Abstract Book 2010 - CIMT Annual Meeting

010 Mikyskova | Therapeutic vaccination
Interleukin 12 genetically-modified vaccines augment the effect
of chemotherapy of human papilloma virus 16-associated
tumours with gemcitabine
Romana Mikyšková, Jana Šímová, Marie Indrová, Jan Bubeník, Jana Bieblová, Milan Reiniš
Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic,
Prague, Czech Republic
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Experiments were designed to examine whether
local administration of genetically-modified interleukin
12 (IL-12)-producing vaccine can enhance
the chemotherapy of human papilloma virus (HPV)
16-associated tumour with gemcitabine, a cytostatic
agent that is known to reduce myeloid derived
suppressor cells. Major histocompatibility class I
(MHC I) positive non-metastasizing murine carcinoma
TC-1 model was used to examine the effect
of local IL-12 gene therapy in the minimal residual
tumour disease induced by intraperitoneal cytoreductive
therapy with gemcitabine. Mice with
established 0.2-0.3 cm in diameter TC-1 tumours
were treated with gemcitabine and, subsequently,
with irradiated, IL-12-producing tumour cells.
It was found that local administration of IL-12producing
vaccine enhanced the effect of cytoreductive
therapy with gemcitabine in TC-1 (MHC I
positive) tumours. To investigate the antitumour
and antimetastatic effect of IL-12 plus gemcitabine
combination in another clinically relevant setting,
surgical minimal residual tumour disease of MHC
I-deficient MK16 tumours was used. Mice with established
1 cm in diameter MK16 tumours were
operated and subsequently treated with gemcitabine
and/or IL-12-producing vaccine. Combination of
the IL-12 genetically-modified tumour vaccine with
gemcitabine treatment after surgery significantly
reduced the percentage and size of MK16 tumour
recurrences as well as the percentage and number
of lung metastases, as compared to the group of
operated-only mice and groups treated with gemcitabine
or IL-12-producing vaccine alone. The therapeutic
effectiveness exerted by the gemcitabine plus
IL-12 combination in the MK16 tumour model was
demonstrated by the detection of interferon gamma
(IFNγ) production by spleen cells using ELISPOT
and ELISA test. The highest production of IFNγ was
found in the group treated with gemcitabine plus
IL-12-producing cells. The percentage of myeloid
derived suppressor cells (CD11b+/Gr-1+ cells)
was analyzed three days after administration of
the IL-12-producing vaccine. The lowest percentage
of CD11b+/Gr-1+ was found in the group treated
with the combination of gemcitabine plus IL-12producing
cells. Taken together, we conclude that
IL-12 augments the effectiveness of chemotherapy
of HPV16-associated tumours with gemcitabine
and increases the anti-tumour immune response.
This work was supported by grants No. 301/09/1024 and No.
301/07/1410 from the Grant Agency of the Czech Republic and by
grant of the Clinigene project EU-FP6-NOE No. 018933.