Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges

Abstract

The programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes with signal transduction of the T-cell receptor. This leads to suppression of T-cell survival, proliferation, and activity in the tumor microenvironment resulting in compromised anticancer immunity. PD-1/PD-L-1 interaction blockade shown remarkable clinical success in various cancer immunotherapies. To date, most PD-1/PD-L-1 blockers approved for clinical use are monoclonal antibodies (mAbs); however, their therapeutic use are limited owing to poor clinical responses in a proportion of patients. mAbs also displayed low tumor penetration, steep production costs, and incidences of immune-related side effects. This strongly indicates the importance of developing novel inhibitors as cancer immunotherapeutic agents. Recently, advancements in the small molecule-based inhibitors (SMIs) that directly block the PD-1/PD-L-1 axis gained attention from the scientific community involved in cancer research. SMIs demonstrated certain advantages over mAbs, including longer half-lives, low cost, greater cell penetration, and possibility of oral administration. Currently, several SMIs are in development pipeline as potential therapeutics for cancer immunotherapy. To develop new SMIs, a wide range of structural scaffolds have been explored with excellent outcomes; biphenyl-based scaffolds are most studied. In this review, we analyzed the development of mAbs and SMIs targeting PD-1/PD-L-1 axis for cancer treatment. Altogether, the present review delves into the problems related to mAbs use and a detailed discussion on the development and current status of SMIs. This article may provide a comprehensive guide to medicinal chemists regarding the potential structural scaffolds required for PD-1/PD-L-1 interaction inhibition.

PDL1 targeting by miR-138-5p amplifies anti-tumor immunity and Jurkat cells survival in non-small cell lung cancer

“…Interestingly, in recent decades researchers developed some drugs such as Nivolumab 7 and pembrolizumab 8 , 9 as immune checkpoint inhibitors that have blocked the PD1-PDL1 pathway. PD1(also known as CD279) is a transmembrane receptor and apoptosis-associated molecule 10 that was known as a negative regulator of immune response by studying Nishimura and colleagues on PD1-defective mice 11 and expressed in T cells in peripheral tissues. PD-L1 (also known as B7-H1 or CD274) is a member of the B7-H1 transmembrane receptor family encoded by the CD274 gene located on chromosome 9 in the human genome 12 , and it is generally expressed on many cell types like T cells, B cells, and epithelial cells after stimulation and activation by pro-inflammatory cytokines like IFN-γ and IL4 13 .…”