Alternative non-antibody based therapies constitute also a promising approach to target immune checkpoints [18, 19]. Indeed, several examples of small compounds such as sulphonamide derivatives , tri-aromatic structures [18, 21], linear, cyclic macrocyclic peptides [18, 22], hydrolysis-resistant D-peptide , peptidomimetics and cyclic peptidomimetics , as antagonist of PD-1/PD-L1 have already been reported. Some of these compounds are highly effective in antagonizing PD-1 signaling and inhibiting tumor growth and metastasis in preclinical models of cancer. Moreover, those compounds are well tolerated with no obvious toxicity [15, 18].