Checkpoint inhibitor
Checkpoint inhibitor therapy is a form of cancer treatment immunotherapy currently under research. The therapy targets immune checkpoints, key regulators of the immune system that stimulate or inhibit its actions, which tumors can use to protect themselves from attacks by the immune system. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function.[1] The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.[2]
Currently approved checkpoint inhibitors target the molecules CTLA4, PD-1, and PD-L1. PD-1 is the transmembrane programmed cell death 1 protein (also called PDCD1 and CD279), which interacts with PD-L1 (PD-1 ligand 1, or CD274). PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities.[3][4] It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.[5]
The discoveries in basic science allowing checkpoint inhibitor therapies led to James P. Allison and Tasuku Honjo being awarded the Tang Prize in Biopharmaceutical Science and the Nobel Prize in Physiology or Medicine in 2018.[6][7]
Contents
Types[edit]
| Name | Target | Approved |
|---|---|---|
| Ipilimumab | CTLA-4 | 2011 |
| Nivolumab | PD-1 | 2014 |
| Pembrolizumab | PD-1 | 2014 |
| Atezolizumab | PD-L1 | 2016 |
| Avelumab | PD-L1 | 2017 |
| Durvalumab | PD-L1 | 2017 |
CTLA-4 blockade[edit]
The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma.[2] It blocks the immune checkpoint molecule CTLA-4. Clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs.[8][9] In on-going trials the combination of CTLA-4 blockade with PD-1 or PD-L1 inhibitors is tested on different types of cancer.[10][11]
However, patients treated with check-point blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of suffering from immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions.[12] These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the blood stream.
Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood.[13] At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events.[13]
PD-1 inhibitors[edit]
Initial clinical trial results with IgG4 PD1 antibody Nivolumab (under the brand name Opdivo and developed by Bristol-Myers Squibb) were published in 2010.[1] It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma.[14] A 2016 clinical trial of Nivolumab for non-small cell lung cancer failed to meet its primary endpoint for treatment in the first line setting, but is FDA approved in subsequent lines of therapy.[15][11] This trial failure caused Bristol-Myers Squibb (BMS) to lose 16% of its market value.[16]
Pembrolizumab (brand name Keytruda) is another PD1 inhibitor that was approved by the FDA in 2014 and was the second checkpoint inhibitor approved in the United States.[17] Keytruda is approved to treat melanoma and lung cancer and is produced by Merck.[14]Antibody BGB-A317 is a PD-1 inhibitor (designed to not bind Fc gamma receptor I) in early clinical trials.[18]
In 2016, PD-1 inhibitor treatment Keytruda had relieved former US president Jimmy Carter from a metastatic melanoma which had spread to his liver and brain.[17][19]
Spartalizumab (PDR001) is a PD-1 inhibitor currently being developed by Novartis to treat both solid tumors and lymphomas [20] [21] [22]. .
PD-L1 inhibitors[edit]
In May 2016, PD-L1 inhibitor atezolizumab[23] was approved for treating bladder cancer.
Anti-PD-L1 antibodies currently in development include avelumab[24] and durvalumab (under the brand name Imfinzi and developed by Medimmune/AstraZeneca),[25][11] in addition to an affimer biotherapeutic.[26]
Other[edit]
Other modes of enhancing [adoptive] immunotherapy include targeting so-called intrinsic checkpoint blockades e.g. CISH.
Adverse effects[edit]
Immunological adverse effects may be caused by checkpoint inhibitors. Altering checkpoint inhibition can have diverse effects on most organ systems of the body. The precise mechanism is unknown, but differs in some respects based on the molecule targeted.[27] [28]
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