28P - Optimising dendritic cell vaccines for adoptive therapy in glioblastoma

Date 20 November 2015
Event ESMO Symposium on Immuno-Oncology 2015
Session Welcome reception and general Poster viewing
Topics Cancer Immunology and Immunotherapy
Central Nervous System Malignancies
Presenter Jason Adhikaree
Citation Annals of Oncology (2015) 26 (suppl_8): 5-14. 10.1093/annonc/mdv514
Authors J. Adhikaree1, P. Bilimoria2, C. Televantos2, L. Hogan2, A. Jackson2, P. Patel2
  • 1Cancer And Stem Cell Division, University of Nottingham, NG51PB - Nottingham/UK
  • 2Cancer And Stem Cell Division, University of Nottingham, Nottingham/UK

Abstract

Aim

Glioblastoma (GBM) has a poor prognosis and limited treatment options. GBM evades immune detection and thus antigen presenting dendritic cell (DC) vaccines are an attractive therapeutic option. However, in-vitro generated autologous monocyte-derived DCs have proved of limited efficacy in early phase trials and require optimisation. We discuss the feasibility of alternative circulating DC subsets through novel enumeration and functional data in GBM patients. We support this with in-vitro data of healthy adults Myeloid type 1 DCs (MDC1) exposed to dexamethasone (DEX) and GBM tumour lysate (TL). Finally, we aimed to optimise MDC1 function through manipulation of mitogen activated protein kinase pathway (MAPK) p38, known to control cytokine secretion.

Methods

9-parameter whole-blood flow cytometry was used to measure the abundance of circulating DC (MDC1, myeloid type 2 –MDC2, Slan DC and plasmacytoid DC –pDC) of both GBM patients (n = 16) and age matched healthy controls (n = 14). Patients were unselected to represent the clinical breadth of disease status and standard therapies. MDC1 were isolated from GBM patients (n = 5) using magnetic bead selection of CD1c+ cells from peripheral blood and matured ex-vivo. Likewise healthy volunteers MDC1s were isolated and exposed to GBM tumour lysate (n = 9) and DEX (n = 8). Finally p38 inhibitor – p38i (BIRB0796) was added to the aforementioned conditions. IL-12, which polarises a T helper type 1 cell (Th1) response, and immunosuppressive IL-10 levels were measured by ELISA.

Results

Only pDC were significantly reduced compared to age matched control but not MDC1, MDC2 or Slan DCs, despite a heavily treated patient group. Cytokine secretion of IL-12 and IL-10 were significantly decreased in MDC1s from GBM patients compared to healthy controls. Likewise healthy volunteers' MDC1's secretion of IL-12 was decreased when exposed to TL and DEX, while IL-10 increased when exposed to TL. This unfavourable profile was reversed by the p38i.

Conclusions

MDC1 are available in sufficient numbers to consider novel adoptive transfer in cancer vaccines for GBM patients. Functionally GBM patients' MDC1s secrete low IL-12, unfavourable for anti-cancer response, which may be due to DEX or tumour. A p38i can reverse this and thus a potential vaccine adjunct.

Clinical trial identification

Disclosure

All authors have declared no conflicts of interest.