title: Gene therapy of malignant solid tumors by targeting erbB2 receptors and by activating T cells.
abstract: One of the strategies to improve the outcome of anti-erbB2-mediated immunotherapy is to combine anti-erbB2 antibodies with T-cell-based adoptive immunotherapy, which can be achieved by expressing anti-erbB2 mAb on the surface of T cells. A single-chain variable fragment (scFv) from an anti-erbB2 mAb has been expressed on T cell surface to bind to erbB2-positive cells, and CD3ζ has been expressed as a fusion partner at C terminus of this scFv to transduce signals. T cells grafted with this chimeric scFv/CD3ζ were able to specifically attack target tumor cells with no MHC/Ag restriction. To test the effects of CD28 signal on cellular activation and antitumor effectiveness of chimeric scFv/CD3ζ-modified T cells, we constructed a recombinant anti-erbB2 scFv/Fc/CD28/CD3ζ gene in a retroviral vector. T cells expressing anti-erbB2 scFv/Fc/CD28/CD3ζ specifically lyzed erbB2-positive target tumor cells and secreted not only interferon-γ (IFN-γ) but also IL-2 after binding to their target cells. Our data indicate that CD3 and CD28 signaling can be delivered in one molecule, which is sufficient for complete T cell activation without exogenous B7/CD28 co-stimulation.
authors.affiliation: Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical College, Wenzhou, People's Republic of China.
authors.forename: Wang-Xiong
authors.initials: WX
authors.lastname: Hu
authors.forename: He-Ping
authors.initials: HP
authors.lastname: Chen
authors.forename: Kang
authors.initials: K
authors.lastname: Yu
authors.forename: Lu-Xi
authors.initials: LX
authors.lastname: Shen
authors.forename: Chao-Yan
authors.initials: CY
authors.lastname: Wang
authors.forename: Shi-Zhen
authors.initials: SZ
authors.lastname: Su
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Sui
authors.forename: Da-Ming
authors.initials: DM
authors.lastname: Shan
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D019677:Artificial Gene Fusion; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018106:CD28 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019169:Jurkat Cells; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D061986:MCF-7 Cells; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D007135:Immunoglobulin Variable Region; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C121704:CD3 antigen, zeta chain