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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

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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.

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Acknowledgments

This research was funded by BRIGHT: Better Research Into Gastrointestinal cancer Health and Treatment, registered charity number 1064857. The TeloVac Trial was funded by Cancer Research UK and KAEL-Gemvax.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. University of Surrey, Guildford, UK

    Nicola E. Annels, Rachel F. Gabitass & Hardev Pandha

  2. Liverpool Cancer Research UK Centre, Liverpool, UK

    Victoria E. Shaw & John P. Neoptolemos

  3. School of Cancer Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK

    Lucinda Billingham & Gary Middleton

  4. Addenbrookes Hospital, Cambridge, UK

    Pippa Corrie

  5. Belfast City Hospital, Belfast, Northern Ireland, UK

    Martin Eatock

  6. Christie Hospital, Manchester, UK

    Juan Valle

  7. The Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK

    David Smith

  8. Weston Park Hospital, Sheffield, UK

    Jonathan Wadsley

  9. Royal Marsden Hospital, Sutton, UK

    David Cunningham

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  1. Nicola E. Annels
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  2. Victoria E. Shaw
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  3. Rachel F. Gabitass
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  4. Lucinda Billingham
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  10. David Cunningham
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  11. Hardev Pandha
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  12. John P. Neoptolemos
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  13. Gary Middleton
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Corresponding author

Correspondence to Gary Middleton.

Additional information

Nicola E. Annels and Victoria E. Shaw have contributed jointly to this work.

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Annels, N.E., Shaw, V.E., Gabitass, R.F. et al. 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. Cancer Immunol Immunother 63, 175–183 (2014). https://doi.org/10.1007/s00262-013-1502-y

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  • DOI: https://doi.org/10.1007/s00262-013-1502-y

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