title: A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR.
abstract: Clinical-grade T cells are genetically modified ex vivo to express a chimeric antigen receptor (CAR) to redirect specificity to a tumor associated antigen (TAA) thereby conferring antitumor activity in vivo. T cells expressing a CD19-specific CAR recognize B-cell malignancies in multiple recipients independent of major histocompatibility complex (MHC) because the specificity domains are cloned from the variable chains of a CD19 monoclonal antibody. We now report a major step toward eliminating the need to generate patient-specific T cells by generating universal allogeneic TAA-specific T cells from one donor that might be administered to multiple recipients. This was achieved by genetically editing CD19-specific CAR(+) T cells to eliminate expression of the endogenous αβ T-cell receptor (TCR) to prevent a graft-versus-host response without compromising CAR-dependent effector functions. Genetically modified T cells were generated using the Sleeping Beauty system to stably introduce the CD19-specific CAR with subsequent permanent deletion of α or β TCR chains with designer zinc finger nucleases. We show that these engineered T cells display the expected property of having redirected specificity for CD19 without responding to TCR stimulation. CAR(+)TCR(neg) T cells of this type may potentially have efficacy as an off-the-shelf therapy for investigational treatment of B-lineage malignancies.
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Torikai
authors.forename: Andreas
authors.initials: A
authors.lastname: Reik
authors.forename: Pei-Qi
authors.initials: PQ
authors.lastname: Liu
authors.forename: Yuanyue
authors.initials: Y
authors.lastname: Zhou
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Sourindra
authors.initials: S
authors.lastname: Maiti
authors.forename: Helen
authors.initials: H
authors.lastname: Huls
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Miller
authors.forename: Partow
authors.initials: P
authors.lastname: Kebriaei
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovich
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovitch
authors.forename: Dean A
authors.initials: DA
authors.lastname: Lee
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Rebar
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.forename: Michael C
authors.initials: MC
authors.lastname: Holmes
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
mesh_terms: D000328:Adult; D000938:Antigen-Presenting Cells / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002478:Cells, Cultured; D004720:Endonucleases / Q000378:metabolism; D000939:Epitopes / Q000276:immunology*; D055786:Gene Knockout Techniques; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016335:Zinc Fingers
chemical_list: D018941:Antigens, CD19; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017252:CD3 Complex; D000939:Epitopes; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D004720:Endonucleases