1230P - Targeting myeloid-derived suppressor cells and T cells: Combination treatment with MTL-CEBPA and PD-1 antibody in a mouse syngeneic CT26 model

Abstract

BackgroundMTL-CEBPA is a myeloid modifier saRNA therapy which upregulates CEBPalpha and is the first saRNA therapy to enter clinical trials. We hypothesise that targeting myeloid-derived suppressor cells (MDSCs) with MTL-CEBPA and T cells with PD-1 antibody may enhance the therapeutic efficacy of each individual therapy. MethodsCT26 syngeneic mice were randomised into 4 groups (n=10) and treated with vehicle control, PD-1 antibody (10mg/kg, i.p., d1/d4 schedule, 7 doses), MTL-CEBPA (5mg/kg, i.v, d1/d3 schedule, 7 doses) or a combination of both compounds. RNA extracted from tumours at termination were analysed by Nanostring IO360 and myeloid innate immunity codeset. ResultsAt 21 days of treatment, the average tumonur volumes in the MTL-CEBPA/PD-1 treated group were smallest and 3.0-fold smaller (p<0.05) than the closest group. Nanostring analysis shows that only tumours from the combination group display significant increase in tumour infiltrating lymphocytes (2.4-fold versus control, p<0.05) and pathway analysis reveals that 5 of the 6 tumours in this group have the highest increase in expression of genes for various immune pathways including lymphoid compartment, antigen presentation and cytotoxicity when compared against all tumour samples. At the level of individual genes, we observed synergy in gene expression changes in combination of PD-1 antibody and MTL-CEBPA as illustrated in table.Table1230P Individual genes that show synergistic effect. Calcilated as fold versus vehicle control. * p<0.05 and ** p<0.01TablePD-1 mAbMTL-CEBPACombinationCd41.811.537.63 (*)Cd8a1.291.223.68 (*)Cd8b11.51 (*)1.024.62 (*)Cd3e1.221.114.48 (*)Gzma1.381.142.39 (*)Gzmb1.761.51 (*)3.86Ifng2.201.244.71 (**)Vegfa1.181.040.94Mki671.000.84 (**)0.62 (**) ConclusionsThe study indicates enhanced anti-tumour activity when combining MTL-CEBPA with PD-1 antibody in the immunocompetent mouse CT26 colorectal cancer model. The combination treatment appears to result in increased penetration of TILs through modulation of immune activity in the tumour microenvironment. Legal entity responsible for the studyMiNA Therapeutics. FundingMiNA Therapeutics. DisclosureM. Sodergren: Research grant / Funding (self): MiNA Therapeutics. C. Tan: Honoraria (self), Research grant / Funding (self): MiNA Therapeutics. V. Reebye: Honoraria (self), Leadership role, Research grant / Funding (self): MiNA Therapeutics. R. Habib: Honoraria (self), Leadership role: MiNA Therapeutics. D. Blakey: Honoraria (self), Leadership role: MiNA Therapeutics. N. Habib: Leadership role, Research grant / Funding (self): MiNA Therapeutics.