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

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.

A2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model

“…IR with a single 5-Gy dose was performed on the tumor areas and samples were collected at 2, 4, 24, 48 and 72 h after IR. Free extracellular adenosine concentrations in the TME were approximately 200-250 nM without IR treatment, similar to the levels in previous report [16]. IR caused a rapid increase in adenosine level, which could be observed as early as 2 h. The peak level of approximately 600 nM appeared 48 h later but declined to 400 nM at 72 h ( Figure 2B).…”

“…Cytokines such as IFN-γ can predict the response to immune checkpoint inhibitors [20]. T cell function-related gene expression was reported to be associated with the therapeutic efficacy of A 2A R blockade [16]. To evaluate the correlation between therapy efficacy and T cell function, IFN-γ mRNA expression in tumor tissues was measured by ISH.…”

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Extracellular adenosine accumulates in tumors and suppresses cytotoxic T cells and natural killer cells (66)(67)(68). Multiple studies using syngeneic and/or spontaneous tumor models show tumor growth and metastasis is significantly reduced by genetic deletion or pharmacological blockade of CD73 or A2AR; this effect is largely due to restoring antitumor immunity (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(67)(68)(69)(70). These mice also benefit from increased chemotherapy sensitivity (36,71) and reduced angiogenesis (71,72).…”

“…CD73's potential as an immunotherapy target has advanced rapidly within the last decade (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(67)(68)(69)(70). Current studies focus on combination strategies, including ICIs, adoptive transfer, chemotherapy, and targeted therapy.…”

“…Preclinical studies have shown ciforadenant combined with anti-PD-L1 or anti-CTLA-4 therapy eliminates tumors in up to 90% of mice, restores antitumor immunity, and is effective in mice that failed prior anti-PD-L1 or anti-CTLA-4 therapy (68). Moreover, ciforadenant produced an antitumor memory response in which tumor growth was completely inhibited in mice with cleared tumors when later rechallenged (68). In clinical trials, cirforadenant combined with atezolizumab (anti-PD-L1 therapy) provide great disease control and survival benefit in patients, yet without high objective response rates (124).…”