Ipilimumab

{{Short description|Pharmaceutical drug}} {{Use dmy dates|date=August 2025}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 458270765 | type = mab | image = Ipilimumab 5TRU.png | alt = | caption = Fab fragment of ipilimumab (blue) binding CTLA-4 (green). From PDB entry {{PDBe|5TRU}}.

| mab_type = mab | source = u | target = CTLA-4

| pronounce = i pi lim′ ue mab | tradename = Yervoy | Drugs.com = {{drugs.com|monograph|ipilimumab}} | MedlinePlus = a611023 | DailyMedID = Ipilimumab | pregnancy_AU = C | pregnancy_AU_comment = | pregnancy_category= | routes_of_administration = Intravenous | class = | ATC_prefix = L01 | ATC_suffix = FX04

| legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = /{{nbsp}}Schedule D<ref>{{cite web | title=Regulatory Decision Summary for Yervoy | website=Drug and Health Products Portal | date=7 December 2023 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1706819201300 | access-date=2 April 2024}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref>{{cite web | title=Yervoy 5 mg/ml concentrate for solution for infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=3 August 2020 | url=https://www.medicines.org.uk/emc/product/4683 | access-date=2 October 2020}}</ref> | legal_US = Rx-only | legal_US_comment = <ref name="Yervoy FDA label">{{cite web | title=Yervoy- ipilimumab injection | website=DailyMed | date=13 August 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2265ef30-253e-11df-8a39-0800200c9a66 | access-date=2 October 2020}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Yervoy EPAR">{{cite web | title=Yervoy EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/yervoy | access-date=2 October 2020}}</ref> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 477202-00-9 | CAS_supplemental = | PubChem = | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB06186 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = none | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 6T8C155666 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D04603 | ChEBI_Ref = | ChEBI = | ChEMBL_Ref = | ChEMBL = 1789844 | NIAID_ChemDB = | PDB_ligand = | synonyms = BMS-734016,<ref>{{cite web|title=Yervoy, ipilimumab (BMS-734016) - Product Profile - BioCentury|url=http://www.biocentury.com/products/bms-734016|website=BioCentury Online Intelligence|publisher=BioCentury Publications|access-date=11 August 2016}}</ref> MDX-010,<ref>{{cite press release | url = http://www.ama-assn.org/resources/doc/usan/ipilimumab2.doc | title = STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL - ipilimumab | author = USAN | publisher = American Medical Association (AMA) | access-date = 12 January 2013 | archive-date = 23 February 2016 | archive-url = https://web.archive.org/web/20160223223857/http://www.ama-assn.org/resources/doc/usan/ipilimumab2.doc | url-status = dead }}</ref> MDX-101

| C=6742 | H=9972 | N=1732 | O=2004 | S=40 }}

'''Ipilimumab''', sold under the brand name '''Yervoy''', is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction.<ref name="pmid29208439">{{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> Ipilimumab turns off this inhibitory mechanism and boosts the body's immune response against cancer cells.<ref name="pmid29208439"/><ref name="Ribas"/>

Ipilimumab was approved by the US Food and Drug Administration in March 2011, for the treatment of melanoma, renal cell carcinoma (RCC), colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC), malignant pleural mesothelioma, and esophageal cancer.<ref>{{cite web |title=Yervoy |url=https://www.opdivo.com/ |website=Opdivo |publisher=Bristol Myers Squibb |access-date=7 February 2024}}</ref><ref name="FDA approval package">{{cite web | title=Drug Approval Package: Yervoy (ipilimumab) Injection NDA #125377 | website=U.S. Food and Drug Administration (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125377Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20131103110052/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125377Orig1s000TOC.cfm | url-status=dead | archive-date=3 November 2013 | access-date=2 October 2020}}</ref><ref>{{cite book| vauthors = Lacroix M |title=Targeted Therapies in Cancer|date=2014|publisher=Nova Sciences Publishers|location=Hauppauge, NY|isbn=978-1-63321-687-7|url=https://www.novapublishers.com/catalog/product_info.php?products_id=50994|access-date=13 July 2014|archive-url=https://web.archive.org/web/20150626172243/https://www.novapublishers.com/catalog/product_info.php?products_id=50994|archive-date=26 June 2015|url-status=dead}}</ref><ref name="NYT-20150529">{{cite news | vauthors = Pollack A |title=New Class of Drugs Shows More Promise in Treating Cancer |url=https://www.nytimes.com/2015/05/30/business/new-class-of-drugs-shows-more-promise-in-treating-cancer.html |date=29 May 2015 |work=New York Times |access-date=30 May 2015 }}</ref> It is undergoing{{when|date=October 2020}} clinical trials for the treatment of bladder cancer<ref name="NCT991">{{ClinicalTrialsGov|NCT01524991|First-Line Gemcitabine, Cisplatin + Ipilimumab for Metastatic Urothelial Carcinoma}} (completed)</ref> and metastatic hormone-refractory prostate cancer.<ref>{{ClinicalTrialsGov|NCT00323882|Phase I/II Study of MDX-010 in Patients With Metastatic Hormone-Refractory Prostate Cancer (MDX010-21)}} (completed)</ref>

The concept of using anti-CTLA4 antibodies to treat cancer was first developed by James P. Allison while he was director of the Cancer Research Laboratory at the University of California, Berkeley.<ref name="auto">{{cite journal | vauthors = Leach DR, Krummel MF, Allison JP | title = Enhancement of antitumor immunity by CTLA-4 blockade | journal = Science | volume = 271 | issue = 5256 | pages = 1734–1736 | date = March 1996 | pmid = 8596936 | doi = 10.1126/science.271.5256.1734 | s2cid = 7215817 | bibcode = 1996Sci...271.1734L }}</ref><ref>{{Cite web|url=https://crl.berkeley.edu/discoveries/the-story-of-yervoy-ipilimumab/|title=UC Berkeley Cancer Research Lab » The Story of Yervoy (Ipilimumab)|website=crl.berkeley.edu}}</ref> Clinical development of anti-CTLA4 was initiated by Medarex, which was later acquired by Bristol-Myers Squibb. For his work in developing ipilimumab, Allison was awarded the Lasker Award in 2015.<ref>{{cite web|url=http://www.laskerfoundation.org/awards/2015_c_description.htm|title=Deep brain stimulation for Parkinson's disease|author=Lasker Foundation|work=The Lasker Foundation}}</ref> Allison later was the co-winner of the 2018 Nobel Prize in Physiology or Medicine.<ref>{{cite web | url=https://ki.se/en/news/the-nobel-prize-in-physiology-or-medicine-2018-to-james-p-allison-and-tasuku-honjo | title=The Nobel Prize in Physiology or Medicine 2018 to James P. Allison and Tasuku Honjo | access-date=1 October 2018 | archive-date=24 December 2018 | archive-url=https://web.archive.org/web/20181224054528/https://ki.se/en/news/the-nobel-prize-in-physiology-or-medicine-2018-to-james-p-allison-and-tasuku-honjo | url-status=dead }}</ref>

== Medical uses == Ipilimumab was approved by the US Food and Drug Administration in March 2011, to treat people with late-stage melanoma that has spread or cannot be removed by surgery.<ref name="pmid29208439"/><ref name="FDA approval package" /><ref name="FDA PR 20110325">{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm |title=FDA approves new treatment for a type of late-stage skin cancer |date=25 March 2011 |archive-url=https://web.archive.org/web/20110327063147/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm |archive-date=27 March 2011 |publisher=U.S. Food and Drug Administration (FDA) |access-date=25 March 2011 | url-status=dead }}</ref><ref>{{cite news |url=https://www.nytimes.com/2011/03/26/business/26drug.html |title=Approval for Drug That Treats Melanoma | vauthors = Pollack A |date=25 March 2011 |work=The New York Times |access-date=27 March 2011 }}</ref><ref name="Drugs.com" /> It was later approved by the FDA in October 2015, for stage 3 patients as adjuvant therapy.<ref>{{cite press release |title=FDA approves Yervoy to reduce the risk of melanoma returning after surgery |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469944.htm |publisher=U.S. Food and Drug Administration (FDA) |date=28 October 2015 |access-date=8 April 2019 | archive-url=https://web.archive.org/web/20151029103812/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469944.htm | archive-date=29 October 2015 |url-status=dead }}</ref> On 1 February 2012, Health Canada approved ipilimumab for "treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease."<ref>{{cite press release |author= |title=First an only treatment to extend survival for people with metastatic melanoma, the most deadly form of skin cancer, approved in Canada |url=https://www.bms.com/ca/en/media/press-release-listing/2012-02-07-press-release.html |publisher=Bristol-Myers Squibb |date=7 February 2012 |access-date=8 April 2019 |archive-date=8 April 2019 |archive-url=https://web.archive.org/web/20190408193124/https://www.bms.com/ca/en/media/press-release-listing/2012-02-07-press-release.html |url-status=dead }}</ref> Ipilimumab was authorized in the European Union (EU), for second line treatment of metastatic melanoma in November 2012.<ref>{{cite press release|url=https://news.bms.com/news/r-and-d/2012/Bristol-Myers-Squibb-Receives-Positive-Decision-from-National-Institute-of-Health-and-Clinical-Excellence-NICE-for-YERVOY-ipilimumab/default.aspx|title=Bristol-Myers Squibb Receives Positive Decision from National Institute of Health and Clinical Excellence (NICE) for Yervoy (ipilimumab)|date=1 November 2012|access-date=17 December 2012|archive-date=5 February 2017|archive-url=https://web.archive.org/web/20170205103404/http://news.bms.com/press-release/rd-news/bristol-myers-squibb-receives-positive-decision-national-institute-health-and-|url-status=dead}}</ref><ref>{{cite journal | vauthors = Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, He Y, Burrall B, Duong C, Kloxin AM, Sultani H, Wilken R, Martinez SR, Patel F | title = Metastatic melanoma - a review of current and future treatment options | journal = Acta Dermato-Venereologica | volume = 95 | issue = 5 | pages = 516–524 | date = May 2015 | pmid = 25520039 | doi = 10.2340/00015555-2035 | doi-access = free }}</ref>

Nivolumab, in combination with ipilimumab is indicated for treating the following:

* intermediate or poor risk, previously untreated advanced renal cell carcinoma<ref name="Yervoy FDA label" /><ref>{{cite web | title=FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma | website=U.S. Food and Drug Administration (FDA) | date=16 April 2018 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell | archive-url=https://web.archive.org/web/20190614030318/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell | url-status=dead | archive-date=14 June 2019 | access-date=2 October 2020}} {{PD-notice}}</ref>

* people aged 12 years and older with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.<ref name="Yervoy FDA label" /><ref>{{cite web | title=FDA grants accelerated approval to ipilimumab for MSI-H or dMMR metastatic colorectal cancer | website=U.S. Food and Drug Administration (FDA) | date=10 July 2018 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ipilimumab-msi-h-or-dmmr-metastatic-colorectal-cancer | archive-url=https://web.archive.org/web/20190928090526/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ipilimumab-msi-h-or-dmmr-metastatic-colorectal-cancer | url-status=dead | archive-date=28 September 2019 | access-date=2 October 2020}} {{PD-notice}}</ref>

* people with hepatocellular carcinoma who have been previously treated with sorafenib.<ref name="Yervoy FDA label" /><ref>{{cite web | title=FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma | website=U.S. Food and Drug Administration (FDA) | date=10 March 2020 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma | archive-url=https://web.archive.org/web/20200901190503/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma | url-status=dead | archive-date=1 September 2020 | access-date=2 October 2020}} {{PD-notice}}</ref>

* a first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test.<ref name="Yervoy FDA label" /><ref>{{cite web | title=FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%) | website=U.S. Food and Drug Administration (FDA) | date=15 May 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1 | archive-url=https://web.archive.org/web/20200527175524/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1 | url-status=dead | archive-date=27 May 2020 | access-date=2 October 2020}} {{PD-notice}}</ref><ref>{{cite web | title=FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC | website=U.S. Food and Drug Administration (FDA) | date=26 May 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc | archive-url=https://web.archive.org/web/20200606115328/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc | url-status=dead | archive-date=6 June 2020 | access-date=2 October 2020}} {{PD-notice}}</ref>

In October 2020, the FDA approved the combination of nivolumab with ipilimumab for the first-line treatment of adults with malignant pleural mesothelioma that cannot be removed by surgery.<ref name="FDA PR 20201002">{{cite press release | title=FDA Approves Drug Combination for Treating Mesothelioma | website=U.S. Food and Drug Administration (FDA) | date=2 October 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-drug-combination-treating-mesothelioma | archive-url=https://web.archive.org/web/20201004060617/https://www.fda.gov/news-events/press-announcements/fda-approves-drug-combination-treating-mesothelioma | url-status=dead | archive-date=4 October 2020 | access-date=2 October 2020}} {{PD-notice}}</ref> This is the first drug regimen approved for mesothelioma in 16 years and the second FDA-approved systemic therapy for mesothelioma.<ref name="FDA PR 20201002" />

In April 2025, the FDA approved nivolumab with ipilimumab for people aged 12 years and older with unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer.<ref name="FDA 20250408" /> The FDA also converted the accelerated approval to regular approval for single agent nivolumab for people aged 12 years and older with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer, that has progressed following fluoropyrimidine, oxaliplatin, and irinotecan.<ref name="FDA 20250408">{{cite web | title=FDA approves nivolumab with ipilimumab for colorectal cancer | website=U.S. Food and Drug Administration | date=8 April 2025 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer | access-date=10 April 2025}} {{PD-notice}}</ref>

== Adverse effects == A major drawback of ipilimumab therapy is its association with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation, occurring in 10% to 20% of patients.<ref name=2015therAdvRev>{{cite journal | vauthors = Johnson DB, Peng C, Sosman JA | title = Nivolumab in melanoma: latest evidence and clinical potential | journal = Therapeutic Advances in Medical Oncology | volume = 7 | issue = 2 | pages = 97–106 | date = March 2015 | pmid = 25755682 | pmc = 4346215 | doi = 10.1177/1758834014567469 }}</ref> Serious adverse effects include stomach pain, bloating, constipation, diarrhea, fever, trouble breathing, and urinating problems. A "risk evaluation and mitigation strategy" informs prescribers of the potential risks.<ref name="Drugs.com">Drugs.com: [https://www.drugs.com/yervoy.html Yervoy]</ref><ref>{{cite web | url = http://www.genengnews.com/gen-news-highlights/fda-rubber-stamps-bristol-myers-squibb-s-melanoma-mab/81244882/ | title = FDA Rubber-Stamps Bristol-Myers Squibb's Melanoma mAb | date = 28 March 2011 | publisher = Genetic Engineering & Biotechnology News | access-date = 28 March 2011 | archive-date = 1 April 2011 | archive-url = https://web.archive.org/web/20110401210253/http://www.genengnews.com/gen-news-highlights/fda-rubber-stamps-bristol-myers-squibb-s-melanoma-mab/81244882/ | url-status = dead }}</ref>

Between 5.7% and 9.1% of individuals treated with ipilimumab develop checkpoint inhibitor induced colitis.<ref name=Bella>{{cite journal | vauthors = Bellaguarda E, Hanauer S | title = Checkpoint Inhibitor-Induced Colitis | journal = The American Journal of Gastroenterology | volume = 115 | issue = 2 | pages = 202–210 | date = February 2020 | pmid = 31922959 | doi = 10.14309/ajg.0000000000000497 | s2cid = 210150535 | doi-access = }}</ref>

Individual cases of severe neurologic disorders following ipilimumab have been observed, including acute inflammatory demyelination polyneuropathy and an ascending motor paralysis, and myasthenia gravis.<ref>{{cite web | url = http://www.medscape.com/viewarticle/824347 | title = Two Cases of Myasthenia Gravis Seen With Ipilimumab | date = 29 April 2014 }}</ref>

== Interactions == The combination of ipilimumab with either leflunomide or vemurafenib may lead to increased hepatotoxicity.<ref name="Yervoy FDA label" /><ref name="Arava FDA label">{{cite web | title=Arava- leflunomide tablet, film coated | website=DailyMed | date=30 October 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=320f63f2-fac3-4aee-aff8-85724e00ef52 | access-date=10 April 2025}}</ref><ref>{{cite journal | vauthors = Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J | title = Hepatotoxicity with combination of vemurafenib and ipilimumab | journal = The New England Journal of Medicine | volume = 368 | issue = 14 | pages = 1365–1366 | date = April 2013 | pmid = 23550685 | doi = 10.1056/NEJMc1302338 | doi-access = free }}</ref><ref name="Zelboraf FDA label">{{cite web | title=Zelboraf- vemurafenib tablet, film coated | website=DailyMed | date=8 November 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38eea320-7e0c-485a-bc30-98c3c45e2763 | access-date=10 April 2025}}</ref>

== Mechanism of action == T lymphocytes can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows the lymphocytes to continue to destroy cancer cells.<ref name="Ribas">{{cite journal | vauthors = Ribas A | title = Tumor immunotherapy directed at PD-1 | journal = The New England Journal of Medicine | volume = 366 | issue = 26 | pages = 2517–2519 | date = June 2012 | pmid = 22658126 | doi = 10.1056/nejme1205943 }}</ref>

Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes. The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.<ref name="Ribas"/>

Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells.<ref name="Ribas"/><ref name="pmid20616954">{{cite journal | vauthors = Tarhini AA, Iqbal F | title = CTLA-4 blockade: therapeutic potential in cancer treatments | journal = OncoTargets and Therapy | volume = 3 | pages = 15–25 | date = June 2010 | pmid = 20616954 | pmc = 2895779 | doi = 10.2147/ott.s4833 | doi-access = free }}</ref><ref name="pmid19648604">{{cite journal | vauthors = Robert C, Ghiringhelli F | title = What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? | journal = The Oncologist | volume = 14 | issue = 8 | pages = 848–861 | date = August 2009 | pmid = 19648604 | doi = 10.1634/theoncologist.2009-0028 | doi-access = free }}</ref><ref>{{cite book| vauthors = Wilkes GM, Barton-Burke M |title=2010 oncology nursing drug handbook|url=https://books.google.com/books?id=3_zMtsAA39MC&pg=RA1-PA588|access-date=30 March 2011|date=11 December 2009|publisher=Jones & Bartlett Learning|isbn=978-0-7637-8124-8|pages=1–}}</ref><ref>{{cite book| vauthors = Reddy LH, Couvreur P |title=Macromolecular Anticancer Therapeutics|url=https://books.google.com/books?id=fYPRZ7cJQE4C&pg=PA522|access-date=30 March 2011|date=1 June 2009|publisher=Springer|isbn=978-1-4419-0506-2|pages=522–}}</ref><ref>{{cite book| vauthors = An Z |title=Therapeutic Monoclonal Antibodies: From Bench to Clinic|url=https://books.google.com/books?id=agdx2rtK7E0C&pg=PA134|access-date=30 March 2011|date=8 September 2009|publisher=John Wiley and Sons|isbn=978-0-470-11791-0|pages=134–}}</ref><ref>{{cite book| vauthors = Blum R, Scholz M |title=Invasion of the Prostate Snatchers: No More Unnecessary Biopsies, Radical Treatment Or Loss of Sexual Potency|url=https://archive.org/details/invasionofprosta00blum|url-access=registration|access-date=30 March 2011|date=24 August 2010|publisher=Other Press, LLC|isbn=978-1-59051-342-2|pages=[https://archive.org/details/invasionofprosta00blum/page/227 227]–}}</ref> In 2014 a study indicated that the antibody works by allowing the patients' T cells to target a greater variety of antigens rather than by increasing the number attacking a single antigen.<ref>{{Cite journal|title = Cancer immunotherapy expands T cell attack|journal = Science|pages = 1463|volume = 345|issue = 6203|doi = 10.1126/science.345.6203.1463-c| vauthors = Colmone AC |year = 2014|bibcode = 2014Sci...345Q1463C}}</ref>

== Pharmacokinetics == The elimination half-life of ipilimumab is about 15{{nbsp}}days.<ref name="Yervoy FDA label" />

== History == Following the 1987 cloning of CTLA-4 in mice,<ref>{{cite journal | vauthors = Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P | title = A new member of the immunoglobulin superfamily--CTLA-4 | journal = Nature | volume = 328 | issue = 6127 | pages = 267–270 | date = Jul 1987 | pmid = 3496540 | doi = 10.1038/328267a0 | s2cid = 4316396 | bibcode = 1987Natur.328..267B }}</ref> its conservation in humans and similarities with CD28 were soon noticed.<ref>{{cite journal | vauthors = Harper K, Balzano C, Rouvier E, Mattéi MG, Luciani MF, Golstein P | title = CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location | journal = Journal of Immunology | volume = 147 | issue = 3 | pages = 1037–1044 | date = August 1991 | pmid = 1713603 | doi = 10.4049/jimmunol.147.3.1037 | s2cid = 25735978 | doi-access = free }}</ref> CD28 at that time was a recently identified "T cell costimulatory" molecule important for T cell activation.<ref>{{cite journal | vauthors = Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP | title = CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones | journal = Nature | volume = 356 | issue = 6370 | pages = 607–609 | date = April 1992 | pmid = 1313950 | doi = 10.1038/356607a0 | s2cid = 4333730 | bibcode = 1992Natur.356..607H }}</ref> Anti-CTLA-4 blockade, the invention that gave rise to ipilimumab, was conceived by Allison and Krummel along with CTLA-4's inhibitory role in T cell activation.<ref>Krummel, M.F. (1995). Identification and Characterization of a CTLA-4 Dependent Regulatory Mechanism for T Cell Activation (University of California, Berkeley).</ref> They were able to demonstrate that CTLA-4 signaling in T cells inhibited T cell responses.<ref>{{cite journal | vauthors = Krummel MF, Allison JP | title = CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation | journal = The Journal of Experimental Medicine | volume = 182 | issue = 2 | pages = 459–465 | date = August 1995 | pmid = 7543139 | pmc = 2192127 | doi = 10.1084/jem.182.2.459 }}</ref> They then injected intact antibodies and demonstrated that CTLA-4 blockade enhanced T cell responses in mice responding to vaccines and to super antigens.<ref>{{cite journal | vauthors = Krummel MF, Sullivan TJ, Allison JP | title = Superantigen responses and co-stimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and in vivo | journal = International Immunology | volume = 8 | issue = 4 | pages = 519–523 | date = April 1996 | pmid = 8671638 | doi = 10.1093/intimm/8.4.519 | doi-access = free }}</ref> Leach, a new postdoctoral fellow, was tasked by Allison with applying these in tumor models. Antibody-treated mice showed significantly less cancer growth than the controls.<ref name="auto"/>

Bluestone and Linsley separately studied the similarities between CD28 and CTLA-4. Bluestone's lab published studies, one together with Krummel and Allison, for ''in vitro'' studies of CTLA-4 function.<ref>{{cite journal | vauthors = Walunas TL, Bakker CY, Bluestone JA | title = CTLA-4 ligation blocks CD28-dependent T cell activation | journal = The Journal of Experimental Medicine | volume = 183 | issue = 6 | pages = 2541–2550 | date = June 1996 | pmid = 8676075 | pmc = 2192609 | doi = 10.1084/jem.183.6.2541 }}</ref><ref>{{cite journal | vauthors = Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA | title = CTLA-4 can function as a negative regulator of T cell activation | journal = Immunity | volume = 1 | issue = 5 | pages = 405–413 | date = August 1994 | pmid = 7882171 | doi = 10.1016/1074-7613(94)90071-x }}</ref> In collaboration with Mark Jenkins, they were able to see effects of anti-CTLA-4 antibodies ''in vivo'' in an immunization setting,<ref>{{cite journal | vauthors = Kearney ER, Walunas TL, Karr RW, Morton PA, Loh DY, Bluestone JA, Jenkins MK | title = Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4 | journal = Journal of Immunology | volume = 155 | issue = 3 | pages = 1032–1036 | date = August 1995 | pmid = 7543510 | doi = 10.4049/jimmunol.155.3.1032 | s2cid = 23874889 | doi-access = free }}</ref> but did not effectively carry this into tumor biology. Linsley and colleagues had made antibodies against CTLA-4 three years prior to those of Krummel/Allison or Walunas/Bluestone. They concluded that the molecule functioned similarly to CD28 and was a "positive costimulator".<ref>{{cite journal | vauthors = Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, Damle NK | title = Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes | journal = The Journal of Experimental Medicine | volume = 176 | issue = 6 | pages = 1595–1604 | date = December 1992 | pmid = 1334116 | pmc = 2119471 | doi = 10.1084/jem.176.6.1595 }}</ref> They apparently did not pursue CTLA-4 tumor targeting, although BMS licensed the Allison/Leach/Krummel patent through their acquisition of Medarex and the fully humanized antibody MDX010, which later became ipilimumab. === Clinical trial history ===

In the 2000s, ipilimumab clinical trials were under way on patients with melanoma, renal cell carcinoma, prostate cancers, urothelial carcinoma and ovarian cancer.<ref name=sa15>{{cite journal | vauthors = Sharma P, Allison JP | title = The future of immune checkpoint therapy | journal = Science | volume = 348 | issue = 6230 | pages = 56–61 | date = April 2015 | pmid = 25838373 | doi = 10.1126/science.aaa8172 | s2cid = 4608450 | bibcode = 2015Sci...348...56S }}</ref> By 2007, there were two fully human anti CTLA-4<ref>{{cite web | url = http://www.healthvalue.net/ctlaigenglish.html | title = CTLA-4 strategies: Abatacept / Belatacept | publisher = healthvalue.net | access-date = 24 June 2009 | archive-date = 5 December 2008 | archive-url = https://web.archive.org/web/20081205034856/http://www.healthvalue.net/ctlaigenglish.html | url-status = dead }}</ref> monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.<ref name="pmid19088949">{{cite journal | vauthors = Tomillero A, Moral MA | title = Gateways to clinical trials | journal = Methods and Findings in Experimental and Clinical Pharmacology | volume = 30 | issue = 8 | pages = 643–672 | date = October 2008 | pmid = 19088949 | doi = 10.1358/mf.2008.30.5.1236622 }}</ref><ref name="pmid19052265">{{cite journal | vauthors = Poust J | title = Targeting metastatic melanoma | journal = American Journal of Health-System Pharmacy | volume = 65 | issue = 24 Suppl 9 | pages = S9–S15 | date = December 2008 | pmid = 19052265 | doi = 10.2146/ajhp080461 | s2cid = 207291355 }}</ref>

====Melanoma==== In December 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma.<ref>{{cite web|url=https://www.bms.com/ |title=Top-Line Data Available from Three Ipilimumab Pivotal Trials in Patients with Advanced Metastatic Melanoma |date=10 December 2007 |publisher=Medarex, Inc. |access-date=24 June 2009 |url-status=dead |archive-url=https://web.archive.org/web/20081020042102/https://www.bms.com/ |archive-date=20 October 2008 }}</ref> The three studies tested 487 patients with advanced skin cancer. One of the three studies failed to meet its primary goal of shrinking tumors in at least 10.0% of the study's 155 patients.  Side effects included rashes, diarrhea, and hepatitis.

In 2010, a study was presented that showed a median survival of ten months in advanced melanoma patients treated with ipilimumab, compared with 6.4 months for those treated with gp100, an experimental vaccine (n=676), and 10.1 months for those treated with both the vaccine and ipilimumab.<ref name="PMID20525992">{{cite journal | vauthors = Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ | title = Improved survival with ipilimumab in patients with metastatic melanoma | journal = The New England Journal of Medicine | volume = 363 | issue = 8 | pages = 711–723 | date = August 2010 | pmid = 20525992 | pmc = 3549297 | doi = 10.1056/NEJMoa1003466 }}</ref> The phase III clinical studies on the drug were controversial for their unconventional use of a control arm (as opposed to using a placebo or standard treatment). Ipilimumab gained FDA approval in March 2011.<ref name="FDA approval package" /><ref name="FDA PR 20110325" />

====Prostate cancer==== In 2008/09 Medarex performed a phase I/II dose escalation clinical trial of ipilimumab in metastatic hormone-refractory prostate cancer (HRPC). Some of the patients with advanced prostate cancer had their tumors drastically shrink, promoting further trials.<ref>{{cite news | url = https://news.bbc.co.uk/2/hi/health/8110103.stm | title = 'Surprise' prostate result probed | date = 19 June 2009 | publisher = BBC News | access-date = 24 June 2009}}</ref>

In June 2009, the Mayo Clinic reported two prostate cancer patients involved in a phase II study using MDX-010 therapy who had been told initially that their condition was inoperable but had their tumors shrunk by the drug such that operation was possible and are now cancer-free as a result.<ref>{{cite web | url = http://www.mayoclinic.org/news2009-rst/5318.html | title = Mayo Researchers: Dramatic Outcomes in Prostate Cancer Study | date = 1 June 2009 | publisher = Mayo Clinic | access-date = 24 June 2009 | archive-date = 23 June 2009 | archive-url = https://web.archive.org/web/20090623054534/http://www.mayoclinic.org/news2009-rst/5318.html | url-status = dead }}</ref> This press report was criticized as premature and inaccurate, because the clinical trials were still at an early stage and were run alongside other treatments, which could have been the main reason for the tumor shrinkage.<ref>{{cite web | url = http://www.webmd.com/prostate-cancer/news/20090619/new-therapy-may-fight-prostate-cancer | title = New Therapy May Fight Prostate Cancer | vauthors = Boyles S | date = 19 June 2009 | publisher = WebMD | access-date = 24 June 2009}}</ref> Thus, it was too early to say whether ipilimumab made any difference.<ref>{{cite web | url = https://www.science.org/content/blog-post/medarex-ipilimumab-prostate-cancer-and-reality | title = Medarex, Ipilimumab, Prostate Cancer, And Reality | vauthors = Lowe D | author-link = Derek Lowe (chemist) | date = 23 June 2009 | publisher = Science Translational Medicine | access-date = 11 August 2016}}</ref>

In 2016, a phase II study using ipilimumab and nivolumab in AR-V7-expressing metastatic castration-resistant prostate cancer was opened.<ref>{{Cite web | url = https://clinicaltrials.gov/ct2/show/NCT02601014 | title = Biomarker-Driven Therapy With Nivolumab and Ipilimumab in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Expressing AR-V7 - Full Text View - ClinicalTrials.gov | website = clinicaltrials.gov | access-date = 27 February 2016 }}</ref><ref name="Silberstein_2016">{{cite journal | vauthors = Silberstein JL, Taylor MN, Antonarakis ES | title = Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer | journal = Current Urology Reports | volume = 17 | issue = 4 | pages = 29 | date = April 2016 | pmid = 26902623 | pmc = 4888068 | doi = 10.1007/s11934-016-0584-4 }}</ref> AR-V7 is an androgen receptor splice variant that can be detected in circulating tumor cells of metastatic prostate cancer patients.<ref name="Silberstein_2016"/><ref>{{cite journal | vauthors = Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J | title = AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer | journal = The New England Journal of Medicine | volume = 371 | issue = 11 | pages = 1028–1038 | date = September 2014 | pmid = 25184630 | pmc = 4201502 | doi = 10.1056/NEJMoa1315815 }}</ref>

====Lung cancer==== CHECKMATE-227<ref name="Hellmann_2019">{{cite journal | vauthors = Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS | title = Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer | journal = The New England Journal of Medicine | volume = 381 | issue = 21 | pages = 2020–2031 | date = November 2019 | pmid = 31562796 | doi = 10.1056/NEJMoa1910231 | doi-access = free | hdl = 10668/14563 | hdl-access = free }}</ref> tested the combination of nivolumab and ipilimumab in patients with stage IV or recurrent non-small cell lung cancer (NSCLC) without previous treatment.<ref name="Nasser_2020">{{cite journal | vauthors = Nasser NJ, Gorenberg M, Agbarya A | title = First line Immunotherapy for Non-Small Cell Lung Cancer | journal = Pharmaceuticals | volume = 13 | issue = 11 | pages = 373 | date = November 2020 | pmid = 33171686 | pmc = 7695295 | doi = 10.3390/ph13110373 | doi-access = free }}</ref><ref name="Hellmann_2019" /> Patients with a PD-L1 expression level of 1% or more were randomized in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy.<ref name="Nasser_2020" /><ref name="Hellmann_2019" /> The chemotherapy used was cisplatin or carboplatin, combined with gemcitabine for patient with squamous cell NSCLC, or pemetrexed for patients with nonsquamous disease.<ref name="Nasser_2020" /><ref name="Hellmann_2019" /> The overall survival (OS) was 17.1, 15.7 and 14.9 months, respectively.<ref name="Nasser_2020" /><ref name="Hellmann_2019" /> The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy.<ref name="Nasser_2020" /><ref name="Hellmann_2019" /> The OS was 17.2, 15.2 and 12.2 months, respectively.<ref name="Nasser_2020" /><ref name="Hellmann_2019" />

CHECKMATE-9LA<ref name="Reck_2020">{{Cite journal| vauthors = Reck M, Ciuleanu TE, Dols MC, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A |date=20 May 2020|title=Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA.|url=https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.9501|journal=Journal of Clinical Oncology|volume=38|issue=15_suppl|pages=9501|doi=10.1200/JCO.2020.38.15_suppl.9501|s2cid=219780650|issn=0732-183X|url-access=subscription}}</ref> randomized patients with stage IV NSCLC, to nivolumab 360 mg Q3W + ipilimumab 1 mg/kg Q6W + two cycles of chemotherapy or 4 cycles of chemotherapy alone.<ref name="Nasser_2020" /> The chemotherapy used was Cisplatin or Carboplatin combined with Pemetrexed or Paclitaxel. The data were presented in an abstract format and as a lecture during the American Society of Clinical Oncology (ASCO) 2020 annual meeting.<ref name="Reck_2020" /> Median OS was 15.6 and 10.9 months, in the immunotherapy-chemotherapy and the chemotherapy only groups, respectively.<ref name="Reck_2020" /><ref name="Nasser_2020" />

====Urothelial cancer, including cancer of the bladder, urethra, ureters and renal pelvis==== A phase II clinical trial was first reported in 2015.<ref>{{cite web|url=http://meetinglibrary.asco.org/content/153523-156|title=Impact of gemcitabine + cisplatin + ipilimumab on circulating immune cells in patients (pts) with metastatic urothelial cancer (mUC). - 2015 ASCO Annual Meeting - Abstracts - Meeting Library|access-date=7 March 2016|archive-date=8 March 2016|archive-url=https://web.archive.org/web/20160308003335/http://meetinglibrary.asco.org/content/153523-156|url-status=dead}}</ref> Thirty-six patients were treated with chemotherapy, adding ipilimumab after the second 21-day cycle. Though the study did not meet its primary endpoint, a significant expansion of circulating CD4 cells was noted upon addition of ipilimumab, which correlated with improved survival, especially in patients with deleterious somatic DNA damage response mutations.<ref>{{cite journal | vauthors = Galsky MD, Wang H, Hahn NM, Twardowski P, Pal SK, Albany C, Fleming MT, Starodub A, Hauke RJ, Yu M, Zhao Q, Sonpavde G, Donovan MJ, Patel VG, Sfakianos JP, Domingo-Domenech J, Oh WK, Akers N, Losic B, Gnjatic S, Schadt EE, Chen R, Kim-Schulze S, Bhardwaj N, Uzilov AV | title = Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes | journal = European Urology | volume = 73 | issue = 5 | pages = 751–759 | date = May 2018 | pmid = 29248319 | doi = 10.1016/j.eururo.2017.12.001 }}</ref>

==== Combination trials ====

===== Advanced melanoma ===== In 2013, a trial was running that compared ipilimumab alone against ipilimumab in combination with nivolumab. The response rate (tumours shrinking by at least 30%) was 58% for the combination, 44% for nivolumab alone, and 19% for ipilimumab alone.<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/behindtheheadlines/news/2015-06-01-immunotherapy-drug-combo-could-combat-melanoma/|title=Immunotherapy drug combo could combat melanoma|author=pmhdev|work=PubMed Health}}{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}}</ref> This combination gained approval for melanoma by the US Food and Drug Administration in October 2015.

In March 2014, an open-label, randomized, two agent, single center trial started combining ipilimumab with phosphatidylserine-targeting immunotherapy bavituximab for the treatment of advanced melanoma. The number of treated patients in arm A (ipilimumab plus bavituximab) was to be 16, with 8 in arm B (ipilimumab only).<ref>{{cite web|title=Peregrine Pharmaceuticals Announces Initiation of an Investigator-Sponsored Trial Combining Its Immunotherapy Bavituximab and Ipilimumab (Yervoy) in Advanced Melanoma|publisher=Peregrine Pharmaceuticals, Inc|url=http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=841892|access-date=20 May 2014|archive-url=https://web.archive.org/web/20151014212117/http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=841892|archive-date=14 October 2015|url-status=dead}}</ref> The trial was terminated in April 2016 due to low enrollment.<ref>{{ClinicalTrialsGov|NCT01984255|A Two-arm, Single Center Phase 1b Trial of Bavituximab Plus Ipilimumab in Advanced Melanoma Patients}}</ref> Previous, preclinical studies showed that PS targeting antibodies (such as bavituximab) enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.<ref>{{cite news | url = https://www.reuters.com/article/2014/04/09/idUSnMKWDgVlta+1e8+MKW20140409 | archive-url = https://web.archive.org/web/20140521031338/http://www.reuters.com/article/2014/04/09/idUSnMKWDgVlta+1e8+MKW20140409 | url-status = dead | archive-date = 21 May 2014 | title = Data Presented at AACR Support Potential of Peregrine's PS-Targeting Immunotherapy Bavituximab to Enhance Anti-Tumor and Immune-Stimulating Effects of Anti-CTLA-4 and Anti-PD-1 Treatments in Models of Melanoma and Colon Cancer | date = 9 April 2014 | publisher = Reuters | access-date = 9 April 2014}}</ref>

== References == {{Reflist}}

== External links == * {{cite web | title=Ipilimumab | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/ipilimumab }} * {{cite web | title=Ipilimumab | website=National Cancer Institute | date=21 April 2011 | url=https://www.cancer.gov/about-cancer/treatment/drugs/ipilimumab }}

{{Targeted cancer therapeutic agents}} {{Monoclonals for tumors}} {{Monoclonals for immune system}} {{Portal bar | Medicine}} {{Authority control}}

Category:Drugs developed by Bristol Myers Squibb Category:Monoclonal antibodies for tumors