ANTITUMOR-ACTIVITY OF TUMOR-NECROSIS-FACTOR IN COMBINATION WITH INTERFERON-GAMMA IS NOT AFFECTED BY PRIOR TOLERIZATION

Repetitive administration of low doses of tumor necrosis factor (TNF) results in a state of selective tolerance to some of its effects. We h ave demonstrated that tolerance does not impair the therapeutic effica cy of TNF against a syngeneic murine B16BL6 melanoma and allows a comp lete cure. Another study, performed with a distinct tumor model, came to apparently contradictory results. To clarify this, we investigated whether the outcome depended on the tumor type and on the inclusion of interferon-gamma (IFN gamma) in the treatment. Three syngeneic tumors of different histological origin, i.e., B16BL6 melanoma, Lewis lung c arcinoma (LLC) and EL4 lymphoma, were compared in C57BL/6 mice. The an ti-tumor efficacy of TNF against BI6BL6 and EL4 was not impaired in to lerant mice, but the effect of TNF against UC was slightly, though sig nificantly, reduced. Inclusion of IFN gamma in the treatment regimen, however, abolished this difference and resulted in complete cure for a ll 3 tumor systems. As therapeutically optimal doses were lethal in no rmal mice, only tolerance allowed a long-term cure. We conclude that t he influence of tolerance on the anti-tumor activity of TNF as a singl e agent depends on the tumor type; in combination therapy with IFN gam ma, however, tolerance allowed us to dissociate lethal toxicity from a nti-tumor activity, irrespective of the tumor type tested. (C) 1995 Wi ley-Liss, Inc.