Checkpoint inhibitor

Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. 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 winning the Tang Prize in Biopharmaceutical Science and the Nobel Prize in Physiology or Medicine in 2018.[6][7]

Types

Approved checkpoint inhibitors

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
Cemiplimab	PD-1	2018

CTLA-4 blockade

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]

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.[10] 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.[11] 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.[11]

PD-1 inhibitors

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.[12]

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.[13] Keytruda is approved to treat melanoma and lung cancer and is produced by Merck.[12]

Spartalizumab (PDR001) is a PD-1 inhibitor currently being developed by Novartis to treat both solid tumors and lymphomas [14][15][16]

PD-L1 inhibitors

In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer.[17]

Other

Other modes of enhancing [adoptive] immunotherapy include targeting so-called intrinsic checkpoint blockades e.g. CISH.

Adverse effects

Immunological adverse effects may be caused by checkpoint inhibitors. Altering checkpoint inhibition can have diverse effects on most organ systems of the body. Colitis (inflammation of the colon) occurs commonly. The precise mechanism is unknown, but differs in some respects based on the molecule targeted.[18]

See also

• Cancer immunotherapy
• Chimeric antigen receptor

References

1. Pardoll DM (March 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nature Reviews. Cancer. 12 (4): 252–64. doi:10.1038/nrc3239. PMC 4856023. PMID 22437870.
2. Cameron F, Whiteside G, Perry C (May 2011). "Ipilimumab: first global approval". Drugs. 71 (8): 1093–104. doi:10.2165/11594010-000000000-00000. PMID 21668044.
3. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (July 2007). "Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses". Immunity. 27 (1): 111–22. doi:10.1016/j.immuni.2007.05.016. PMC 2707944. PMID 17629517.
4. Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (October 2011). "PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells". EMBO Molecular Medicine. 3 (10): 581–92. doi:10.1002/emmm.201100165. PMC 3191120. PMID 21739608.
5. Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (2017). "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID 29208439.
6. "2014 Tang Prize in Biopharmaceutical Science". Archived from the original on 2016-06-20. Retrieved 2016-06-18.
7. Devlin, Hannah (2018-10-01). "James P Allison and Tasuku Honjo win Nobel prize for medicine". the Guardian. Retrieved 2018-10-01.
8. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M (June 2012). "Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study". Journal of Clinical Oncology. 30 (17): 2046–54. doi:10.1200/JCO.2011.38.4032. PMID 22547592.
9. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA (September 2013). "Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer". Journal of Immunotherapy. 36 (7): 382–9. doi:10.1097/CJI.0b013e31829fb7a2. PMC 3779664. PMID 23924790.
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11. van Hooren L, Sandin LC, Moskalev I, Ellmark P, Dimberg A, Black P, Tötterman TH, Mangsbo SM (February 2017). "Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer". European Journal of Immunology. 47 (2): 385–393. doi:10.1002/eji.201646583. PMID 27873300.
12. Pollack A (2016-05-18). "F.D.A. Approves an Immunotherapy Drug for Bladder Cancer". The New York Times. ISSN 0362-4331. Retrieved 2016-05-21.
13. "Enrolling the immune system in the fight against cancer". The Economist. Retrieved 2017-10-01.
14. World Health Organization (2017). "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 31 (2).
15. Immuno-Oncology News. "PDR001".
16. National Cancer Institute. "NCI Drug Dictionary".
17. Heimes, Anne-Sophie; Schmidt, Marcus (January 2019). "Atezolizumab for the treatment of triple-negative breast cancer". Expert Opinion on Investigational Drugs. 28 (1): 1–5. doi:10.1080/13543784.2019.1552255. ISSN 1744-7658. PMID 30474425.
18. Postow, Michael A.; Sidlow, Robert; Hellmann, Matthew D. (10 January 2018). "Immune-Related Adverse Events Associated with Immune Checkpoint Blockade". New England Journal of Medicine. 378 (2): 158–168. doi:10.1056/nejmra1703481. PMID 29320654.