1. Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions
- Author
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Ramon Vilella, Josep M. Canals, Miguel Caballero, Jaime Tabera, Raquel Martín-Ibáñez, Pablo Engel, Valentín Ortiz-Maldonado, Guillermo Suñe, Clara Bueno, Carles Serra-Pagès, Berta Marzal, Miquel Lozano, Julio Castaño, Europa Azucena González-Navarro, Susana Rives, Beatriz Martín-Antonio, Lorena Perez-Amill, Anna Boronat, Patricia Pérez-Galán, Joan Cid, Maria Castella, Julio Delgado, Pablo Menendez, Anna Vilarrodona, Daniel Benitez-Ribas, Alvaro Urbano-Ispizua, Esteve Trias, Olga Balagué, Jordi Yagüe, Elias Campo, Tycho Baumann, Vanina Rodriguez, Manel Juan, and Universitat de Barcelona
- Subjects
0301 basic medicine ,Limfomes ,lcsh:QH426-470 ,T cell ,medicine.medical_treatment ,Immunoteràpia ,T cells ,lymphoma ,Immunotheraphy ,CD19 ,Article ,Viral vector ,4-1BB ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Cytotoxic T cell ,lcsh:QH573-671 ,preclinical studies ,Molecular Biology ,B cell ,Leukemia ,biology ,chimeric antigen receptor ,lcsh:Cytology ,business.industry ,leukemia ,Leucèmia ,Immunotherapy ,Chimeric antigen receptor ,3. Good health ,lcsh:Genetics ,030104 developmental biology ,medicine.anatomical_structure ,Cèl·lules T ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Molecular Medicine ,Lymphomas ,immunotherapy ,business ,CD8 - Abstract
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-Prkdcscid Il2rdtm1Wjl/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. Keywords: chimeric antigen receptor, CD19, leukemia, lymphoma, immunotherapy, 4-1BB, T cell, preclinical studies
- Published
- 2019