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

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 logisti...

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Detalles Bibliográficos
Autores: Tirado, Néstor, Fidyt, Klaudyna, Mansilla, María José, Garcia-Perez, Alba, Martínez-Moreno, Alba, Vinyoles, Meritxell, Alcain, Juan, García-Peydró, Marina, Roca-Ho, Heleia, Fernandez-Fuentes, Narcís, Guerrero-Murillo, Mercedes, Falgàs, Aïda, Velasco-Hernandez, Talia, Bueno, Clara, Panelli, Patrizio, Mulens-Arias, Vladimir, Apostolov, Apostol, Engel Rocamora, Pablo, González Navarro, E. Azucena, Vick, Binje, Jeremias, Irmela, Caye-Eude, Aurélie, Baruchel, André, Cavé, Hélène, Genescà, Eulàlia, Ribera, Jordi, Díaz Beyà, Marina, Martínez-Sánchez, María Victoria, Fuster, José Luis, Escudero López, Adela, Minguillón, Jordi, Pérez-Martínez, Antonio, Ramírez-Orellana, Manuel, Torrebadell, Montserrat, Díaz, Víctor M., Toribio, María L., Sánchez-Martínez, Diego, Menéndez Buján, Pablo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/227381
Acceso en línea:https://hdl.handle.net/2445/227381
Access Level:acceso abierto
Palabra clave:Leucèmia
Oncologia
Leukemia
Oncology
Descripción
Sumario: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 patientderived xenografts. Importantly, CCR9/CD1a dual-targeting CAR-T cells showed higher efficacy than single-targeting CAR-T cells, particularly in T-ALL cases with phenotypically heterogeneous leukemic populations. Dual CD1a/CCR9 CAR-T therapy may prevent T cell aplasia and obviate the need for allogeneic transplantation and regulatory-challenging genome engineering approaches in T-ALL.

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