A TIM-3–Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia
Abstract
Abstract Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging disease with dismal prognosis. Despite the revolutionary impact of CD19-directed chimeric antigen receptor (CAR19) T-cell therapy, >50% of patients relapse within a year. Both leukemia cell–intrinsic factors favoring immune escape and poor CAR T-cell persistence contribute to clinical failure. Moreover, the expression of immune checkpoint receptors (ICRs) and their ligands within the bone marrow (BM) microenvironment may contribute to leukemia progression and therapy resistance. Here, we characterized the expression of ICRs and their ligands in leukemic blasts, T cells, and mesenchymal stromal cells (MSCs) from B-ALL BM samples at diagnosis and relapse, comparing them with age-matched healthy BM controls. Our findings reveal a significantly upregulated expression of TIM-3 in T cells and its ligand, galectin-9, in both blasts and MSCs throughout disease progression. The expression of galectin-9 in B-ALL blasts and TIM-3 in CAR19 T cells negatively correlates with clinical outcome. Furthermore, we demonstrate that galectin-9 impairs CAR19 T-cell homeostasis and cytotoxicity. Notably, an engineered TIM-3–Fc decoy receptor, delivered either by primary T cells coadministered with CAR19 T cells or via a bicistronic all-in-one CAR19–TIM-3–Fc construct, improved the antileukemia efficacy and persistence of CAR19 T cells in B-ALL xenograft models. Mechanistically, CAR19–TIM-3–Fc T-cell treatment promotes the in vivo expansion of transduced and bystander effector and memory T cells, as determined by spectral flow cytometry. Collectively, these TIM-3–Fc decoy–armored CAR19 T cells offer a promising therapeutic strategy for patients with R/R B-ALL.
Article Details
Authors (35)
Aïda Falgàs
1Stem Cell Biology, Developmental Leukemia and Immunotherapy Group, Josep Carreras Leukemia Research Institute, Madrid, Spain
Rodrigo Lázaro-Gorines
3Cancer Immunotherapy Unit, Immunology Department, Hospital Universitario 12 Octubre, Madrid, Spain
Samanta Romina Zanetti
1Stem Cell Biology, Developmental Leukemia and Immunotherapy Group, Josep Carreras Leukemia Research Institute, Madrid, Spain
Laura Rubio-Pérez
3Cancer Immunotherapy Unit, Immunology Department, Hospital Universitario 12 Octubre, Madrid, Spain
Alba Martinez-Moreno
Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine,, Barcelona, Spain
Meritxell Vinyoles
Mercedes Guerrero-Murillo
Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Narcís Fernandez-Fuentes
Josep Carreras Leukemia Research Institute., Barcelona, Spain
Heleia Roca-Ho
IJC, Barcelona, Spain
Néstor Tirado
1Stem Cell Biology, Developmental Leukemia and Immunotherapy Group, Josep Carreras Leukemia Research Institute, Madrid, Spain
Carla Panisello
1Stem Cell Biology, Developmental Leukemia and Immunotherapy Group, Josep Carreras Leukemia Research Institute, Madrid, Spain
Talia Velasco-Hernandez
6University of Barcelona, Department of Biomedical Sciences, Barcelona, Spain
Andrea Mayado
8Department of Medicine and Cytometry Service, Cancer Research Center, Instituto de Biologia Molecular y Celular del Cancer, Instituto BioSanitario de Salamanca-Centro Superior de Investigaciones Cientificas, Universidad de Salamanca, Salamanca, Spain
Alba Pérez-Pons
1Department of Medicine, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Universidad de Salamanca, Salamanca, Spain
Eulalia Genesca
Josep Carreras Leukemia Research Institute (IJC), Badalona, Spain
Josep-Maria Ribera
Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
Jordi Ribera
Josep Carreras Leukemia Research Institute (IJC), Badalona, Spain
Mireia Camos
11Department of Hematology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Manuel Ramírez-Orellana
2Red Española de Terapias Avanzadas, Instituto de Salud Carlos III, Madrid, Spain
Eduardo Anguita
15Department of Hematology, Hospital San Carlos-IdSSC Medical School, Department of Medicine, Complutense University, Madrid, Spain
Paola Ballerini
16Department of Pediatric Hemato-oncology, Hospital Armand Trousseau, Paris, France
José Luis Fuster
Hospital Clínico Universitario Virgen de la Arrixaca. Instituto Murciano de Investigación Biosanitaria (IMIB), Pilar de la Horadada. Alicante, Spain
Manel Juan
Europa Azucena González-Navarro
19Department of Immunology, Hospital Clínic, Barcelona, Spain
Franco Locatelli
IRCCS Ospedale Pediatrico Bambino Gesù Rome, Rome
Ronald W. Stam
Sergi Querol
Pablo Velasco
Hospital Vall d'Hebrón. Universitat Autonoma de Barcelona, Barcelona, Spain
Valentin Ortiz-Maldonado
1Hospital Clínic de Barcelona, Department of Hematology, Barcelona, Spain
Nuria Martínez-Cibrian
Hematology Department. Hospital Clínic, Barcelona, Spain
Julio Delgado
Alberto Orfao
Luis Alvarez-Vallina
Clara Bueno
Josep Carreras Leukemia Research Institute, Barcelona, Spain
Pablo Menendez