肿瘤细胞治疗研究
英文原题：Equecabtagene Autoleucel in Patients With Relapsed or Refractory Multiple Myeloma: The FUMANBA-1 Nonrandomized Clinical Trial.
Equecabtagene Autoleucel in Patients With Relapsed or Refractory Multiple Myeloma: The FUMANBA-1 Nonrandomized Clinical Trial.
在这项试验中，eque-cel 使接受过多线治疗的复发/难治性多发性骨髓瘤（RRMM）患者获得早期、深度且持久的缓解，安全性特征可控。
重要性：全人源B细胞成熟抗原靶向嵌合抗原受体（CAR）T细胞疗法厄卡卡基奥仑赛（eque-cel）显示出治疗复发或难治性多发性骨髓瘤（RRMM）的潜力，仍需在更大患者队列中进一步研究。 目的：评估eque-cel是否能使RRMM患者获益，并确定输注后的总缓解率。 设计、场所与研究对象：FUMANBA-1试验是一项单臂、开放标签、Ib/II期研究，评估eque-cel治疗成人RRMM的效果。研究于2020年4月开始招募，患者在输注后至少随访15年。截至2022年9月，来自14家中心、既往至少接受过3线治疗的重度经治RRMM患者入组。分析数据收集于2020年4月至2022年9月。 干预：患者经淋巴细胞清除后，单次输注剂量为每千克体重1.0×10^6个CAR阳性T细胞的eque-cel。 主要结局指标：主要目标为疗效，次要目标为安全性、药代动力学和药效学。 结果：103例接受eque-cel输注的患者中，55例（53.4%）为男性；年龄中位数（范围）为58（39–70）岁。101例可评估疗效。中位随访13.8个月（范围0.4–27.2个月）时，总缓解率为96.0%（101例中97例），75例（103例中75例；74.3%）达到完全缓解或更佳疗效。既往接受过CAR T细胞治疗的12例患者中，75%（12例中9例）获得应答。PFS中位数尚未达到，12个月PFS率为78.8%（95% CI：68.6%–86.0%）。96例患者（95.0%）在10^-5敏感度阈值下达到微小残留病阴性。总体不良事件可控：103例中96例（93.2%）发生细胞因子释放综合征，其中95例（92.3%）为1至2级；2例（1.9%）发生1至2级免疫效应细胞相关神经毒性综合征。所有神经毒性病例和96例CRS中的94例经治疗后均缓解。此外，仅20例患者（19.4%）产生抗药抗体。细胞动力学分析证实所有患者体内均可检测到CAR阳性T细胞，最长持续时间为735天。 结论与意义：本试验中，eque-cel使重度经治RRMM患者获得早期、深度且持久的应答，安全性可管理。既往接受过CAR T细胞治疗的患者也可从eque-cel中获益。 试验注册：中国临床试验注册号：ChiCTR2000033946。
IMPORTANCE: Equecabtagene autoleucel (eque-cel), a fully human-derived B-cell maturation antigen-targeting chimeric antigen receptor (CAR) T-cell therapy, has exhibited potential for the treatment of relapsed or refractory multiple myeloma (RRMM), and further investigation in a larger cohort is necessary. OBJECTIVE: To evaluate whether eque-cel can benefit patients with RRMM and determine the overall response rate postinfusion. DESIGN, SETTING, AND PARTICIPANTS: The FUMANBA-1 trial was a single-arm, open-label, phase 1b/2 trial that evaluated eque-cel in adult patients with RRMM. Enrollment began in April 2020, and patients who received eque-cel will be monitored for a minimum of 15 years following the infusion. As of September 2022, patients with heavily pretreated RRMM who received at least 3 prior courses of therapy from 14 centers were enrolled. Data were analyzed from April 2020 to September 2022. INTERVENTIONS: Patients received a single infusion of eque-cel at 1.0 106 CAR-positive T cells/kg after the lymphodepletion. MAIN OUTCOMES AND MEASURES: Efficacy was the primary objective, and safety, pharmacokinetics, and pharmacodynamics were secondary objectives. RESULTS: Of 103 patients who received an eque-cel infusion, 55 (53.4%) were male, and the median (range) age was 58 (39-70) years. A total of 101 patients were evaluable for efficacy. At a median (range) follow-up of 13.8 (0.4-27.2) months, the overall response rate was 96.0% (97 of 101), with 74.3% (75 of 103) achieving a complete response or better. Among the 12 patients who had prior CAR T-cell treatment, 75% (9 of 12) achieved a response. The median progression-free survival was not reached, with a 12-month progression-free survival rate of 78.8% (95% CI, 68.6-86.0). A total of 96 patients (95.0%) achieved minimal residual disease negativity at a sensitivity threshold of 10-5. Adverse events were favorable: 96 of 103 patients (93.2%) experienced cytokine release syndrome (grade 1 to 2 in 95 patients [92.3%]) and 2 (1.9%) experienced immune effector cell-associated neurotoxicity syndrome (grade 1 to 2). All cases of immune effector cell-associated neurotoxicity syndrome and 94 of 96 cases of cytokine release syndrome resolved with treatment. Additionally, only 20 patients (19.4%) developed antidrug antibodies. Cellular kinetic analysis confirmed CAR-positive T cells in all patients, with the longest duration at 735 days. CONCLUSIONS AND RELEVANCE: In this trial, eque-cel led to early, deep, and durable responses in patients with heavily pretreated RRMM with a manageable safety profile. Patients with prior CAR T-cell therapy also benefitted from eque-cel. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR2000033946.
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