56P - Modulation of the tumor microenvironment by the TLR9 agonist EnanDIM and combination with checkpoint inhibition for cancer immunotherapy (56P)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Palliative Care
Palliative and Supportive Care
Presenter Kerstin Kapp
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors K. Kapp1, B. Volz1, D. Oswald1, B. Wittig2, M. Schmidt1
  • 1Translational Research, Mologen AG, 14195 - Berlin/DE
  • 2Foundation Institute Molecular Biology And Bioinformatics, Freie Universitaet Berlin, 14195 - Berlin/DE

Abstract

Background

The EnanDIM® family consists of linear single-stranded DNA molecules containing non-methylated CG-motifs for TLR9 activation and L-deoxyribonucleotides at their 3’-ends to prevent degradation. They initiate a broad activation of the innate and adaptive immune system. The conversion of non-immunogenic (“cold”) tumors into immunogenic (“hot”) tumors, characterized by their T cell infiltration, is a pre-requisite for a response to checkpoint inhibitors. This may be achieved by EnanDIM® due to induced IP-10/CXCL10 secretion. Furthermore, the mode-of-action of EnanDIM® starts upstream of the initiation points of checkpoint inhibitors (CPI). Therefore EnanDIM® likely provides the relevant immune activation required for effectiveness of CPI and thus resulting in an enhanced anti-tumor effect in combination approaches.

Methods

The colon carcinoma model CT26 was used for evaluation of the influence of EnanDIM® on the tumor microenvironment (TME) and to investigate the anti-tumor effect of EnanDIM® in combination with anti-PD-1. In addition, the impact of EnanDIM® on T cell responses was analyzed employing an in vitro assay with human peripheral blood mononuclear cells (PBMC) stimulated with CEF-peptides recognized by recall-antigen-specific CD8+ T cells (CMV, EBV, Flu).

Results

An increased infiltration of T cells, especially CD8+ T cells, into the tumor was associated with an anti-tumor response after intratumoral injection of EnanDIM® in the CT26 model. The moderate anti-tumor effect of aPD-1 was substantially augmented by a combination with EnanDIM®. After stimulation with CEF-peptides, human PBMC were treated with either EnanDIM® or aPD-1. Resulting IFN-gamma secretion was higher for EnanDIM® than for aPD-1 and was further enhanced by the combined treatment.

Conclusions

TLR9 agonist EnanDIM® activated CD8+ cytotoxic T cells and initiated their infiltration into the tumor complementing the mode-of-action of CPI. Indeed EnanDIM® enhanced the limited anti-tumor effect of aPD-1 in a murine colon carcinoma model in vivo. These data show the promising potential of EnanDIM® for the combination with CPI in clinical trials.

Clinical trial identification

Legal entity responsible for the study

Mologen AG

Funding

Mologen AG

Disclosure

K. Kapp, B. Volz, D. Oswald, M. Schmidt: Employee at Mologen AG. B. Wittig: Stock ownership, consults Mologen