Analyses of Recombinant Vaccinia and Fowlpox Vaccine Vectors Expressing Transgenes for Two Human Tumor Antigens and Three Human Costimulatory Molecules

Purpose: The poor immunogenicity of tumor antigens and the antigenic heterogeneity of tumors call for vaccine strategies to enhance T-cell responses to multiple antigens. Two antigens expressed noncoordinately on most human carcinomas are carcinoembryonic antigen (CEA) and MUC-1. We report here the...

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Bibliographic Details
Published in:Clinical cancer research 2005-02, Vol.11 (4), p.1597-1607
Main Authors: TSANG, Kwong Y, PALENA, Claudia, MANSON, Kelledy, PANICALI, Dennis, SCHLOM, Jeffrey, YOKOKAWA, Junko, ARLEN, Philip M, GULLEY, James L, MAZZARA, Gail P, GRITZ, Linda, GOMEZ YAFAL, Alicia, OGUETA, Sandra, GREENHALGH, Patricia
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
B7-1 Antigen - genetics
B7-1 Antigen - immunology
Biological and medical sciences
Cancer vaccine
Cancer Vaccines - genetics
Cancer Vaccines - immunology
Carcinoembryonic antigen
Carcinoembryonic Antigen - genetics
Carcinoembryonic Antigen - immunology
CD58 Antigens - genetics
CD58 Antigens - immunology
Cell Line
Cell Line, Tumor
Cells, Cultured
Cytotoxicity, Immunologic - immunology
Dendritic Cells - cytology
Dendritic Cells - immunology
Dendritic Cells - metabolism
Flow Cytometry
Fowlpox virus - genetics
Genetic Vectors - genetics
Humans
Immunoblotting
Intercellular Adhesion Molecule-1 - genetics
Intercellular Adhesion Molecule-1 - immunology
Interferon-gamma - biosynthesis
Medical sciences
MUC-1
Mucin-1 - genetics
Mucin-1 - immunology
Pharmacology. Drug treatments
poxvirus
Recombination, Genetic
T-cell costimulation
T-Lymphocytes - cytology
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Transfection
Transgenes - genetics
Transgenes - immunology
Vaccinia virus
Vaccinia virus - genetics
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Summary:Purpose: The poor immunogenicity of tumor antigens and the antigenic heterogeneity of tumors call for vaccine strategies to enhance T-cell responses to multiple antigens. Two antigens expressed noncoordinately on most human carcinomas are carcinoembryonic antigen (CEA) and MUC-1. We report here the construction and characterization of two viral vector vaccines to address these issues. Experimental Design: The two viral vectors analyzed are the replication-competent recombinant vaccinia virus (rV-) and the avipox vector, fowlpox (rF-), which is replication incompetent in mammalian cells. Each vector encodes the transgenes for three human costimulatory molecules (B7-1, ICAM-1, and LFA-3, designated TRICOM) and the CEA and MUC-1 transgenes (which also contain agonist epitopes). The vectors are designated rV-CEA/MUC/TRICOM and rF-CEA/MUC/TRICOM. Results: Each of the vectors is shown to be capable of faithfully expressing all five transgenes in human dendritic cells (DC). DCs infected with either vector are shown to activate both CEA- and MUC-1–specific T-cell lines to the same level as DCs infected with CEA-TRICOM or MUC-1-TRICOM vectors. Thus, no evidence of antigenic competition between CEA and MUC-1 was observed. Human DCs infected with rV-CEA/MUC/TRICOM or rF-CEA/MUC/TRICOM are also shown to be capable of generating both MUC-1- and CEA-specific T-cell lines; these T-cell lines are in turn shown to be capable of lysing targets pulsed with MUC-1 or CEA peptides as well as human tumor cells endogenously expressing MUC-1 and/or CEA. Conclusion: These studies provide the rationale for the clinical evaluation of these multigene vectors in patients with a range of carcinomas expressing MUC-1 and/or CEA.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-04-1609