The in vivo immunomodulatory effects of recombinant interferon gamma plus recombinant tumor necrosis factor-alfa.

We conducted a phase I study in which an intramuscular injection of interferon gamma (IFN gamma) at 10, 50, or 100 micrograms/m2 was followed 5 minutes later by an intramuscular injection of 10, 50, or 100 micrograms/m2 of tumor necrosis factor-alfa (TNF alpha) at another site every other day for 20 days (10 doses). The addition of TNF alpha to IFN gamma reduced both the magnitude and duration of IFN gamma-mediated effects on peripheral blood monocyte expression of Fc receptors (FcRs) and HLA-DR and production of hydrogen peroxide. This inhibition was related to the dose of TNF alpha. On the other hand, TNF alpha and IFN gamma appeared to have an additive stimulatory effect on the production of neopterin by monocytes. The highest serum levels of neopterin were detected in patients who received the highest doses of both IFN gamma and TNF alpha. Thus, conflicting conclusions regarding the effect of the combination on immune activation are possible. If the activation of peripheral blood monocytes is the appropriate surrogate measure of the immune enhancement of the combination, then the simultaneous administration of IFN gamma and TNF alpha is ineffective, and future attempts to exploit the potential additive or synergistic effects of this combination of cytokines in humans may need to explore sequential administration schemata. On the other hand, if serum neopterin levels are a more reliable index of immune activation, simultaneous administration of 100 micrograms/m2 IFN gamma and 50 micrograms/m2 TNF alpha every other day (the maximally tolerated dose [MTD]) should be used in phase II testing. This dilemma points out the limitations of currently available methods of human immune assessment and the inadequacies in our capacity to gauge what particular immune measure or set of measures predict for in vivo antitumor effects.