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Influence of varying doses of granulocyte-macrophage colony-stimulating factor on pharmacokinetics and antibody-dependent cellular cytotoxicity

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Abstract

Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) is used in immunotherapy for correction of neutropoenia. The optimal dose for activation of immune functions and the pharmacokinetics following repeated administrations is less analysed in depth. In this study, the pharmacokinetics and the effects on haematological functions and antibody-dependent cellular cytotoxicity (ADCC) were analysed in 50 patients with metastatic colorectal carcinoma receiving monoclonal antibody based therapy in combination with Escherichia coli-derived GM-CSF (molgramostim) administered s.c. once daily for 10 days every month over a period of 4 months. Thirty-three patients received a GM-CSF dose of 200–250 μg/m2/day. Seventeen patients received GM-CSF doses varying between 65 and 325 μg/m2/day in the different treatment cycles. Serum GM-CSF concentration was measured (ELISA) before and 3–4 h after (peak serum concentration) GM-CSF administration days 1, 5 and 10. Prior to therapy, GM-CSF was not detectable in serum. Following repeated daily administrations, the peak serum concentration of GM-CSF gradually decreased on days 5 and 10 compared to day 1 (P < 0.05). During a 10-day treatment cycle, the total number of leukocytes, neutrophils, eosinophils, monocytes and lymphocytes increased. A dose-dependent increment in total white blood cell count and neutrophils was observed. The total numbers of GM-CSF receptor (α-subunit) expressing cells (granulocytes and monocytes) increased significantly during treatment while a transient decline in expression intensity was observed at day 5, suggesting a receptor-mediated removal of GM-CSF as a mechanism for the elimination of GM-CSF from circulation. ADCC of peripheral mononuclear cells was decreased at day 10 compared to baseline. An inverse correlation between the dose and ADCC was noted. The data might indicate that high doses of GM-CSF may have a negative impact on ADCC.

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Acknowledgements

This study was supported by grants from the Swedish Cancer Society, Cancer Society in Stockholm, King Gustav V Jubilee Fund, Cancer and Allergy Foundation, Torsten and Ragnar Söderberg Foundation and Karolinska Institute Foundations. We thank Lena Virving, Birgitta Hagström and Juan Castro for skillful technical assistance and Leila Relander for excellent typing of the manuscript.

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Authors and Affiliations

  1. Department of Oncology and Pathology (Radiumhemmet), Cancer Centre Karolinska, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden

    Maria Liljefors, Håkan Mellstedt & Jan-Erik Frödin

  2. Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital Solna, Stockholm, Sweden

    Maria Liljefors, Håkan Mellstedt & Jan-Erik Frödin

  3. Department for Cancer Epidemiology, Karolinska University Hospital Solna, Stockholm, Sweden

    Bo Nilsson

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  1. Maria Liljefors
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Correspondence to Håkan Mellstedt.

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Liljefors, M., Nilsson, B., Mellstedt, H. et al. Influence of varying doses of granulocyte-macrophage colony-stimulating factor on pharmacokinetics and antibody-dependent cellular cytotoxicity. Cancer Immunol Immunother 57, 379–388 (2008). https://doi.org/10.1007/s00262-007-0377-1

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