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...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/227381 |
| Acceso en línea: | https://hdl.handle.net/2445/227381 |
| Access Level: | acceso abierto |
| Palabra clave: | Leucèmia Oncologia Leukemia Oncology |
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oai:recercat.cat:2445/227381 |
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CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia.Tirado, NéstorFidyt, KlaudynaMansilla, María JoséGarcia-Perez, AlbaMartínez-Moreno, AlbaVinyoles, MeritxellAlcain, JuanGarcía-Peydró, MarinaRoca-Ho, HeleiaFernandez-Fuentes, NarcísGuerrero-Murillo, MercedesFalgàs, AïdaVelasco-Hernandez, TaliaBueno, ClaraPanelli, PatrizioMulens-Arias, VladimirApostolov, ApostolEngel Rocamora, PabloGonzález Navarro, E. AzucenaVick, BinjeJeremias, IrmelaCaye-Eude, AurélieBaruchel, AndréCavé, HélèneGenescà, EulàliaRibera, JordiDíaz Beyà, MarinaMartínez-Sánchez, María VictoriaFuster, José LuisEscudero López, AdelaMinguillón, JordiPérez-Martínez, AntonioRamírez-Orellana, ManuelTorrebadell, MontserratDíaz, Víctor M.Toribio, María L.Sánchez-Martínez, DiegoMenéndez Buján, PabloLeucèmiaOncologiaLeukemiaOncologyT 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.BioMed Central2026202620252026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion16 p.application/pdfhttps://hdl.handle.net/2445/227381Articles publicats en revistes (Biomedicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/s13045-025-01715-0Journal of Hematology & Oncology, 2025, vol. 18, num.1https://doi.org/10.1186/s13045-025-01715-0cc-by-nc-nd (c) Tirado, Néstor et al., 2025https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2273812026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia. |
| title |
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia. |
| spellingShingle |
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia. Tirado, Néstor Leucèmia Oncologia Leukemia Oncology |
| title_short |
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia. |
| title_full |
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia. |
| title_fullStr |
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia. |
| title_full_unstemmed |
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia. |
| title_sort |
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia. |
| dc.creator.none.fl_str_mv |
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 |
| author |
Tirado, Néstor |
| author_facet |
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 |
| author_role |
author |
| author2 |
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 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Leucèmia Oncologia Leukemia Oncology |
| topic |
Leucèmia Oncologia Leukemia Oncology |
| description |
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. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 2026 2026 2026 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/227381 |
| url |
https://hdl.handle.net/2445/227381 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1186/s13045-025-01715-0 Journal of Hematology & Oncology, 2025, vol. 18, num.1 https://doi.org/10.1186/s13045-025-01715-0 |
| dc.rights.none.fl_str_mv |
cc-by-nc-nd (c) Tirado, Néstor et al., 2025 https://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc-by-nc-nd (c) Tirado, Néstor et al., 2025 https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
16 p. application/pdf |
| dc.publisher.none.fl_str_mv |
BioMed Central |
| publisher.none.fl_str_mv |
BioMed Central |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Biomedicina) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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1869402750350000128 |
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15,812429 |