Development of anti-tumor immunity involves the coordinated activity of multiple immune cell types that mediate antigen presentation to effector cell populations which then invade tumors and target tumor cells that harbor the “foreign” antigen. Over time, suppressive mechanisms are initiated that are normally involved in regulating the extent of effector cell activity during inflammation. These self-regulatory mechanisms are often co-opted by tumors to evade the immune system.

Therapeutic agents are being developed that stimulate activation and inhibit specific suppressive mechanisms and these agents are demonstrating robust clinical activity in subsets of patients in multiple tumors types. Generation and release of extracellular adenosine during inflammation is known to be an important suppressive mechanism that regulates immune responses and inflammation through activation of receptors that are expressed on effector cells. Accumulation of adenosine in the tumor microenvironment is emerging as an important immune checkpoint, leading to suppression of anti-tumor immunity through inhibition of function of multiple immune cell types, including NK and T cells. CPI-444 is a novel, selective inhibitor of adenosine 2A receptor (A2AR), the key mediator of adenosine mediated immune suppression. In preclinical studies, CPI-444 demonstrated strong anti-tumor activity as a single agent and synergy in combination with multiple immune targeted agents, including anti-PD-L1 antibodies. CPI-444 is being evaluated in a multicenter Phase 1/1b clinical trial in patients with various solid tumors both as a single agent and in combination with TECENTRIQ (atezolizumab), Genentech\’s investigational cancer immunotherapy that targets PD-L1. Insights into the underlying biological mechanisms of adenosine activity in tumors from ongoing preclinical and clinical studies of CPI-444 will be discussed.