74P - Effect of Ciclopirox Olamine in immunotherapy effect by stimulating immunogenic cell death in pancreatic cancer (74P)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Palliative and Supportive Care
Presenter Chrysovalantou Mihailidou
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors C. Mihailidou1, P. Papakotoulas2, D. Schizas3, A. Papalampros3, M. Vailas3, E. Felekouras3, T. Liakakos3, A. Papavassiliou1, M.V. Karamouzis4
  • 1Department Of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 - Goudi/GR
  • 22nd Department Of Medical Oncology, Theagenion Hospital, 54007 - Thessaloniki/GR
  • 3First Department Of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 - Goudi/GR
  • 4Department Of Biological Chemistry & First Department Of Internal Medicine, Laikon General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 - Goudi/GR

Abstract

Background

Ciclopirox Olamine (CPX) is an antifungal agent that has displayed anti-neoplastic activity in solid tumors. Antifungal agents appear to have immunomodulatory effects. These prompted us to assess the antitumor effect of CPX alone and in combination with anti-PD-1 antibodies Pembrolizumab (P), Nivolumab (N) and/or anti-CTL-4 antibody Ipilimumab (I), in a pancreatic cancer xenograft mouse model.

Methods

We assessed the in vivo anti-tumor action of CPX alone and in combination with immunoglobulin G (IgG) or (P) or (N) and/or (I), in C57BL/6 mice (n = 60) bearing tumor mouse cell line Panc02. On day 15, following a hemisplenectomy, livers and spleens were collected for flow cytometry analysis (FACS) of infiltrating lymphocytes (TILs). We also assessed PD-L1 expression of tumor cells. Mouse IFNγ enzyme-linked immunosorbent assay was used to examine IFNγ production by CD8+T cells in splenocytes and TILs. A Kaplan-Meier method was conducted and a log-rank test was applied.

Results

We showed that CPX significant upregulated PD-L1 expression in tumors and microenvironment compared to anti-PD-1 or anti-CTL-4 antibodies which exhibited minor PD-L1 expression. Triple combination [(CPX with (P) or (N) plus (I))] robustly increased effector CD4+, CD8+ T cells, dramatically decreased CD4+CD25+Foxp3+ regulatory T cells (Tregs) and exhibited significant IFNγ production in CD8+T cells compared to monotherapy [(IgG) or (P) or (N) or (I) or CPX)] and to dual combination [CPX with (IgG) or (P) or (N) or (I)] within the tumor microenvironment. A trend towards enhanced survival was observed with triple combination therapy (OS:91 days) compared to CPX (69 days, p = 0.13) or to (P) or (N) or (I) (approximately OS: 39 days, p = 0.33) or to (I) plus (P) or (N) therapy (OS:52 days, p = 0.225) vs control (IgG) (OS:21 days). The triple combination therapy cured a larger percentage of mice (75%) compared to CPX (38.5%), (P)(12,75%) or (N) (13%) or (I) (20%) single agent or to anti-PD-1 plus (I) combination (22%).

Conclusions

Our findings demonstrate that the triple combination (anti-PD-1 with anti-CTL-4 plus CPX) deplete Tregs and increase proliferation of CD8+ and CD4+. This strategy may be used to overcome immunosuppressive resistance in pancreatic cancer.

Clinical trial identification

Legal entity responsible for the study

Karamouzis Michalis

Funding

None

Disclosure

All authors have declared no conflicts of interest.