Ipilimumab: Difference between revisions

{{short description|Pharmaceutical drug}}

| Watchedfields = changed

| verifiedrevid = 458270765

| image = Ipilimumab 5TRU.png

| caption = [[Fragment antigen-binding|Fab fragment]] of ipilimumab (blue) binding CTLA-4 (green). From [[Protein Data Bank|PDB]] entry {{PDBe|5TRU}}.

<!-- Monoclonal antibody data -->

<!-- Clinical data -->

| pronounce = i pi lim′ ue mab

| tradename = Yervoy

| Drugs.com = {{drugs.com|monograph|ipilimumab}}

| DailyMedID = Ipilimumab

| pregnancy_AU = C

| pregnancy_AU_comment =

| pregnancy_category=

| routes_of_administration = [[Intravenous therapy|Intravenous]] (IV)

| class =

| ATC_prefix = L01

| ATC_suffix = FX04

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| 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 = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| 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_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 = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability =

| protein_bound =

| metabolism =

| metabolites =

| onset =

| elimination_half-life =

| duration_of_action =

| excretion =

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 477202-00-9

| CAS_supplemental =

| PubChem =

| IUPHAR_ligand =

| DrugBank = DB06186

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = none

| 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 = 2013-01-12 | archive-date = 2016-02-23 | archive-url = https://web.archive.org/web/20160223223857/http://www.ama-assn.org/resources/doc/usan/ipilimumab2.doc | url-status = dead }}</ref> MDX-101

<!-- Chemical and physical data -->

| 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]] (FDA) 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, 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 | 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=2014-07-13|archive-url=https://web.archive.org/web/20150626172243/https://www.novapublishers.com/catalog/product_info.php?products_id=50994|archive-date=2015-06-26|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=May 29, 2015 |work=[[New York Times]] |access-date=May 30, 2015 | name-list-style=vanc }}</ref> It is undergoing{{when|date=October 2020}} [[clinical trial]]s 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=2018-10-01 | archive-date=2018-12-24 | 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 U.S. [[Food and Drug Administration]] (FDA) 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=2011-03-25 |archive-url=https://web.archive.org/web/20110327063147/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm |archive-date=2011-03-27 |publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=2011-03-25 | 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=2011-03-25 |work=[[The New York Times]] |access-date=2011-03-27 | name-list-style=vanc }}</ref><ref name="Drugs.com" /> It was later approved by the US FDA on October 28, 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=2019-04-08 | archive-url=https://web.archive.org/web/20151029103812/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469944.htm | archive-date=2015-10-29 |url-status=dead }}</ref> On February 1, 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=<!--Staff writer(s); no by-line.--> |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=2019-04-08 |archive-date=2019-04-08 |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 approved 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=November 1, 2012|access-date=December 17, 2012|archive-date=February 5, 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 | display-authors = 6 | 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 the treatment of 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 | access-date=2 October 2020}} {{PD-notice}}</ref>

Ipilimumab, in combination with nivolumab, is indicated for the treatment of adults and adolescents twelve years and older with [[microsatellite instability]]-high or [[Mismatch repair cancer syndrome|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 | access-date=2 October 2020}} {{PD-notice}}</ref>

Ipilimumab, in combination with nivolumab, is indicated for the treatment of 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 | access-date=2 October 2020}} {{PD-notice}}</ref>

Ipilimumab, in combination with nivolumab, is indicated for the 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 | 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 | access-date=2 October 2020}} {{PD-notice}}</ref>

In October 2020, the U.S. 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 | access-date=2 October 2020}} {{PD-notice}}</ref> This is the first drug regimen approved for mesothelioma in sixteen years and the second FDA-approved systemic therapy for mesothelioma.<ref name="FDA PR 20201002" />

{{expand section|date=March 2016}}

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 ten to twenty percent 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 = 2011-03-28 | publisher = Genetic Engineering & Biotechnology News | access-date = 2011-03-28 | archive-date = 2011-04-01 | 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><!-- what rates of incidence -->

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 = 2014-04-29 }}</ref>

The combination of ipilimumab with either [[leflunomide]] or [[vemurafenib]] may lead to increased [[hepatotoxicity]].<ref name="Leflunomide package insert">{{cite web|title=Arava (leflunomide) [package insert]|url=http://products.sanofi.com.au/aus_pi_arava.pdf|publisher=Australia: Sanofi-Aventis, July 2014|access-date=2 November 2014|archive-date=2 November 2014|archive-url=https://web.archive.org/web/20141102230854/http://products.sanofi.com.au/aus_pi_arava.pdf|url-status=dead}}</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>{{cite web|title=Zelboraf (vemurafenib) [package insert]|url=http://www.gene.com/download/pdf/zelboraf_prescribing.pdf|publisher=South San Francisco, CA: Genentech USA, Inc.; March 2013|access-date=29 October 2014}}</ref><ref name="Package insert">{{cite web|title=Yervoy (ipilimumab) [package insert] |url=http://packageinserts.bms.com/pi/pi_yervoy.pdf |publisher=Princeton, NJ: Bristol-Myers Squibb Company; Dec 2013 |access-date=29 October 2014 |url-status=dead |archive-url=https://web.archive.org/web/20150206103033/http://packageinserts.bms.com/pi/pi_yervoy.pdf |archive-date=6 February 2015 }}</ref>

Systemic [[corticosteroids]] should be avoided before starting ipilimumab; however, systemic corticosteroids may be used to treat an immune-related [[adverse reaction]] that arises from ipilimumab treatment.<ref name="European product information">{{cite web|title=Yervoy Annex I: Summary of Product Characteristics|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002213/WC500109299.pdf|access-date=2 November 2014|archive-date=20 December 2014|archive-url=https://web.archive.org/web/20141220131813/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002213/WC500109299.pdf|url-status=dead}}</ref>

Patients taking [[anticoagulants]] with ipilimumab should be monitored due to an increased risk of [[gastrointestinal bleeding]].<ref name="European product information" />

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>

== Identifying patients most likely to respond ==

During "cancer immunoediting", tumor cells can produce antigens that provoke a reduced immune response and/or establish an immunosuppressive [[tumor microenvironment]] (TME). The latter can arise as a consequence of repeated, ineffective T cell stimulation. This triggers the [[Immune checkpoint|checkpoint]] that ipilumumab targets. Many patients do not benefit from treatment, which may be related to reduced mutation load and/or missense point mutation-derived neoantigens.<ref name="pmid29208439"/> Tumor antigens can either be improperly expressed normal proteins or abnormal proteins with tumor-specific expression. Somatic cancer mutations can produce "nonself" tumor-specific mutant antigens (neoantigens).<ref name="Gubin_2015">{{cite journal | vauthors = Gubin MM, Schreiber RD | title = CANCER. The odds of immunotherapy success | journal = Science | volume = 350 | issue = 6257 | pages = 158–159 | date = October 2015 | pmid = 26450194 | doi = 10.1126/science.aad4140 | s2cid = 206643238 | bibcode = 2015Sci...350..158G }}</ref>

Sequencing and [[epitope]] prediction algorithms identified neoantigens in mouse tumors that functioned as tumor-specific T cell targets. Neoantigens were recognized by T cells in melanoma patients and were likely the major contributor to positive clinical effects of [[adoptive cell transfer]]. Mouse models established that neoantigens were the targets of T cells activated by checkpoint blockade therapy and that synthetic long [[peptides]] comprising these neoantigens were effective when administered as vaccines with CTLA-4 and/or PD-1 mAbs. Cancers with higher mutation burdens, and an associated likelihood of expressing neoantigens, appear most likely to respond to checkpoint therapy.<ref name="pmid29208439" /> In melanoma and certain other cancers, the numbers of mutations and neoantigens correlate with patient response. Increased PD ligand 2 (PD-L2) transcript expression and an immune "cytolytic" [[gene signature]] also correlated with neoantigen load and tumor response. CTLA-4 expression was a response indicator, which along with PD-L2 were likely expressed in [[tumor-infiltrating immune cell]]s. An inflamed TME prior to treatment is also associated with response.<ref name="Gubin_2015" />

Nearly all neoantigens in one study were patient-specific and most likely reflected mutations that do not directly contribute to tumorigenesis. However, none revealed features or motifs exclusive to responders.<ref name="Gubin_2015" />

== 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 = 2009-06-24 | archive-date = 2008-12-05 | 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 [[Immunoglobulin G|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>

On December 10, 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=2007-12-10 |publisher=Medarex, Inc. |access-date=2009-06-24 |url-status=dead |archive-url=https://web.archive.org/web/20081020042102/https://www.bms.com/ |archive-date=October 20, 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 are often considered acceptable risks for cancer drugs given the severity of the disease, and ipilimumab is no exception.--> Side effects included rashes, diarrhea, and hepatitis. <!-- Despite the weaker-than-anticipated results, the companies are still planning to meet with regulatory agencies to discuss moving ahead with the medication since patients with extremely serious diseases like melanoma have so few treatment options, the companies believe that even the marginal success rate will be appealing to some. -->

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 [[Gp100:209-217(210M)|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 | display-authors = 6 | 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" />

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 = http://news.bbc.co.uk/2/hi/health/8110103.stm | title = 'Surprise' prostate result probed | date = 2009-06-19 | publisher = BBC News | access-date = 2009-06-24}}</ref>

On June 19, 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 = 2009-06-01 | publisher = Mayo Clinic | access-date = 2009-06-24 | archive-date = 2009-06-23 | archive-url = https://web.archive.org/web/20090623054534/http://www.mayoclinic.org/news2009-rst/5318.html | url-status = dead }}</ref> This press report however was criticized as premature and somewhat inaccurate. The clinical trials were still at an early stage and were run alongside other treatments – which could have been the real explanation 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 = 2009-06-19 | publisher = WebMD | access-date = 2009-06-24}}</ref> 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 = 2009-06-23 | publisher = [[Science Translational Medicine]] | access-date = 2016-08-11}}</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 = 2016-02-27

}}</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 | display-authors = 6 | 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>

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 | display-authors = 6 | 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 }}</ref> tested the combination of [[nivolumab]] and ipilimumab in patients with stage IV or recurrent 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 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 | display-authors = 6 |date=2020-05-20|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}}</ref> randomized patients with stage IV NSCLC, to [[nivolumab]] 360&nbsp;mg Q3W + ipilimumab 1&nbsp;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 2 clinical trial entitled [https://clinicaltrials.gov/ct2/show/results/NCT01524991 First-Line Gemcitabine, Cisplatin + Ipilimumab for Metastatic Urothelial Carcinoma] 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=2016-03-07|archive-date=2016-03-08|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 | display-authors = 6 | 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===

To increase response rate and reduce adverse reactions, various drug combinations are being tested.

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}}</ref> This combination gained FDA approval for melanoma 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=2014-05-20|archive-url=https://web.archive.org/web/20151014212117/http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=841892|archive-date=2015-10-14|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 = 2014-05-21 | 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 = 2014-04-09 | publisher = Reuters | access-date = 2014-04-09}}</ref>

== Development ==

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 [[James P. Allison|Allison]] and [[Matthew Krummel|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|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 | display-authors = 6 | 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.

== 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}}

[[Category:Drugs developed by Bristol Myers Squibb]]

[[Category:Monoclonal antibodies for tumors]]