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Abstract
Checkpoint receptor blockers, known to act by blocking the pathways that inhibit immune
cell activation and stimulate immune responses against tumor cells, have been immensely
successful in the treatment of cancer. Among several checkpoint receptors of immune
cells, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death
protein-1 (PD-1), T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin-3
(TIM-3) and lymphocyte activation gene 3 (LAG-3) are the most commonly targeted checkpoints
for cancer immunotherapy. Six drugs including one CTLA-4 blocker (ipilimumab), two
PD-1 blockers (nivolumab and pembrolizumab) and three PD-L1 blockers (atezolizumab,
avelumab and durvalumab) are approved for the treatment of different types of cancers
including both solid tumors such as melanoma, lung cancer, head and neck cancer, bladder
cancer and Merkel cell cancer as well as hematological tumors such as classic Hodgkin's
lymphoma. The main problem with checkpoint blockers is that only a fraction of patients
respond to the therapy. Insufficient immune activation is considered as one of the
main reason for low response rates and combination of checkpoint blockers has been
proposed to increase the response rates. The combination of checkpoint blockers was
successful in melanoma but had significant adverse events. A combination that is selected
based on the mechanistic differences between checkpoints and the differences in expression
of checkpoints and their ligands in the tumor microenvironment could have a synergistic
effect in a given cancer subtype and also have a manageable safety profile. This review
aims to help in design of optimal checkpoint blocker combinations by discussing the
mechanistic details and outlining the subtle differences between major checkpoints
targeted for cancer immunotherapy.