小鼠模型中的炎症、肾脏疾病和自身抗体的产生。 我们希望通过将这项技术推进到IND研究中来改善SLE的结果。

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.