| 词条 | PD-1 and PD-L1 inhibitors | |||||||||||||||||||||
| 释义 |
PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand 1 (PD-L1) with its receptor, programmed cell death protein 1 (PD-1). The interaction of these cell surface proteins is involved in the suppression of the immune system and occurs following infection to limit the killing of bystander host cells and prevent autoimmune disease.[2] This immune checkpoint is also active in pregnancy,[3] following tissue allografts,[4] and in different types of cancer.[5]
HistoryThe concept of blocking PD-1 and PD-L1 for the treatment of cancer was first published in 2001.[6] Pharmaceutical companies began attempting to develop drugs to block these molecules, and the first clinical trial was launched in 2006, evaluating nivolumab. As of 2017, more than 500 clinical trials involving PD-1 and PD-L1 inhibitors have been conducted in more than 20,000 patients.[7] By the end of 2017, PD-1/PD-L1 inhibitors had been approved for the treatment of nine forms of cancer.[7] Cancer immunotherapyIn the cancer disease state, the interaction of PD-L1 on the tumor cells with PD-1 on a T-cell reduces T-cell function signals to prevent the immune system from attacking the tumor cells.[8] Use of an inhibitor that blocks the interaction of PD-L1 with the PD-1 receptor can prevent the cancer from evading the immune system in this way.[8] Several PD-1 and PD-L1 inhibitors are being trialled within the clinic for use in advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other cancer types.[5] Immunotherapy with these immune checkpoint inhibitors appears to shrink tumours in a higher number of patients across a wider range of tumour types and is associated with lower toxicity levels than other immunotherapies, with durable responses.[5] However, de-novo and acquired resistance is still seen in a large proportion of patients.[8] Hence PD-L1 inhibitors are considered to be the most promising drug category for many different cancers.[5][9] PD-1 and PD-L1 inhibitors are closely related to CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitors, such as ipilimumab. PD-1 and CTLA-4 are both expressed on activated T cells, but at different phases of immune response.[10] Current clinical trials are evaluating anti-PD-1 and PD-L1 drugs in combination with other immunotherapy drugs blocking LAG3, B7-H3, KIR, OX40, PARP, CD27, and ICOS.[10] TherapeuticsPD-1Pembrolizumab (formerly MK-3475 or lambrolizumab, Keytruda) was developed by Merck and first approved by the Food and Drug Administration in 2014 for the treatment of melanoma. It was later approved for metastatic non-small cell lung cancer and head and neck squamous cell carcinoma. In 2017, it became the first immunotherapy drug approved for use based on the genetic mutations of the tumor rather than the site of the tumor. It was shown, that patients with higher non-synonymous mutation burden in their tumors respond better to the treatment. Both their objective response rate and progression-free survival was shown to be higher than in patients with low non-synonymous mutation burden.[11]Nivolumab (Opdivo) was developed by Bristol-Myers Squibb and first approved by the FDA in 2014 for the treatment of melanoma. It was later approved for squamous cell lung cancer, renal cell carcinoma, and Hodgkin's lymphoma. Cemiplimab (Libtayo) was developed by Regeneron and first approved by the FDA in 2018 for the treatment of cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. ExperimentalAs of 2017, at least five PD-1 inhibitors were under development.[10]
PD-L1Atezolizumab (Tecentriq) is a fully humanised IgG1 (immunoglobulin 1 antibody developed by Roche Genentech. In 2016, the FDA approved atezolizumab for urothelial carcinoma and non-small cell lung cancer. Avelumab (Bavencio) is a fully human IgG1 antibody developed by Merck Serono and Pfizer. Avelumab is FDA approved for the treatment of metastatic merkel-cell carcinoma. It failed phase III clinical trials for gastric cancer.[12]Durvalumab (Imfinzi) is a fully human IgG1 antibody developed by AstraZeneca. Durvalumab is FDA approved for the treatment of urothelial carcinoma and unresectable non-small cell lung cancer after chemoradiation.[13]ExperimentalAt least two PD-L1 inhibitors are in the experimental phase of development.
Adverse effects{{Technical|section|reason=medical words that need definition with more understandable terms or links are used|date=April 2018}}Immunotherapies as a group have off-target effects and toxicities common to them. Some of these include interstitial pneumonitis, colitis, skin reactions, immune thrombocytopenia, neutropenia, encephalopathy, myelitis, neuromuscular adverse events[15] including myositis, Guillain-Barré syndrome, myasthenia gravis; myocarditis and cardiac insufficiency, acute adrenal insufficiency, and nephritis.[10] See also
References1. ^{{cite journal | vauthors = Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, Iyer AK | title = PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome | journal = Frontiers in Pharmacology | volume = 8 | pages = 561 | date = 23 August 2017 | pmid = 28878676 | pmc = 5572324 | doi = 10.3389/fphar.2017.00561 }} 2. ^{{cite journal | vauthors = Francisco LM, Sage PT, Sharpe AH | title = The PD-1 pathway in tolerance and autoimmunity | journal = Immunological Reviews | volume = 236 | pages = 219–42 | date = July 2010 | pmid = 20636820 | pmc = 2919275 | doi = 10.1111/j.1600-065X.2010.00923.x }} 3. ^{{cite journal | vauthors = Zhang YH, Tian M, Tang MX, Liu ZZ, Liao AH | title = Recent Insight into the Role of the PD-1/PD-L1 Pathway in Feto-Maternal Tolerance and Pregnancy | journal = American Journal of Reproductive Immunology | volume = 74 | issue = 3 | pages = 201–8 | date = September 2015 | pmid = 25640631 | doi = 10.1111/aji.12365 }} 4. ^{{cite journal | vauthors = Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, Murayama T, Grimm M, Waaga AM, Ueno T, Padera RF, Yagita H, Azuma M, Shin T, Blazar BR, Rothstein DM, Sayegh MH, Najafian N | title = PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection | journal = Journal of Immunology | volume = 179 | issue = 8 | pages = 5204–10 | date = October 2007 | pmid = 17911605 | pmc = 2291549 | doi = 10.4049/jimmunol.179.8.5204 }} 5. ^1 2 3 {{cite journal | vauthors = Sunshine J, Taube JM | title = PD-1/PD-L1 inhibitors | journal = Current Opinion in Pharmacology | volume = 23 | pages = 32–8 | date = August 2015 | pmid = 26047524 | pmc = 4516625 | doi = 10.1016/j.coph.2015.05.011 }} 6. ^{{cite web | title = The Science of PD-1 and Immunotherapy | url = http://blog.dana-farber.org/insight/2015/05/the-science-of-pd-1-and-immunotherapy/ | website = Dana-Farber Cancer Institute | date = 13 May 2015 }} 7. ^{{cite journal |last1=Gong |first1=Jun |last2=Chehrazi-Raffle |first2=Alexander |last3=Reddi |first3=Srikanth |last4=Salgia |first4=Ravi |title=Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations |journal=Journal for Immunotherapy of Cancer |date=23 January 2018 |volume=6 |pages=8 |doi=10.1186/s40425-018-0316-z |pmid=29357948 |pmc=5778665 |issn=2051-1426}} 8. ^1 2 {{cite journal | vauthors = Syn NL, Teng MW, Mok TS, Soo RA | title = De-novo and acquired resistance to immune checkpoint targeting | journal = The Lancet. Oncology | volume = 18 | issue = 12 | pages = e731–e741 | date = December 2017 | pmid = 29208439 | doi = 10.1016/s1470-2045(17)30607-1 }} 9. ^{{cite journal | vauthors = Guha M | name-list-format = vanc | title = Immune checkpoint inhibitors bring new hope to cancer patients | url = http://www.pharmaceutical-journal.com/news-and-analysis/feature/immune-checkpoint-inhibitors-bring-new-hope-to-cancer-patients/20067127.article | journal = The Pharmaceutical Journal | date = 2014 }} 10. ^1 2 3 4 {{cite journal | vauthors = Iwai Y, Hamanishi J, Chamoto K, Honjo T | title = Cancer immunotherapies targeting the PD-1 signaling pathway | journal = Journal of Biomedical Science | volume = 24 | issue = 1 | pages = 26 | date = April 2017 | pmid = 28376884 | pmc = 5381059 | doi = 10.1186/s12929-017-0329-9 }} 11. ^{{cite journal | vauthors = Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA | display-authors = 6 | title = Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer | journal = Science | volume = 348 | issue = 6230 | pages = 124–128 | date = April 2015 | pmid = 25765070 | pmc = 4993154 | doi = 10.1126/science.aaa1348 }} 12. ^{{cite web | first = Jason M. | last = Broderick | name-list-format = vanc | date = 28 November 2017 | title = Avelumab Falls Short in Phase III Gastric Cancer Trial | url = http://www.onclive.com/web-exclusives/avelumab-falls-short-in-phase-iii-gastric-cancer-trial | work = OncLive}} 13. ^[https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-approves-imfinzi-for-unresectable-stage-iii-non-small-cell-lung-cancer-180202018.html AstraZeneca press release, 19 February 2018] 14. ^[https://ir.checkpointtx.com/file/Index?KeyFile=1001234069 Checkpoint Therapeutics press release, 21 March 2018] 15. ^{{Cite journal|last=Johansen|first=Annette|last2=Christensen|first2=Søren Just|last3=Scheie|first3=David|last4=Højgaard|first4=Joan L.S.|last5=Kondziella|first5=Daniel|date=2019-03-08|title=Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies: Systematic review|url=http://www.neurology.org/lookup/doi/10.1212/WNL.0000000000007235|journal=Neurology|language=en|volume=|pages=|doi=10.1212/WNL.0000000000007235|issn=0028-3878|via=}} 2 : Human proteins|Cancer treatments |
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