Cancer Immunotherapy: An Overview on Small Molecules as Inhibitors of the Immune Checkpoint PD-1/PD-L1 (2015-2021)

In 2018, James Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of tumor therapy inhibition of negative immune regulation. Immunotherapy stimulates T-cells to fight cancer cells by blocking different immune checkpoint pathways. The interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 (Programmed cell death ligand 1), is one of the main immune checkpoints. Of note, interfering with this pathway is already exploited in clinical cancer therapy, demonstrating that it is one of the key factors involved in cancer immune escape. The development of monoclonal antibodies (mAbs) that possess the ability to inhibit the interactions between PD-1/PD-L1 has radically made the difference in cancer immunotherapy. Yet, because of the many drawbacks that this therapy possesses, the research moved its efforts towards the development of novel small molecules. This may constitute a hope, but also an arduous challenge in fighting cancer. This paper reviews the recent primary literature concerning the development of novel small molecules able to blockade the interaction between PD-1 and its ligand PD-L1.