ONO-4007 INDUCES SPECIFIC ANTITUMOR IMMUNITY MEDIATED BY TUMOR-NECROSIS-FACTOR-ALPHA

We investigated the therapeutic effects of ONO-4007, a novel synthetic lipid A derivative with low toxic activities, on transplanted hepatoc ellular carcinoma KDH-8 in WKAH rats. ONO-4007 brought about complete cures in about 60% of rats bearing tumor necrosis factor (TNF)-alpha-s ensitive KDH-8 cells, whereas no complete cure was observed in rats be aring cKDH-8/11 which is identical to KDH-8 but a TNF-alpha-resistant cell line, KMT-17 and KEG-1. Then we examined the influence of rabbit anti-TNF-alpha antibody on the therapeutic effects of ONO-4007 against the TNF-alpha-sensitive KDH-8. The concomitant administration of the rabbit anti-TNF-alpha antibody completely abrogated the therapeutic ef fects of ONO-4007. On the other hand, rechallenged tumor cells of both KDH-8 and cKDH-8/11 were completely rejected in the rats cured of KDH -8 tumor, although no rejection of KEG-1 was observed. Moreover, Winn assay, i.e. the tumor cell neutralizing assay, indicated that CD4(+) T cells were involved in the antigen-specific transplantation resistanc e. These findings suggest that antigen-specific T cell responses are i nvolved in the complete cure of tumors after the treatment with ONO-40 07, although its therapeutic effect is initiated by TNF-alpha. [(C) 19 98 Rapid Science Ltd.].