González-Martínez Berta, Galán-Gómez Víctor, Navarro-Zapata Alfonso, Mirones-Aguilar Isabel, Cobo Marta, Pernas-Sánchez Alicia, Vallejo Susana, Sánchez-Zapardiel Elena, León-Triana Odelaisy, Echecopar Carlos, Martínez-Romera Isabel, Guerra-García Pilar, San Román-Pacheco Sonsoles, Escudero Adela, Izquierdo Elisa, Izquierdo Manuel, Naharro Sara, Martín-Ayuso Alicia, Bareke Halin, París-Muñoz Andrés, Hu Peirong, Schneider Dina, Orentas Rimas J, Minguillón Jordi, Pérez-Martínez Antonio
Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain; CIBERER-ISCIII, IdiPAZ-CNIO Translational Research Unit in Pediatric Hemato-Oncology, La Paz University Hospital Research Institute, Spanish National Cancer Center, Madrid, Spain.
CIBERER-ISCIII, IdiPAZ-CNIO Translational Research Unit in Pediatric Hemato-Oncology, La Paz University Hospital Research Institute, Spanish National Cancer Center, Madrid, Spain.
EBioMedicine. 2025 Aug;118:105872. doi: 10.1016/j.ebiom.2025.105872. Epub 2025 Aug 5.
BACKGROUND: Chimeric antigen receptor (CAR) T-cells targeting CD19 have shown impressive outcomes in refractory/relapsed B-cell acute lymphoblastic leukaemia (r/r B-ALL); however, frequent relapse demands multi-targeted approaches. METHODS: We report Spanish clinical data on the safety and efficacy of tandem anti-CD19/CD22 CAR T-cells administered on a compassionate use basis in a cohort of 10 heavily pretreated paediatric, adolescent, and young adult (AYA) patients with r/r B-ALL. FINDINGS: Most (9/10) of the patients had relapsed B-ALL, 7 having received previous anti-CD19 CAR T-cell therapy and 6 haematopoietic stem cell transplantation (HSCT). Two patients had Down syndrome. Increased high-grade CRS/ICANS and proinflammatory markers (IL-6, LDH and ferritin) correlated with patients with a high tumour burden (TB) before lymphodepletion. Complete remission on day +28 post-infusion was achieved in 8/10 patients (7 with MRD-), and 5/7 patients received HSCT as consolidative therapy within three months post-infusion. Two patients with early relapse after tandem anti-CD19/CD22 CAR received rescue therapy and HSCT. At the 18-month follow up, overall survival (OS) was 70% (95% CI, 47%-100%). INTERPRETATION: Tandem anti-CD19/CD22 CAR T-cell administration combined with consolidative HSCT is a promising therapeutic approach, though managing bridging therapy and reducing the TB prior to infusion remain key challenges (REALL_CART trial, NCT06709469, EudraCT 2023-509723-41-01). FUNDING: This work was supported by a grant from the Instituto de Salud Carlos III to APM PI22/01226, two grants from CRIS Cancer Foundation to Beat Cancer as part of the projects "Advanced Cell Therapy Unit Hospital Universitario La Paz" and JM "Proyecto Mateo: CAR T-cell therapy for juvenile myelomonocytic leukaemia" and "Terapia avanzada CAR-T CD19/CD22", Ayuda Nominativa de la Consejería de Investigación, Comunidad de Madrid, Spain. Work in MI lab was funded by a grant from the Spanish Ministry of Science and Innovation (PID2020-114148RB-I00). VGG was granted with Río Hortega (AES 2022 exp. Nº. CM22/00078) and Juan Rodés (AES 2024 exp. Nº. JR24/00003) contracts from the Carlos III Health Institute (ISCIII) through the European Funds of the Recovery, Transformation and Resilience Plan and financed by the European Union NextGenerationEU.
背景：靶向CD19的嵌合抗原受体（CAR）T细胞在难治性/复发性B细胞急性淋巴细胞白血病（r/r B-ALL）中显示出令人瞩目的疗效；然而，频繁复发需要多靶点治疗方法。 方法：我们报告了西班牙的临床数据，这些数据涉及在同情用药基础上给予10例经过大量预处理的儿童、青少年和青年（AYA）r/r B-ALL患者串联抗CD19/CD22 CAR T细胞的安全性和有效性。 研究结果：大多数（9/10）患者患有复发性B-ALL，7例曾接受过抗CD19 CAR T细胞治疗，6例接受过造血干细胞移植（HSCT）。2例患者患有唐氏综合征。在淋巴细胞清除前，高级别CRS/ICANS和促炎标志物（IL-6、乳酸脱氢酶和铁蛋白）升高与肿瘤负荷（TB）高的患者相关。输注后第28天，8/10例患者实现完全缓解（7例微小残留病阴性），5/7例患者在输注后三个月内接受HSCT作为巩固治疗。2例串联抗CD19/CD22 CAR治疗后早期复发的患者接受了挽救治疗和HSCT。在18个月的随访中，总生存率（OS）为70%（95%CI，47%-100%）。 解读：串联抗CD19/CD22 CAR T细胞给药联合巩固性HSCT是一种有前景的治疗方法，尽管管理桥接治疗和在输注前降低TB仍然是关键挑战（REALL_CART试验，NCT06709469，EudraCT 2023-509723-41-01）。 资助：这项工作得到了卡洛斯三世卫生研究所授予APM的PI22/01226资助、CRIS癌症基金会授予战胜癌症的两项资助，这是“拉巴斯大学医院高级细胞治疗单元”项目以及JM的“马泰奥项目：青少年骨髓单核细胞白血病的CAR T细胞治疗”和“先进的CAR-T CD19/CD22治疗”的一部分，西班牙马德里自治区研究委员会的指定资助。MI实验室的工作由西班牙科学与创新部授予的PID2020-114148RB-I00资助。VGG获得了卡洛斯三世卫生研究所（ISCIII）通过复苏、转型和韧性计划的欧洲基金授予的里奥斯·奥尔特加（AES 2022，编号CM22/00078）和胡安·罗德斯（AES 2024，编号JR24/00003）合同，并由欧盟下一代欧盟资助。
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