Phase 1/2 Clinical Study of Humanized Anti-BCMA CAR T Cells in Relapsed/Refractory Multiple Myeloma (MM)

摘要 多发性骨髓瘤（MM）每年在全球夺去超过80，000人的生命。虽然有几种新的治疗方法 在过去的十年中，几乎所有的患者都复发了，中位生存期仅为5年。 治疗反应的深度与复发的时间和在疾病早期根除肿瘤细胞相关 这可能是实现临床治愈所必需的。一种潜在的治疗方法是自体细胞疗法 其中嵌合抗原受体（CAR）T细胞重定向至靶抗原。对于MM，有吸引力的靶抗原 是B细胞成熟抗原（BCMA），一种对 骨髓瘤和浆细胞。SBIR提案中描述的实验涵盖了早期临床研究 用mRNA（Descartes-11）产生的自体抗BCMA CAR T细胞产物的I/II期临床试验 以克服与永久修饰的CAR T细胞相关的毒性。具体目标 目的是1）确定Descartes-11在患有以下疾病的患者中的安全性、耐受性和最大耐受剂量： 复发性/难治性MM; 2）在复发性/难治性MM患者中确立MTD的Descartes-11的初步临床获益 MM; 3）定义Descartes-11治疗患者中安全性和疗效的相关生物标志物。使用mRNA 产生Descartes-11能够实现可预测的药代动力学，提供受控CAR T细胞的前景 在疾病的早期治疗MM。

ABSTRACT Multiple myeloma (MM) claims over 80,000 lives globally each year. Although several new therapies have been approved over the past decade, virtually all patients relapse, and the median survival remains at only 5 years. The depth of therapeutic response correlates with time to relapse, and eradicating tumor cells early in the disease process may be necessary to achieve clinical cure. A potentially curative approach is autologous cell therapy with chimeric antigen receptor (CAR) T-cells redirected to a target antigen. For MM, an attractive target antigen is B cell maturation antigen (BCMA), an antigen marker with extremely high sensitivity and specificity for myeloma and plasma cells. Experiments described in this SBIR proposal cover early-stage clinical research (Phase I/II Clinical Trial) of an autologous anti-BCMA CAR T-cell product generated with mRNA (Descartes-11) in order to overcome the toxicities associated with permanently modified CAR T-cells. The goals of the Specific Aims are to 1) determine the safety, tolerability and Maximum Tolerated Dose of Descartes-11 in patients with relapsed/refractory MM; 2) establish preliminary clinical benefit of Descartes-11 at MTD in relapsed/refractory MM; 3) define correlative biomarkers of safety and efficacy in Descartes-11-treated patients. Use of mRNA to generate Descartes-11 enables predictable pharmacokinetics, providing the prospect of controlled CAR T-cell treatment of MM early in the course of the disease.