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, Martin-Ibanez, R, Rodriguez, V, Sune, G, Caballero, M, Marzal, B, Perez-Amill, L, Martin-Antonio, B, Castano, J, Bueno, C, Balague, O, Gonzalez-Navarro, EA, Serra-Pages, C, Engel, P, Vilella, R, Benitez-Ribas, D, Ortiz-Maldonado, V, Cid, J, Tabera, J, Canals, JM, Lozano, M, Baumann, T, Vilarrodona, A, Trias, E, Campo, E, Menendez, P, Urbano-Ispizua, A, Yague, J, Perez-Galan, P, Rives, S, Delgado, J and Juan, M
Publicada:
15 mar 2019
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:
Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Boronat, A:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Martin-Ibanez, R:
Univ Barcelona, Stem Cells & Regenerat Med Lab, Prod & Validat Ctr Adv Therapies Creatio, Dept Biomed Sci, Casanova 143, E-08036 Barcelona, Spain
Rodriguez, V:
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
IDIBAPS, Physiopathol & Mol Bases Hematol Grp, Rossello 153, Barcelona 08036, Spain
Sune, G:
Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Caballero, M:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Univ Barcelona, Hosp St Joan de Deu, Inst Recerca Pediat, Passeig St Joan de Deu 2, Barcelona 08950, Spain
Marzal, B:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Perez-Amill, L:
Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Martin-Antonio, B:
Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Castano, J:
Univ Barcelona, Sch Med, Dept Biomed, Josep Carreras Leukemia Res Inst, Casanova 143, E-08036 Barcelona, Spain
:
Univ Barcelona, Sch Med, Dept Biomed, Josep Carreras Leukemia Res Inst, Casanova 143, E-08036 Barcelona, Spain
Balague, O:
IDIBAPS, Hosp Clin, Dept Pathol, Villarroel 170, Barcelona 08036, Spain
Gonzalez-Navarro, EA:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Serra-Pages, C:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Univ Barcelona, Casanova 143, E-08036 Barcelona, Spain
Engel, P:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Univ Barcelona, Dept Biomed Sci, Immunol Unit, Casanova 143, E-08036 Barcelona, Spain
Vilella, R:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Benitez-Ribas, D:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Ortiz-Maldonado, V:
Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain
Cid, J:
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Hosp Clin Barcelona, ICMHO, Dept Hemotherapy & Hemostasis, Villarroel 170, E-08036 Barcelona, Spain
Tabera, J:
Hosp Clin Barcelona, Blood & Tissue Bank BST, Unit Adv Therapies, Passeig Taulat 106, Barcelona 08005, Spain
Canals, JM:
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Univ Barcelona, Casanova 143, E-08036 Barcelona, Spain
Lozano, M:
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Hosp Clin Barcelona, ICMHO, Dept Hemotherapy & Hemostasis, Villarroel 170, E-08036 Barcelona, Spain
Baumann, T:
Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain
Vilarrodona, A:
Hosp Clin Barcelona, Blood & Tissue Bank BST, Unit Adv Therapies, Passeig Taulat 106, Barcelona 08005, Spain
Trias, E:
Hosp Clin Barcelona, Blood & Tissue Bank BST, Unit Adv Therapies, Passeig Taulat 106, Barcelona 08005, Spain
Campo, E:
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
IDIBAPS, Physiopathol & Mol Bases Hematol Grp, Rossello 153, Barcelona 08036, Spain
Univ Barcelona, Casanova 143, E-08036 Barcelona, Spain
Ctr Invest Biomed Red Canc ISCIII CIBERONC, Barcelona, Spain
:
Univ Barcelona, Sch Med, Dept Biomed, Josep Carreras Leukemia Res Inst, Casanova 143, E-08036 Barcelona, Spain
Ctr Invest Biomed Red Canc ISCIII CIBERONC, Barcelona, Spain
ICREA, Barcelona, Spain
Urbano-Ispizua, A:
Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Univ Barcelona, Sch Med, Dept Biomed, Josep Carreras Leukemia Res Inst, Casanova 143, E-08036 Barcelona, Spain
Univ Barcelona, Casanova 143, E-08036 Barcelona, Spain
Yague, J:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Univ Barcelona, Casanova 143, E-08036 Barcelona, Spain
Perez-Galan, P:
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
IDIBAPS, Physiopathol & Mol Bases Hematol Grp, Rossello 153, Barcelona 08036, Spain
Ctr Invest Biomed Red Canc ISCIII CIBERONC, Barcelona, Spain
Rives, S:
Univ Barcelona, Hosp St Joan de Deu, Inst Recerca Pediat, Passeig St Joan de Deu 2, Barcelona 08950, Spain
Delgado, J:
Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Univ Barcelona, Casanova 143, E-08036 Barcelona, Spain
Ctr Invest Biomed Red Canc ISCIII CIBERONC, Barcelona, Spain
Juan, M:
Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain
Univ Barcelona, Hosp St Joan de Deu, Inst Recerca Pediat, Passeig St Joan de Deu 2, Barcelona 08950, Spain
Univ Barcelona, Casanova 143, E-08036 Barcelona, Spain
Green Published, gold
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