PO-425 Combined administration of anti-IL6 and anti-PD-L1 antibodies prevents ketogenic failure, reduces tumour progression, and increases overall survival in an autochthonous murine pancreatic cancer model

Introduction Tumour associated IL-6 downregulates hepatic ketogenesis and thus predisposes to metabolic stress during caloric deficiency. Stress induced glucocorticoids are immune suppressive and can cause failure of cancer immunotherapy. Here, we investigate if this convergence of host metabolism and anti-tumour immunity offers a target for combination therapy with anti-IL-6 and anti-PD-L1 antibodies. Material and methods Combined anti-IL-6 and anti-PD-L1 antibodies (n=13) or equimolar control antibodies (n=12) were administered to mice bearing autochthonous pancreatic cancer (KPC: KrasLSL.G12D/+; p53R172H/+; Pdx-Cre/+). Mice in both study arms received one day 1 dose of gemcitabine. Groups were matched with regard to tumour location and size, body weight, sex, and age. Tumour volumes were monitored by ultrasound. Body weight and food intake were recorded. Histopathological analyses of the liver and tumour were performed and the biochemical profile of mice was characterised. For statistical analysis, differences between groups were determined using an unpaired two-tailed Student’s t-test and were considered significant if p-value≤0.05. Overall survival (OS) was analysed on an intention-to-treat basis using the Kaplan-Meier method and by applying Log-rank (Mantel-Cox) statistics. The correlation between IL-6-JAK-STAT-3 pathway transcription and overall survival of patients from The Cancer Genome Atlas (TCGA) database was examined. Results and discussions Overall survival increased significantly in anti-IL-6 and anti-PD-L1 treated mice compared to control mice (OS: 25 days vs. 11 days, p=0.04). Day 7 measurements revealed delayed tumour progression in the combination immunotherapy cohort (volume increase in%: 118+/-5.4 vs. 138+/-5.6, p=0.02). Detailed metabolic analyses are ongoing. The combined analysis of expression from 55 505 transcripts from 9345 patients using GSEA identified an association between IL-6 pathway transcription and shorter OS (p Conclusion Combination treatment with anti-IL-6 and anti-PD-L1 antibodies significantly increased OS and slowed tumour growth in an autochthonous mouse model of pancreatic cancer. The results of our work provide further justification to explore this treatment combination in patients with cancer associated elevation of IL-6.