title: Treatment of minimal residual disease after surgery or chemotherapy in mice carrying HPV16-associated tumours: Cytokine and gene therapy with IL-2 and GM-CSF.
abstract: Moderately immunogenic HPV16-associated tumours TC-1 (MHC class I+, HPV16 E6/E7+, G12V Ha-ras+) and MK16/1/IIIABC (MK16, MHC class I-, HPV16 E6/E7+, G12V Ha-ras+), both of the H-2b haplotype and transplanted in syngeneic mice, were used to examine the effects of local IL-2 and GM-CSF cytokine or gene therapy in the treatment of minimal residual tumour disease. The mice carrying MHC class I+ TC-1 tumour residua after surgery were injected into the site of the surgery either with irradiated, IL-2 gene-modified MK16 tumour cells, or with recombinant IL-2. It has been found that both, the recombinant IL-2 and the IL-2 gene-modified tumour vaccine substantially reduced the percentage of tumour recurrences in the operated mice. Similarly, when the mice carrying TC-1 tumour residua after surgery were injected with recombinant GM-CSF, the recombinant GM-CSF inhibited growth of the tumour residua in the operated mice. Gene therapy with irradiated, GM-CSF secreting MK16 cells did not produce any tumour-inhibitory effect. In further experiments, mice bearing s.c. TC-1 tumours were injected i.p. with ifosfamide derivative CBM-4A and 8 days later, peritumourally, either with IL-2 gene-modified and IL-2-producing MK16 cells, or with recombinant IL-2. It has been found that both, the recombinant IL-2 and the IL-2 gene therapy substantially reduced the percentage of tumour-bearing mice. When the mice bearing s.c. TC-1 tumours were injected i.p. with ifosfamide derivative CBM-4A and then, peritumourally, either with irradiated, GM-CSF gene-modified and GM-CSF-producing MK16 cells, or with recombinant GM-CSF, it was found that both, the recombinant GM-CSF and GM-CSF gene therapy inhibited growth of tumour residua. Comparative experiments were performed with the MHC class I-, metastasizing tumour MK16. It has been found that both, recombinant IL-2 and GM-CSF, can inhibit growth of the tumour residua after surgery or chemotherapy. The lung metastases in mice with surgical minimal residual tumour disease or in mice with tumour residua after chemotherapy were inhibited by IL-2 but not by GM-CSF. The MK16 tumour vaccine producing IL-2 inhibited growth of tumour residua after chemotherapy, but not the tumour residua after surgery. The GM-CSF-producing vaccine was without significant effect in both, surgically- and chemotherapeutically-induced minimal residual MK16 tumour disease. In conclusion, the MHC class I+ and MHC class I-, HPV16-associated tumours were found to be sensitive to IL-2 and GM-CSF therapy after surgery or after cytoreductive chemotherapy. It is yet to be addressed if this is more general case with HPV16-associated experimental tumours. If so, it would be of interest to further investigate whether such adjuvant therapy can also help to eradicate the residua after surgery and chemotherapy in patients carrying HPV16-associated neoplasms.
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague 6, Czech Republic.
authors.forename: Romana
authors.initials: R
authors.lastname: Mikysková
authors.forename: Marie
authors.initials: M
authors.lastname: Indrová
authors.forename: Jana
authors.initials: J
authors.lastname: Símová
authors.forename: Tána
authors.initials: T
authors.lastname: Jandlová
authors.forename: Jana
authors.initials: J
authors.lastname: Bieblová
authors.forename: Pavel
authors.initials: P
authors.lastname: Jinoch
authors.forename: Jan
authors.initials: J
authors.lastname: Bubeník
authors.forename: Vladimír
authors.initials: V
authors.lastname: Vonka
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D016207:Cytokines / Q000008:administration & dosage* / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000235:genetics; D007376:Interleukin-2 / Q000008:administration & dosage / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D018365:Neoplasm, Residual / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009369:Neoplasms / Q000188:drug therapy / Q000601:surgery / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D027383:Papillomaviridae / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D011897:Random Allocation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D012097:Repressor Proteins; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; C068651:E6 protein, Human papillomavirus type 16; D007376:Interleukin-2; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D016178:Granulocyte-Macrophage Colony-Stimulating Factor