Beyond PD-1/PD-L1 Axis Blockade: New Combination Strategies in Metastatic Melanoma Treatment

Metastatic melanoma treatment has dramatically changed in the last few years, having a breakthrough with the introduction of targeted agents and immunotherapy. PD-1/PD-L1 pathway is one of the physiologic mechanisms of peripheral immune tolerance, but it also represents a mechanism of tumor immune escape. PD-1/PD-L1 inhibitors represent new immune-checkpoint drugs currently used in metastatic melanoma treatment. Resistance to PD-1/PD-L1 axis blockade, which is the main cause of therapeutic failure during therapeutic use of these drugs, could be linked to several mechanism of immune escape. In fact, other inhibitory receptor such as CTLA-4, LAG-3, TIM-3 and TIGIT might be co-expressed on T cells, deleting the effect of anti-PD-1/PD-L1; overexpression of the enzyme IDO could cause immunosuppression through the depletion of tryptophan in the tumor microenvironment; defective c ostimulation (through reduced activity of 4-1BB and OX40 receptors) could result in T-cell energy. Combination of anti-PD-1/PD-L1 with drugs targeting inhibitory or costimulatory receptors, intracellular pathways, enzymes or neoangiogenesis could be a possible strategy to overcome resistance to single PD-1/PD-L1 blockade. Clinical trials evaluating combination therapies have already showed interesting results, although most of them are still on going.