CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia.
Por:
Tirado N, Fidyt K, Mansilla MJ, 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, González EA, Vick B, Jeremias I, Caye-Eude A, Baruchel A, Cavé H, Genescà E, Ribera J, Díaz-Beyá M, Martínez-Sánchez MV, Fuster JL, Escudero López A, Minguillón J, Pérez-Martínez A, Ramírez-Orellana M, Torrebadell-Burriel M, Díaz VM, Toribio ML, Sánchez-Martínez D and Menéndez P
Publicada:
1 jul 2025
Ahead of Print:
1 jul 2025
Resumen:
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.
Filiaciones:
Tirado N:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Fidyt K:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Mansilla MJ:
OneChain Immunotherapeutics S.L, Barcelona, Spain
Garcia-Perez A:
OneChain Immunotherapeutics S.L, Barcelona, Spain
Martínez-Moreno A:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Vinyoles M:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Alcain J:
Centro de Biologia Molecular Severo Ochoa CSIC-UAM, Madrid, Spain
García-Peydró M:
Centro de Biologia Molecular Severo Ochoa CSIC-UAM, Madrid, Spain
Roca-Ho H:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Fernandez-Fuentes N:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Guerrero-Murillo M:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Falgàs A:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
Velasco-Hernandez T:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Bueno C:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
Panelli P:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Mulens-Arias V:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Apostolov A:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Engel P:
Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
González EA:
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Department of Immunology, Hospital Clínic de Barcelona, Barcelona, Spain
Vick B:
Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Munich, German Research Center for Environmental Health (HMGU), Munich, Germany
Jeremias I:
Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Munich, German Research Center for Environmental Health (HMGU), Munich, Germany
Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany
Caye-Eude A:
Department of Genetics, University Hospital Robert Debré
INSERM Institut de Recherche Saint Louis, Paris, France
Baruchel A:
Department of Genetics, University Hospital Robert Debré
INSERM Institut de Recherche Saint Louis, Paris, France
Cavé H:
Department of Genetics, University Hospital Robert Debré
INSERM Institut de Recherche Saint Louis, Paris, France
Genescà E:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Ribera J:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Department of Hematology, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Badalona, Spain
Díaz-Beyá M:
Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain
Martínez-Sánchez MV:
Immunology Service, Clinical University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Sanitaria (IMIB), University of Murcia, Murcia, Spain
Fuster JL:
Sección de Oncohematología Pediátrica, Hospital Clínico Universitario Virgen de la Arrixaca
Instituto Murciano de Investigación Sanitaria (IMIB), University of Murcia, Murcia, Spain
Escudero López A:
Department of Genetics, Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain
Minguillón J:
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
CIBERER-ISCIII, IdiPAZ-CNIO Translational Research Unit in Pediatric Hemato-Oncology, La Paz University Hospital Research Institute
Spanish National Cancer Center, Madrid, Spain
Advanced Therapies Mixed Unit, CIEMAT/IIS-FJD, Madrid, Spain
Pérez-Martínez A:
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
CIBERER-ISCIII, IdiPAZ-CNIO Translational Research Unit in Pediatric Hemato-Oncology, La Paz University Hospital Research Institute
Spanish National Cancer Center, Madrid, Spain
Advanced Therapies Mixed Unit, CIEMAT/IIS-FJD, Madrid, Spain
Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain
Ramírez-Orellana M:
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Hospital Infantil Universitario Niño Jesús, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
Torrebadell-Burriel M:
Institut de Recerca Pediàtrica Sant Joan de Déu
Department of Hematology, Hospital Sant Joan de Déu, Barcelona, Spain
Díaz VM:
OneChain Immunotherapeutics S.L, Barcelona, Spain
Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain
Toribio ML:
Centro de Biologia Molecular Severo Ochoa CSIC-UAM, Madrid, Spain
Sánchez-Martínez D:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Aragon Health Research Institute (IIS Aragon), Zaragoza, Spain
Aragon Foundation for Research & Development (ARAID), Zaragoza, Spain
:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III, Madrid, Spain
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Institut de Recerca Hospital Sant Joan de Déu-Pediatric Cancer Center Barcelona (SJD-PCCB), Barcelona, Spain
Green Published, Green Submitted, gold
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