title: Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma.
abstract: Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies.
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Giedre
authors.initials: G
authors.lastname: Krenciute
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: David
authors.initials: D
authors.lastname: Torres
authors.affiliation: Department of Biostatistics, Shared Resource Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.affiliation: Department of Biostatistics, Shared Resource Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapell Hill, North Carolina, USA.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.affiliation: Department of Surgery, The Brain Tumor Center, University of Chicago, Chicago, Illinois, USA.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
authors.affiliation: Department of Surgery, The Brain Tumor Center, University of Chicago, Chicago, Illinois, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Balyasnikova
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA. Electronic address: smgottsc@txch.org.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gottschalk
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D057127:Single-Chain Antibodies / Q000276:immunology* / Q000627:therapeutic use; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D053663:Interleukin-13 Receptor alpha2 Subunit; D057127:Single-Chain Antibodies