Adenosine-Axis and PD-1 Blockade
Briefly, PD-1 is an immunosuppressive receptor that upon binding to its ligands, PDL-1 and PDL-2, dampens T-cell activity thereby enabling tumors to evade immune-destruction. Blockade of the PD-1-PDL-1/2 signaling axis results in durable complete responses in the clinic for a fraction of treated patients (1), and many pre-clinical and clinical studies have explored concomitant inhibition of adenosine production, or antagonism of A2AR and A2BR, to improve response rates.
It has been demonstrated that CD73+ tumor cells are resistant to PD-1 ICB (401) and that simultaneous mAb-mediated blockade of CD73 and PD-1 synergistically enhances tumor control and survival in mice (382, 385). Mechanistically, the dual therapy augments intra-tumoral CD8+ tumor-specific T cells (382, 385) and IFNγ mRNA levels (382) as compared to single-agent treatments. Several clinical trials assessing anti-CD73 mAb treatment along with anti-PD-1 mAb (NCT03454451, NCT03549000) or anti-PDL-1 mAb (NCT02503774, NCT03773666, NCT03267589, NCT03334617) of advanced solid tumors are recruiting or underway. Intra-tumoral upregulation of CD38 and subsequent adenosine production was recently identified as a mechanism of acquired resistance to PD-1/PD-L1 blockade and mAb-mediated or pharmacologic inhibition of CD38 was shown to significantly improve the anti-tumor efficacy of an anti-PDL-1 mAb (96). In terms of mechanisms, tumors from mice receiving the combinatorial therapy displayed higher accumulation of CD8+ T cells, effector memory CD8+ T cells, ICOS+ CD4+ T cells and lower levels of MDSCs and Tregs as compared to tumors from single-agent treated mice (96).
The potential for synergy between the co-administration of A2R antagonists with anti-PD-1 mAb is underscored by the observations that PD-1 blockade enhances A2AR expression on tumor-infiltrating CD8+ T cells (401), as well as that PD-1 blockade is more efficacious, in terms of increasing the survival of tumor-bearing mice, when these mice lack the A2AR (400). Vice versa, A2AR triggering on the surface of CD8+ T cells derived from tumor tissue (382), tumor draining lymph nodes or spleen (396) promotes PD-1 expression suggesting that simultaneous PD-1 blockade would boost the anti-tumor efficacy of A2A antagonism. Indeed, several groups demonstrated that concurrent provision of PD-1 checkpoint inhibitors along with A2AR antagonists is more effective than single-agent treatments at reducing tumor growth rate (96, 396, 400, 401) and metastasis formation (394, 401), as well as at improving survival (394, 396, 401). Moreover, the combination enables increased production of IFNγ and GzB by CD8+ tumor infiltrating T cells (401) while augmenting the intra-tumoral presence of NK cells (394). Five clinical trials for the treatment of solid-tumor patient cohorts with A2AR antagonists along with anti-PD-1 Ab (NCT02403193, NCT03207867) or anti-PD-L1 Ab (NCT02655822, NCT03337698, NCT02740985) are ongoing. Finally, dual therapy comprising A2BR antagonism and PD-1 blockade is superior to either monotherapy at decreasing metastasis and improving survival of tumor-bearing mice (359). However, no clinical trials have been launched to date to explore this combination in human cancer patients.