Phase I Trial of Recombinant Macrophage Colony-stimulating Factor and Recombinant γ-Interferon: Toxicity, Monocytosis, and Clinical Effects

Macrophage colony-stimulating factor (M-CSF) is a known inducer of proliferation and differentiation of cells of the mononuclear phagocyte lineage, and γ-interferon (γ-IFN) is a known activator of mononuclear phagocytes. In this Phase I clinical trial of combined therapy with M-CSF and γ-IFN, 36 patients were treated with 14-day continuous infusions of M-CSF at doses ranging from 10 to 140 µg/kg/day. In all but five patients, γ-IFN was administered by daily s.c. injection on days 8–14 of the M-CSF infusion at doses of 0.05 or 0.1 mg/m2/day. A total of 73 courses of M-CSF and 66 courses of γ-IFN were administered. The maximally tolerated dose combination was 120 µg/kg/day M-CSF, 0.1 mg/m2/day γ-IFN. The addition of γ-IFN did not alter the maximally tolerated dose of M-CSF therapy, although some additional toxicities were noted with combined therapy. At the 140-µg/kg/day M-CSF dose level, grade 4 thrombocytopenia occurred in 2 of 3 patients, with a median platelet count nadir of 26,000/mm3 after 7–10 days of M-CSF infusion. At this dose level, there was one reversible grade 3 hepatic toxicity, and one grade 3 exacerbation of underlying chronic obstructive lung disease. Peripheral blood monocytosis was observed at all M-CSF dose levels exceeding 40 µg/kg/day, approaching 3-fold elevations at the 100-µg/kg/day M-CSF dose level. The induction of monocytosis was correlated with the development of thrombocytopenia. At the conclusion of therapy with 100 µg/kg/day M-CSF, 0.1 mg/m2/day γ-IFN, 78% of peripheral blood monocytes expressed the low affinity Fcγ receptor for aggregated immunoglobulin, FcγRIII (CD16), and CD14 was expressed by only 36% of the cells. This phenotype has been shown previously to be associated with cellular activation. In contrast, 35% of monocytes from patients treated with M-CSF therapy alone at the same dose expressed CD16 and 88% expressed CD14. A partial clinical response was noted in a patient with metastatic renal cell carcinoma, and minor clinical responses were observed in patients with a diffuse/follicular lymphoma, metastatic renal cell carcinoma, and metastatic thymoma. At M-CSF doses exceeding 20 µg/kg/day within the maximally tolerated dose range, γ-IFN did not modulate the ability of M-CSF to reliably induce peripheral blood monocytosis. This study shows that M-CSF and γ-IFN therapy induces the proliferation and differentiation of circulating mononuclear phagocytes.