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‐γ) and the chemokine MIP1‐α 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‐γ response of the induced T cells in mice. Interestingly, IFN‐γ secretion of splenocytes did not strictly correlate with tumor response in tumor regression experiments. Gene‐encoded MIP‐1α applied 5 days prior to E7SH‐immunization combined with IFN‐γ 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. © 2009 UICC