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

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 microg/m(2)/day. Seventeen patients received GM-CSF doses varying between 65 and 325 microg/m(2)/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 (alpha-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.

Granulocyte-Macrophage Colony Stimulating Factor Exerts Protective and Immunomodulatory Effects in Cortical Trauma

“…The work parallels prior pre-clinical studies that have shown that Il-10 expressing T-cells peak at seven days following experimental stroke (Liesz et al, 2013) and human pharmacodynamics studies have shown that GM-CSF induces a T cell response over prolonged periods of administration (Liljefors et al, 2008). Seven days post-injury, CCI produced cortical tissue loss at and around the impact site in all animals (Fig 1a).…”

Innate Immune Function and Mortality in Critically Ill Children With Influenza

“…In these studies, augmentation of innate immune function occurred without worsening systemic inflammation. Although our nonsurvivors had higher serum levels of GM-CSF than survivors, these levels (median 52 pg/mL) were far below the peak serum concentrations seen in patients undergoing GM-CSF therapy for reconstitution of bone marrow after chemotherapy, which are typically >1000 pg/mL (54). Some authors have advocated for immunosuppressive therapies in the setting of severe influenza, including glucocorticoids or peroxisome proliferator-activated receptor-γ agonists (19, 21).…”

Induction of IgM, IgA and IgE Antibodies in Colorectal Cancer Patients Vaccinated with a Recombinant CEA Protein

“…Blood were drawn for immunological analyses at pre-immunization and once monthly at 1, 2, 4, 6, 7, 9, 12, 15, 18, 21, 24, 30 and 36 months. Due to the shortage of samples only the following time points were used for the serological assays: preimmunization, month 1, 2, 4, 6,9,12,15,18,24, and 36.…”

“…ADCC was performed as previously described [24]. In brief, cell lines were labeled with 2.8 MBq sodium 51 Cr (PerkinElmer Inc. Wellesley, MA, USA) for 2 h. After 3 washings with DMEM medium (Invitrogen, Carlsbad, CA, USA) 10,000 cells in 100 μl medium were added to each roundbottomed microtiter well (Nunc) and Ficoll-isopaque isolated PBMC of healthy donors (n04) as effector cells to yield target:effector cell ratios of 1:25 and 1:50 to a final volume of 200 μl.…”