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Tirado, N.* ; Fidyt, K.* ; Mansilla, M.J.* ; Garcia-Perez, A.* ; Martínez-Moreno, A.* ; Vinyoles, M.* ; Alcain, J.* ; García-Peydró, M.* ; Roca-Ho, H.* ; Fernandez-Fuentes, N.* ; Guerrero-Murillo, M.* ; Falgàs, A.* ; Velasco-Hernandez, T.* ; Bueno, C.* ; Panelli, P.* ; Mulens-Arias, V.* ; Apostolov, A.* ; Engel, P.* ; Gonzalez, E.A.* ; Vick, B. ; Jeremias, I. ; Caye-Eude, A.* ; Baruchel, A.* ; Cavé, H.* ; Genescà, E.* ; Ribera, J.* ; Díaz-Beyá, M.* ; Martínez-Sánchez, M.V.* ; Fuster, J.L.* ; Escudero López, A.* ; Minguillón, J.* ; Pérez-Martínez, A.* ; Ramírez-Orellana, M.* ; Torrebadell, M.* ; Díaz, V.M.* ; Toribio, M.L.* ; Sánchez-Martínez, D.* ; Menéndez, P.*

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

J. Hematol. Oncol. 18:69 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Chimeric Antigen Receptor; Chemokine Receptor; Expression; Therapy; Relapse; Risk; 1st-in-human; Ccr9/ccl25; Antagonist; Thymocytes
e-ISSN 1756-8722
Journal Journal of Hematology & Oncology
Quellenangaben Volume: 18, Issue: 1, Pages: , Article Number: 69 Supplement: ,
Publisher BioMed Central
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Grants Asociacion Pablo Ugarte (APU)
Health Merck Foundation
European Union NextGenerationEU/PRTR
MICIU/AEI
FEDER Funds
Spanish Research Agency (AEI) MCIN/AEI
European Research Council
Fundacio Josep Carreras-Obra Social la Caixa
European Regional Development Fund (ERDF)/EU
AEI
European Union
Spanish Ministry of Science and Innovation
Torres Quevedo contract
Juan de la Cierva postdoctoral fellowship
European Union (EU)
Instituto de Salud Carlos III (ISCIII) through the Spanish Network of Advanced Therapies (RICORS/TERAV+)
Uno Entre Cien Mil Foundation
Spanish Association Against Cancer (AECC)
CERCA/Generalitat de Catalunya