The adenosine surge was long in coming. “I've been trying to push adenosine for the last 15 years” for cancer, with little success until now, says Joel Linden, an immunologist at the La Jolla Institute for Allergy and Immunology in California. Adenosine is one of many normal immune regulators, or checkpoints, hijacked by tumors to evade immune attack, and adenosine blockade has the potential to work in patients who fail treatment with the five anti-PD-1 and PD-L1 checkpoint inhibitors that are now approved for eight cancer types. But although experts consider Corvus' early clinical results promising, the stock market has punished the company. If they are to survive, Corvus and its competitors must clinically distinguish this immunotherapy drug class from at least a dozen others also targeting the 80–90% of eligible patients who don't respond to (or who relapse following) anti-PD-1 treatment alone.
Adenosine's precursor, adenosine triphosphate (ATP), plays an important extracellular role in providing a pro-inflammatory 'danger' signal to immune cells. To calibrate the duration and intensity of an immune response, the ATP released by dying cells is degraded first to AMP by the cell surface enzyme CD39 and then to adenosine by the CD73 enzyme. Adenosine signaling through adenosine 2A (A2A) receptors on immune cells is immunosuppressive, limiting the inflammation. Because adenosine levels in the tumor microenvironment are orders of magnitude higher than normal—due to the massive ATP release from cell lysis and necrosis—tumors manage to escape immune attack. Hypoxia, present in most solid tumors, also upregulates CD39 and CD73 on cells, generating even more adenosine. “An adenosine cloud, a halo, surrounds the inflammatory environment and tumor,” says oncologist Robert Leone, an adenosine researcher at Johns Hopkins University in Baltimore.
This is a preview of subscription content, access via your institution