Enhancement of immunogenicity of a therapeutic cervical cancer DNA-based vaccine by co-application of sequence-optimized genetic adjuvants.
Treatment of patients with cervical cancer by conventional methods (mainly surgery, but also radiotherapy and chemotherapy) results in a significant loss in quality of life. A therapeutic DNA vaccine directed to tumor-specific antigens of the human papilloma virus (HPV) could be an attractive treatment option. We have developed a nontransforming HPV-16 E7-based DNA vaccine containing all putative T cell epitopes (HPV-16 E7SH). DNA vaccines, however, are less immunogenic than protein- or peptide-based vaccines in larger animals and humans. In this study, we have investigated an adjuvant gene support of the HPV-16 E7SH therapeutic cervical cancer vaccine. DNA encoded cytokines (IL-2, IL-12, GM-CSF, IFN-gamma) and the chemokine MIP1-alpha were co-applied either simultaneously or at different time points pre- or post-E7SH vaccination. In addition, sequence-optimized adjuvant genes were compared to wild type genes. Three combinations investigated lead to an enhanced IFN-gamma response of the induced T cells in mice. Interestingly, IFN-gamma secretion of splenocytes did not strictly correlate with tumor response in tumor regression experiments. Gene-encoded MIP-1alpha applied 5 days prior to E7SH-immunization combined with IFN-gamma or IL-12 (3 days) or IL-2 (5 days) postimmunization lead to a significantly enhanced tumor response that was clearly associated with granzyme B secretion and target cells lysis. Our results suggest that a conditioning application and combination with adjuvant genes may be a promising strategy to enhance synergistically immune responses by DNA immunization for the treatment of cervical cancer.
Universität Konstanz, Biologie/Immunologie, Konstanz, Germany. peter.oehlschlaeger@uni-konstanz.de
Peter
P
Ohlschläger
Michael
M
Quetting
Gerardo
G
Alvarez
Matthias
M
Dürst
Lutz
L
Gissmann
Andreas M
AM
Kaufmann
D000276:Adjuvants, Immunologic; D000818:Animals; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology*
D000276:Adjuvants, Immunologic; D054405:Chemokine CCL3; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019444:Vaccines, DNA; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor