Therapeutic strategies based on the insertion of cytokine or other immunostimulatory genes into the genome of tumour cells followed by vaccination with the resulting, genetically modified, cytokine-producing vaccines represent a new potential prospect for the treatment of cancer patients. HPV 16 is the aetiological agent of more than 60 percent human cervical carcinomas (CC). At present, two prophylactic vaccines against HPV 16 are available (GlaxoSmithKline "Cervarix" and Merck "Gardasil"). These vaccines can almost completely protect the immunized individuals against both, persistent HPV 16 infection and HPV 16-related pathological findings in cervical cytology. In contrast, no clinically utilizable therapeutic vaccines against CC are available. During the last decade animal models have substantially contributed to the development of the therapeutic vaccines against HPV 16-associated tumours. It has been demonstrated that the HPV 16 E6/E7 oncoproteins can serve as tumour rejection antigens (TRA) and that the HPV 16-associated tumour cells can be genetically modified with DNA encoding immunostimulatory cytokines (IL-2, IL-12, GM-CSF) or other immunostimulatory molecules, used for vaccination, and inhibit tumour growth. To improve the HPV 16 antigen presentation in tumour-bearing individuals, dendritic cell-based vaccines loaded with HPV 16 E6/E7 DNA or hybrids of the dendritic and tumour cells have also been successfully employed. Unfortunately, when these encouraging approaches used in animal models were translated into clinical trials, the results were less optimistic. The problems that are still to be faced before the therapeutic vaccines against high-risk HPV-associated tumours can be approved for clinical purposes are discussed.

Institute of Molecular Genetics Academy of Sciences of the Czech Republic v v i Videnska 1083 142 20 Prague 4 Czech Republic

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Immunotherapy augments the effect of 5-azacytidine on HPV16-associated tumours with different MHC class I-expression status