Visions of the Hereafter: Releasing the Brakes of the Immune System by Checkpoint Inhibition Immunotherapy

Activation and control of the immune system is regulated by costimulatory molecules as well as by checkpoint inhibitors. Checkpoints are essential in maintaining self-tolerance and minimizing collateral damage by modulating the immune response. Evasion of the immune system, one of the hallmarks of cancer, has been found to include interference with checkpoints by tumor cells as one of the evasive mechanisms. Tumor cells express molecules that when bound to their respective ligand or receptor, send out inhibitory signals that block T-cell activation. Specific antibodies have been engineered against these immunosuppresive molecules (mainly CTLA-4 and PD-1) such that the T-cells can exert cytotoxic anti-tumor effects. These antibody therapies have been found to be very effective for a number of malignancies, especially melanoma and lung cancer. The downside is that this therapy comes with serious adverse immune-mediated events, a direct consequence of releasing the brakes of the immune system. In comparison with patients with a deficiency in the Autoimmune Regulator (AIRE) transcription factor, the side effects however are manageable and certainly acceptable in light of the otherwise fatal underlying disease. Combination of different checkpoint inhibition antibodies, including novel immunoregulatory molecules may further enhance the effectiveness of this form of therapy and broaden the range of susceptible tumors. The vision of the hereafter for immunotherapy by checkpoint inhibition therefore looks bright.