Combinations of Adenosine-Axis Blockade Agents
Concurrent mAb-mediated (418) or pharmacologic (47) inhibition of CD39 and CD73 failed to potentiate CD73-blockade-induced suppression of adenosine production by Tregs and ovarian cancer cell lines. These findings are corroborated by the observation that skin biopsies derived from CD39−/−CD73−/− mice have identical capacity to produce adenosine upon injury induction with counterpart biopsies derived from CD73−/− mice (424).
Alone the same lines, others addressed whether simultaneous blockade of CD73 and of A2AR would result in higher anti-tumor efficacy. Of note, CD73−/−A2AR−/− mice present superior tumor control as compared to single knockout mice (384). Moreover, tumors in A2AR-null mice express twice as much CD73 at their core when compared to tumors formed in wild-type mice (384). Indeed, dual therapy with an anti-CD73 mAb and an A2AR agonist confers superior tumor protection as compared to either one as a monotherapy (384). However, this additive effect is lost when CD73 is targeted with a pharmacologic inhibitor, thus underscoring the capacity of CD73 to promote tumor progression in a catalytic activity-independent manner (384). In light of these studies, Evotec and Exscientia have partnered to develop A2AR/CD73 bi-specific inhibitory molecules (425), whereas NCT03454451, NCT03549000 as well as the Phase Ib/II clinical trial NCT03381274 sponsored by MedImmune all include solid tumor-bearing patient cohorts scheduled to be treated with combinations of an anti-CD73 mAb along with a pharmacologic A2AR antagonist.