Elevated levels of adenosine found in the tumor microenvironment have been highlighted as a potential mechanism contributing to the restricted efficacy of immune checkpoint inhibitors. While the advent of these inhibitors has brought significant benefit to patients with cancer, there is still significant unmet need even in disease indications for which these agents are approved. Adenosine has an immune-suppressive effect in tumors, and pre-clinical and early clinical evidence indicates that antagonists of the GPCR family of adenosine receptors are able to relieve that suppression and restore anti-tumor immune cell activity. EXS21546 is a non-furan, selective antagonist of the A2A receptor with low brain penetration. Using EXS21546, we show that activity at the A2A receptor is sufficient for complete restoration of T-cell function in the presence of high concentrations of adenosine analogue. Translational studies with EXS21546 have been undertaken using patient samples to better understand its activity in signaling and disease-relevant endpoints. We will present data characterizing the activity of EXS21546 ex vivo in patient-derived whole blood samples. Interrogation of primary cancer cells from pancreatic and lung cancer patients treated with EXS21546 ex vivo by phenotypic image-based screening, demonstrated that EXS21546 reduces the relative fraction of viable cancer cells while inducing an expansion of the viable CD8+ T cell fraction in the presence of high concentrations of an adenosine analogue. Together, these data indicate the potential for EXS21546 may have a role in cancer therapy. EXS21546 has completed pre-IND studies in preparation for initiation of first-in-human clinical studies.
Andrew Payne, Pierre Fons, Isabella Alt, Joost Van Ham, Christina Taubert, Andy Bell, Stephanie Versluys, Florie Bertrand, Virgile Visentin, Emilie Mirey, Emilie Pelissier, Michael Paillasse, Sabrina Pagliarusco, Gregory Vladimer, Mark Whittaker. Exscientia Ltd, Oxford, United Kingdom, Evotec, Toulouse, France, Allcyte, Vienna, Austria, Evotec, Verona, Italy, Evotec, Abingdon, United Kingdom
A. Payne: ; Exscientia Ltd. P. Fons: ; Evotec. I. Alt: ; Allcyte. J. van Ham: ; Allcyte. C. Taubert: ; Allcyte. A. Bell: ; Exscientia Ltd. S. Versluys: ; Evotec. F. Bertrand: ; Evotec. V. Visentin: ; Evotec. E. Mirey: ; Evotec. E. Pelissier: ; Evotec. M. Paillasse: ; Evotec. S. Pagliarusco: ; Evotec. G. Vladimer: ; Allcyte. M. Whittaker: ; Evotec.