Analyses of recombinant vaccinia and fowlpox vaccine vectors expressing transgenes for two human tumor antigens and three human costimulatory molecules.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Tsang
Kwong Y
KY
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, 10 Center Drive, Bethesda, MD 20892, USA.
Palena
Claudia
C
Yokokawa
Junko
J
Arlen
Philip M
PM
Gulley
James L
JL
Mazzara
Gail P
GP
Gritz
Linda
L
Yafal
Alicia Gómez
AG
Ogueta
Sandra
S
Greenhalgh
Patricia
P
Manson
Kelledy
K
Panicali
Dennis
D
Schlom
Jeffrey
J
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D018968:CD58 Antigens / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005587:Fowlpox virus / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D019076:Transgenes / Q000235:genetics* / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
D018122:B7-1 Antigen; D018968:CD58 Antigens; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D018396:Mucin-1; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma