Immune Checkpoint Inhibitors: Recent Clinical Advances and Future Prospects.

ABSTRACT

Immune checkpoints are vital molecules and pathways of the immune system with defined roles of controlling immune responses from being destructive to the healthy cells in the body. They include inhibitory receptors and ligands, which check the recognition of most cancers by the immune system. This happens when proteins on the surface of T cells called immune checkpoint proteins identify partner proteins on the cancer cells and bind to them, sending brake signals to the T cells to evade immune attack. However, drugs called immune checkpoint inhibitors block checkpoint proteins from binding to their partner proteins, thereby inhibiting the brake signals from being sent to T cells. This eventually allows the T cells to destroy cancer cells and arbitrate robust tumor regression. Many such inhibitors have already been approved and are in various developmental stages. The well-illustrated inhibitory checkpoints include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Though many molecules blocking these checkpoints have shown promise in treating many malignancies, such treatment options have limited success in terms of the immune response in most patients. Against this backdrop, exploring new pathways and next-generation inhibitors becomes imperative for developing more responsive and effective immune checkpoint therapy. Owing to the complex biology and unexplored ambiguities in the mechanistic aspects of immune checkpoint pathways, analysis of the activity profile of new drugs is the subject of strenuous investigation. We herein report the recent progress in developing new inhibitory pathways and potential therapeutics and delineate the developments based on their merit. Further, the ensuing challenges towards developing efficacious checkpoint therapies and the impending opportunities are also discussed.