Ciforadenant

A potent, orally active, adenosine A2A receptor antagonist that is being investigated in solid tumors as a single agent and in combination with the anti-PD-L1 antibody atezolizumab; dose-dependent inhibits tumor growth in mouse model MC38; induces anti-tumor immunity in mouse tumor models and inhibits adenosine signaling in lymphocytes of treated humans.Lung Cancer Phase 2 Clinical (In Vitro) :Ciforadenant is a potent, oral, selective A2AR antagonist. CD8+ T cell depletion abrogates the efficacy of Ciforadenant treatment as a single agent as well as in combination with anti-PD-L1, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. Anti-tumor efficacy of Ciforadenant±anti-PD-L1 is associated with increased CD8+ cell infiltration and activation in MC38 tumor tissues, and a corresponding rise in PD-1 expression on CD8+ T cells in the spleen. Additionally, levels of immune checkpoints are modulated by treatment with Ciforadenant, including GITR, OX40, and LAG3 on tumor infiltrating lymphocytes and circulating T cells, suggesting a broad role for adenosine mediated immunosuppression. (In Vivo) :Daily treatment of the syngeneic mouse model MC38 with Ciforadenant (1, 10, 100 mg/kg) leads to dose-dependent inhibition of tumor growth, leading to tumor elimination in ~30% of treated mice. Combining Ciforadenant (100 mg/kg, qd, 14 days) with anti-PD-L1 (200 μg, 3qw, 4 doses) treatment in MC38 models synergistically inhibits tumor growth and eliminates tumors in 90% of treated mice. When cured mice are later re-challenged with MC38 cells, tumor growth is rejected in 100% of challenged mice, indicating that Ciforadenant induces systemic anti-tumor immune memory.