A carcinoembryonic antigen polynucleotide vaccine for human clinical use.
We have constructed a plasmid DNA encoding the full-length complementary DNA for human carcinoembryonic antigen (CEA) under transcriptional regulatory control of the cytomegalovirus early promoter/enhancer (pCEA) and demonstrated that this plasmid can function as a polynucleotide vaccine to elicit a CEA-specific immune response. This immune response protects against tumor challenge with syngeneic CEA-transduced colon carcinoma cells in mice. In the present work, the pCEA construct and purification method were modified to eliminate nonessential viral sequences, the ampicillin selectable marker, mutagens, and endotoxin to produce a reagent suitable for human clinical trials. The human use plasmid (pGT37) directs CEA expression at levels comparable with the original pCEA plasmid and can be propagated to yield large quantities of plasmid DNA based on kanamycin selection. A simple extraction technique greatly reduces contamination by endotoxin. Six weekly intramuscular injections of pGT37 elicited CEA-specific lymphoblastic transformation and antibody response in five of five mice and fully protected 10 of 10 mice against tumor challenge with syngeneic CEA-expressing colon cancer cells 42 days from the first plasmid injection. Thus, pGT37 encoding a tumor-associated antigen (CEA) has been shown to elicit cellular and humoral immune responses and mediate antitumor effects in vivo. This plasmid is suitable for human use and can be easily propagated in the laboratory.
Conry
R M
RM
University of Alabama at Birmingham, Comprehensive Cancer Center, L.B. Wallace Tumor Institute-249, 35294-3300, USA.
LoBuglio
A F
AF
Loechel
F
F
Moore
S E
SE
Sumerel
L A
LA
Barlow
D L
DL
Pike
J
J
Curiel
D T
DT
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy*; D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology*; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000628:therapy*; D003587:Cytomegalovirus / Q000235:genetics; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005260:Female; D005813:Genes, Synthetic; D005822:Genetic Vectors; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D007273:Injections, Intramuscular; D007518:Isoantibodies / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation / Q000276:immunology; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology*
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D018076:DNA, Complementary; D007518:Isoantibodies; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic