Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions.
Por:
Castella M, Boronat A, Martín-Ibáñez R, Rodríguez V, Suñé G, Caballero M, Marzal B, Pérez-Amill L, Martín-Antonio B, Castaño J, Bueno C, Balagué O, González-Navarro EA, Serra-Pages C, Engel P, Vilella R, Benitez-Ribas D, Ortiz-Maldonado V, Jordi Cid Colom, Tabera J, Canals JM, Lozano M, Baumann T, Vilarrodona A, Trias E, ELENA CAMPO, Menendez P, Urbano-Ispizua Á, Yagüe-Ribes J, Pérez-Galán P, Rives-Solà S, Delgado J and Juan M
Publicada:
15 mar 2019
Ahead of Print:
6 dic 2018
Resumen:
Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells in vitro, inducing secretion of pro-inflammatory cytokines and CAR T cell proliferation. In vivo, A3B1 CAR T cells are able to fully control disease progression in an NOD.Cg-Prkdc (scid) Il2rd (tm1Wjl) /SzJ (NSG) xenograph B-ALL mouse model. Based on the pre-clinical data, we conclude that our CART19 is clearly functional against CD19+ cells, to a level similar to other CAR19s currently being used in the clinic. Concurrently, we describe the implementation of our CAR T cell production system, using lentiviral vector and CliniMACS Prodigy, within a medium-sized academic institution. The results of the validation phase show our system is robust and reproducible, while maintaining a low cost that is affordable for academic institutions. Our model can serve as a paradigm for similar institutions, and it may help to make CAR T cell treatment available to all patients.
Filiaciones:
Castella M:
Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Boronat A:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Martín-Ibáñez R:
Stem Cells and Regenerative Medicine Laboratory, Production and Validation Center of Advanced Therapies (Creatio), Department of Biomedical Sciences, University of Barcelona, Casanova 143, 08036 Barcelona, Spain
Rodríguez V:
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Physiopathology and Molecular Bases in Hematology Group, IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Suñé G:
Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Caballero M:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Universidad de Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain
Marzal B:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Pérez-Amill L:
Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Martín-Antonio B:
Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Castaño J:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain
Bueno C:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain
Balagué O:
Department of Pathology, Hospital Clínic, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain
González-Navarro EA:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Serra-Pages C:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain
Engel P:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Immunology Unit, Department of Biomedical Sciences, University of Barcelona, Casanova 143, 08036 Barcelona, Spain
Vilella R:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Benitez-Ribas D:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Ortiz-Maldonado V:
Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Jordi Cid Colom:
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Department of Hemotherapy and Hemostasis, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Tabera J:
Unit of Advanced Therapies, Hospital Clinic de Barcelona, Blood and Tissue Bank -BST-, Passeig del Taulat, 106, 08005 Barcelona, Spain
Canals JM:
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Stem Cells and Regenerative Medicine Laboratory, Production and Validation Center of Advanced Therapies (Creatio), Department of Biomedical Sciences, University of Barcelona, Casanova 143, 08036 Barcelona, Spain
Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain
Lozano M:
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Department of Hemotherapy and Hemostasis, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Baumann T:
Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Vilarrodona A:
Unit of Advanced Therapies, Hospital Clinic de Barcelona, Blood and Tissue Bank -BST-, Passeig del Taulat, 106, 08005 Barcelona, Spain
Trias E:
Unit of Advanced Therapies, Hospital Clinic de Barcelona, Blood and Tissue Bank -BST-, Passeig del Taulat, 106, 08005 Barcelona, Spain
ELENA CAMPO:
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Physiopathology and Molecular Bases in Hematology Group, IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Department of Pathology, Hospital Clínic, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain
Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain
Centro de Investigación Biomedica en Red de Cancer (ISCIII-CIBERONC), Barcelona, Spain
Menendez P:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain
Centro de Investigación Biomedica en Red de Cancer (ISCIII-CIBERONC), Barcelona, Spain
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Urbano-Ispizua Á:
Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain
Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain
Yagüe-Ribes J:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain
Pérez-Galán P:
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Physiopathology and Molecular Bases in Hematology Group, IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Centro de Investigación Biomedica en Red de Cancer (ISCIII-CIBERONC), Barcelona, Spain
Rives-Solà S:
Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Universidad de Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain
Delgado J:
Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain
Centro de Investigación Biomedica en Red de Cancer (ISCIII-CIBERONC), Barcelona, Spain
Juan M:
Department of Immunology, CDB, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS, Rosselló 153, 08036 Barcelona, Spain
Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Universidad de Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain
Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain
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