Orchestrating immune check-point blockade for cancer immunotherapy in combinations

• Immunity against cancer is negatively regulated by lymphocyte surface receptors.
• Cellular immunity against cancer can be unleashed by mAbs acting on such receptors.
• Clinical trial evidence has shown efficacy with ipilimumab (a CTLA-4-blocking mAb).
• Blockade of the PD-1/PD-L1 axis shows very promising activity in cancer patients.
• Combination strategies under development attain synergistic effects.

Inhibitory receptors on immune system cells respond to membrane-bound and soluble ligands to abort or mitigate the intensity of immune responses by raising thresholds of activation, halting proliferation, favoring apoptosis or inhibiting/deviating effector function differentiation. Such evolutionarily selected inhibitory mechanisms are termed check-points and therefore check-point inhibitors empower any ongoing anti-cancer immune response that might have been too weak or exhausted. Monoclonal antibodies (mAb) interfering with CTLA-4-CD80/86, PD-1 — PD-L1, TIM-3-GAL9 and LAG3-MHC-II belong to this category of check-point inhibitors. The anti-CTLA-4 mAb ipilimumab has been approved for metastatic melanoma. Anti-PD-1 and anti-PD-L1 mAbs have shown extremely encouraging clinical activity. The potential of combination strategies with these agents has recently been highlighted by clinical observations on CTLA-4 + PD-1 combined blockade in melanoma patients.