title: Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors.
abstract: Tumor cells are usually weakly immunogenic as they largely express self-antigens and can down-regulate major histocompatability complex/peptide molecules and critical costimulatory ligands. The challenge for immunotherapies has been to provide vigorous immune effector cells that circumvent these tumor escape mechanisms and eradicate established tumors. One promising approach is to engineer T cells with single-chain antibody receptors, and since T cells require 2 distinct signals for optimal activation, we have compared the therapeutic efficacy of erbB2-reactive chimeric receptors that contain either T-cell receptor zeta (TCR-zeta) or CD28/TCR-zeta signaling domains. We have demonstrated that primary mouse CD8(+) T lymphocytes expressing the single-chain Fv (scFv)-CD28-zeta receptor have a greater capacity to secrete Tc1 cytokines, induce T-cell proliferation, and inhibit established tumor growth and metastases in vivo. The suppression of established tumor burden by cytotoxic T cells expressing the CD28/TCR-zeta chimera was critically dependent upon their interferon gamma (IFN-gamma) secretion. Our study has illustrated the practical advantage of engineering a T-cell signaling complex that codelivers CD28 activation, dependent only upon the tumor's expression of the appropriate tumor associated antigen.
authors.affiliation: Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Institute, Royal Melbourne Hospital Research Foundation, A'Beckett Street, Victoria, Australia 8006.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Michèle W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Jackson
authors.forename: Loretta
authors.initials: L
authors.lastname: Cerruti
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Jane
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
mesh_terms: D016475:3T3 Cells; D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000556:secondary / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019556:COS Cells; D002522:Chlorocebus aethiops; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins; D012513:Sarcoma, Experimental / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017252:CD3 Complex; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D007371:Interferon-gamma; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C054979:antigen T cell receptor, zeta chain