Adenosine is the key immunometabolite responsible for immune tolerance in tumors. It is present in normal tissue in low concentrations, having various physiological functions. In the tumor, its concentration increases rapidly, as a result of overexpression of enzymes producing adenosine, additionally enhanced by hypoxia and inflammation. Adenosine inhibits the biological functions of T lymphocytes infiltrating the cancer tissue by binding to the A2A receptor. The affinity to A2B receptor is believed to attenuate the response of dendritic cells and other parts of innate system. Thus blocking simultaneously the effects mediated by both receptor subtypes with dual inhibitor seems to be a viable approach to a single agent cancer immunotherapy or a combination with current immunotherapeutic agents.

We have discovered a novel series of potent and selective A2A/A2B inhibitors. Best compounds present subnanomolar activity in both in vitro recombinant cellular model and in primary human cells. Our antagonists dose-dependently restore the adenosine agonist-impaired functional activity of CD4+ and CD8+ human T-lymphocytes (cytokine release assays). We observe also the relieve of adenosine-related suppression in NK cells cytotoxicity. Most importantly tested compounds present improved primary pharmacological profile in comparison to A2A inhibitors currently tested in clinical trials. Further validation in in vivo models showed efficacy standalone and in combination with checkpoint inhibitors.

Citation Format: Michal Galezowski, Paulina Wegrzyn, Aneta Bobowska, Claude Commandeur, Katarzyna Dziedzic, Marcin Nowogrodzki, Alicja Obara, Joanna Szeremeta-Spisak, Anna Dzielak, Iwona Lozinska, Marcelina Dudek, Anita Janiga, Jacek Reus, Marek Wronowski, Mateusz Swirski, Adam Radzimierski, Magdalena Ziembik, Joanna Mierzwicka, Katarzyna Wojcik-Jaszczynska, Elzbieta Gocek, Karolina Grycuk, Aniela Golas, Olga Pierzchala, Julian Zachmann, Mateusz Nowak. Characterization of novel dual A2A/A2B adenosine receptor antagonists for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3770.