双顺反子CD19/CD22 CAR-T细胞疗法治疗儿童B细胞急性淋巴细胞白血病：非随机临床试验
Bicistronic CD19/CD22 CAR T-Cell Therapy in Pediatric B-Cell Acute Lymphoblastic Leukemia: A Nonrandomized Clinical Trial
靶向CD19的CAR-T细胞疗法在复发/难治B细胞急性淋巴细胞白血病（B-ALL）中缓解率高，但抗原丢失导致的复发仍是难题。这项开放标签、多中心、2期非随机试验在中国5家中心纳入308例儿童B-ALL患者，最终261例可评估。患者接受双顺反子慢病毒载体转导的CD19/CD22双靶点CAR-T细胞，回输前进行氟达拉滨联合环磷酰胺清淋。结果显示，259例（99.2%）达到微小残留病灶阴性完全缓解；12、24、36个月无事件生存率分别为70.9%、63.2%和61.7%。接受巩固移植者24个月无事件生存率（85.7%）优于未移植者（57.9%）。3-4级细胞因子释放综合征发生率为49.4%，免疫效应细胞相关神经毒性发生率为13.0%。
为什么推荐给您：大样本双靶点CAR-T治疗儿童B-ALL的2期非随机试验，疗效显著但非随机设计，属重要扩展证据。
不需要生物学背景，多打比方
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摘要Abstract
IMPORTANCE: CD19-directed chimeric antigen receptor (CAR) T-cell therapy induces high remission rates in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), but relapse, which is often due to antigen loss, remains a major challenge. Dual-targeting CD19/CD22 CAR T-cell strategies may be associated with reduced antigen-negative relapse and improved remission durability.
OBJECTIVE: To evaluate the safety and efficacy of bicistronic CD19/CD22 CAR T-cell therapy in pediatric patients with relapsed or refractory B-ALL.
DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicenter, phase 2 nonrandomized clinical trial enrolled pediatric patients with B-ALL at 5 major medical centers in China from January 2022 to August 2024, with a data cutoff of February 28, 2026. Median follow-up was 35.7 months (IQR, 29.8-41.0 months). Of 346 screened, 38 (11.0%) were excluded and 308 (89.0%) were eligible. A safety run-in established the recommended phase 2 dose, followed by cohorts with refractory disease, hematologic relapse, or isolated extramedullary relapse.
INTERVENTION: CD3-positive T cells were activated and transduced with a bicistronic lentiviral vector that encoded anti-CD19 and anti-CD22 CARs, then infused fresh after 5 to 7 days in culture. Lymphodepleting chemotherapy included fludarabine and cyclophosphamide. Consolidative transplant was reserved for patients with KMT2A- or ZNF384-rearranged acute lymphoblastic leukemia.
MAIN OUTCOMES AND MEASURES: Primary end points were safety, recommended phase 2 dose, event-free survival (EFS), and toxic effects of bicistronic CAR-T therapy in relapsed or refractory B-ALL, with or without transplant.
RESULTS: Among 261 patients (98 girls [37.6%]; mean [SD] age, 8.2 [3.8] years) with relapsed or refractory disease, 259 (99.2%) achieved complete remission with negative minimal residual disease. EFS was 70.9% (95% CI, 65.6%-76.7%) at 12 months, 63.2% (95% CI, 57.6%-69.4%) at 24 months, and 61.7% (95% CI, 55.9%-68.0%) at 36 months. Consolidative transplant was associated with improved EFS; the 24-month EFS was 57.9% (95% CI, 51.6%-65.0%) in patients without a transplant vs 85.7% (95% CI, 76.5%-96.1%) in patients with a transplant (P = .004). In 20 patients with isolated central nervous system relapse and 20 with testicular relapse, 24-month EFS was 60.0% (95% CI, 43.6%-82.6%) and 80.0% (95% CI, 64.3%-99.6%), respectively. Grade 3 to 4 cytokine release syndrome occurred in 129 patients (49.4%), and immune effector cell-associated neurotoxic effects occurred in 34 patients (13.0%).
CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, bicistronic CD19/CD22 CAR T-cell therapy induced high rates of minimal residual disease-negative remission, with durable EFS in pediatric B-ALL. These findings support further evaluation in prospective trials.
TRIAL REGISTRATION: Chinese Clinical Trial Register Identifier: ChiCTR2000032211.