INDUCTION OF ANTITUMOR IMMUNITY BY SUICIDE-GENE-MODIFIED HPV-16-TRANSFORMED HAMSTER-CELLS

From K3/II, which is a highly oncogenic HPV16-transformed Syrian hamst er cell line, thymidine-kinase(TK)-less cells, denoted B 49, were deri ved. B49 cells were transfected by a plasmid containing the herpes sim plex-virus TK gene (HSV TK) and several sub-lines expressing this gene were isolated from the transfected cultures. The HSV TK+ cells were h ighly sensitive to ganciclovir (GCV) and other anti-viral substances w hose inhibitory effect is based on their phosphorylation by HSV TIC On e of the cell lines, denoted KL1/6, exhibited relatively high stabilit y of the HSV TKf phenotype and was used in subsequent experiments. Whe n KL1/6 cells were co-cultivated in the presence of GCV with various o ther cell lines of hamster, mouse or monkey origin, the by-stander eff ect (BE) was observed. GCV treatment of hamsters prevented development of tumours after the administration of KL1/6 cells but not K3/II cell s. The treatment of animals with already established KL1/6-induced tum ours resulted in tumour regression in all instances, but complete regr ession was observed only in animals carrying small tumours. The BE of KL1/6 cells on K3/II cells was also seen in vivo. In addition, concomi tant immunity was observed in animals simultaneously inoculated with K L1/6 cells and K3/II cells at 2 separate sites of the body. This effec t was evident not only in animals in which KL1/6 tumours developed, bu t also in those in which tumour outgrowth was prevented by GCV treatme nt. In other experiments it was demonstrated that one KL1/6 + GCV trea tment resulted in partial resistance, 2 such treatments in complete re sistance to the challenge with K3/II cells. (C) 1998 Wiley-Liss, Inc.