(1) Arroyo-Ródenas J (2) Falgas A (3) Díez-Alonso L (4) Martinez-Moreno A (5) Roca-Ho H (6) Gil-Etayo FJ (7) Pérez-Pons A (8) Aguilar-Sopeña O (9) Velasco-Sidro M (10) Gómez-Rosel M (11) Jiménez-Matías B (12) Muñoz-Sánchez G (13) Pacheco Y (14) Bravo-Martín C (15) Ramírez-Fernández A (16) Jiménez-Reinoso A (17) González-Navarro EA (18) Juan M (19) Orfao A (20) Blanco B (21) Roda-Navarro P (22) Bueno C (23) Menéndez P (24) Alvarez-Vallina L

Journal for immunotherapy of cancer | Free PMC Article

To minimize tumor antigen loss and reduce the risk of CD19+ leukemia progression in r/r B-ALL, Arroyo-Ródenas ‍and Falgas et al. developed dual-targeted CD22 CAR T cells secreting an anti-CD19 T cell-engaging antibody (CAR-STAb-T). Compared to other validated dual CD19/22-targeted therapies (single-tandem TAN-CAR and pooled CAR-Ts), CAR-STAb-T cells recruited bystander non-transduced T cells efficiently at limiting E:T ratios, resulting in more potent and rapid cytotoxicity of B-ALL cells in long- and short-term cultures, and better leukemia control in a heterogeneous B cell model and in PDX mouse models under limiting T cell conditions. 

Contributed by Katherine Turner

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.

Author Info: (1) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investig

Author Info: (1) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (2) Josep Carreras Leukaemia Research Institute, Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. (3) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (4) Josep Carreras Leukaemia Research Institute, Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. (5) Josep Carreras Leukaemia Research Institute, Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. (6) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. (7) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain. Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC; CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain. Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain. (8) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (i+12), Madrid, Spain. (9) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (10) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (11) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. (12) Servicio de Inmunolog’a, Hospital Cl’nic de Barcelona, Barcelona, Spain. (13) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (14) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (i+12), Madrid, Spain. (15) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (16) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (17) Servicio de Inmunolog’a, Hospital Cl’nic de Barcelona, Barcelona, Spain. (18) Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. Servicio de Inmunolog’a, Hospital Cl’nic de Barcelona, Barcelona, Spain. (19) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain. Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC; CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain. Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain. (20) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (21) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (i+12), Madrid, Spain. (22) Josep Carreras Leukaemia Research Institute, Barcelona, Spain lalvarezv@ext.cnio.es cbueno@carrerasresearch.org pmenendez@carrerasresearch.org. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC; CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain. (23) Josep Carreras Leukaemia Research Institute, Barcelona, Spain lalvarezv@ext.cnio.es cbueno@carrerasresearch.org pmenendez@carrerasresearch.org. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC; CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain. Instituci— Catalana de Recerca i Estudis Avanats (ICREA), Barcelona, Spain. Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain. Institut de Recerca Hospital Sant Joan de DŽu-Pediatric Cancer Center Barcelona (SJD-PCCB), Barcelona, Spain. (24) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain lalvarezv@ext.cnio.es cbueno@carrerasresearch.org pmenendez@carrerasresearch.org. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. CNIO-HMRIB Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Hospital del Mar Research Institute Barcelona (HMRIB), Madrid/Barcelona, Spain. Banc de Sang i Teixits (BST), Barcelona, Spain.

Citation: J Immunother Cancer 2025 Apr 30 13: Epub04/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40306957

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