ONO-4007 induces specific anti-tumor 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 hepatocellular carcinoma KDH-8 in WKAH rats. ONO-4007 brought about complete cures in about 60% of rats bearing tumor necrosis factor (TNF)-alpha-sensitive KDH-8 cells, whereas no complete cure was observed in rats bearing 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 effects 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 resistance. These findings suggest that antigen-specific T cell responses are involved in the complete cure of tumors after the treatment with ONO-4007, although its therapeutic effect is initiated by TNF-alpha.
Matsushita
K
K
Laboratory of Pathology, Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan.
Kobayashi
M
M
Totsuka
Y
Y
Hosokawa
M
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D008050:Lipid A / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D000906:Antibodies; D000970:Antineoplastic Agents; D007375:Interleukin-1; D008050:Lipid A; C086889:ONO 4007; D014409:Tumor Necrosis Factor-alpha