Immune Checkpoint Inhibitors in 10 Years: Contribution of Basic Research and Clinical Application in Cancer Immunotherapy

Abstract

Targeting immune evasion via immune checkpoint pathways has changed the treatment paradigm in cancer. Since CTLA-4 antibody was first approved in 2011 for treatment of metastatic melanoma, eight immune checkpoint inhibitors (ICIs) centered on PD-1 pathway blockade are approved and currently administered to treat 18 different types of cancers. The first part of the review focuses on the history of CTLA-4 and PD-1 discovery and the preclinical experiments that demonstrated the possibility of anti-CTLA-4 and anti-PD-1 as anti-cancer therapeutics. The approval process of clinical trials and clinical utility of ICIs are described, specifically focusing on non-small cell lung cancer (NSCLC), in which immunotherapies are most actively applied. Additionally, this review covers the combination therapy and novel ICIs currently under investigation in NSCLC. Although ICIs are now key pivotal cancer therapy option in clinical settings, they show inconsistent therapeutic efficacy and limited responsiveness. Thus, newly proposed action mechanism to overcome the limitations of ICIs in a near future are also discussed.

The Treatment of Advanced Melanoma: Therapeutic Update

“…Immune checkpoint inhibitors are drugs which act through the blockage of small proteins produced by immune cells and cancer cells called “ checkpoints ” [ 8 , 9 ]. In particular, programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) are checkpoints which downregulate T cell activation, produced by cancer cells in order to escape from immunity system, producing immune tolerance [ 8 , 9 ].…”

“…Immune checkpoint inhibitors are drugs which act through the blockage of small proteins produced by immune cells and cancer cells called “ checkpoints ” [ 8 , 9 ]. In particular, programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) are checkpoints which downregulate T cell activation, produced by cancer cells in order to escape from immunity system, producing immune tolerance [ 8 , 9 ]. The binding of PD-1, also known the cluster of differentiation 279 (CD279), which is expressed on the surface of monocytes, T cells, and B and NK cells, to its ligand PDL-1 promotes the apoptosis of T cells and activates the regulatory T cells, thus preventing the inflammation pathway [ 8 , 9 ].…”

“…In particular, programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) are checkpoints which downregulate T cell activation, produced by cancer cells in order to escape from immunity system, producing immune tolerance [ 8 , 9 ]. The binding of PD-1, also known the cluster of differentiation 279 (CD279), which is expressed on the surface of monocytes, T cells, and B and NK cells, to its ligand PDL-1 promotes the apoptosis of T cells and activates the regulatory T cells, thus preventing the inflammation pathway [ 8 , 9 ]. CTLA-4, also known as CD152, is constitutively expressed in regulatory T cells and inhibits the activation of T cells [ 8 , 9 ].…”

“…The binding of PD-1, also known the cluster of differentiation 279 (CD279), which is expressed on the surface of monocytes, T cells, and B and NK cells, to its ligand PDL-1 promotes the apoptosis of T cells and activates the regulatory T cells, thus preventing the inflammation pathway [ 8 , 9 ]. CTLA-4, also known as CD152, is constitutively expressed in regulatory T cells and inhibits the activation of T cells [ 8 , 9 ]. Targeting these pathways is a valuable weapon to reduce melanoma immune escape.…”

Golden Age of Immunotherapy: Challenges and Opportunities

“…In the current issue of Immune Network , a series of review articles discusses up-to-date findings of immunotherapies for cancer, autoimmune and allergic diseases. For instance, strategies to overcome limitations of immune checkpoint blockers (ICBs) are frequently conferred ( 3 ). One of these strategies is to use specific microbes, as commensal microbiota is shown to be required for successful cancer immunotherapy ( 4 ).…”