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

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.