Willingham et al. established CPI-444 as a potent and selective small molecule inhibitor of the immunosuppressive adenosine receptor A2AR. In vitro, CPI-444 restored human T cell signaling, activation, and Th1 cytokine (IL-2 and IFNγ) release in the presence of inhibitory adenosine analogs. In mouse tumor models, CPI-444 reduced tumor growth, mediating complete and durable regression in some animals. Combinations with anti-PD-1 or anti-CTLA-4 showed enhanced antitumor efficacy. Treatment with CPI-444 also increased tumor expression of CD73 (plays a role in adenosine production), which may indicate a mechanism of tumor immune escape.

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 IFNgamma production that were suppressed by adenosine analogs 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 nM 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 re-challenged, 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.

Author Info: (1) Research, Corvus Pharmaceuticals swillingham@corvuspharma.com. (2) Research, Corvus Pharmaceuticals. (3) Research, Corvus Pharmaceuticals. (4) Research, Corvus Pharmaceuticals. (5) Research, Corvus Pharmaceuticals. (6) Research, Corvus Pharmaceuticals

Author Info: (1) Research, Corvus Pharmaceuticals swillingham@corvuspharma.com. (2) Research, Corvus Pharmaceuticals. (3) Research, Corvus Pharmaceuticals. (4) Research, Corvus Pharmaceuticals. (5) Research, Corvus Pharmaceuticals. (6) Research, Corvus Pharmaceuticals. (7) Research, Corvus Pharmaceuticals. (8) Research, Corvus Pharmaceuticals. (9) Research, Corvus Pharmaceuticals. (10) Research, Corvus Pharmaceuticals.

Less