title: T-cell killing of heterogenous tumor or viral targets with bispecific chimeric immune receptors.
abstract: We have previously described several novel chimeric immune receptors (CIRs) that redirect human T cells to kill malignant or HIV-infected cells. These CIRs comprise a cancer- or virus-specific ligand or single-chain antibody fused to the signaling domain of the T-cell receptor CD3-zeta subunit. Binding of the ligand- or antibody-based CIR to the target antigen (Ag) triggers T-cell-mediated cytolysis of the tumor- or virus-infected cell independent of target cell major histocompatibility complex class I expression. A new type of CIR was developed to mediate the lysis of cells that expressed one or more distinct viral or tumor Ags; three bispecific CIRs (BCIRs) were generated that recognized the carcinoembryonic Ag (CEA) and TAG-72 tumor Ags or, alternatively, distinct epitopes in the HIV envelope (HIVenv). T cells expressing the antitumoral Ag BCIR lysed both CEA- and TAG-72-expressing targets and did not kill Ag-negative targets or target cells expressing other members of the CEA family. Similarly, T cells expressing the anti-HIVenv BCIR lysed target cells expressing both the wild-type HIVenv and a mutant HIVenv that lacked the epitopes recognized by the monospecific CIRs. This approach permits the generation of T cells with a broader spectrum of activity capable of killing virus-infected cells and malignant cells and reduces the potential of progression of disease due to Ag loss variants.
authors.affiliation: Cell Genesys Inc., Foster City, California 94404, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: Moskalenko
authors.forename: T
authors.initials: T
authors.lastname: Tian
authors.forename: D
authors.initials: D
authors.lastname: Smith
authors.forename: R
authors.initials: R
authors.lastname: McGuinness
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: G A
authors.initials: GA
authors.lastname: Winslow
authors.forename: S
authors.initials: S
authors.lastname: Kashmiri
authors.forename: J
authors.initials: J
authors.lastname: Schlom
authors.forename: C P
authors.initials: CP
authors.lastname: Stanners
authors.forename: M H
authors.initials: MH
authors.lastname: Finer
authors.forename: J G
authors.initials: JG
authors.lastname: McArthur
mesh_terms: D000595:Amino Acid Sequence; D000941:Antigens / Q000276:immunology; D006678:HIV / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D011971:Receptors, Immunologic / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins