PO-417 Anti-tumoural effects of IL-15 and CD40 stimulation as a novel combination immunotherapy for pancreatic cancer

Abstract

IntroductionPancreatic cancer (PC) is the 3rd deadliest cancer worldwide with the lowest 5 year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to expectations. Within the tumour microenvironment, a strong desmoplastic reaction occurs and is held responsible for the formation of a protective shield. Tackling this stromal shield is needed to overcome treatment resistance. CD40 stimulation has already demonstrated moderate anti-tumour responses in PC, including some anti-stroma effects. We have shown that interleukin (IL)−15 stimulated NK cells are capable of tackling both tumour as well as the surrounding desmoplastic stroma. Therefore, we explored a novel combination immunotherapy consisting of an agonistic anti-CD40 monoclonal antibody and IL-15 in two mouse models of PC.Material and methodsC57BL/6 mice bearing subcutaneous Panc02 or KPC tumours were treated over a two-week period with IL-15 and anti-CD40, either as stand-alone or combination therapies. Tumour kinetics and survival were monitored. To investigate therapeutic mechanisms, experiments depleting different immune cell populations were performed. Re-challenge experiments were executed to check for immune memory induction. Tumour infiltrating lymphocytes are being characterised using flow cytometry and immunohistochemistry.Results and discussionsThe combination treatment of IL-15 and anti-CD40 caused a distinct reduction of tumour growth rates in comparison with single agent treatments. Moreover, mice receiving the combination treatment showed significantly increased survival, with 60%–80% of the mice being completely tumour free. Depletion studies revealed both CD8+ T cells and NK cells are mechanistically involved in the anti-tumour effect of this novel treatment. Re-challenge experiments also showed that immune memory was induced. Flow cytometry experiments and immunohistochemistry experiments are being performed to provide more details on the phenotype of the tumour infiltrating lymphocytes and their spatial distribution within the tumour.ConclusionTo our knowledge, this is the first study demonstrating that combination of IL-15 and anti-CD40 exhibits a profound anti-tumour response in two mouse models of PC resulting in prolonged survival and even total eradication of >60% of PCs. These data provide a solid proof of principle to advance with this combination strategy to a phase I clinical trial.