CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia

作者：Néstor Tirado, Klaudyna Fidyt, María José Mansilla, A. García-Pérez, Alba Martínez‐Moreno, Meritxell Vinyoles, Juan Alcaín, Marina García-Peydró, Heleia Roca-Ho, Narcís Fernández‐Fuentes, Mercedes Guerrero-Murillo, Aïda Falgàs, Talía Velasco-Hernández, Clara Bueno, Patrizio Panelli, Vladimir Mulens‐Arias, Apostol Apostolov, Pablo Engel, Europa Azucena González, Binje Vick, Irmela Jeremias, Aurélie Caye‐Eude, André Baruchel, Hélène Cavé, Eulàlia Genescà, Jordi Ribera, Marina Díaz‐Beyá, María V. Martínez‐Sánchez, José Luís Fuster, Adela Escudero, Jordi Minguillón, Antonio Pérez-Martínez, Manuel Ramı́rez, Montserrat Torrebadell, Víctor M. Diaz, Marı́a L. Toribio, Diego Sánchez‐Martínez, Pablo Menéndez · 发表于：Journal of Hematology & Oncology · 年份：2025 · DOI：10.1186/s13045-025-01715-0 · 被引用次数：8 · 研究领域：CAR-T cell therapy research、Virus-based gene therapy research、Immune Cell Function and Interaction

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by high rates of induction failure and relapse, and effective targeted immunotherapies are lacking. Despite promising clinical progress with genome-edited CD7-directed CAR-T cells, which present significant logistical and regulatory issues, CAR-T cell therapy in T-ALL remains challenging due to the shared antigen expression between malignant and healthy T cells. This can result in CAR-T cell fratricide, T cell aplasia, and the potential for blast contamination during CAR-T cell manufacturing. Recently described CAR-T cells target non-pan-T antigens, absent on healthy T cells but expressed on specific T-ALL subsets. These antigens include CD1a (NCT05679895), which is expressed in cortical T-ALL, and CCR9. We show that CCR9 is expressed on >70% of T-ALL patients (132/180) and is maintained at relapse, with a safe expression profile in healthy hematopoietic and non-hematopoietic tissues. Further analyses showed that dual targeting of CCR9 and CD1a could benefit T-ALL patients with a greater blast coverage than single CAR-T cell treatments. We therefore developed, characterized, and preclinically validated a novel humanized CCR9-specific CAR with robust and specific antileukemic activity as a monotherapy in vitro and in vivo against cell lines, primary T-ALL samples, and patient-derived xenografts. Importantly, CCR9/CD1a dual-targeting CAR-T cells showed higher efficacy than single-targeting CAR...