Differential immunologic and microRNA effects of 2 dosing regimens of recombinant human granulocyte/macrophage colony stimulating factor.
Recombinant human (rh) granulocyte/macrophage colony stimulating factor (GM-CSF) has demonstrated antitumor immunologic activity in prostate and other cancers. Dosing has been empiric, and biomarkers of effect have not been established. Eight patients with biochemical relapse of prostate cancer were randomized into group A, in which they received rhGM-CSF at 250 µg/m days 1-14 of a 28-day cycle, and 8 were randomized into group B, in which they received 250 µg 3 times a week continuously. Blood dendritic cell (DC), immune suppressor cell, cytokine, and microRNA (miR) levels were examined using flow cytometric, enzyme-linked immunosorbent, and/or polymerase chain reaction-based assays. Group A had greater increases in myeloid DC and in granulocyte and monocytes. In croup B, plasmacytoid DC decreased. In group A, DC production of interleukin-12 relative to interleukin-10 decreased; this ratio increased in group B. Increases in myeloid-derived suppressor cells were observed in both the groups with increases greater in group A. Increases in regulatory T cells and in serum tumor necrosis and vascular endothelial growth factors were only observed in group A. Serum miR-155 decreased in group A. An increase in serum miR-223 and a decrease in miR-125b and miR-146a were observed in group B. The dosing of rhGM-CSF influences immune and miR effects. More DC activation and fewer myeloid-derived suppressor and regulatory T cells are observed when administered at lower doses intermittently and continuously compared with when administered at higher doses daily and cyclically. Serum levels of miRs are potentially useful biomarkers of these effects.
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA. triozzp@ccf.org
Pierre L
PL
Triozzi
Susan
S
Achberger
Wayne
W
Aldrich
Paul
P
Elson
Jorge
J
Garcia
Robert
R
Dreicer
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D000368:Aged; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D002985:Clinical Protocols; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D054796:Drug Dosage Calculations; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D035683:MicroRNAs / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D054316:Biomarkers, Pharmacological; D016207:Cytokines; D035683:MicroRNAs; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor