肿瘤细胞治疗研究
英文原题：Coadministration of CD19- and CD22-Directed Chimeric Antigen Receptor T-Cell Therapy in Childhood B-Cell Acute Lymphoblastic Leukemia: A Single-Arm, Multicenter, Phase II Trial.
CD19-/CD22-CAR T细胞疗法在复发或难治性B急性淋巴细胞白血病患儿中实现了相对持久的缓解，包括孤立性或合并髓外复发的患儿。
我们确定了在难治性疾病或高危血液学复发或孤立性髓外复发的B-急性淋巴细胞白血病患者中，联合使用CD19-和CD22-嵌合抗原受体（CAR）T细胞的安全性和有效性。
这项II期试验在2019年9月17日至2021年12月31日期间入组了225例年龄20岁的可评估患者。我们首先进行了安全性导入阶段以确定推荐剂量。在对前30例接受治疗的患者（27例接受推荐剂量）进行中期分析显示治疗安全有效后，研究按照研究设计入组了更多患者。
194例难治性白血病或血液学复发的患者中，99.0%达到完全缓解，全部微小残留病阴性。其12个月总无事件生存（EFS）率为73.5%（95% CI，67.3至80.3）。43例患者复发（24例为CD19 + /CD22 + 复发，16例为CD19 - /CD22 +，1例为CD19 - /CD22 -，2例未知）。巩固性移植和6个月时持续性B细胞缺乏与良好结局相关。78例接受移植的患者12个月EFS率为85.0%（95% CI，77.2至93.6），116例未移植患者为69.2%（95% CI，60.8至78.8）（P = .03，时间依赖性协变量Cox模型）。25例6个月时持续性B细胞缺乏的患者在12个月时全部保持缓解。20例孤立性睾丸复发患者的12个月EFS率为95.0%（95% CI，85.9至100），10例孤立性CNS复发患者为68.6%（95% CI，44.5至100）。198例（88.0%）患者发生细胞因子释放综合征，47例（20.9%）发生CAR T细胞神经毒性，导致3例死亡。
PURPOSE: We determined the safety and efficacy of coadministration of CD19- and CD22-chimeric antigen receptor (CAR) T cells in patients with refractory disease or high-risk hematologic or isolated extramedullary relapse of B-acute lymphoblastic leukemia. PATIENTS AND METHODS: This phase II trial enrolled 225 evaluable patients age 20 years between September 17, 2019, and December 31, 2021. We first conducted a safety run-in stage to determine the recommended dose. After interim analysis of the first 30 patients treated (27 at the recommended dose) showing that the treatment was safe and effective, the study enrolled additional patients according to the study design. RESULTS: Complete remission was achieved in 99.0% of the 194 patients with refractory leukemia or hematologic relapse, all negative for minimal residual disease. Their overall 12-month event-free survival (EFS) was 73.5% (95% CI, 67.3 to 80.3). Relapse occurred in 43 patients (24 with CD19 + /CD22 + relapse, 16 CD19 - /CD22 + , one CD19 - /CD22 - , and two unknown). Consolidative transplantation and persistent B-cell aplasia at 6 months were associated with favorable outcomes. The 12-month EFS was 85.0% (95% CI, 77.2 to 93.6) for the 78 patients treated with transplantation and 69.2% (95% CI, 60.8 to 78.8) for the 116 nontransplanted patients ( P = .03, time-dependent covariate Cox model). All 25 patients with persistent B-cell aplasia at 6 months remained in remission at 12 months. The 12-month EFS for the 20 patients with isolated testicular relapse was 95.0% (95% CI, 85.9 to 100), and for the 10 patients with isolated CNS relapse, it was 68.6% (95% CI, 44.5 to 100). Cytokine release syndrome developed in 198 (88.0%) patients, and CAR T-cell neurotoxicity in 47 (20.9%), resulting in three deaths. CONCLUSION: CD19-/CD22-CAR T-cell therapy achieved relatively durable remission in children with relapsed or refractory B-acute lymphoblastic leukemia, including those with isolated or combined extramedullary relapse. UNLABELLED: [Media: see text].
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