Targeting the A3 adenosine receptor to treat cytokine release syndrome in cancer immunotherapy

Cancer patients undergoing immunotherapy may develop cytokine release syndrome (CRS), an inflammatory cytokine storm condition, followed by neurotoxic manifestations and may be life-threatening. The current treatments for CRS successfully reduce the inflammatory response but may limit the anticancer effect of the given immunotherapy and fail to overcome the neurotoxic adverse events. Adenosine, a ubiquitous purine nucleoside, induces a plethora of effects in the body via its binding to four adenosine receptors A(1), A(2a), A(2b), and the A(3). Highly selective agonists to the A(3) adenosine receptor act as inhibitors of proinflammatory cytokines, possess robust anti-inflammatory and anticancer activity, and concomitantly, induce neuro-protective effects. Piclidenoson and namodenoson belong to this group of compounds, are effective upon oral administration, show an excellent safety profile in human clinical studies, and therefore, may be considered as drug candidates to treat CRS. In this article, the detailed anti-inflammatory characteristics of these compounds and the rationale to use them as drugs to combat CRS are described.