To engage bystander T cells and prevent multiple myeloma (MM) relapse, “STAb-T” cells were designed to secrete bispecific T cell engagers (anti-BCMA linked to anti-CD3). Both STAb-T and standard CAR T cells formed an immunological synapse with BCMA+ target cells and differentiated into memory populations in vivo. However, STAb-T cells demonstrated superior cytotoxicity against target cell lines and patient MM samples compared to CAR T cells, especially at low effector:target ratios, and were more effective in vivo. Even when physically separated, STAb-T cells enabled tumor killing by recruiting unactivated T cells.
Contributed by Alex Najibi
ABSTRACT: Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell-limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.
Author Info: (1) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de In
Author Info: (1) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (2) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. Red Espaola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. (3) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (4) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. (5) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. (6) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (7) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Red Espaola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. (8) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (9) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain. Centro de Investigacin Biomdica en Red-Oncologa (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain. (10) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain. Centro de Investigacin Biomdica en Red-Oncologa (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain. (11) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigacin Sanitaria 12 de Octubre (imas12), 28041 Madrid, Spain. (12) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (13) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (14) Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, 08036 Barcelona, Spain. (15) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (16) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (17) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Chair for Immunology UFV/Merck, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcn, 28223 Madrid, Spain. (18) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain. Centro de Investigacin Biomdica en Red-Oncologa (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain. (19) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. (20) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. (21) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigacin Sanitaria 12 de Octubre (imas12), 28041 Madrid, Spain. (22) Centro de Biologa Molecular Severo Ochoa CSIC-UAM, 28049 Madrid, Spain. Instituto de Investigacin Sanitaria La Princesa, 28006 Madrid, Spain. (23) Centro de Biologa Molecular Severo Ochoa CSIC-UAM, 28049 Madrid, Spain. Instituto de Investigacin Sanitaria La Princesa, 28006 Madrid, Spain. (24) Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, 28222 Madrid, Spain. (25) Department of Medicine, Medical School, Universidad Complutense de Madrid, 28040 Madrid, Spain. Department of Hematology, IML, IdISSC, Hospital Clnico San Carlos, 28040 Madrid, Spain. (26) H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 28029 Madrid, Spain. Department of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. (27) H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 28029 Madrid, Spain. Department of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. (28) Red Espaola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Division of Hematopoietic Innovative Therapies, Biomedical Innovation Unit, Centro de Investigaciones Energticas Medioambientales y Tecnolgicas (CIEMAT), 28040 Madrid, Spain. Centro de Investigacin Biomdica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain. Instituto de Investigacin Sanitaria Fundacin Jimnez Daz, Universidad Autnoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain. (29) Red Espaola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, 08036 Barcelona, Spain. Servei d'Immunologia, Hospital Clnic de Barcelona, 08036 Barcelona, Spain. Plataforma Immunoterapia, Hospital Sant Joan de Deu, 08950 Barcelona, Spain. Universitat de Barcelona, 08007 Barcelona, Spain. (30) Red Espaola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 28029 Madrid, Spain. Department of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. (31) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigacin Sanitaria 12 de Octubre (imas12), 28041 Madrid, Spain. (32) Department of Experimental Hematology, Instituto de Investigacin Sanitaria Fundacin Jimnez Diaz, (IIS-FJD), Universidad Autnoma de Madrid, 28040 Madrid, Spain. (33) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain. Centro de Investigacin Biomdica en Red-Oncologa (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain. (34) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. Red Espaola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Centro de Investigacin Biomdica en Red-Oncologa (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08007 Barcelona, Spain. Instituci Catalana de Recerca i Estudis Avanats (ICREA), 08010 Barcelona, Spain. (35) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. Red Espaola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Centro de Investigacin Biomdica en Red-Oncologa (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. (36) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Chair for Immunology UFV/Merck, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcn, 28223 Madrid, Spain.
