人源CART22.19治疗难治性儿童B-ALL：来自指定患者队列的见解
Human CART22.19 therapy in refractory pediatric B-ALL: insights from a named-patient cohort
CD19 CAR-T治疗儿童B细胞急性淋巴细胞白血病（B-ALL）后，抗原逃逸导致的复发仍是主要限制。研究者开发了全人源串联CD19/CD22 CAR（CAR22.19），在指定患者项目中治疗9例重度经治的复发或难治性B-ALL儿童。结果显示，治疗耐受良好，无治疗相关死亡和≥3级神经毒性，≥3级细胞因子释放综合征发生在38.5%的输注中并可缓解。78%（7/9）患者获得初始完全分子学缓解，12个月总生存率为55.6%。CD19阴性/CD22阳性疾病获得完全缓解，说明CD22靶向结构域有功能贡献；但既往CD19 CAR-T无效的患者均早期复发。1例对自体CAR22.19无效的患者，在减低强度预处理异基因移植后输注供者来源CAR22.19，获得了持久缓解和持续功能持久性。结论认为双靶向可控制CD19阴性白血病，但CAR-T持久性有限是持续缓解的重要障碍。
为什么推荐给您：全人源双靶点CD19/CD22 CAR-T首次在儿童难治B-ALL中显示临床活性，属新模态早期阳性结果。
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摘要Abstract
BACKGROUND: CD19-directed chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment landscape for pediatric B-cell acute lymphoblastic leukemia (B-ALL), yet relapses driven by antigen escape remain a major limitation. Dual-targeting CAR approaches recognizing CD19 and CD22 have shown promising clinical activity, but sustained remissions are limited by insufficient CAR T-cell persistence.
METHODS: CAR22.19, a fully human tandem CD19/CD22 CAR, was developed and administered under a named-patient program to nine heavily pretreated pediatric patients with relapsed or refractory B-ALL. Treatment indications were CD19-negative blast population (n=5), relapse after CD19 CAR T (n=3) and/or restricted access to approved CAR T-cell products (n=3). Autologous and donor-derived CAR22.19 T-cells (CART22.19) were manufactured using a good manufacturing practice-compliant, semiautomated fresh-in-fresh-out process. Safety and efficacy were assessed through standardized clinical monitoring, measurable residual disease analysis, and CAR T-cell kinetics.
RESULTS: Preclinical validation demonstrated antigen-specific cytotoxicity and dual antigen activity. Clinically, CART22.19 were well tolerated, with no treatment-related deaths and no grade ≥3 neurotoxicity, while grade ≥3 cytokine release syndrome occurred in 38.5% (5/13) of infusions and resolved with standard interventions. An initial complete molecular remission was achieved in 78% (7/9) of patients, with a 12-month overall survival rate of 55.6% (95% CI, 20.4-80.5%). Complete remission in CD19⁻CD22⁺ disease underscores the functional contribution of the CD22-targeting domain, whereas all patients refractory to prior CD19 CAR T-cell therapy relapsed early despite retained CD19⁺CD22⁺ expression. Limited in vivo persistence may represent a contributing factor to treament failure. Notably, durable remission and sustained functional persistence of CART22.19 was achieved in one patient refractory to autologous CART22.19 following infusion of donor-derived CART22.19 after reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) in nonremission.
CONCLUSIONS: CART22.19 therapy demonstrated a favorable safety profile and promising clinical activity in a high-risk pediatric population, with dual targeting enabling disease control in CD19-negative leukemia. Nonetheless, limited CAR T-cell persistence may represent an important obstacle to sustained remission. Our findings support further clinical development of CART22.19 and indicate that donor-derived CAR T-cells following RIC alloHSCT may represent a potential therapeutic strategy to enhance persistence and improve outcomes in heavily pretreated pediatric patients.