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词条 Checkpoint inhibitor
释义

  1. Types

      CTLA-4 blockade    PD-1 inhibitors    PD-L1 inhibitors    Other  

  2. Adverse effects

  3. See also

  4. References

Checkpoint inhibitor therapy is a form of cancer 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.[2][3] 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.[4]

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.[5][6]

Types

Approved checkpoint inhibitors
NameTargetApproved
IpilimumabCTLA-42011
Nivolumab PD-12014
Pembrolizumab PD-1 2014
Atezolizumab PD-L1 2016
AvelumabPD-L12017
Durvalumab PD-L12017
Cemiplimab PD-12018

CTLA-4 blockade

The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma.[7] 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

{{main|PD-L1 inhibitor}}In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer.{{cn|date=November 2018}}

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. The precise mechanism is unknown, but differs in some respects based on the molecule targeted.[17]

See also

  • Cancer immunotherapy
  • Chimeric antigen receptor

References

1. ^1 {{cite journal | vauthors = Pardoll DM | title = The blockade of immune checkpoints in cancer immunotherapy | journal = Nature Reviews. Cancer | volume = 12 | issue = 4 | pages = 252–64 | date = March 2012 | pmid = 22437870 | pmc = 4856023 | doi = 10.1038/nrc3239 }}
2. ^{{cite journal | vauthors = Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ | title = Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses | journal = Immunity | volume = 27 | issue = 1 | pages = 111–22 | date = July 2007 | pmid = 17629517 | pmc = 2707944 | doi = 10.1016/j.immuni.2007.05.016 }}
3. ^{{cite journal | vauthors = Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D | title = PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells | journal = EMBO Molecular Medicine | volume = 3 | issue = 10 | pages = 581–92 | date = October 2011 | pmid = 21739608 | pmc = 3191120 | doi = 10.1002/emmm.201100165 }}
4. ^{{Cite journal|last=Syn|first=Nicholas L|last2=Teng|first2=Michele W L|last3=Mok|first3=Tony S K|last4=Soo|first4=Ross A|title=De-novo and acquired resistance to immune checkpoint targeting|url=http://linkinghub.elsevier.com/retrieve/pii/S1470204517306071|journal=The Lancet Oncology|language=en|volume=18|issue=12|pages=e731–e741|doi=10.1016/s1470-2045(17)30607-1|pmid=29208439|year=2017}}
5. ^{{Cite web |url=https://web.archive.org/web/20171020051653/http://www.tang-prize.org/en/owner.php?cat=11&y=2 |title=2014 Tang Prize in Biopharmaceutical Science |access-date=2016-06-18 |archive-url= |archive-date=2016-06-20 |dead-url=no |df= }}
6. ^{{cite web | last=Devlin | first=Hannah | title=James P Allison and Tasuku Honjo win Nobel prize for medicine | website=the Guardian | date=2018-10-01 | url=https://www.theguardian.com/science/2018/oct/01/james-p-allison-and-tasuku-honjo-win-nobel-prize-for-medicine | access-date=2018-10-01}}
7. ^1 {{cite journal | vauthors = Cameron F, Whiteside G, Perry C | title = Ipilimumab: first global approval | journal = Drugs | volume = 71 | issue = 8 | pages = 1093–104 | date = May 2011 | pmid = 21668044 | doi = 10.2165/11594010-000000000-00000 }}
8. ^{{cite journal | vauthors = Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M | title = 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 = Journal of Clinical Oncology | volume = 30 | issue = 17 | pages = 2046–54 | date = June 2012 | pmid = 22547592 | doi = 10.1200/JCO.2011.38.4032 }}
9. ^{{cite journal | vauthors = Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA | title = Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer | journal = Journal of Immunotherapy | volume = 36 | issue = 7 | pages = 382–9 | date = September 2013 | pmid = 23924790 | pmc = 3779664 | doi = 10.1097/CJI.0b013e31829fb7a2 }}
10. ^{{cite journal | vauthors = Postow MA, Callahan MK, Wolchok JD | title = Immune Checkpoint Blockade in Cancer Therapy | journal = Journal of Clinical Oncology | volume = 33 | issue = 17 | pages = 1974–82 | date = June 2015 | pmid = 25605845 | pmc = 4980573 | doi = 10.1200/JCO.2014.59.4358 }}
11. ^1 {{cite journal | vauthors = van Hooren L, Sandin LC, Moskalev I, Ellmark P, Dimberg A, Black P, Tötterman TH, Mangsbo SM | title = Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer | journal = European Journal of Immunology | volume = 47 | issue = 2 | pages = 385–393 | date = February 2017 | pmid = 27873300 | doi = 10.1002/eji.201646583 }}
12. ^1 {{Cite news|url=https://www.nytimes.com/2016/05/19/business/food-and-drug-administration-immunotherapy-bladder-cancer.html|title=F.D.A. Approves an Immunotherapy Drug for Bladder Cancer|last=Pollack|first=Andrew|date=2016-05-18|newspaper=The New York Times|access-date=2016-05-21|issn=0362-4331|name-list-format=vanc}}
13. ^{{Cite news|url=https://www.economist.com/news/technology-quarterly/21728782-it-can-have-spectacular-results-enrolling-immune-system-fight-against-0|title=Enrolling the immune system in the fight against cancer|work=The Economist|access-date=2017-10-01|language=en}}
14. ^{{cite journal | author = World Health Organization | title = International Nonproprietary Names for Pharmaceutical Substances (INN)|journal = WHO Drug Information | volume = 31 | issue = 2 | year = 2017 | url = http://www.who.int/medicines/publications/druginformation/innlists/PL117.pdf }}
15. ^{{cite web|url=https://immuno-oncologynews.com/pdr001/|title=PDR001|last1=Immuno-Oncology News}}
16. ^{{cite web|url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/spartalizumab/|title=NCI Drug Dictionary|last1=National Cancer Institute}}
17. ^{{cite journal|last1=Postow|first1=Michael A.|last2=Sidlow|first2=Robert|last3=Hellmann|first3=Matthew D.|title=Immune-Related Adverse Events Associated with Immune Checkpoint Blockade|journal=New England Journal of Medicine|date=10 January 2018|volume=378|issue=2|pages=158–168|doi=10.1056/nejmra1703481|pmid=29320654|language=EN}}

2 : Cancer treatments|Immune system
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