Development of a Novel Anti-CD19 Chimeric Antigen Receptor

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...

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Autores: Castellà, Maria, Boronat, Anna|||0000-0003-0852-3634, Martín-Ibáñez, Raquel, Rodríguez, Vanina, Suñé, Guillermo|||0000-0002-4034-4348, Caballero, Miguel|||0000-0002-2313-7988, Marzal, Berta, Pérez-Amill, Lorena|||0000-0003-0674-4660, Martín-Antonio, B.|||0000-0003-0612-2693, Castaño Cardoso, Julio|||0000-0002-0712-5856, Bueno, Clara|||0000-0003-1442-6216, Balagué, Olga|||0000-0002-5099-3675, González-Navarro, Europa Azucena|||0000-0003-3310-5557, Serra-Pages, Carles, Engel, Pablo|||0000-0001-8410-252X, Vilella, Ramon, Benítez Ribas, Daniel|||0000-0002-2346-5324, Ortiz-Maldonado, Valentín|||0000-0003-4699-6862, Cid, Joan|||0000-0001-5445-4508, Tabera, Jaime|||0000-0002-5430-0151, Canals, Josep M.|||0000-0001-6829-7670, Lozano, Miquel|||0000-0003-2593-833X, Baumann, Tycho|||0000-0003-4421-0088, Vilarrodona, Ana|||0000-0001-6984-1834, Trias, Esteve|||0000-0001-7635-4428, Campo, Elias|||0000-0001-9850-9793, Menéndez Bujan, Pablo|||0000-0001-9372-1007, Urbano Ispizua, Álvaro|||0000-0002-7529-9399, Yagüe, Jordi|||0000-0001-8210-1929, Pérez-Galán, Patricia|||0000-0003-3895-5024, Rives, Susana|||0000-0002-5658-1831, Delgado, Julio|||0000-0002-5157-4376, Juan, Manel|||0000-0002-3064-1648
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:285231
Acceso en línea:https://ddd.uab.cat/record/285231
https://dx.doi.org/urn:doi:10.1016/j.omtm.2018.11.010
Access Level:acceso abierto
Palabra clave:4-1BB
CD19
T cell
Chimeric antigen receptor
Immunotherapy
Leukemia
Lymphoma
Preclinical studies
Descripción
Sumario: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 Il2rd/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.

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