Autologous T-cells Expressing a Chimeric Antigen Receptor Directed to B-Cell Maturation Antigen (BCMA) in patients with Generalized Myasthenia Gravis (MG)

项目摘要/摘要 重症肌无力(MG)在美国影响着6万人，是一种由 攻击神经肌肉接头的自身抗体。对于许多MG患者来说，没有安全、选择性和 有效的治疗，MG仍然是一种慢性、衰弱和潜在的致命疾病。今天，尽管有知识 这种疾病是由异常浆细胞(PC)产生的自身抗体介导的，治疗 泛发性MG仍然依赖于全身类固醇或非类固醇的不加区别的免疫抑制 免疫调节剂。以PC限制性抗原为靶点将消除产生异常自身抗体的血浆 细胞克隆，减少致病自身抗体，并可改善疾病症状。其中一个靶抗原是 B细胞成熟抗原(BCMA)，在所有健康PC和恶性PC(即多发性多发性硬化症)上表达 骨髓瘤(MM))。自体抗BCMA嵌合抗原受体(CAR)T细胞的临床研究 通过基因转移进行永久性修改对复发/难治性MM显示出前所未有的疗效，但是永久性的 T细胞的基因修饰会导致体内不受控制的增殖和不可预测的药代动力学。 由此产生的毒性可能是严重的和致命的。为了保存CAR T细胞的效力而大幅降低 毒性，笛卡尔治疗公司率先开发抗BCMA CAR T细胞(命名为笛卡尔-08) 通过将CAR mRNA导入T细胞而不是通过基因转移，具有明确、可控的药代动力学。 本课题旨在探讨转基因CAR-T治疗泛发性MG的可行性。 细胞。需要检验的假设是，笛卡尔-08的剂量等于或低于最大耐受量(MTD) 重症全身性MG患者的临床缓解率较高。

Project Summary/ Abstract Myasthenia Gravis (MG), which affects 60,000 people in the U.S., is an autoimmune disease caused by autoantibodies that attack the neuromuscular junction. For many MG patients, there is no safe, selective, and effective therapy, and MG remains a chronic, debilitating, and potentially fatal disease. Today, despite knowledge that the disease is mediated by autoantibodies produced by aberrant plasma cells (PCs), treatment of generalized MG still relies on indiscriminate immunosuppression with systemic steroids or steroid-sparing immunomodulators. Targeting a PC-restricted antigen would eliminate aberrant autoantibody-producing plasma cell clones, reduce pathogenic autoantibody, and could improve disease symptoms. One such target antigen is B-Cell Maturation Antigen (BCMA), which is expressed on all healthy PCs and on malignant PCs (i.e., multiple myeloma (MM)). Clinical trials with autologous anti-BCMA Chimeric Antigen Receptor (CAR) T-cells permanently modified by gene transfer show unprecedented efficacy in relapsed/refractory MM, but permanent genetic modification of T-cells leads to uncontrolled proliferation and unpredictable pharmacokinetics in vivo. The resulting toxicity can be severe and lethal. In order to preserve CAR T-cell efficacy but significantly reduce toxicity, Cartesian Therapeutics pioneered development of anti-BCMA CAR T-cells (named as Descartes-08) with defined, controllable pharmacokinetics by transfecting T-cells with CAR mRNA instead of by gene transfer. This project is intended to determine the feasibility of treating generalized MG with mRNA-transfected CAR T- cells. The hypothesis to be tested is that dosing Descartes-08 at or below the maximal tolerated dose (MTD) will achieve a high rate of clinical remission in patients with severe generalized MG.