CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice.
A murine monoclonal anti-idiotype (Id) antibody, 3H1 has been developed and characterized previously. Anti-Id 3H1 mimics a specific epitope of carcinoembryonic antigen (CEA) and can be used as a surrogate antigen for CEA. 3H1 induced anti-CEA immunity in different species of animals as well as humans and showed promise as a potential vaccine candidate in phase I/II clinical trials for colon cancer patients. One area of interest to us has been the development of new immune adjuvants that may augment the potency of 3H1 as a tumor vaccine. Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. In this study, we have evaluated the efficacy of 3H1 as a tumor vaccine when admixed with a select CpG ODN 1826 in transgenic mice that express human CEA. The vaccine potential of 3H1 was also assessed in the presence of another widely used adjuvant, QS-21. 3H1 coupled to keyhole limpet hemocyanin (KLH) and mixed with Freund's adjuvant (FA) was used as a gold standard in this system. 3H1 vaccination with different adjuvants induced both humoral and cellular anti-3H1, as well as anti-CEA immunity in CEA transgenic mice. The immune sera could lyse CEA-transfected murine colon carcinoma cells, C15 effectively in an antibody-dependent cellular cytotoxicity assay. The anti-CEA antibody responses were somewhat comparable in each adjuvant-treated group of mice, whereas cellular immune responses were significantly greater when CpG was used as an adjuvant. Splenocytes obtained from 3H1-CpG-immunized mice showed an increased proliferative CD4(+) Th1-type T-cell response when stimulated in vitro with 3H1 or CEA and secreted elevated levels of Th1 cytokines (IL-2, IFN-gamma). This vaccine also induced MHC class I antigen-restricted CD8(+) T-cell responses. In a solid tumor model, C15 tumor growth was significantly inhibited by 3H1 vaccinations. In 3H1-CpG-vaccinated mice, the duration of survival was, however, longer compared to the 3H1-QS21-vaccinated mice. These findings suggest that 3H1-CpG vaccinations can break peripheral tolerance to CEA and induce protective antitumor immunity in this murine model transgenic for human CEA.
Saha
Asim
A
Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, OH, USA.
Baral
Rathindra Nath
RN
Chatterjee
Sunil K
SK
Mohanty
Kartik
K
Pal
Smarajit
S
Foon
Kenneth A
KA
Primus
F James
FJ
Krieg
Arthur M
AM
Weiner
George J
GJ
Bhattacharya-Chatterjee
Malaya
M
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D018797:Cell Cycle Proteins; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D003598:Cytoskeletal Proteins; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000627:therapeutic use*; D012503:Saponins / Q000276:immunology / Q000627:therapeutic use
D000276:Adjuvants, Immunologic; D000888:Antibodies, Anti-Idiotypic; D000951:Antigens, Neoplasm; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; D012503:Saponins; C078785:saponin QA-21V1; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin