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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / immunology
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Adenocarcinoma / prevention & control
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Adjuvants, Immunologic / administration & dosage
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Adjuvants, Immunologic / biosynthesis
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Adjuvants, Immunologic / genetics
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Animals
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Binding Sites, Antibody / genetics
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CD28 Antigens / administration & dosage
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CD28 Antigens / genetics
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CD28 Antigens / immunology*
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Carcinoembryonic Antigen / administration & dosage
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Carcinoembryonic Antigen / biosynthesis
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Carcinoembryonic Antigen / genetics
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Carcinoembryonic Antigen / immunology
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Cells, Cultured
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Colonic Neoplasms / genetics
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Colonic Neoplasms / immunology
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Colonic Neoplasms / pathology
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Colonic Neoplasms / prevention & control*
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Cytotoxicity, Immunologic / genetics
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / metabolism
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Graft Rejection / genetics
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Graft Rejection / immunology*
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / biosynthesis
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Growth Inhibitors / genetics
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Humans
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Immunoglobulin Variable Region / administration & dosage
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Immunoglobulin Variable Region / genetics
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Immunoglobulin Variable Region / immunology*
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Immunotherapy, Adoptive / methods*
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interferon-gamma / physiology
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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Perforin
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Pore Forming Cytotoxic Proteins
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Receptors, Immunologic / administration & dosage*
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Receptors, Immunologic / biosynthesis*
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Receptors, Immunologic / genetics
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / metabolism*
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T-Lymphocytes, Cytotoxic / transplantation
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Transplantation, Isogeneic
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Tumor Cells, Cultured
Substances
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Adjuvants, Immunologic
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CD28 Antigens
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Carcinoembryonic Antigen
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Epitopes, T-Lymphocyte
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Growth Inhibitors
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Immunoglobulin Variable Region
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Membrane Glycoproteins
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Membrane Proteins
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Pore Forming Cytotoxic Proteins
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Receptors, Antigen, T-Cell
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Receptors, Immunologic
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Recombinant Fusion Proteins
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antigen T cell receptor, zeta chain
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Perforin
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Interferon-gamma