Immune checkpoint inhibitors (ICIs)

The initial therapeutic hypothesis underlying the anti-PD-1 /PD-L1 immune checkpoint blockade mechanism was built around the premise that it acts locally in the tumor, reversing the exhaustion of PD-1hi CD8+ T cells by “releasing the brakes.”
Budimir et al. 2022 Cancer Immunol Res 10:146–53

Immune-checkpoint inhibitors (ICI) are primarily effective in patients with immune-responsive tumors. Unfortunately, most patients with cancer either do not respond to Immune checkpoint inhibitors (ICIs) or experience disease progression after an initial response period.
Karasarides et al. 2022 Cancer Immunol Res 10: 372-83

Checkpoint inhibitors (CPIs) are usually ineffective in patients with immune-cold microsatellite stable colorectal cancer (MSS-CRC) or pancreatic cancer (PDAC) and in those who progressed on previously treated with Anti-PD-1 antibodies / PD-1 inhibitors or Anti-PD-L1 antibodies / PD-L1 inhibitors

Immune checkpoint inhibitors (ICIs) have been employed to treat about 50 cancer types, either late-line, first-line (1L), or neoadjuvant therapies.
Vivarelli et al. 2021a Int. J. Oncol. 59: 75

They are administered either as single agents or in combination (with chemotherapy or another ICI)
Twomey & Zhang 2021 AAPS J 23: 39

Despite substantial clinical success, the administration of Immune checkpoint inhibitors (ICIs) is accompanied by some limitations.
Vivarelli et al. 2021a Int. J. Oncol. 59: 75

In the past decade, Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for many cancers by:

• Enabling better therapeutic control


• Resuming immune surveillance


• Suppressing tumor immunosuppression


• Restoring antitumor immune function

Hwang et al. 2020a

However, Immune Checkpoint Inhibitors (ICIs) Therapy is effective only in a small subset of patients and show limited therapeutic potential due to their inability to demonstrate efficacy in ‘cold’ or unresponsive tumor microenvironments (TMEs)
Hwang et al. 2020a

More than 60% of all ongoing oncology clinical trials are currently studying immune checkpoint inhibitors (ICIs).
Alsaab et al. 2017 Front Pharmacol 8: 561
Xin et al. 2019 Nat Rev Drug Discov 18: 899-900

Checkpoint inhibitors, which include a variety of antibodies, have demonstrated significant effectiveness in treating cancer patients. It is important to note that while antibodies make up the majority of these inhibitors, small molecules can also be engineered to serve as checkpoint inhibitors.
Smith et al. 2019 Am. J. Transl. Res.11(2): 529-541

Checkpoint inhibitors are immunomodulatory antibodies that directly activate and rejuvenate suppressed T-cell effector function.
Vinay & Kwon 2018 Immunotherapy 10: 1265–1284

Impressively, the use of immune checkpoint inhibitors (ICIs) has resulted in a significant long-term remission for several stubborn and otherwise incurable tumors. These include metastatic melanoma, and advanced non-small cell lung cancer (NSCLC).
Weber et al. 2017
Eggermont et al. 2018

Checkpoint inhibitors are crafted to attach to checkpoint proteins and stop their activation, thereby keeping the immune system perpetually in 'fight mode'. When PD-1 engages with its ligands PD-L1 and PD-L2, it results in the apoptosis of T cells. Antibodies like nivolumab, which is an anti-PD-1 antibody, and avelumab, an anti-PDL1 antibody, work by blocking this interaction.
Pardoll 2012

The dual blockade of CD223 (Lymphocyte Activation Gene 3 Protein) (LAG-3) and CD279 (Programmed cell death protein 1 (PD-1) is a promising combinatorial strategy for cancer.
Woo et al. 2012

Checkpoint inhibitors represent a unique category of drugs that have recently attracted considerable attention. Immune checkpoints are receptors within the immune system that typically serve to stop the immune system from attacking the body's own cells following an immune challenge. Regrettably, some tumors can exploit this mechanism to their benefit by activating checkpoint receptors, which leads to a weakened antitumor immune response.
Dong et al. 2002 Nat. Med. 8(8): 793-800

CTLA-4 is an inhibitory receptor that is expressed on T cells when they become activated. When CD80 or CD86 binds to CTLA-4, it results in the inhibition of T cells. Ipilimumab is an anti-CTLA-4 antibody that blocks this interaction, which in turn enhances T-cell activity against tumors. In a similar manner, PD-1 is another inhibitory receptor that is expressed on T cells.
Shields et al. 2001 J Biol Chem 276(9): 6591-6604

see also:
Cancer Immunotherapy / Immuno-Oncology
Immune Checkpoint Inhibitors (ICIs) & Examples
Immune Checkpoint Inhibitors (ICIs) & Preclinical/Clinical Data
Tumor Immune Response