Abstract
Successful approaches to tumor immunotherapy must overcome the physiological state of tolerance of the immune system to self-tumor antigens. Immunization with appropriate variants of syngeneic antigens can achieve this. However, improvements in vaccine design are needed for efficient cancer immunotherapy. Here we explore nine different chimeric vaccine designs, in which the antigen of interest is expressed as an in-frame fusion with polypeptides that impact antigen processing or presentation. In DNA immunization experiments in mice, three of nine fusions elevated relevant CD8(+) T-cell responses and tumor protection relative to an unfused melanoma antigen. These fusions were: Escherichia coli outer membrane protein A (OmpA), Pseudomonas aeruginosa exotoxin A, and VP22 protein of herpes simplex virus-1. The gains of immunogenicity conferred by the latter two are independent of epitope presentation by major histocompatibility complex class II (MHC II). This finding has positive implications for immunotherapy in individuals with CD4(+) T-cell deficiencies. We present evidence that antigen instability is not a sine qua non condition for immunogenicity. Experiments using two additional melanoma antigens identified different optimal fusion partners, thereby indicating that the benefits of fusion vectors remain antigen specific. Therefore large fusion vector panels such as those presented here can provide information to promote the successful advancement of gene-based vaccines.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP Ribose Transferases / genetics
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ADP Ribose Transferases / immunology
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Animals
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Antigen Presentation
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology*
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Bacterial Outer Membrane Proteins / genetics
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Bacterial Outer Membrane Proteins / immunology
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Bacterial Toxins / genetics
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Bacterial Toxins / immunology
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CD8-Positive T-Lymphocytes / immunology
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COS Cells
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Cancer Vaccines / genetics
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Cancer Vaccines / immunology*
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Cancer Vaccines / therapeutic use
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Chlorocebus aethiops
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Escherichia coli Proteins / genetics
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Escherichia coli Proteins / immunology
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Exotoxins / genetics
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Exotoxins / immunology
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Female
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Histocompatibility Antigens Class II / immunology
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Humans
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Melanoma, Experimental / immunology
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Melanoma, Experimental / therapy
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Mice
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Mice, Inbred C57BL
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Pseudomonas aeruginosa Exotoxin A
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology*
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Vaccination
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Vaccines, DNA / genetics
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Vaccines, DNA / immunology*
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Vaccines, DNA / therapeutic use
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Viral Structural Proteins / genetics
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Viral Structural Proteins / immunology
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Virulence Factors / genetics
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Virulence Factors / immunology
Substances
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Antigens, Neoplasm
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Bacterial Outer Membrane Proteins
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Bacterial Toxins
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Cancer Vaccines
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Escherichia coli Proteins
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Exotoxins
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Histocompatibility Antigens Class II
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Recombinant Fusion Proteins
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Vaccines, DNA
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Viral Structural Proteins
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Virulence Factors
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herpes simplex virus type 1 protein VP22
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OMPA outer membrane proteins
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ADP Ribose Transferases