Improving combination therapies: Targeting A2B adenosine receptor to modulate metabolic tumor microenvironment and immunosuppression

Jason V. Evans, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Shankar Suman, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Mounika Uttam Goruganthu, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Elena E. Tchekneva, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Shuxiao Guan, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Rajeswara Rao Arasada, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Anneliese Antonucci, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Longzhu Piao, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Irina Ilgisonis, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
Andrey A. Bobko, In Vivo Multifunctional Magnetic Resonance Center.
Benoit Driesschaert, In Vivo Multifunctional Magnetic Resonance Center.

Abstract

BACKGROUND: We investigated the role of A2B-adenosine receptor (A2BAR) in regulating immunosuppressive metabolic stress in the tumor microenvironment (TME). Novel A2BAR antagonist PBF-1129 was tested for anti-tumor activity in animals and evaluated for safety and immunological efficacy in a phase-I clinical trial in non-small-cell lung cancer (NSCLC) patients. METHODS: Anti-tumor efficacy of A2BAR antagonists and impact on metabolic and immune TME was evaluated in lung, melanoma, colon, breast and EGFR-inducible transgenic cancer models. Employing Electron Paramagnetic Resonance, we assessed changes in TME metabolic parameters including pO2, pH, and inorganic phosphate (Pi) during tumor growth and evaluated the immunological effects of PBF-1129, including its pharmacokinetics, safety, and toxicity in NSCLC patients. RESULTS: Levels of metabolic stress correlated with tumor growth, metastasis, and immunosuppression. Tumor interstitial Pi emerged as a correlative and cumulative measure of TME stress and immunosuppression. A2BAR inhibition alleviated metabolic stress, downregulated expression of adenosine-generating ecto-nucleotidases, increased expression of adenosine deaminase (ADA), decreased tumor growth and metastasis, increased IFN-γ-production and enhanced the efficacy of anti-tumor therapies following combination regimens in animal models (anti-PD-1 vs. anti-PD-1 plus PBF-1129 treatment hazard ratio [HR] = 11.74, 95% CI = 3.35 to 41.13, n = 10, P <.001, 2-sided F-test). In NSCLC patients, PBF-1129 was well tolerated with no dose-limiting toxicities, demonstrated pharmacological efficacy, modulated adenosine generation system, and improved anti-tumor immunity. CONCLUSIONS: Data identify A2BAR as a valuable therapeutic target to modify metabolic and immune TME to reduce immunosuppression, enhance the efficacy of immunotherapies, and support clinical application of PBF-1129 in combination therapies.