title: Chemotherapy, IL-12 gene therapy and combined adjuvant therapy of HPV 16-associated MHC class I-proficient and -deficient tumours.
abstract: Moderately immunogenic HPV 16-associated murine tumour cell line mimicking human HPV 16-associated neoplasms TC-1 (MHC class I(+)) and its variants, TC-1/P3C10 and TC-1/A9, with a marked down-regulation of MHC I molecules, were used to examine the effect of local interleukin 12 (IL-12) gene therapy for the treatment of early tumour transplants and minimal residual tumour disease obtained after cytoreductive chemotherapy (CMRTD). Experiments were designed to examine whether down-regulation of MHC class I molecules plays a role during chemotherapy and gene therapy of early tumour transplants. It was found that peritumoral administration of IL-12-producing tumour cell vaccines (single dose, day 8 after tumour cell administration) inhibited the growth of both TC-1 (MHC class I positive) tumours and their MHC class I-deficient variants. To investigate the antitumour effects in a clinically relevant setting, IL-12 gene therapy was utilised for the treatment of minimal residual tumour disease after cytoreductive chemotherapy. Intra-peritoneal treatment of tumour-bearing mice with ifosfamide derivative, CBM-4A, produced a significant tumour-inhibitory effect. This treatment was followed by peritumoral s.c. administration of genetically modified TC-1 (MHC class I positive) or MK16/I/IIIABC (MHC class I negative) vaccines producing IL-12 (single dose, day 7 after chemotherapy) or with recombinant interleukin 12 (rIL-12) in two cycles of 5 daily doses (days 8-19) after chemotherapy. This combined therapy significantly inhibited the growth of TC-1 and TC-1/A9 (MHC class I-) tumours. When the combined therapy of TC-1 (MHC class I positive) tumours was followed by peritumoral administration of bone marrow dendritic cell (BMDC) vaccines, the IL-12-mediated inhibitory effect was significantly boosted. In the next set of experiments, the impacts of chemotherapy and IL-12 adjuvant therapy on MHC class I surface expression were assessed. Chemotherapy and gene therapy of tumours led to the up-regulation of MHC I expression on MHC class I-deficient tumours (TC-1/A9 and TC-1/P3C10) and to down-regulation on MHC I-proficient tumours (TC-1). These findings indicate that the MHC I phenotype is not stable during tumour progression and treatment. Collectively, these results illustrate the efficacy of IL-12 gene therapy in combination with chemotherapy on HPV-associated tumours regardless of the level of MHC class I expression on the tumour cells.
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 166 37 Prague 6, Czech Republic. indrova@img.cas.cz
authors.forename: Marie
authors.initials: M
authors.lastname: Indrová
authors.forename: Jana
authors.initials: J
authors.lastname: Bieblová
authors.forename: Tána
authors.initials: T
authors.lastname: Jandlová
authors.forename: Vladimír
authors.initials: V
authors.lastname: Vonka
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pajtasz-Piasecka
authors.forename: Milan
authors.initials: M
authors.lastname: Reinis
mesh_terms: D000818:Animals; D019496:Cancer Vaccines; D004195:Disease Models, Animal; D015536:Down-Regulation; D005805:Genes, MHC Class I; D015316:Genetic Therapy; D006680:HLA Antigens / Q000096:biosynthesis*; D052162:Human papillomavirus 16 / Q000472:pathogenicity*; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives / Q000494:pharmacology; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D018365:Neoplasm, Residual; D009374:Neoplasms, Experimental / Q000821:virology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D019496:Cancer Vaccines; D006680:HLA Antigens; C097983:chlorobromofosfamide; D018664:Interleukin-12; D007069:Ifosfamide