Blanco and Ramírez-Fernández et al. compared the efficacy of T cells expressing either soluble anti-CD19/CD3 BiTEs (STAb-T19) or conventional 2nd generation anti-CD19 CARs (CAR-T19). STAb-T19 cells were as effective as CAR-T19 cells in short-term models, but outperformed CAR-T19 cells in inducing cytotoxicity and bystander cell activation, avoiding leukemia escape in vitro and preventing relapse in vivo. In a long-term patient-derived xenograft model, STAb-T19 cells eradicated leukemia cells, whereas leukemia relapsed after CAR-T19. Mechanistically, STAb-19 cells prevented CD19 downmodulation and induced canonical immune synapses.
Contributed by Katherine Turner
ABSTRACT: Chimeric antigen receptor (CAR)-modified T cells have revolutionized the treatment of CD19-positive hematologic malignancies. Although anti-CD19 CAR-engineered autologous T cells can induce remission in patients with B-cell acute lymphoblastic leukemia, a large subset relapse, most of them with CD19-positive disease. Therefore, new therapeutic strategies are clearly needed. Here, we report a comprehensive study comparing engineered T cells either expressing a second-generation anti-CD19 CAR (CAR-T19) or secreting a CD19/CD3-targeting bispecific T-cell engager antibody (STAb-T19). We found that STAb-T19 cells are more effective than CAR-T19 cells at inducing cytotoxicity, avoiding leukemia escape in vitro, and preventing relapse in vivo. We observed that leukemia escape in vitro is associated with rapid and drastic CAR-induced internalization of CD19 that is coupled with lysosome-mediated degradation, leading to the emergence of transiently CD19-negative leukemic cells that evade the immune response of engineered CAR-T19 cells. In contrast, engineered STAb-T19 cells induce the formation of canonical immunologic synapses and prevent the CD19 downmodulation observed in anti-CD19 CAR-mediated interactions. Although both strategies show similar efficacy in short-term mouse models, there is a significant difference in a long-term patient-derived xenograft mouse model, where STAb-T19 cells efficiently eradicated leukemia cells, but leukemia relapsed after CAR-T19 therapy. Our findings suggest that the absence of CD19 downmodulation in the STAb-T19 strategy, coupled with the continued antibody secretion, allows an efficient recruitment of the endogenous T-cell pool, resulting in fast and effective elimination of cancer cells that may prevent CD19-positive relapses frequently associated with CAR-T19 therapies.
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 Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain. (2) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. (3) Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain. Josep Carreras Leukemia Research Institute, Barcelona, Spain. Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. (4) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (5) Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spain. (6) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. (7) Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain. Josep Carreras Leukemia Research Institute, Barcelona, Spain. (8) Josep Carreras Leukemia Research Institute, Barcelona, Spain. (9) Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain. (10) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. (11) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. (12) Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain. (13) Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain. (14) Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain. (15) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (16) Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain. (17) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (18) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. (19) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. Chair for Immunology UFV/Merck, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain. (20) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. (21) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. (22) Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spain. (23) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. (24) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. (25) Department of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain. (26) Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain. (27) Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spain. (28) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigacin Sanitaria 12 de Octubre (imas12), Madrid, Spain. (29) Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain. Servei d'Immunologia, Hospital Clínic de Barcelona, Barcelona, Spain. Plataforma Immunoteràpia Hospital Sant Joan de Déu, Barcelona, Spain. Universitat de Barcelona, Barcelona, Spain. (30) Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain. Josep Carreras Leukemia Research Institute, Barcelona, Spain. Centro de Investigación Biomdica en Red-Oncologa (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. (31) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain. Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark.
