title: The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer.
abstract: In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42% of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen.
authors.affiliation: University of Surrey, Guildford, UK, n.annels@surrey.ac.uk.
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Annels
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Shaw
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Gabitass
authors.forename: Lucinda
authors.initials: L
authors.lastname: Billingham
authors.forename: Pippa
authors.initials: P
authors.lastname: Corrie
authors.forename: Martin
authors.initials: M
authors.lastname: Eatock
authors.forename: Juan
authors.initials: J
authors.lastname: Valle
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wadsley
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.forename: John P
authors.initials: JP
authors.lastname: Neoptolemos
authors.forename: Gary
authors.initials: G
authors.lastname: Middleton
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D039481:CD11b Antigen / Q000032:analysis; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D019098:Telomerase / Q000276:immunology; D014611:Vaccination; D000093542:Gemcitabine
chemical_list: D039481:CD11b Antigen; C509295:ITGAM protein, human; D015850:Interleukin-6; D010446:Peptide Fragments; D003841:Deoxycytidine; D000069287:Capecitabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C514987:GV1001 peptide; D019098:Telomerase; D005472:Fluorouracil; D000093542:Gemcitabine