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Effects of parenteral recombinant human macrophage colony-stimulating
factor on monocyte number, phenotype, and antitumor cytotoxicity in
nonhuman primates
DH Munn, MB Garnick and NK Cheung
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York,
NY 10021.
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 micrograms/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/microL to a peak of 3,495 +/- 712
cells/microL on day 5 to 7. Many of these cells were large, granular, and
extensively vacuolated. The expanded cell population expressed HLA-DR,
LFA3, CD11b (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 (IgG3, anti-ganglioside GD2). Under the same
conditions, monocytes from control animals showed little ADCC (17% versus
82%, P less than .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.
Volume 75,
Issue 10,
pp. 2042-2048,
05/15/1990
Copyright © 1990 by The American Society of Hematology
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