A TIM-3-Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia.
Por:
Falgàs A, Lázaro-Gorines R, Zanetti SR, Rubio-Pérez L, Martinez-Moreno A, Vinyoles M, Guerrero-Murillo M, Fernandez-Fuentes N, Roca-Ho H, Tirado N, Panisello C, Velasco-Hernandez T, Mayado A, Pérez-Pons A, Genesca E, Ribera JM, Ribera J, Camós-Guijosa M, Ramírez-Orellana M, Anguita E, Ballerini P, Fuster JL, Juan M, González-Navarro EAA, Locatelli F, Stam RWW, Querol S, Velasco P, Ortiz-Maldonado V, Martínez-Cibrian N, Delgado J, Orfao A, Alvarez-Vallina L, Bueno C and Menendez P
Publicada:
29 may 2025
Ahead of Print:
1 may 2025
Resumen:
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.
Filiaciones:
Falgàs A:
Josep Carreras Leukemia Research Institute, Barcelona, Spain
Lázaro-Gorines R:
Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
Zanetti SR:
Josep Carreras Leukemia Research Institute, Barcelona, Spain
Rubio-Pérez L:
Hospital Universitario 12 de Octubre, Madrid, Spain
Martinez-Moreno A:
Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine,, Barcelona, Spain
Vinyoles M:
Josep Carreras Leukemia Research Institute, Barcelona, Spain
Guerrero-Murillo M:
Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Fernandez-Fuentes N:
Josep Carreras Leukemia Research Institute., Barcelona, Spain
Roca-Ho H:
IJC, Barcelona, Spain
Tirado N:
Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Panisello C:
Josep Carreras Leukemia Research Institute, Barcelona, Spain
Velasco-Hernandez T:
University of Barcelona, Barcelona, Spain
Mayado A:
Centro de Investigación del Cáncer (IBMCC-CSIC/USAL and IBSAL),Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto de Salud Carlos III, Salamanca, Spain
Pérez-Pons A:
University of Salamanca. Cancer Research Center (IBMCC, USAL-CSIC) and IBSAL, Salamanca, Spain
Genesca E:
Josep Carreras Leukaemia Research Institute, Badalona, Spain
Ribera JM:
Institut Català d'Oncologia-Hospital Germans Trias i Pujol. Josep Carreras Research Institute. Badalona. Universitat Autònoma de Barcelona, Badalona, Spain
Ribera J:
ICO-Hospital Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras, Badalona, Spain
Camós-Guijosa M:
Hospital Sant Joan de Déu, Barcelona, Spain
Ramírez-Orellana M:
Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
Anguita E:
University Complutense, Madrid, Spain
Ballerini P:
Hopital A. TROUSSEAU, Sorbonne Université, AP-HP, Paris, France
Fuster JL:
Hospital Clínico Universitario Virgen de la Arrixaca. Instituto Murciano de Investigación Biosanitaria (IMIB), Pilar de la Horadada. Alicante, Spain
Juan M:
Hospital Clínic de Barcelona, Barcelona, Spain
González-Navarro EAA:
Hospital Clinic, Barcelona, Spain
Locatelli F:
Bambino Gesù Children's Hospital, Roma, Italy
Stam RWW:
Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands
Querol S:
Fundació Internacional Josep Carreras, Barcelona, Spain
Velasco P:
University Hospital Vall d´Hebron, BARCELONA, Spain
Ortiz-Maldonado V:
Hospital Clinic, Barcelona, Spain
Martínez-Cibrian N:
Hospital Clinic, Barcelona, Spain
Delgado J:
Hospital Clinic, Barcelona, Spain
Orfao A:
University of Salamanca, Salamanca, Spain
Alvarez-Vallina L:
Spanish National Cancer Reserach Centre (CNIO), Madrid, Spain
Bueno C:
Josep Carreras Leukemia Research Institute, Barcelona, Spain
:
Josep Carreras Leukaemia Research Institute, Barcelona, Spain
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