Abstract 3770: Characterization of novel dual A2A/A2B adenosine receptor antagonists for cancer immunotherapy

Abstract

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.

Adenosine Signaling Is Prognostic for Cancer Outcome and Has Predictive Utility for Immunotherapeutic Response

“…One example of a factor with broad immunosuppressive effects is the adenosine signaling axis (11), which has been shown to suppress natural killer (NK) and CD8 þ T-cell cytolytic activity while enhancing suppressive macrophage and dendritic cell polarization as well as Treg and myeloid-derived suppressor cell (MDSC) proliferation (12). Beginning with landmark research by Ohta and colleagues (13), a series of preclinical studies (14)(15)(16)(17)(18) have been reported and clinical trials (19)(20)(21) initiated targeting adenosine signaling. In addition, preclinical evidence supports a role for adenosine axis antagonists in chimeric antigen receptor T-cell therapy (22), adoptive cell therapy (13), and cancer vaccines (23).…”

Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

“…The failure of preladenant in a phase 1 trial, however, suggested that A 2A R antagonists originally developed for neurological conditions may not be sufficiently efficacious for cancer treatment . Studies from iTeos and Selvita research groups have revealed that some of the A 2A R antagonists designed for Parkinson’s disease dramatically lost potency in a high adenosine environment. , Generally, much higher extracellular adenosine levels are present in the TME than in the conditions of Parkinson’s disease. A reasonable speculation is that more or stronger A 2A R antagonists are needed to overcome the elevated adenosine levels.…”

“…However, CPI-444 and AZD4635 (a clinical compound to be discussed later) almost completely lost their activities in high adenosine environment, with EC 50 > 10 000 nM. 137 Notably, both compounds 43 and 44 exclusively restored the function of monocyte-derived dendritic cells (moDC cells, driven by A 2B R) compared to A 2A R antagonists such as CPI-444. Further results from in vivo testing were disclosed for compound 44.…”

“…The Selvita research group has also discovered a novel series of potent dual A 2A /A 2B adenosine receptor antagonists . SEL330-584 ( 43 , Figure A) displayed very high potency for A 2A R/A 2B R in the presence of 0.1 μM adenosine (EC 50 = 0.26/3.6 nM) and high potency in the presence of 100 μM adenosine (EC 50 = 92/634 nM).…”

“…SEL330-639 ( 44 , Figure A) also displayed very high potency for A 2A R/A 2B R in the presence of 0.1 μM of adenosine (EC 50 = 0.25/6.4 nM) and high potency in the presence of 100 μM of adenosine (EC 50 = 4.2/1618 nM). However, CPI-444 and AZD4635 (a clinical compound to be discussed later) almost completely lost their activities in high adenosine environment, with EC 50 > 10 000 nM . Notably, both compounds 43 and 44 exclusively restored the function of monocyte-derived dendritic cells (moDC cells, driven by A 2B R) compared to A 2A R antagonists such as CPI-444.…”