Elevated extracellular adenosine in the tumor microenvironment generates an immunosuppressive niche that promotes tumor growth and metastasis. Adenosine signaling via A2A receptor (A2AR) on immune cells suppresses anti-tumor immunity and may also limit efficacy of immunotherapies such as anti-PD-L1 and anti-PD-1 antibodies.
CPI-444 is a potent, oral, selective A2AR antagonist that has been well tolerated in Ph 1 and 2 studies in non-oncology indications. The efficacy of CPI-444 ± Anti-PD-L1 or Anti-PD-1 was evaluated in MC38 and CT26 syngeneic mouse tumor models.
In MC38, daily treatment of mice with CPI-444 (1, 10, 100 mg/kg) led to dose-dependent inhibition of tumor growth, leading to tumor elimination in 9/30 mice. Combining CPI-444 with anti-PD-L1 treatment in MC38 synergistically inhibited tumor growth and eliminated tumors in 90% of treated mice. In an additional model, CT26, CPI-444 alone or anti-PD-1 alone led to non-significant reductions in tumor growth; however, the combination of CPI-444 and anti-PD-1 led to a synergistic inhibition of tumor growth and prolonged survival compared to either agent alone. When cured mice were later re-challenged with MC38 cells, tumor growth was fully inhibited, indicating that CPI-444 induced systemic anti-tumor immune memory. CD8+ T cell depletion abrogated the efficacy of CPI-444 ± anti-PD-L1 treatment, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. Anti-tumor efficacy of CPI-444 ± anti-PD-L1 was associated with increased CD8+ cell infiltration and activation in MC38 tumor tissues. Additionally, levels of immune checkpoints were modulated by treatment with CPI-444, including GITR, OX40, and LAG3 on tumor infiltrating lymphocytes and circulating T cells, suggesting a broad role for adenosine mediated immunosuppression.
Based on these results and others, we have initiated a Phase 1b clinical trial to examine safety, tolerability, biomarkers, and preliminary efficacy of CPI-444 as a single agent and in combination the investigational anti-PD-L1 antibody, Atezolizumab, in patients with solid tumors.
Clinical trial identification
Legal entity responsible for the study
S. Willingham, P. Ho, C. Choy, I. McCaffery, R. Miller: Employee and stock holder of Corvus Pharmaceuticals. R. Leone, J. Powell: Grant support and stock from Corvus Pharmaceuticals.