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

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

Abstract 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 significan...

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Main Authors: Néstor Tirado, Klaudyna Fidyt, María José Mansilla, Alba Garcia-Perez, Alba Martínez-Moreno, Meritxell Vinyoles, Juan Alcain, Marina García-Peydró, Heleia Roca-Ho, Narcis Fernandez-Fuentes, Mercedes Guerrero-Murillo, Aïda Falgàs, Talia Velasco-Hernandez, 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 Victoria Martínez-Sánchez, José Luis Fuster, Adela Escudero López, Jordi Minguillón, Antonio Pérez-Martínez, Manuel Ramírez-Orellana, Montserrat Torrebadell, Víctor M Díaz, María L Toribio, Diego Sánchez-Martínez, Pablo Menéndez
Format: Article
Language:English
Published: BMC 2025-07-01
Series:Journal of Hematology & Oncology
Online Access:https://doi.org/10.1186/s13045-025-01715-0
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Summary:Abstract 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-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.
ISSN:1756-8722

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