CD22 CAR-T cells secreting CD19 T-cell engagers for improved control of B-cell acute lymphoblastic leukemia progression.

BACKGROUND: CD19-directed cancer immunotherapies, based on engineered T cells bearing chimeric antigen receptors (CARs, CAR-T cells) or the systemic administration of bispecific T cell-engaging (TCE) antibodies, have shown impressive clinical responses in relapsed/refractory B-cell acute lymphoblast...

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Detalles Bibliográficos
Autores: Arroyo-Ródenas, J, Falgas, A, Díez-Alonso, L, Martinez-Moreno, A, Roca-Ho, H, Gil-Etayo, FJ, Pérez-Pons, A, Aguilar-Sopeña, O, Velasco-Sidro, M, Gómez-Rosel, M, Jiménez-Matías, B, Muñoz-Sánchez, G, Pacheco, Y, Bravo-Martín, C, Ramírez-Fernández, A, Jiménez-Reinoso, A, González-Navarro, EA, Juan, ME, Orfao, A, Blanco, B, Roda-Navarro, P, Bueno, C, Menéndez, P, Alvarez-Vallina, L
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p29339
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=29339
Access Level:acceso abierto
Palabra clave:Adoptive cell therapy - ACT
Bispecific T cell engager - BiTE
Chimeric antigen receptor - CAR
Hematologic Malignancies
Immunotherapy
Descripción
Sumario:BACKGROUND: CD19-directed cancer immunotherapies, based on engineered T cells bearing chimeric antigen receptors (CARs, CAR-T cells) or the systemic administration of bispecific T cell-engaging (TCE) antibodies, have shown impressive clinical responses in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, more than half of patients relapse after CAR-T or TCE therapy, with antigen escape or lineage switching accounting for one-third of disease recurrences. To minimize tumor escape, dual-targeting CAR-T cell therapies simultaneously targeting CD19 and CD22 have been developed and validated both preclinically and clinically. METHODS: We have generated the first dual-targeting strategy for B-cell malignancies based on CD22 CAR-T cells secreting an anti-CD19 TCE antibody (CAR-STAb-T) and conducted a comprehensive preclinical characterization comparing its therapeutic potential in B-ALL with that of previously validated dual-targeting CD19/CD22 tandem CAR cells (TanCAR-T cells) and co-administration of two single-targeting CD19 and CD22 CAR-T cells (pooled CAR-T cells). RESULTS: We demonstrate that CAR-STAb-T cells efficiently redirect bystander T cells, resulting in higher cytotoxicity of B-ALL cells than dual-targeting CAR-T cells at limiting effector:target ratios. Furthermore, when antigen loss was replicated in a heterogeneous B-ALL cell model, CAR-STAb T cells induced more potent and effective cytotoxic responses than dual-targeting CAR-T cells in both short- and long-term co-culture assays, reducing the risk of CD19-positive leukemia escape. In vivo, CAR-STAb-T cells also controlled leukemia progression more efficiently than dual-targeting CAR-T cells in patient-derived xenograft mouse models under T cell-limiting conditions. CONCLUSIONS: CD22 CAR-T cells secreting CD19 T-cell engagers show an enhanced control of B-ALL progression compared with CD19/CD22 dual CAR-based therapies, supporting their potential for clinical testing.

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