18P - TKI pazopanib impaires immunostimulatory properties of monocytes: Implication for monocyte-derived DC-based anti-cancer vaccine preparation

Date 05 November 2016
Event ESMO Symposium on Immuno-Oncology 2016
Session Lunch and general poster viewing
Presenter Lenka Zdrazilova Dubska
Citation Annals of Oncology (2016) 27 (suppl_8): viii4-viii17. 10.1093/annonc/mdw527
Authors L. Zdrazilova Dubska1, L. Fedorova2, K. Pilatova3, P. Mudry4, E. Hlavackova4, E. Matoulkova3, L. Flajsarova3, R. Demlova3, D. Valik3, J. Sterba4
  • 1Department Of Pharmacology, Masaryk University Faculty of Medicine, 62500 - Brno/CZ
  • 2Recamo, Masaryk Memorial Cancer Institute, Brno/CZ
  • 3Department Of Pharmacology, Masaryk University Faculty of Medicine, Brno/CZ
  • 4Department Of Pediatric Oncology, University Hospital Brno-Children's Medical Centre, Brno/CZ

Abstract

Aim/Background

We manufacture fully personalized monocyte-derived dendritic cell-based vaccines that are evaluated in investigator-initiated clinical trial „Combined antitumor therapy with ex vivo manipulated dendritic cells producing interleukin-12 in children, adolescents and young adults with progressive, recurrent of primarily metastatic high-risk tumours”. Immunobiological part of quality control (QC) of DC batches revealed variability in immunostimulatory properties. We analyzed DC parametres within the context of patients medical history and explore the effect of anti-cancer compound on monocyte functional properties.

Methods

DC-based vaccine, called MyDendrix, was manufactured under GMP: mononuclear cells collection by leukapheresis; elutriation of monocytes; DC differentiation with IL-4 and GM-CSF; charging of DC with autologous tumor lysate antigens; short maturation with LPS and IFNγ; aliquoting and cryopreservation. QC included IL-12, IL-10 production, surface markers expression, stimulation of allogenic and autologous T-lymphocytes. QC parametres were evaluated in the context of patients medical history. To assess the impact of pazopanib on the biological functions of monocytes, peripheral blood from pazopanib-treated metastatic renal cancer and controls was ex vivo treated with 10 ng/ml of LPS for 4 h and expression of surface and intracellular molecules was quantified.

Results

Two out of 8 DC-based vaccines i/did not pass the immunobiological QC criteria such as co-stimulatory molecule expresion and IL-12 production, ii/exhibited no stimulatory capability towards autologous T-lymphocytes (while in released vaccines autoMLR ranged from 5 to 37%), iii/were not released for application and iv/were derived from monocytes of patients treated with pazopanib. Pazopanib-treated monocytes had increased CD64 and inhibitory molecule ILT3 expression and exhibited lower capacity to upregulate HLA-Dr upon LPS stimulation.

Conclusions

Stimulatory functions of monocyte-derived DC are modified by pre-leukapheresis anti-cancer treatment. TKI pazopanib-treated monocytes exhibited impaired immunobiological properties relevant to DC stimulatory functions.

Clinical trial identification

EudraCT 2014-003388-39

Legal entity responsible for the study

State Institute for Drug Control

Funding

Ministry of Education, Youth and Sports via large infrastructure project for ACIU (LM2011017) and for CZECRIN (LM2015090)

Disclosure

All authors have declared no conflicts of interest.