IDDF2020-ABS-0166 Novel mirna-based drug CD5–2 reduces liver tumour growth in diethylnitrosamine (DEN)-treated mice by normalising tumour vasculature and altering immune infiltrate

Background Hepatocellular carcinomas (HCC) exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. The normalisation of tumour vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is an oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial specific cadherin. We previously showed CD5-2 normalises tumour vasculature by increasing VE-Cadherin expression (Zhao et al.Cancer Res. 2017). We studied the effect of CD5-2 combined with checkpoint inhibition on liver tumour growth, vasculature and immune infiltrate in the DEN-induced mouse model. Methods DEN was given (25 mg/kg intraperitoneally) to male C57BL/6 mice at postnatal day 14. CD5-2 (30 mg/kg intravenously fortnightly) and/or anti-PD1 antibody (250µg intraperitoneally every 4 days) with their respective controls (4 groups) were given to the mice from age 7-months until harvest at age 9-months. Livers from treated and untreated mice were analysed. Results We analysed human HCC data from The Cancer Genome Atlas and found high miR-27a and low VE-Cadherin were both associated with poorer survival (Log-Rank P=0.02 and P=0.01, respectively). In untreated mice, miR-27a expression was significantly increased in tumours compared to adjacent normal tissue (figure 1A). Mice treated with CD5-2 + anti-PD1 antibody had significantly smaller tumours (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice (figure 1B). Histologically, tumours in the CD5-2 + anti-PD1 group exhibited a more favourable immune infiltrate (significantly higher CD3+ and CD8+ T-cells and lower Ly6G+ neutrophils) compared to tumours in other groups (figure 1C). Tumours in CD5-2-treated mice had less leaky vasculature (as measured by Dextran beads extravasation) and less tumour hypoxia (carbonic anhydrase IX staining) compared to non-CD5-2-treated mice (figure 1D). Conclusions In the DEN model, CD5-2 normalised tumour vasculature and reduced tumour hypoxia. CD5-2 plus anti-PD1 antibody reduced tumour size possibly by altering immune infiltrate to being immunosupportive. The combination of vascular normalisation by targetting VE-Cadherin and immunotherapy is a promising novel approach to treat HCC.