View source for Biology:PD-1 and PD-L1 inhibitors

{{Short description|Class of anticancer drugs}}
[[Image:PD-L1_positive_lung_adenocarcinoma_--_high_mag.jpg|right|thumb|200px|upright=.85|[[Micrograph]] showing a PD-L1 positive lung adenocarcinoma. 
Positive immunostaining can predict response to the treatment.]]
'''PD-1 inhibitors''' and '''PD-L1 inhibitors''' are a group of [[Biology:Checkpoint inhibitor|checkpoint inhibitor]] anticancer drugs that block the activity of PD-1 and PDL1 [[Biology:Immune checkpoint|immune checkpoint]] proteins present on the surface of cells. Immune checkpoint inhibitors are emerging as a front-line treatment for several types of cancer.<ref name=FIP>{{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 | doi-access = free }}</ref>

PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand 1 ([[Biology:PD-L1|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 [[Biology:Immune system|immune system]] and occurs following infection to limit the killing of bystander host cells and prevent [[Medicine:Autoimmune disease|autoimmune disease]].<ref name="Francisco">{{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 }}</ref> This immune checkpoint is also active in pregnancy,<ref name="Zhang">{{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 | s2cid = 206987352 }}</ref> following tissue allografts,<ref name="Tanaka">{{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 | display-authors = 6 | 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 }}</ref> and in different types of [[Medicine:Cancer|cancer]].<ref name="Sunshine">{{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 }}</ref>
{| class="wikitable floatright"
|+Approved PD-1/PD-L1 inhibitors
!Name
!Target
!Approved
|-
| [[Chemistry:Nivolumab|Nivolumab]]
| PD-1
| 2014
|-
| [[Chemistry:Pembrolizumab|Pembrolizumab]]
| PD-1
| 2014
|-
| [[Chemistry:Atezolizumab|Atezolizumab]]
| [[Biology:PD-L1|PD-L1]]
| 2016
|-
| [[Chemistry:Avelumab|Avelumab]]
| [[Biology:PD-L1|PD-L1]]
| 2017
|-
| [[Chemistry:Durvalumab|Durvalumab]]
| [[Biology:PD-L1|PD-L1]]
| 2017
|-
| [[Chemistry:Cemiplimab|Cemiplimab]]
| PD-1
| 2018 
|-
| [[Chemistry:Dostarlimab|Dostarlimab]]
| PD-1
| 2021
|-
| [[Chemistry:Retifanlimab|Retifanlimab]]
| PD-1
| 2023
|-
| [[Chemistry:Toripalimab|Toripalimab]]
| PD-1
| 2023
|}

== History ==
The concept of blocking PD-1 and PD-L1 for the treatment of cancer was first published in 2001.<ref>{{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 }}</ref> Pharmaceutical companies began attempting to develop drugs to block these molecules, and the first clinical trial was launched in 2006, evaluating [[Chemistry:Nivolumab|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.<ref name=JBS/> By the end of 2017, PD-1/PD-L1 inhibitors had been approved for the treatment of nine forms of cancer.<ref name=gong>{{cite journal | vauthors = Gong J, Chehrazi-Raffle A, Reddi S, Salgia R | 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 | volume = 6 | issue = 1 | pages = 8 | date = January 2018 | pmid = 29357948 | pmc = 5778665 | doi = 10.1186/s40425-018-0316-z | doi-access = free }}</ref>

==Cancer immunotherapy==
In 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.<ref name="Syn_2017">{{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 }}</ref> 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.<ref name="Syn_2017" /> 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.<ref name="Sunshine"/><ref>{{cite journal | vauthors = Goldkuhle M, Dimaki M, Gartlehner G, Monsef I, Dahm P, Glossmann JP, Engert A, von Tresckow B, Skoetz N | display-authors = 6 | title = Nivolumab for adults with Hodgkin's lymphoma (a rapid review using the software RobotReviewer) | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | pages = CD012556 | date = July 2018 | issue = 7 | pmid = 30001476 | pmc = 6513229 | doi = 10.1002/14651858.CD012556.pub2 | editor-last = Cochrane Haematological Malignancies Group }}</ref>

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.<ref name="Sunshine"/> However, de-novo and acquired resistance is still seen in a large proportion of patients.<ref name="Syn_2017" /> Hence PD-L1 inhibitors are considered to be the most promising drug category for many different cancers.<ref name="Sunshine"/><ref name="Guha">{{cite journal | vauthors = Guha M | 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 }}</ref>

Not all patients respond to PD-1/PD-L1 inhibitors. The FDA has approved several assays to measure the level of PD-L1 expressed by tumor cells, in order to predict the likelihood of response to an inhibitor. PD-L1 levels have been found to be highly predictive of response. Higher mutation burden is also predictive of response to anti-PD-1/PD-L1 agents.<ref name=gong/>

PD-1 and PD-L1 inhibitors are closely related to CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitors, such as [[Chemistry:Ipilimumab|ipilimumab]]. PD-1 and CTLA-4 are both expressed on activated T cells, but at different phases of immune response.<ref name=JBS>{{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 | doi-access = free }}</ref>

Current clinical trials are evaluating anti-PD-1 and PD-L1 drugs in combination with other immunotherapy drugs blocking [[Biology:LAG3|LAG3]], B7-H3, [[Biology:Killer-cell immunoglobulin-like receptor|KIR]], OX40, PARP, [[Biology:CD27|CD27]], and ICOS.<ref name=JBS/>

==Therapeutics==
=== PD-1 ===

'''[[Chemistry:Pembrolizumab|Pembrolizumab]]''' (Keytruda, formerly MK-3475 and lambrolizumab) was developed by Merck and first approved by the [[Organization:Food and Drug Administration|Food and Drug Administration]] in 2014 for the treatment of [[Medicine:Melanoma|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.<ref>{{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 = 124–8 | date = April 2015 | pmid = 25765070 | pmc = 4993154 | doi = 10.1126/science.aaa1348 }}</ref>

'''[[Chemistry:Nivolumab|Nivolumab]]''' (Opdivo) was developed by [[Company:Bristol-Myers Squibb|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 [[Medicine:Hodgkin's lymphoma|Hodgkin's lymphoma]].

'''[[Chemistry:Cemiplimab|Cemiplimab]]''' (Libtayo) was developed by Regeneron Pharmaceuticals 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.

'''[[Chemistry:Dostarlimab|Dostarlimab]]''' (Jemperli) – was developed by [[Company:GlaxoSmithKline|GlaxoSmithKline]] and was first approved for the treatment of mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer by the FDA in April of 2021.<ref>{{cite journal | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-endometrial-cancer | title=FDA grants accelerated approval to dostarlimab-gxly for DMMR endometrial cancer | journal=FDA | date=11 June 2021 }}</ref>  On August 17, 2021, the FDA granted accelerated approval for the treatment of mismatch repair deficient (dMMR) recurrent or advanced solid tumors.<ref>{{cite journal | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors | title=FDA grants accelerated approval to dostarlimab-gxly for DMMR advanced solid tumors | journal=FDA | date=February 2022 }}</ref>

'''[[Chemistry:Retifanlimab|Retifanlimab]]''' (Zynyz) was developed by Incyte and first granted accelerated approval by the FDA in March 2023 for the treatment of Merkel cell carcinoma (MCC).

'''[[Chemistry:Toripalimab|Toripalimab]]''' (Loqtorzi) is a humanized IgG4 monoclonal antibody against PD-1 approved in China in 2018 and in the United States in 2023.<ref>{{Cite web|url=https://adisinsight.springer.com/drugs/800046697|title=Toripalimab - Shanghai Junshi Biosciences - AdisInsight|website=adisinsight.springer.com|access-date=2019-08-25}}</ref><ref name=Keam>{{cite journal | author = Keam, S.J. | title = Toripalimab: First Global Approval | journal = Drugs | volume = 79 | pages = 573–578 | date = 2019 | issue = 5 | doi = 10.1007/s40265-019-01076-2 | pmid = 30805896 | doi-access = free }}</ref><ref>{{cite web | url = https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-toripalimab-tpzi-nasopharyngeal-carcinoma | title = FDA approves toripalimab-tpzi for nasopharyngeal carcinoma | publisher = US Food and Drug Administration | date = October 27, 2023}}</ref>

==== Experimental ====
Currently, many PD-1 inhibitors are under development:<ref name=JBS/>
*Vopratelimab (JTX-4014) by [https://jouncetx.com/our-pipeline/#our-pipeline Jounce Therapeutics]<ref>{{Cite web|title=Our Pipeline {{!}} Jounce Therapeutics|url=https://jouncetx.com/our-pipeline/|access-date=2020-09-19|language=en-US}}</ref>  As of 2020 entered Phase I trial<ref>{{Cite journal|last=Jounce Therapeutics, Inc.|date=2020-09-02|title=Phase 1 First in Human Study of Programmed Cell Death Receptor-1 (PD-1) Inhibitor Monoclonal Antibody (mAb) JTX-4014 in Adult Subjects With Advanced Refractory Solid Tumor Malignancies|url=https://clinicaltrials.gov/ct2/show/NCT03790488}}</ref>
*Spartalizumab (PDR001) is a PD-1 inhibitor developed by [[Company:Novartis|Novartis]] to treat both solid tumors and lymphomas, which as of 2018 has entered Phase III trials.<ref>{{cite journal | vauthors = Kopp-Kubel S | title = International Nonproprietary Names (INN) for pharmaceutical substances | journal = Bulletin of the World Health Organization | volume = 73 | issue = 3 | pages = 275–9 | date = 1978-04-01 | pmid = 7614659 | pmc = 2486664 | doi = 10.1093/ajhp/35.4.477a }}</ref><ref>{{Cite web|url=https://immuno-oncologynews.com/pdr001/|title=PDR001|website=Immuno-Oncology News|date=2017-10-25|access-date=2019-08-24}}</ref><ref>{{Cite web|url=https://www.cancer.gov/publications/dictionaries/cancer-drug|title=NCI Drug Dictionary|date=2011-02-02|website=National Cancer Institute|access-date=2019-08-24}}</ref>
*Camrelizumab (SHR1210) is an anti-PD-1 monoclonal antibody introduced by Jiangsu HengRui Medicine Co., Ltd. that recently received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma.<ref>{{cite journal | vauthors = Markham A, Keam SJ | title = Camrelizumab: First Global Approval | journal = Drugs | volume = 79 | issue = 12 | pages = 1355–1361 | date = August 2019 | pmid = 31313098 | doi = 10.1007/s40265-019-01167-0 | s2cid = 197422122 }}</ref>
*[[Chemistry:Sintilimab|Sintilimab]]  (IBI308), a human anti-PD-1 antibody developed by Innovent and [[Company:Eli Lilly and Company|Eli Lilly]] for patients with non-small cell lung cancer (NSCLC).<ref>{{Cite web|url=https://adisinsight.springer.com/drugs/800048000|title=Sintilimab - Eli Lilly/Innovent Biologics - AdisInsight|website=adisinsight.springer.com|access-date=2019-08-25}}</ref> 
*Tislelizumab (BGB-A317) is a humanized IgG4 anti–PD-1 monoclonal antibody in pivotal Phase 3 and Phase 2 clinical trials in solid tumors and hematologic cancers.<ref>{{Cite journal|date=1889-01-01|journal=The Library|volume=s1-1|issue=1|pages=215|doi=10.1093/library/s1-1.1.215-b|issn=0024-2160|title=Library Association-Annual Meeting}}</ref>
*INCMGA00012 (MGA012) is a humanized IgG4 monoclonal antibody developed by Incyte and MacroGenics.<ref>{{Cite web|url=https://investor.incyte.com/news-releases/news-release-details/incyte-and-macrogenics-announce-global-collaboration-and|title=Incyte Press Release|website=investor.incyte.com|access-date=2020-04-20}}</ref>
*AMP-224 by [[Company:AstraZeneca|AstraZeneca]]/[[Company:MedImmune|MedImmune]] and [[Company:GlaxoSmithKline|GlaxoSmithKline]]<ref>{{Cite web|url=https://clinicaltrials.gov/ct2/show/NCT01352884|title=Study to Assess the Safety, Tolerability, and Pharmacokinetics of AMP-224 in Patients With Advanced Cancer|website=www.clinicaltrials.gov|access-date=2020-04-24}}</ref>
*AMP-514 (MEDI0680) by [[Company:AstraZeneca|AstraZeneca]]<ref>{{Cite web|url=https://www.fiercebiotech.com/biotech/astrazeneca-cans-pd-1-centerpiece-500m-buyout-pipeline-cull|title=AstraZeneca stops monotherapy study at centerpiece of $500M buyout|website=www.fiercebiotech.com|date=2 February 2018 |access-date=2020-04-24}}</ref>
*Acrixolimab (YBL-006) by [https://ybiologics.com/ Y-Biologics]<ref>{{Cite news |last=kgi-admin |date=2023-02-24 |title=Acrixolimab by Y-Biologics for Solid Tumor: Likelihood of Approval |url=https://www.pharmaceutical-technology.com/data-insights/acrixolimab-y-biologics-solid-tumor-likelihood-of-approval/ |access-date=2023-03-07 |website=Pharmaceutical Technology |language=en-US}}</ref>

=== PD-L1 ===

'''[[Chemistry:Atezolizumab|Atezolizumab]]''' (Tecentriq) is a fully humanised [[Biology:Immunoglobulin G#Subclasses|IgG1 (immunoglobulin 1)]] antibody developed by Roche [[Company:Genentech|Genentech]]. In 2016, the FDA approved atezolizumab for urothelial carcinoma and non-small cell lung cancer.

'''[[Chemistry:Avelumab|Avelumab]]''' (Bavencio) is a fully human IgG1 antibody developed by Merck Serono and [[Company:Pfizer|Pfizer]]. Avelumab is FDA approved for the treatment of metastatic [[Medicine:Merkel-cell carcinoma|merkel-cell carcinoma]]. It failed phase III clinical trials for gastric cancer.<ref>{{cite web | first = Jason M. | last = Broderick | name-list-style = 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}}</ref>

'''[[Chemistry:Durvalumab|Durvalumab]]''' (Imfinzi) is a fully human IgG1 antibody developed by [[Company:AstraZeneca|AstraZeneca]]. Durvalumab is FDA approved for the treatment of urothelial carcinoma and unresectable non-small cell lung cancer after chemoradiation.<ref name=AstraZeneca>[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]</ref>

==== Experimental ====
At least two PD-L1 inhibitors are in the experimental phase of development.

*'''KN035''' is the only PD-L1 antibody with subcutaneous formulation currently under clinical evaluations in the US, China, and Japan<ref>{{cite journal | vauthors = Zhang F, Wei H, Wang X, Bai Y, Wang P, Wu J, Jiang X, Wang Y, Cai H, Xu T, Zhou A | display-authors = 6 | title = Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade | journal = Cell Discovery | volume = 3 | issue = 1 | pages = 17004 | date = December 2017 | pmid = 28280600 | pmc = 5341541 | doi = 10.1038/celldisc.2017.4 }}</ref>
*'''Cosibelimab (CK-301)''' by Checkpoint Therapeutics is a PD-L1 inhibitor developed by Dana Farber, and is currently in Phase 3 trials for NSCLC<ref>{{Cite web|title=Checkpoint Therapeutics to Participate in Two Upcoming Investor Conferences|url=https://finance.yahoo.com/news/checkpoint-therapeutics-participate-two-upcoming-123000062.html|access-date=2021-09-20|website=finance.yahoo.com|date=9 September 2021 |language=en-US}}</ref>
*'''AUNP12'''  is a 29-mer peptide as the first peptic PD-1/PD-L1 inhibitor developed by Aurigene and Laboratoires Pierre Fabre that is being evaluated in [[Engineering:Clinical trial|clinical trial]], following promising [[In vitro|''in'' ''vitro'']] results.<ref>{{cite journal | vauthors = Juneja VR, McGuire KA, Manguso RT, LaFleur MW, Collins N, Haining WN, Freeman GJ, Sharpe AH | display-authors = 6 | title = PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity | journal = The Journal of Experimental Medicine | volume = 214 | issue = 4 | pages = 895–904 | date = April 2017 | pmid = 28302645 | pmc = 5379970 | doi = 10.1084/jem.20160801 }}</ref>
*'''CA-170,''' discovered by Aurigene/Curis as the PD-L1 and [[Biology:VISTA (protein)|VISTA]] antagonist, was indicted as a potent small molecule inhibitor ''in vitro''.  Thus, the compound is currently under phase I clinical trial over [[Medicine:Mesothelioma|mesothelioma]] patients.<ref>{{cite journal | vauthors = Okazaki T, Honjo T | title = The PD-1-PD-L pathway in immunological tolerance | journal = Trends in Immunology | volume = 27 | issue = 4 | pages = 195–201 | date = April 2006 | pmid = 16500147 | doi = 10.1016/j.it.2006.02.001 }}</ref>
*'''BMS-986189''' is a [[Chemistry:Macrocycle|macrocyclic]] peptide discovered by [[Company:Bristol-Myers Squibb|Bristol-Myers Squibb]] of which the [[Medicine:Pharmacokinetics|pharmacokinetics]], safety and tolerability is currently being studied on healthy subjects.<ref>{{Cite journal|url=https://clinicaltrials.gov/ct2/show/NCT02739373|title=Pharmacokinetics, Safety, Tolerability and Pharmacodynamics of BMS-986189 in Healthy Subjects - Full Text View - ClinicalTrials.gov|website=clinicaltrials.gov|date=5 February 2018 |access-date=2019-08-24}}</ref>

== Combinational therapy ==

=== Combination with type I Interferons ===
[[Biology:Programmed cell death protein 1|PD-1]]/[[Biology:PD-L1|PD-L1]] blockade therapy is not effective for all patients, as some may exhibit resistance. To overcome resistance, a strategy involving the combination of PD-1/PD-L1 inhibitors with [[Biology:Interferon type I|type I interferons]] has emerged. The combination of PD-1/PD-L1 inhibitors and [[Biology:Interferon type I|type I interferons]] has shown promise in preclinical and clinical studies (phases I and II). This combination therapy leads to increased infiltration and activation of T cells within tumors, the generation of [[Biology:Memory T cell|memory T cells]], and improved overall survival in both animal models and patients. Notably, this approach has demonstrated efficacy in [[Medicine:Melanoma|melanoma]] and renal carcinoma patients. <ref>{{Cite journal |last1=Razaghi |first1=Ali |last2=Durand-Dubief |first2=Mickaël |last3=Brusselaers |first3=Nele |last4=Björnstedt |first4=Mikael |date=2023 |title=Combining PD-1/PD-L1 blockade with type I interferon in cancer therapy |journal=Frontiers in Immunology |volume=14 |doi=10.3389/fimmu.2023.1249330 |pmid=37691915 |pmc=10484344 |issn=1664-3224|doi-access=free }}</ref>

== Adverse effects ==
Immunotherapies as a group have off-target effects and toxicities common to them. Some of these include interstitial pneumonitis, [[Medicine:Colitis|colitis]], hepatitis, thyroiditis, skin reactions, low levels of platelets and white blood cells, inflammation of the brain or spinal cord, neuromuscular adverse events<ref>{{cite journal | vauthors = Johansen A, Christensen SJ, Scheie D, Højgaard JL, Kondziella D | title = Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies: Systematic review | journal = Neurology | volume = 92 | issue = 14 | pages = 663–674 | date = April 2019 | pmid = 30850443 | doi = 10.1212/WNL.0000000000007235 | s2cid = 73496636 }}</ref> including [[Medicine:Myositis|myositis]], Guillain-Barré syndrome, [[Medicine:Myasthenia gravis|myasthenia gravis]]; [[Medicine:Myocarditis|myocarditis]] and cardiac insufficiency, acute adrenal insufficiency, and [[Medicine:Nephritis|nephritis]].<ref name=JBS/>  The most common kidney related changes are acute interstitial nephritis, followed by glomerular diseases and then tubular damage.<ref>{{cite journal | vauthors = Wanchoo R, Karam S, Uppal NN, Barta VS, Deray G, Devoe C, Launay-Vacher V, Jhaveri KD | display-authors = 6 | title = Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review | journal = American Journal of Nephrology | volume = 45 | issue = 2 | pages = 160–169 | year = 2017 | pmid = 28076863 | doi = 10.1159/000455014 | doi-access = free }}</ref> The detailed mechanism of these adverse effects are not fully elucidated;<ref>{{cite journal | vauthors = Postow MA, Sidlow R, Hellmann MD | title = Immune-Related Adverse Events Associated with Immune Checkpoint Blockade | journal = The New England Journal of Medicine | volume = 378 | issue = 2 | pages = 158–168 | date = January 2018 | pmid = 29320654 | doi = 10.1056/NEJMra1703481 | s2cid = 5211582 }}</ref> however, they are clearly different from known autoimmune diseases.<ref>{{cite journal | vauthors = Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, Guminski A, Puzanov I, Lawrence DP, Buchbinder EI, Mudigonda T, Spencer K, Bender C, Lee J, Kaufman HL, Menzies AM, Hassel JC, Mehnert JM, Sosman JA, Long GV, Clark JI | display-authors = 6 | title = Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders | journal = JAMA Oncology | volume = 2 | issue = 2 | pages = 234–40 | date = February 2016 | pmid = 26633184 | doi = 10.1001/jamaoncol.2015.4368 | doi-access = free }}</ref> Immune-mediated adverse reactions are usually attributed to generalised dysregulation of T cells<ref>{{cite journal | vauthors = Oh DY, Cham J, Zhang L, Fong G, Kwek SS, Klinger M, Faham M, Fong L | display-authors = 6 | title = Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire | journal = Cancer Research | volume = 77 | issue = 6 | pages = 1322–1330 | date = March 2017 | pmid = 28031229 | pmc = 5398199 | doi = 10.1158/0008-5472.CAN-16-2324 }}</ref> or development of autoantibodies,<ref>{{cite journal | vauthors = Young A, Quandt Z, Bluestone JA | title = The Balancing Act between Cancer Immunity and Autoimmunity in Response to Immunotherapy | journal = Cancer Immunology Research | volume = 6 | issue = 12 | pages = 1445–1452 | date = December 2018 | pmid = 30510057 | pmc = 6281171 | doi = 10.1158/2326-6066.CIR-18-0487 }}</ref> although memory T cell responses against occult viral infections might also play a role in some patients with advanced melanoma following combined PD-1/CTLA-4 blockade.<ref>{{cite journal | vauthors = Hutchinson JA, Kronenberg K, Riquelme P, Wenzel JJ, Glehr G, Schilling HL, Zeman F, Evert K, Schmiedel M, Mickler M, Drexler K, Bitterer F, Cordero L, Beyer L, Bach C, Koestler J, Burkhardt R, Schlitt HJ, Hellwig D, Werner JM, Spang R, Schmidt B, Geissler EK, Haferkamp S | display-authors = 6 | title = Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis | journal = Nature Communications | volume = 12 | issue = 1 | pages = 1439 | date = March 2021 | pmid = 33664251 | doi = 10.1038/s41467-021-21572-y | pmc = 7933278 | bibcode = 2021NatCo..12.1439H | doi-access = free }}</ref>

When compared with standard chemotherapeutic agents, PD-1/PD-L1 inhibitors had a lower reported incidence of fatigue, sensory neuropathy, diarrhea, bone marrow suppression, loss of appetite, nausea, and constipation.<ref name=gong/>

== See also ==
*[[Chemistry:Cancer immunotherapy#Immune checkpoints|Cancer immunotherapy - Immune checkpoints]]
*[[Biology:Checkpoint inhibitor#Intracellular Checkpoint Inhibitors|Intracellular checkpoints - CISH]]

== References ==
{{Reflist}}

[[Category:Human proteins]]

{{Sourceattribution|PD-1 and PD-L1 inhibitors}}