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

项目概要/摘要 重症肌无力（MG），在美国影响6万人，是一种自身免疫性疾病， 攻击神经肌肉接头的自身抗体对于许多MG患者，没有安全的，选择性的， MG仍然是一种慢性、使人衰弱和潜在致命的疾病。今天，尽管知识 这种疾病是由异常浆细胞（PC）产生的自身抗体介导的， 全身性MG仍然依赖全身性类固醇或类固醇保留的不加选择的免疫抑制 免疫调节剂。靶向PC限制性抗原将消除产生异常自身抗体的血浆 细胞克隆，减少致病性自身抗体，并能改善疾病症状。一种这样的靶抗原是 B细胞成熟抗原（BCMA），其在所有健康PC和恶性PC上表达（即，多 骨髓瘤（MM））。自体抗BCMA嵌合抗原受体（CAR）T细胞的临床试验 通过基因转移永久修饰的MM在复发性/难治性MM中显示出前所未有的疗效，但永久修饰的MM在复发性/难治性MM中显示出前所未有的疗效。 T细胞的遗传修饰导致不受控制的增殖和不可预测的体内药代动力学。 由此产生的毒性可能是严重和致命的。为了保持CAR-T细胞的功效， 毒性，笛卡尔疗法率先开发抗BCMA CAR T细胞（命名为Descartes-08） 通过用CAR mRNA而不是通过基因转移来抑制T细胞，具有确定的、可控的药代动力学。 该项目旨在确定用mRNA转染的CAR T-1治疗全身性MG的可行性。 细胞待检验的假设是以最大耐受剂量（MTD）或低于MTD的剂量给药Descartes-08 将在严重全身性MG患者中实现高临床缓解率。

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.