Clinical and biologic effects of combination therapy with gamma-interferon and tumor necrosis factor

Tumor necrosis factor (TNF) and gamma-interferon (gamma-IFN) are cytokines with synergistic biologic and antiproliferative effects in vitro and in mouse models. The biologic effects of the combination of TNF and gamma-IFN, however, have not been studied well in humans. A Phase I trial was conducted of TNF and gamma-IFN therapy in 24 patients with advanced malignancies to determine the tolerability of the combination and the biologic effects of TNF and gamma-IFN in vivo. Both TNF and gamma-IFN were administered as 30-minute intravenous infusions three times per week. Doses of TNF ranged from 25 to 100 micrograms/m2; all patients received 100 micrograms/m2 of gamma-IFN. Dose-limiting toxicity consisted primarily of orthostatic hypotension and constitutional symptoms. The maximum tolerated dose level (MTDL) of 50 micrograms/m2 of TNF and 100 micrograms/m2 of IFN-gamma was less than the maximum tolerated dose (MTD) observed in previous Phase I trials of gamma-IFN and TNF alone. Biologic responses were studied in seven patients treated at the MTDL. Serum interleukin-2 receptor levels and neopterin secretion were enhanced significantly 24 hours after therapy (P = 0.002); enhancement of monocyte Fc receptor levels had borderline statistical significance (P = 0.07). With the exception of the mean fluorescent intensity on monocytes positive for histocompatibility antigen HLA-DR (P = 0.03), HLA Class I and II cell surface protein expression was not increased. The combination significantly enhanced indoleamine dioxygenase activity and serum beta 2-microglobulin expression (P less than 0.04) but not 2',5'-oligoadenylate synthetase activity, bactericidal function, or chemiluminescence. These results were compared retrospectively with those observed in previous Phase I trials of gamma-IFN and TNF alone. The combination of TNF and gamma-IFN significantly increased urinary kynurenine levels more than either TNF alone or gamma-IFN alone. Given the limitations inherent in any retrospective analysis, however, the enhancement in the other biologic parameters measured at the MTDL during this trial did not differ significantly from the changes observed at the MTD of either TNF or gamma-IFN alone. It was concluded that the combination of TNF and gamma-IFN, when administered at the MTDL of the combination, does not offer any enhancement in biologic responses over either agent alone.