肿瘤细胞治疗研究
英文原题：Human CART22.19 therapy in refractory pediatric B-ALL: insights from a named-patient cohort.
CART22.19 疗法在高危儿科人群中显示出良好的安全性特征和有前景的临床活性，其双靶向设计使 CD19 阴性白血病获得疾病控制。
背景：靶向 CD19 的嵌合抗原受体（CAR）T 细胞疗法已改变儿童 B 急性淋巴细胞白血病（B-ALL）的治疗格局，但抗原逃逸导致的复发仍是主要局限。靶向 CD19 和 CD22 的双靶点 CAR 已显示有希望的临床活性，但 CAR-T 持续性不足限制了持久缓解。 方法：研究者开发全人源串联 CD19/CD22 CAR-T 细胞 CAR22.19，并通过指定患者项目用于 9 名多线治疗后的复发或难治性儿童患者。治疗指征包括 CD19 阴性白血病细胞（n=5）、CD19 CAR-T 后复发（n=3）和/或获批 CAR-T 产品可及性受限（n=3）。采用符合 GMP 标准的半自动化新鲜制备流程，制备自体和供者来源的 CAR22.19 T 细胞（CART22.19）。通过标准化临床监测、可测量残留病分析和 CAR-T 动力学评估安全性及疗效。 结果：临床前验证显示细胞毒性具有抗原特异性，且可靶向双抗原。临床上 CART22.19 耐受性良好，未发生治疗相关死亡或 3 级神经毒性；13 次输注中有 5 次（38.5%）发生 3 级细胞因子释放综合征，经标准干预后缓解。9 名患者中 7 名（78%）初始达到完全分子学缓解，12 个月总生存率为 55.6%（95% CI：20.4%–80.5%）。在 CD19 阴性、CD22 阳性疾病中达到完全缓解，凸显 CD22 靶向结构域的功能贡献；然而，既往对 CD19 CAR-T 耐药的所有患者，即使仍表达 CD19 和 CD22，也早期复发。体内持续性有限可能是治疗失败的因素之一。值得注意的是，一名自体 CART22.19 耐药患者在减低强度预处理（RIC）异基因造血干细胞移植（alloHSCT）后接受供者来源 CART22.19，获得持久缓解和持续功能性 CAR-T 存在。 结论：CART22.19 在高危儿童人群中显示良好安全性和有希望的临床活性，双靶向可控制 CD19 阴性白血病。但 CAR-T 持续性不足可能是维持缓解的重要障碍。结果支持进一步临床开发 CART22.19，并提示 RIC alloHSCT 后使用供者来源 CAR-T 可能提高持续性、改善多线治疗儿童患者结局。
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.
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