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Proffered Paper session - Basic Science

4O - Novel Dendritic Cell based Immunotherapy for Advanced Cancer

Date

28 Sep 2019

Session

Proffered Paper session - Basic Science

Topics

Basic Science

Tumour Site

Presenters

Aanchal Kaur

Citation

Annals of Oncology (2019) 30 (suppl_5): v1-v24. 10.1093/annonc/mdz238

Authors

A.P. Kaur1, J. Adhikaree2, H. Franks3, P. Patel2, A.M. Jackson4

Author affiliations

  • 1 Academic Oncology, University of Nottingham, School of Medicine, NG7 2RD - Nottingham/GB
  • 2 Oncology, Nottingham University Hospitals NHS Trust-City Hospital Campus, NG5 1PB - Nottingham/GB
  • 3 Oncology Department, Nottingham University Hospitals NHS Trust-City Hospital Campus, NG5 1PB - Nottingham/GB
  • 4 Academic Oncology, University of Nottingham, NG5 1PB - Nottingham/GB

Resources

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Abstract 4O

Background

Immune-checkpoint inhibitors (ICI) such as Ipilumimab and Nivolumab have made long-term survival a real possibility for advanced cancer patients. Despite the success, only a proportion of patients receiving ICI show meaningful clinical benefit. Developing a more personalized treatment strategy using patient’s own immune cells may be a promising approach for treating non-responding patients. Natural circulating dendritic cells (nDC) such as CD1c+ DC (cDC2) subset and plasmacytoid DC (pDC) are essential for efficient activation of immune responses after ICI therapy. Thus understanding the condition of these cells in patients and devising new strategies to improve their functions may help improve response to ICI in advanced cancer patients.

Methods

To investigate this we measured the number and phenotype of nDC in 29 advanced cancer patients versus 21 age and gender-matched healthy controls using flow cytometry. We further identified that inhibition of the p38 MAPK pathway using small molecule inhibitors in cDC2 cells increases their immune-stimulatory capacity, measured by functional assays.

Results

The number of pDC were significantly reduced in cancer patients as compared to healthy controls (1221 vs 2843 pDC/mL) (p-value<0.01). Although the number of cDC2 were slightly reduced in cancer patients (4476 vs 5053 of cDC2/mL), a good proportion of patients had sufficient number of DC eligible for a DC-based immunotherapy. Patient cDC2 were immune-suppressed with low secretion of immune-stimulatory cytokines (IL-12) and impaired homing to lymph-nodes. We identified that the p38 MAPK signalling pathway was controlling immune-suppression in cDC2 cells. Inhibiting this pathway restored the secretion of IL-12 in all patients (n = 5), increased the homing of DC to lymph-node chemokines, and prevented them from secreting the immune-suppressive cytokine, IL-10.

Conclusions

The number and phenotype of nDC are suppressed in advanced cancer patients. Inhibition of p38 MAPK can restore the function of patient cDC2 subset. Co-culture of these p38-inhibited cDC2 with pDC further show promising results important for developing advanced DC vaccines. Our study has paved the way for a phase I clinical trial of adoptive transfer of p38-MAPK inhibited cDC2 in 24 advanced cancer patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University of Nottingham.

Funding

University of Nottingham.

Disclosure

All authors have declared no conflicts of interest.

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