Local cytokine treatment of HPV16-associated tumours results in inhibitionof their lung metastases

Experiments were designed to examine whether local cytokine therapy of subc utaneous (s.c.) tumours results in inhibition of their lung metastases. Mod erately immunogenic, major histocompatibility complex (MHC) class I and II negative, B7 negative, metastasizing murine carcinoma MK16 transplantable i n syngeneic mice was obtained by co-transfection of human papilloma virus t ype 16 (HPV16) E6/E7 and activated H-ras oncogene plasmid DNA into C57BL/6 kidney cells. After s.c. transplantation of the malignantly converted MK16 cells, the majority of the transplanted mice developed lung metastases; the number and size of the lung metastases increased with the increasing size of the s.c. tumour. Therapy of 5-day MK16 tumours by peritumoral administra tion of recombinant interleukin-2 (IL-2) and recombinant interleukin-12 (IL -12) inhibited growth of the s.c. MK16 tumour transplants and reduced the n umber of MK16 lung metastases. To investigate the antimetastatic effect of IL-2 and IL-12 in a clinically more relevant setting, surgical minimal resi dual tumour disease was utilized. Subcutaneously growing MK16 carcinomas, 8 -12 mm in diameter, were removed on day 30 and the operated mice were injec ted with IL-2 or IL-12 on days 35-39 and 42-46 at the site of the operation . Treatment with IL-2 significantly reduced the percentage of MK16 tumour r ecurrences as well as the number of lung metastases, whereas the effect of IL-12 was substantially weaker and statistically insignificant.