Therapy of established tumors in a novel murine model transgenic for human carcinoembryonic antigen and HLA-A2 with a combination of anti-idiotype vaccine and CTL peptides of carcinoembryonic antigen.
Induction of potent and sustained antitumor immunity depends on the efficient activation of CD8(+) and CD4(+) T cells. Immunization using dendritic cells loaded with tumor antigens constitute a powerful platform for stimulating cellular immunity. Our previous studies suggested that vaccination with an anti-idiotype antibody 3H1, which mimics a specific epitope of carcinoembryonic antigen (CEA), has the potential to break immune tolerance to CEA and induce anti-CEA antibody as well as CEA-specific CD4(+) T-helper responses in colon cancer patients as well as in mice transgenic for human CEA. Here, we have combined the anti-idiotype 3H1 with the CTL peptides of CEA to augment both T-helper and CTL responses in a clinically relevant mouse model, which is transgenic for both CEA and HLA-A2. We have evaluated the potential of two different HLA-A2-restricted epitopes of CEA pulsed into dendritic cells in a therapeutic setting. The overall immune responses and survival were enhanced in groups of mice immunized with agonist peptide for CEA(691) (YMIGMLVGV)-pulsed dendritic cells or CAP1-6D (YLSGADLNL, agonist peptide for CAP-1)-pulsed dendritic cells. Mice immunized with peptide-pulsed dendritic cells along with 3H1-pulsed dendritic cells resulted in significant increase in survival compared with mice immunized with peptide-pulsed dendritic cells alone (P < 0.02). IFN-gamma ELISPOT and (51)Cr-release assays showed that HLA-A2-restricted, CEA-specific CTL responses were augmented by combined dendritic cell vaccinations. The combined vaccination strategy resulted in increased antigen-specific proliferation of splenocytes and secretion of Th1 cytokines by CD4(+) T cells that correlated with increased survival. These results suggest the potential use of this vaccination strategy for future clinical applications.
Saha
Asim
A
Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0509, USA.
Chatterjee
Sunil K
SK
Foon
Kenneth A
KA
Celis
Esteban
E
Bhattacharya-Chatterjee
Malaya
M
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology*; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D000939:Epitopes; D015789:HLA-A2 Antigen; D010446:Peptide Fragments