Next generation immune-checkpoints for cancer therapy.

The discovery and clinical application of immune-checkpoint inhibitors has dramatically improved the treatments, outcomes and therapeutic concepts in multiple tumor settings. This breakthrough was mainly based on monoclonal antibodies blocking the inhibitory molecule CTLA-4 and or the PD-1/PD-L1 axis, with the aim of counteracting major tumor immune evasion mechanisms. Even acknowledging these important successes, not all the patients benefit from these treatments. Translational and clinical research efforts are ongoing to explore the potentialities of a new generation of immune-modulatory molecules to extend current clinical applications and contrast the unsolved issues of resistance and disease relapse that still affects a considerable rate of patients. New immune-checkpoints, with either stimulatory or inhibitory functions are emerging with key roles in regulating T cell response but also affecting other crucial effectors belonging to the innate immune response (e.g., natural killer). Their therapeutic exploitation, either alone or in strategical combinations, is providing important preclinical results, holding promises currently explored in initial clinical trials. The first results point toward favorable safety profiles with selective hints of activity in challenging settings. Important issues regarding the dose, schedule and rational combinations remain open and data from the clinical studies are needed. Here we provide an overview of the main emerging stimulatory or inhibitory immune-checkpoints exploitable in cancer treatment, briefly reporting their biological function, preclinical activity and preliminary clinical data.