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