Abstract
DNA vaccines can activate immunity against tumor Ags expressed as MHC class I-associated peptides. However, priming of CD8(+) CTL against weak tumor Ags may require adjuvant molecules. We have used a pathogen-derived sequence from tetanus toxin (fragment C (FrC)) fused to tumor Ag sequences to promote Ab and CD4(+) T cell responses. For induction of CD8(+) T cell responses, the FrC sequence has been engineered to remove potentially competitive MHC class I-binding epitopes and to improve presentation of tumor epitopes. The colon carcinoma CT26 expresses an endogenous retroviral gene product, gp70, containing a known H2-L(d)-restricted epitope (AH1). A DNA vaccine encoding gp70 alone was a poor inducer of CTL, and performance was not significantly improved by fusion of full-length FrC. However, use of a minimized domain of FrC, with the AH1 sequence fused to the 3' position, led to rapid induction of high levels of CTL. IFN-gamma-producing epitope-specific CTL were detectable ex vivo and these killed CT26 targets in vitro. The single epitope vaccine was more effective than GM-CSF-transfected CT26 tumor cells in inducing an AH1-specific CTL response and equally effective in providing protection against tumor challenge. Levels of AH1-specific CTL in vivo were increased following injection of tumor cells, and CTL expanded in vitro were able to kill CT26 cells in tumor bearers. Pre-existing immunity to tetanus toxoid had no effect on the induction of AH1-specific CTL. These data demonstrate the power of epitope-specific CTL against tumor cells and illustrate a strategy for priming immunity via a dual component DNA vaccine.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / administration & dosage
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology*
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Cancer Vaccines / administration & dosage
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Cancer Vaccines / chemical synthesis
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Cancer Vaccines / genetics
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Cancer Vaccines / immunology*
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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 / administration & dosage
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology*
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / chemical synthesis
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Growth Inhibitors / genetics
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Growth Inhibitors / immunology
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Injections, Intramuscular
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Interferon-gamma / biosynthesis
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Lymphocyte Activation* / genetics
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Mice
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Mice, Inbred BALB C
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Neoplasm Transplantation
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / chemical synthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology*
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Retroviridae Proteins, Oncogenic / administration & dosage
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Retroviridae Proteins, Oncogenic / genetics
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Retroviridae Proteins, Oncogenic / immunology
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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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Tetanus Toxoid / administration & dosage
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Tetanus Toxoid / immunology
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Vaccines, DNA / administration & dosage
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Vaccines, DNA / chemical synthesis
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Vaccines, DNA / genetics
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Vaccines, DNA / immunology*
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Viral Envelope Proteins / administration & dosage
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Viral Envelope Proteins / genetics
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Viral Envelope Proteins / immunology
Substances
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Antigens, Neoplasm
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Cancer Vaccines
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Epitopes, T-Lymphocyte
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Growth Inhibitors
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Recombinant Fusion Proteins
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Retroviridae Proteins, Oncogenic
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Tetanus Toxoid
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Vaccines, DNA
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Viral Envelope Proteins
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Interferon-gamma