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- W4362545668 abstract "<div>Abstract<p>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 <i>in vitro</i>. 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<sup>+</sup> T-cell depletion abrogated the efficacy of CPI-444 with and without anti–PD-L1 treatment, demonstrating a role for CD8<sup>+</sup> 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. <i>Cancer Immunol Res; 6(10); 1136–49. ©2018 AACR</i>.</p></div>" @default.
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- W4362545668 date "2023-04-03" @default.
- W4362545668 modified "2023-09-30" @default.
- W4362545668 title "Data from A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti–PD-(L)1 and Anti–CTLA-4 in Preclinical Models" @default.
- W4362545668 doi "https://doi.org/10.1158/2326-6066.c.6548078.v1" @default.
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