CD22 CAR-T cells secreting CD19 T-cell engagers for improved control of B-cell acute lymphoblastic leukemia progression.
Por:
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-Otero M, Orfao, A, Blanco, B, Roda-Navarro, P, Bueno, C, Menéndez, P and Alvarez-Vallina, L
Publicada:
30 abr 2025
Ahead of Print:
30 abr 2025
Resumen:
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.
Filiaciones:
Arroyo-Ródenas, J:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
Falgas, A:
Josep Carreras Leukaemia Res Inst, Barcelona, Spain
Inst Salud Carlos III, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Díez-Alonso, L:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
Martinez-Moreno, A:
Josep Carreras Leukaemia Res Inst, Barcelona, Spain
Inst Salud Carlos III, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Spanish Network Mastocytosis REMA, Salamanca, Spain
Roca-Ho, H:
Josep Carreras Leukaemia Res Inst, Barcelona, Spain
Inst Salud Carlos III, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Gil-Etayo, FJ:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Pérez-Pons, A:
Univ Salamanca, Canc Res Ctr IBMCC, Dept Med & Cytometry Serv NUCLEUS, USAL CSIC, Salamanca, Spain
Biomed Res Inst Salamanca IBSAL, Salamanca, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Oncol CIBERONC CB16 12 00400, Madrid, Spain
Spanish Network Mastocytosis REMA, Toledo, Spain
Aguilar-Sopeña, O:
Univ Complutense, Sch Med, Dept Immunol Ophthalmol & ENT, Madrid, Spain
Inst Invest & Sanitaria 12 Octubre, Lymphocyte Immunobiol Grp, Madrid, Spain
Velasco-Sidro, M:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
Gómez-Rosel, M:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
Jiménez-Matías, B:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Muñoz-Sánchez, G:
Hosp Clin Barcelona, Serv Inmunol, Barcelona, Spain
Pacheco, Y:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
Bravo-Martín, C:
Univ Complutense, Sch Med, Dept Immunol Ophthalmol & ENT, Madrid, Spain
Inst Invest & Sanitaria 12 Octubre, Lymphocyte Immunobiol Grp, Madrid, Spain
Ramírez-Fernández, A:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
Jiménez-Reinoso, A:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
González-Navarro, EA:
Hosp Clin Barcelona, Serv Inmunol, Barcelona, Spain
Juan-Otero M:
Inst Salud Carlos III, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Hosp Clin Barcelona, Serv Inmunol, Barcelona, Spain
Orfao, A:
Univ Salamanca, Canc Res Ctr IBMCC, Dept Med & Cytometry Serv NUCLEUS, USAL CSIC, Salamanca, Spain
Biomed Res Inst Salamanca IBSAL, Salamanca, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Oncol CIBERONC CB16 12 00400, Madrid, Spain
Spanish Network Mastocytosis REMA, Toledo, Spain
Spanish Network Mastocytosis REMA, Salamanca, Spain
Blanco, B:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
Roda-Navarro, P:
Univ Complutense, Sch Med, Dept Immunol Ophthalmol & ENT, Madrid, Spain
Inst Invest & Sanitaria 12 Octubre, Lymphocyte Immunobiol Grp, Madrid, Spain
Bueno, C:
Josep Carreras Leukaemia Res Inst, Barcelona, Spain
Inst Salud Carlos III, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Oncol CIBERONC CB16 12 00400, Madrid, Spain
:
Josep Carreras Leukaemia Res Inst, Barcelona, Spain
Inst Salud Carlos III, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Oncol CIBERONC CB16 12 00400, Madrid, Spain
Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inst Recerca Hosp St Joan de Deu, Pediat Canc Ctr Barcelona SJD PCCB, Barcelona, Spain
Alvarez-Vallina, L:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UN, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, H12O CNIO Canc Immunotherapy Clin Res Unit, Madrid, Spain
Hosp del Mar Res Inst Barcelona HMRIB, Spanish Natl Canc Res Ctr CNIO, CNIO HMRIB Canc Immunotherapy Clin Res Unit, Madrid, Spain
Banc Sang & Teixits BST, Barcelona, Spain
Green Accepted, Green Submitted, gold
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