A TIM-3–Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia

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.

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Journal
Blood
Published
2025-03-16
DOI
https://doi.org/10.1182/blood.2024025440
Citations
12
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
12.54
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article

A TIM-3–Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia

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12 citations
Blood
CAR-T cell therapy research
12.54
article

A TIM-3–Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia

Ronald W. Stam, Pablo Menéndez, Alba Pérez‐Pons, Aïda Falgàs, Julio Delgado, Pablo Velasco, Laura Rubio‐Pérez, Mercedes Guerrero-Murillo, Rodrigo Lázaro‐Gorines, Manuel R. Ramírez, Alba Martínez-Moreno, Eulàlia Genescà, Samanta Romina Zanetti, Eduardo Anguita, José Luís Fuster, Luis Álvarez‐Vallina, Andrea Mayado, Valentín Ortiz‐Maldonado, Paola Ballerini, Clara Bueno, Néstor Tirado, Europa Azucena González‐Navarro, Talía Velasco-Hernández, Meritxell Vinyoles, Manel Juan, Carla Panisello, Mireia Camós, Núria Martínez‐Cibrián, Heleia Roca-Ho, Sergio Querol, Josep‐María Ribera, Alberto Órfão, Narcís Fernández‐Fuentes, Jordi Ribera, Franco Locatelli
article en
12 citations

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.

BloodVol. 145(22)
Università Cattolica del Sacro Cuore (IT), Institució Catalana de Recerca i Estudis Avançats (ES), Universidad Complutense de Madrid (ES), Universitat Autònoma de Barcelona (ES), Hospital Sant Joan de Déu Barcelona (ES), Universidad de Salamanca (ES), Instituto de Salud Carlos III (ES), Hospital Clínico San Carlos (ES), Sorbonne Université (FR), Research Institute Hospital 12 de Octubre (ES), Hôpital Armand-Trousseau (FR), Josep Carreras Leukaemia Research Institute (ES), Spanish National Cancer Research Centre (ES), National Library of Catalonia (ES), Assistance Publique – Hôpitaux de Paris (FR), Hospital Universitario 12 De Octubre (ES), Centro Nacional de Epidemiología (ES), Institut Català d'Oncologia (ES), Hospital Infantil Universitario Niño Jesús (ES), Hospital Clínic de Barcelona (ES), Institute for Research in Biomedicine (ES), Bambino Gesù Children's Hospital (IT), Princess Máxima Center (NL), Vall d'Hebron Hospital Universitari (ES), Leukemia Research Foundation (US), Instituto de Investigación Biomédica de Salamanca (ES), Centro de Investigación del Cáncer (ES), Instituto de Recursos Naturales y Agrobiología de Salamanca (ES), Fundación Josep Carreras Contra la Leucemia (ES), Instituto Murciano de Investigación Biosanitaria (ES), Hospital Universitario Virgen de la Arrixaca (ES), Hospital Universitari Germans Trias i Pujol (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Instituto de Investigación de Enfermedades Raras (ES), Universitat de Barcelona (ES)
Good health and well-being
Openalex Percentile: Top 1%
CAR-T cell therapy research
12.54
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