Effects of Parenteral Recombinant Human Macrophage Colony-Stimulating Factor on Monocyte Number, Phenotype, and Antitumor Cytotoxicity in Nonhuman Primates

• Published in: Blood Vol. 75; no. 10; pp. 2042 - 2048
• Main Authors: Munn, David H., Garnick, Marc B., Cheung, Nai-Kong V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.1990
• Subjects: Animals; Antibody-Dependent Cell Cytotoxicity - drug effects; Cell Count - drug effects; Colony-Stimulating Factors - pharmacology; Leukocytes - drug effects; Macaca fascicularis; Macrophage Colony-Stimulating Factor; Male; Monocytes - drug effects; Phenotype; Recombinant Proteins - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V75.10.2042.2042

Recombinant human macrophage colony-stimulating factor (rhM-CSF) was given to cynomolgus monkeys by continuous intravenous infusion or subcutaneous injection, at a dose of 50 to 100 μg/kg/d in repetitive 14-day cycles. Starting within 24 to 48 hours of initiation of rhM-CSF. there was a progressive increase in the number of circulating monocytes, from a baseline of 811 ± 253 cells/μL to a peak of 3.495 ± 712 cells/μL on day 5 to 7. Many of these cells were large, granular, and extensively vacuolated. The expanded cell population expressed HLA-DR, LFA3, CD11 b (904), and CD14 (MY4), and was 77% CD16 (FcRIII) positive by two-color cytofluorometry. In functional assays, fresh monocytes showed little cytotoxicity against cultured human melanoma cells (SKMel-1), with or without prior rhM-CSF treatment. However, after 3 days of in vitro culture in rhM-CSF. monocytes from treated animals mediated efficient antibody-dependent cytotoxicity (ADCC) against SKMel-1 using the murine monoclonal antibody 3F8 (lgG3, anti-ganglioside GD2). Under the same conditions, monocytes from control animals showed little ADCC (17% versus 82%, P < .05). Antitumor cytotoxicity in the absence of antibody was less efficient and was not significantly different between the two groups. There was a mild decrease in platelet count during rhM-CSF treatment. without clinical symptoms. No abnormalities of serum biochemical parameters were seen. We conclude that parenteral rhM-CSF increases the number of circulating monocytes in nonhuman primates, and that these monocytes mediate increased antitumor ADCC after a brief period of in vitro differentiation. This study has implications for the design of possible future clinical trials combining antitumor monoclonal antibodies and rhM-CSF.