title: Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody receptors codelivering CD28 costimulation.
abstract: A new strategy to improve the therapeutic utility of redirected T cells for cancer involves the development of novel Ag-specific chimeric receptors capable of stimulating optimal and sustained T cell antitumor activity in vivo. Given that T cells require both primary and costimulatory signals for optimal activation and that many tumors do not express critical costimulatory ligands, modified single-chain Ab receptors have been engineered to codeliver CD28 costimulation. In this study, we have compared the antitumor potency of primary T lymphocytes expressing carcinoembryonic Ag (CEA)-reactive chimeric receptors that incorporate either TCR-zeta or CD28/TCR-zeta signaling. Although both receptor-transduced T cell effector populations demonstrated cytolysis of CEA(+) tumors in vitro, T cells expressing the single-chain variable fragment of Ig (scFv)-CD28-zeta chimera had a far greater capacity to control the growth of CEA(+) xenogeneic and syngeneic colon carcinomas in vivo. The observed enhanced antitumor activity of T cells expressing the scFv-CD28-zeta receptor was critically dependent on perforin and the production of IFN-gamma. Overall, this study has illustrated the ability of a chimeric scFv receptor capable of harnessing the signaling machinery of both TCR-zeta and CD28 to augment T cell immunity against tumors that have lost expression of both MHC/peptide and costimulatory ligands in vivo.
authors.affiliation: Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Institute, St. Andrew's Place, East Melbourne, Victoria, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Michele 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: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001666:Binding Sites, Antibody / Q000235:genetics; D018106:CD28 Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000008:administration & dosage* / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D002272:Carcinoembryonic Antigen; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C054979:antigen T cell receptor, zeta chain; D054353:Perforin; D007371:Interferon-gamma