Tandem CD19/CD22 CAR T-cells as potential therapy for children and young adults with high-risk r/r B-ALL.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-08-01 Epub Date: 2025-08-05 DOI:10.1016/j.ebiom.2025.105872

Berta González-Martínez, Víctor Galán-Gómez, Alfonso Navarro-Zapata, Isabel Mirones-Aguilar, Marta Cobo, Alicia Pernas-Sánchez, Susana Vallejo, Elena Sánchez-Zapardiel, Odelaisy León-Triana, Carlos Echecopar, Isabel Martínez-Romera, Pilar Guerra-García, Sonsoles San Román-Pacheco, Adela Escudero, Elisa Izquierdo, Manuel Izquierdo, Sara Naharro, Alicia Martín-Ayuso, Halin Bareke, Andrés París-Muñoz, Peirong Hu, Dina Schneider, Rimas J Orentas, Jordi Minguillón, Antonio Pérez-Martínez

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引用次数: 0

Abstract

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.

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串联式CD19/CD22 CAR - t细胞作为儿童和青少年高风险r/r B-ALL的潜在治疗方法

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）中显示出令人印象深刻的结果；然而，频繁复发需要多目标的治疗方法。方法：我们报告了西班牙的临床数据，关于在同情使用基础上给予串联抗cd19 /CD22 CAR - t细胞治疗10例重度预处理的儿童、青少年和年轻成人（AYA） r/r B-ALL患者的安全性和有效性。结果：大多数（9/10）患者复发B-ALL， 7例接受过抗cd19 CAR - t细胞治疗，6例接受过造血干细胞移植（HSCT）。两名患者患有唐氏综合症。高级别CRS/ICANS和促炎标志物（IL-6、LDH和铁蛋白）的增加与淋巴细胞清除前高肿瘤负担（TB）患者相关。8/10例患者（7例MRD-）在输注后第28天完全缓解，5/7例患者在输注后3个月内接受了HSCT作为巩固治疗。2例抗cd19 /CD22串联CAR治疗后早期复发的患者接受了抢救治疗和HSCT。随访18个月，总生存率（OS）为70% （95% CI, 47%-100%）。解释：串联抗cd19 /CD22 CAR - t细胞联合巩固性HSCT是一种很有前景的治疗方法，尽管在输注前管理桥接治疗和减少结核病仍然是关键挑战（real_cart试验，NCT06709469, EudraCT 2023-509723-41-01）。资金：这项工作得到了Salud Carlos III研究所对APM PI22/01226的资助，CRIS癌症基金会对Beat Cancer的两项资助，作为“La Paz大学医院高级细胞治疗单元”和JM“Proyecto Mateo: CAR- t细胞治疗青少年粒细胞白血病”和“Terapia avanzada CAR- t CD19/CD22”项目的一部分，Ayuda Nominativa de La Consejería de Investigación，西班牙马德里市。MI实验室的工作由西班牙科学与创新部资助（PID2020-114148RB-I00）。VGG获得Río Hortega （AES 2022 exp. Nº）认证。CM22/00078)和Juan rodims (AES 2024 exp. Nº。JR24/00003)通过欧洲恢复、转型和复原力计划基金与卡洛斯三世卫生研究所（ISCIII）签订合同，并由欧洲联盟下一代欧盟资助。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.