Plasmid-based vaccines encoding rat neu and immune stimulatory molecules can elicit rat neu-specific immunity.
DNA vaccines are ideally suited for immunizing against tumor antigens because constructs can be formulated that not only encode the tumor antigen but also encode molecules chosen to improve the ability to elicit an antitumor response. Ligands expressed on antigen-presenting cells associated with stimulating a robust T-cell response are excellent candidates for inclusion in a DNA vaccine. Mice transgenic for the HER-2/neu homologue, rat neu, were immunized with full-length rat neu cDNA given alone or in combination with plasmids encoding costimulatory molecules CD80 or CD86 and the ligand for CD137 (CD137L). Intradermal injection of the plasmid constructs resulted in both plasmid transcript and antigen protein expression being detected in lymph nodes draining the injection site. Immunization with plasmids encoding the neu antigen along with plasmids encoding CD137L and either CD80 or CD86 resulted in the generation of neu-specific antibodies that induced phopshorylation of the neu tyrosine kinase and inhibited the growth of cultured tumor cells overexpressing neu. Survival of animals was significantly prolonged after immunization with vaccines encoding neu together with the costimulatory molecules. Although tumors eventually occurred in the vaccinated animals, they were markedly infiltrated with CD4+ T cells. DNA vaccines encoding neu, when given in combination with both CD137L and either CD80 or CD86, can induce cellular and humoral immunity and result in an antitumor effect.
Tumor Vaccine Group, Division of Oncology, University of Washington, Seattle, WA 98195-6527, USA. ndisis@u.washington.edu
Mary L
ML
Disis
Nathalie
N
Scholler
Amber
A
Dahlin
Janice
J
Pullman
Keith L
KL
Knutson
Karl-Erik
KE
Hellström
Ingegerd
I
Hellström
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D008024:Ligands; D008198:Lymph Nodes / Q000378:metabolism; D008207:Lymphatic Metastasis; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014443:Tyrosine / Q000378:metabolism; D019444:Vaccines, DNA
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019496:Cancer Vaccines; D004247:DNA; D018076:DNA, Complementary; D008024:Ligands; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014443:Tyrosine; D019444:Vaccines, DNA; C497965:Cd86 protein, mouse; C497966:Cd86 protein, rat; C505715:Tnfrsf9 protein, mouse