Abstract:
Immunotherapy with immune checkpoint inhibitors has emerged as the most significant advance
in the treatment of cancer in recent years and has revolutionized cancer management (1). Until
recently, it had been assumed that the immune system was not effective in protecting humans
against the development of neoplastic diseases. Checkpoints inhibitors are co-receptors expressed
by T cells. These co-receptors regulate T cell activation negatively and play a central role in the
maintenance of peripheral self-tolerance. Co-inhibitory receptor ligands are significantly expressed
in a variety of malignancies resulting in evasion of anti-cancer immunity. These molecules
include programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen
4 (CTLA-4) and were discovered by Tasuku Honjo and James P. Allison in 1992 and 1996,
respectively (2, 3). These scientists were jointly awarded the 2018 Nobel Prize for Physiology
or Medicine in recognition of this ground-breaking research. Monoclonal antibodies targeting
the CTLA-4 and PD-1 and their ligands have produced significant clinical responses against a
variety of malignancies (4). FDA registered checkpoint inhibitors include pembrolizumab (5),
nivolumab (6), cemiplimab (7), atezolizumab (8), darvolumab (9) and avelumab (10) for numerous
indications including melanoma, lung cancer (small and non-small cell types), bladder cancer,
Hodgkin’s disease and others (5–10). Other co-inhibitory molecules under research include T cell
immunoglobulin and mucin domain-containing molecule-3 (TIM-3) (11), Lymphocyte activation
gene-3 (LAG-3) (12), V-domain Ig-containing Suppressor of T cell Activation (VISTA) (13), and
B- and T-lymphocyte attenuator (BTLA) (14). Treatment with antibodies inhi biting immune
checkpoints are well-tolerated by the vast majority of patients and are less toxic compared
to standard anticancer chemotherapy agents. These immune side-effects are referred to as
immune-related adverse events (IrAE) (15).
