A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti–PD-(L)1 and Anti–CTLA-4 in Preclinical Models

TLDR

Adenosine signaling via A2A receptors on immune cells suppresses antitumor immunity, and CPI‑444 is a potent, selective oral antagonist of this receptor. CPI‑444 blockade of A2AR restored T‑cell cytokine production, inhibited tumor growth dose‑dependently in multiple syngeneic mouse models, synergized with anti‑PD‑L1 or anti‑CTLA‑4 to eliminate tumors in up to 90 % of mice, induced durable antitumor immune memory, and its efficacy depended on CD8⁺ T cells and was accompanied by increased T‑cell activation, compensatory CD73 up‑regulation, and a Th1 gene signature. Published in Cancer Immunology Research 6(10):1136‑49; ©2018 AACR.

Abstract

Adenosine signaling through A2A receptors (A2AR) expressed on immune cells suppresses antitumor immunity. CPI-444 is a potent, selective, oral A2AR antagonist. Blockade of A2AR with CPI-444 restored T-cell signaling, IL2, and IFNγ production that were suppressed by adenosine analogues in vitro CPI-444 treatment led to dose-dependent inhibition of tumor growth in multiple syngeneic mouse tumor models. Concentrations of extracellular adenosine in the tumor microenvironment, measured using microdialysis, were approximately 100-150 nmol/L and were higher than corresponding subcutaneous tissue. Combining CPI-444 with anti-PD-L1 or anti-CTLA-4 treatment eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that incompletely responded to anti-PD-L1 or anti-CTLA-4 monotherapy. Tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. CD8+ T-cell depletion abrogated the efficacy of CPI-444 with and without anti-PD-L1 treatment, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. The antitumor efficacy of CPI-444 with and without anti-PD-L1 was associated with increased T-cell activation, a compensatory increase in CD73 expression, and induction of a Th1 gene expression signature consistent with immune activation. These results suggest a broad role for adenosine-mediated immunosuppression in tumors and justify the further evaluation of CPI-444 as a therapeutic agent in patients with solid tumors. Cancer Immunol Res; 6(10); 1136-49. ©2018 AACR.