肿瘤细胞治疗研究
英文原题：Safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell therapy for patients with relapsed/refractory B-ALL.
hCART19 在复发/难治性 B-ALL 患者中具有良好的短期疗效和可控的毒性。
背景：小鼠CAR-T 细胞疗法已为复发/难治性（R/R）B细胞急性淋巴细胞白血病（B-ALL）患者带来临床获益。然而，小鼠单链可变片段结构域可能具有免疫原性，限制CAR-T细胞持续存留并导致复发。方法：我们开展临床试验，评估自体和异体人源化CD19靶向CAR-T细胞（hCART19）治疗R/R B-ALL的安全性和疗效。2020年2月至2022年3月，共入组并治疗58例患者，年龄13–74岁。终点包括完全缓解（CR）率、总生存期（OS）、无事件生存期（EFS）和安全性。结果：总体上，54/58例（93.1%）患者在第28天达到CR或血细胞计数未完全恢复的CR（CRi），其中53例微小残留病灶检测阴性。中位随访13.5个月时，估计1年OS和EFS分别为73.6%（95%置信区间［CI］62.1%–87.4%）和46.0%（95% CI 33.7%–62.8%）；OS和EFS中位数分别为21.5个月和9.5个月。输注后未观察到人抗小鼠抗体显著升高（p=0.78）。血液中B细胞缺失最长持续616天，长于我们既往mCART19试验中的持续时间。所有毒性均可逆，包括重度细胞因子释放综合征（21/58例，36%）和重度神经毒性（3/58例，5%）。与既往mCART19试验相比，hCART19治疗患者EFS更长，且未增加毒性。此外，数据还提示，hCART19治疗后接受异基因造血干细胞移植或CD22靶向CAR-T细胞等巩固治疗的患者，EFS长于未接受巩固治疗者。结论：hCART19对R/R B-ALL患者短期疗效良好，毒性可控。试验注册号：NCT04532268。
BACKGROUND: Murine chimeric antigen receptor T (CAR-T) cell therapy has demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, the potential immunogenicity of the murine single-chain variable fragment domain may limit the persistence of CAR-T cell, leading to relapse. METHODS: We performed a clinical trial to determine the safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell (hCART19) for R/R B-ALL. Fifty-eight patients (aged 13-74 years) were enrolled and treated between February 2020 and March 2022. The endpoints were complete remission (CR) rate, overall survival (OS), event-free survival (EFS), and safety. RESULTS: Overall, 93.1% (54/58) of patients achieved CR or CR with incomplete count recovery (CRi) by day 28, with 53 patients having minimal residual disease negativity. With a median follow-up of 13.5 months, the estimated 1-year OS and EFS were 73.6% (95% CI 62.1% to 87.4%) and 46.0% (95% CI 33.7% to 62.8%), with a median OS and EFS of 21.5 months and 9.5 months, respectively. No significant increase in human antimouse antibodies was observed following infusion (p=0.78). Duration of B-cell aplasia in the blood was observed for as long as 616 days, which was longer than that in our prior mCART19 trial. All toxicities were reversible, including severe cytokine release syndrome, which developed in 36% (21/58) of patients and severe neurotoxicity, which developed in 5% (3/58) of patients. Compared with our prior mCART19 trial, patients treated with hCART19 had longer EFS without increased toxicity. Additionally, our data also suggest that patients treated with consolidation therapy, including allogeneic hematopoietic stem cell transplantation or CD22-targeted CAR-T cell, following hCART19 therapy had a longer EFS than those without consolidation therapy. CONCLUSION: hCART19 has good short-term efficacy and manageable toxicity in R/R B-ALL patients. TRIAL REGISTRATION NUMBER: NCT04532268.
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