title: Definition and application of good manufacturing process-compliant production of CEA-specific chimeric antigen receptor expressing T-cells for phase I/II clinical trial.
abstract: Adoptive cell therapy employing gene-modified T-cells expressing chimeric antigen receptors (CARs) has shown promising preclinical activity in a range of model systems and is now being tested in the clinical setting. The manufacture of CAR T-cells requires compliance with national and European regulations for the production of medicinal products. We established such a compliant process to produce T-cells armed with a first-generation CAR specific for carcinoembryonic antigen (CEA). CAR T-cells were successfully generated for 14 patients with advanced CEA(+) malignancy. Of note, in the majority of patients, the defined procedure generated predominantly CD4(+) CAR T-cells with the general T-cell population bearing an effector-memory phenotype and high in vitro effector function. Thus, improving the process to generate less-differentiated T-cells would be more desirable in the future for effective adoptive gene-modified T-cell therapy. However, these results confirm that CAR T-cells can be generated in a manner compliant with regulations governing medicinal products in the European Union.
authors.affiliation: Cellular Therapeutics, Grafton Street, Manchester, M13 9XX, UK.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Guest
authors.forename: Natalia
authors.initials: N
authors.lastname: Kirillova
authors.forename: Sam
authors.initials: S
authors.lastname: Mowbray
authors.forename: Hannah
authors.initials: H
authors.lastname: Gornall
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Rothwell
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Cheadle
authors.forename: Eric
authors.initials: E
authors.lastname: Austin
authors.forename: Keith
authors.initials: K
authors.lastname: Smith
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Watt
authors.forename: Klaus
authors.initials: K
authors.lastname: Kühlcke
authors.forename: Nigel
authors.initials: N
authors.lastname: Westwood
authors.forename: Fiona
authors.initials: F
authors.lastname: Thistlethwaite
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: David E
authors.initials: DE
authors.lastname: Gilham
mesh_terms: D019264:Adoptive Transfer; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D020740:Chimerin Proteins / Q000096:biosynthesis*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D002272:Carcinoembryonic Antigen; D020740:Chimerin Proteins; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma