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Weiner LM , Li W , Holmes M , Catalano RB , Dovnarsky M , Padavic K , Alpaugh RK
Phase-I Trial of Recombinant Macrophage-Colony-Stimulating Factor and Recombinant Gamma-Interferon - Toxicity, Monocytosis, and Clinical Effects
Cancer Research. 1994 Aug 1;54(15) :4084-4090
PMID: ISI:A1994NZ24600025   
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Macrophage colony-stimulating factor (M-CSF) is a known inducer of proliferation and differentiation of cells of the mononuclear phagocyte lineage, and gamma-interferon (gamma-IFN) is a known activator of mononuclear phagocytes. In this Phase I clinical trial of combined therapy with M-CSF and gamma-IFN, 36 patients were treated with 14-day continuous infusions of M-CSF at doses ranging from 10 to 140 mu g/kg/day. In all but five patients, gamma-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/m(2)/day. A total of 73 courses of M-CSF and 66 courses of gamma-IFN were administered. The maximally tolerated dose combination was 120 mu g/kg/day M-CSF, 0.1 mg/m(2)/day gamma- IFN. The addition of gamma-IFN did not alter the maximally tolerated dose of M-CSF therapy, although some additional toxicities were noted with combined therapy. At the 140-mu g/kg/day M-CSF dose level, grade 4 thrombocytopenia occurred in 2 of 3 patients, with a median platelet count nadir of 26,000/mm(3) 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 mu g/kg/day, approaching 3-fold elevations at the 100-mu g/kg/day M-CSF dose level. The induction of monocytosis was correlated with the development of thrombocytopenia. At the conclusion of therapy with 100 mu g/kg/day M-CSF, 0.1 mg/m(2)/day gamma-IFN, 78% of peripheral blood monocytes expressed the low affinity Icy receptor for aggregated immunoglobulin, Fc gamma RIII (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 mu g/kg/day within the maximally tolerated dose range, gamma-IFN did not modulate the ability of M-CSF to reliably induce peripheral blood monocytosis. This study shows that M-CSF and gamma-IFN therapy induces the proliferation and differentiation of circulating mononuclear phagocytes.
English Article NZ246 CANCER RES