Evaluation of Combination Strategies for the A2AR Inhibitor AZD4635 Across Tumor Microenvironment Conditions via a Systems Pharmacology Model

Abstract

BackgroundAdenosine receptor type 2 (A2AR) inhibitor, AZD4635, has been shown to reduce immunosuppressive adenosine effects within the tumor microenvironment (TME) and to enhance the efficacy of checkpoint inhibitors across various syngeneic models. This study aims at investigating anti-tumor activity of AZD4635 alone and in combination with an anti-PD-L1-specific antibody (anti-PD-L1 mAb) across various TME conditions and at identifying, via mathematical quantitative modeling, a therapeutic combination strategy to further improve treatment efficacy.MethodsThe model is represented by a set of ordinary differential equations capturing: 1) antigen-dependent T cell migration into the tumor, with subsequent proliferation and differentiation into effector T cells (Teff), leading to tumor cell lysis; 2) downregulation of processes mediated by A2AR or PD-L1, as well as other immunosuppressive mechanisms; 3) A2AR and PD-L1 inhibition by, respectively, AZD4635 and anti-PD-L1 mAb. Tumor size dynamics data from CT26, MC38, and MCA205 syngeneic mice treated with vehicle, anti-PD-L1 mAb, AZD4635, or their combination were used to inform model parameters. Between-animal and between-study variabilities (BAV, BSV) in treatment efficacy were quantified using a non-linear mixed-effects methodology.ResultsThe model reproduced individual and cohort trends in tumor size dynamics for all considered treatment regimens and experiments. BSV and BAV were explained by variability in T cell-to-immunosuppressive cell (ISC) ratio; BSV was additionally driven by differences in intratumoral adenosine content across the syngeneic models. Model sensitivity analysis and model-based preclinical study simulations revealed therapeutic options enabling a potential increase in AZD4635-driven efficacy; e.g., adoptive cell transfer or treatments affecting adenosine-independent immunosuppressive pathways.ConclusionsThe proposed integrative modeling framework quantitatively characterized the mechanistic activity of AZD4635 and its potential added efficacy in therapy combinations, across various immune conditions prevailing in the TME. Such a model may enable further investigations, via simulations, of mechanisms of tumor resistance to treatment and of AZD4635 combination optimization strategies.

CD39/CD73/A2AR pathway and cancer immunotherapy

“…The blockage of the binding by ciforadenant and the A2AR inhibitor were reported to restore T-cell signaling, IL-2 and IFN-γ production [ 57 , 111 , 112 ]. AZD4635, a high-affinity oral A2AR antagonist, could reverse T-cell inhibition induced by the treatment with the adenosine analog 5′- n -ethylcarboxylated adenosine in vitro and in vivo [ 113 ]. It is currently on phase I clinical trials in patients with a variety of solid tumors [ 114 ].…”

Dynamic Adjust of Non‐Radiative and Radiative Attenuation of AIE Molecules Reinforces NIR‐II Imaging Mediated Photothermal Therapy and Immunotherapy

“…AZD4635 as a single agent and in combination with durvalumab (anti‐PD‐L1 antibody) in patients with solid malignancies which is currently in clinical trials. [ 27,28 ] It proves that AZD4635 has good safety and therapeutic effect.…”

Discovery of Novel Benzo[4,5]imidazo[1,2-a]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A2A Adenosine Receptor Antagonists

“…Over the past years, various anticancer A 2A AR antagonists have been identified using structural optimizations or modifications. ,,,,,, Some antagonists (Figure ), such as AZD4635, , CPI-444, , PBF-509, AB928, have entered clinical trial for cancer immunotherapy alone and in combination with other agents. ,,, Structurally, the antitumor A 2A AR antagonists can be divided into two classes, i.e., the xanthine-based and nonxanthine heterocyclic derivatives. , These derivatives generally have high molecular weight and poor water solubility, and commonly contain a furan group that is inclined to oxidative metabolism. ,, Consequently, the anticancer A 2A AR antagonists have limited structural diversity, and there is ongoing demand for the discovery of new antagonists with novel scaffolds.…”