{"entity":{"id":"ctla4","kind":"target","name":"CTLA-4","aka":[],"tldr":"The first immune brake ever targeted for cancer; releasing it won a Nobel Prize and cures a fraction of melanomas.","summary":"CTLA-4 is a checkpoint on activated and regulatory T cells that competes with CD28 for B7 ligands during T-cell priming; antibodies against it broaden the T-cell response and, through Fc effector function, deplete regulatory T cells inside tumours. Ipilimumab (2011) was the first checkpoint inhibitor, and the concept later shared a Nobel Prize. Combined with nivolumab it yields 10-year survival near 50 percent in advanced melanoma (CheckMate 067), and the pair is used in RCC, MSI-high colorectal cancer, HCC and mesothelioma. The cost is frequent immune-related toxicity such as colitis and hypophysitis, and because it acts on immune cells there is no tumour biomarker to select patients. Fc-engineered and probody CTLA-4 antibodies aim to reduce toxicity. Releasing this brake was the first proof that the immune system can cure some cancers.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/CTLA-4","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/CTLA-4"}],"tags":["checkpoint"],"related":[],"cancers":["melanoma","rcc","colorectal","hcc","mesothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":["gotistobart","bcd-217","adg126","botensilimab","jk08","lorigerlimab","ba3071"],"companies":["xilio-therapeutics"],"institutions":[],"pathways":["pd1-checkpoint"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"symbol":"CTLA4","role":["immune-checkpoint"],"sources":[],"specificity":"immune-microenvironment","distribution":"many-types","specificityNote":"Immune or microenvironment target: the record's class is immune checkpoint. HPA CTLA4: RNA tissue enriched (lymphoid tissue 35 nTPM); blood lineage lineage enriched (T-cells 43 nTPM); no normal tissue stained high. Distribution: 5 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Skin cancer (all types), Renal cell carcinoma, Colorectal cancer, Hepatocellular carcinoma, Mesothelioma); approvals of single-target medicines aimed at it also list Lung cancer (all types), not counted; Open Targets associates it with 6 specific cancer types at or above 0.5 (autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, non-small cell lung carcinoma, melanoma, hepatocellular carcinoma, renal cell carcinoma, basal cell carcinoma). (Rule 1 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas CTLA4 tissue","url":"https://www.proteinatlas.org/ENSG00000163599-CTLA4/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"UniProt P16410","url":"https://www.uniprot.org/uniprotkb/P16410/entry","note":"involvement in disease"},{"label":"Open Targets ENSG00000163599 associations","url":"https://platform.opentargets.org/target/ENSG00000163599/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:2505","ensembl":"ENSG00000163599","uniprot":"P16410","entrez":"1493","firstDescribed":1988,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Dariavach et al, Eur. J. Immunol, 1988, \"Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/3220103/","biology":"Competes with CD28 for B7 ligands during T-cell priming; also depletes regulatory T cells via Fc effector function.","whereFound":["Activated and regulatory T cells"],"targetClass":"checkpoint","prevalence":[{"cancerId":"melanoma","pct":"n/a","measure":"Immune-cell target; no tumour prevalence","source":"https://en.wikipedia.org/wiki/CTLA-4"}]},"route":"/targets/ctla4/","neighbours":{"cancer":[{"id":"advanced-melanoma","kind":"cancer","name":"Advanced melanoma (unresectable stage III and stage IV)","route":"/cancers/advanced-melanoma/"},{"id":"cervical","kind":"cancer","name":"Cervical cancer","route":"/cancers/cervical/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"hcc","kind":"cancer","name":"Hepatocellular carcinoma","route":"/cancers/hcc/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"merkel-cell-carcinoma","kind":"cancer","name":"Merkel cell carcinoma","route":"/cancers/merkel-cell-carcinoma/"},{"id":"mesothelioma","kind":"cancer","name":"Mesothelioma","route":"/cancers/mesothelioma/"},{"id":"msi-high-pdac","kind":"cancer","name":"Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma","route":"/cancers/msi-high-pdac/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"},{"id":"mucosal-melanoma","kind":"cancer","name":"Mucosal melanoma","route":"/cancers/mucosal-melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"esophageal","kind":"cancer","name":"Oesophageal cancer","route":"/cancers/esophageal/"},{"id":"pdl1-high-nsclc","kind":"cancer","name":"PD-L1-high non-small-cell lung cancer without a driver mutation","route":"/cancers/pdl1-high-nsclc/"},{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"},{"id":"stage-iii-melanoma","kind":"cancer","name":"Stage III melanoma (after surgery)","route":"/cancers/stage-iii-melanoma/"},{"id":"uveal-melanoma","kind":"cancer","name":"Uveal melanoma","route":"/cancers/uveal-melanoma/"},{"id":"vascular-tumours","kind":"cancer","name":"Vascular tumours (angiosarcoma, epithelioid haemangioendothelioma, kaposiform haemangioendothelioma)","route":"/cancers/vascular-tumours/"}],"drug":[{"id":"adg126","kind":"drug","name":"ADG126","route":"/drugs/adg126/"},{"id":"ba3071","kind":"drug","name":"BA3071","route":"/drugs/ba3071/"},{"id":"bcd-217","kind":"drug","name":"BCD-217","route":"/drugs/bcd-217/"},{"id":"botensilimab","kind":"drug","name":"Botensilimab","route":"/drugs/botensilimab/"},{"id":"cadonilimab","kind":"drug","name":"Cadonilimab","route":"/drugs/cadonilimab/"},{"id":"gotistobart","kind":"drug","name":"Gotistobart","route":"/drugs/gotistobart/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"jk08","kind":"drug","name":"JK08","route":"/drugs/jk08/"},{"id":"lorigerlimab","kind":"drug","name":"Lorigerlimab","route":"/drugs/lorigerlimab/"},{"id":"tremelimumab","kind":"drug","name":"Tremelimumab","route":"/drugs/tremelimumab/"}],"company":[{"id":"agenus","kind":"company","name":"Agenus","route":"/companies/agenus/"},{"id":"xilio-therapeutics","kind":"company","name":"Xilio Therapeutics","route":"/companies/xilio-therapeutics/"}],"pathway":[{"id":"hepatocellular-carcinoma-signalling","kind":"pathway","name":"Hepatocellular carcinoma (KEGG map)","route":"/pathways/hepatocellular-carcinoma-signalling/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"t-cell-exhaustion","kind":"pathway","name":"T-cell exhaustion","route":"/pathways/t-cell-exhaustion/"},{"id":"cancer-immunity-cycle","kind":"pathway","name":"The cancer-immunity cycle","route":"/pathways/cancer-immunity-cycle/"},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/"}],"trial":[{"id":"ca184-043-ipilimumab","kind":"trial","name":"CA184-043","route":"/trials/ca184-043-ipilimumab/"},{"id":"checkmate-142","kind":"trial","name":"CheckMate 142","route":"/trials/checkmate-142/"},{"id":"checkmate-204","kind":"trial","name":"CheckMate 204","route":"/trials/checkmate-204/"},{"id":"checkmate-238","kind":"trial","name":"CheckMate 238","route":"/trials/checkmate-238/"},{"id":"checkmate-648","kind":"trial","name":"CheckMate 648","route":"/trials/checkmate-648/"},{"id":"checkmate-8hw","kind":"trial","name":"CheckMate 8HW","route":"/trials/checkmate-8hw/"},{"id":"checkmate-9dw","kind":"trial","name":"CheckMate 9DW","route":"/trials/checkmate-9dw/"},{"id":"checkmate-9la","kind":"trial","name":"CheckMate 9LA","route":"/trials/checkmate-9la/"},{"id":"compassion-16","kind":"trial","name":"COMPASSION-16 / AK104-303","route":"/trials/compassion-16/"},{"id":"dreamseq","kind":"trial","name":"DREAMseq (ECOG-ACRIN EA6134)","route":"/trials/dreamseq/"},{"id":"himalaya","kind":"trial","name":"HIMALAYA","route":"/trials/himalaya/"},{"id":"keynote-006","kind":"trial","name":"KEYNOTE-006","route":"/trials/keynote-006/"},{"id":"nadina","kind":"trial","name":"NADINA","route":"/trials/nadina/"}],"idea":[{"id":"idea-immunotherapy-mss-crc","kind":"idea","name":"Making microsatellite-stable colorectal cancer immunotherapy-responsive","route":"/ideas/idea-immunotherapy-mss-crc/"},{"id":"idea-crc-mss-immunotherapy-by-biomarker-not-by-line","kind":"idea","name":"Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed","route":"/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/"}],"paper":[{"id":"paper-asco-irae-guideline-jco-2021","kind":"paper","name":"ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint 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nivolumab after surgery in stage III melanoma","route":"/key-papers/paper-nadina-nejm-2024/"},{"id":"paper-niche-2-nejm-2024","kind":"paper","name":"NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients","route":"/key-papers/paper-niche-2-nejm-2024/"},{"id":"paper-checkmate-227-n-engl-j-med-2018","kind":"paper","name":"Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden","route":"/key-papers/paper-checkmate-227-n-engl-j-med-2018/"},{"id":"paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024","kind":"paper","name":"Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW)","route":"/key-papers/paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024/"},{"id":"paper-pardoll-immune-checkpoint-blockade-nrc-2012","kind":"paper","name":"Pardoll 2012: the blockade of immune checkpoints in cancer 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with anti-PD-L1 immunotherapy in pancreatic cancer","route":"/key-papers/paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","route":"/roadmaps/colorectal-roadmap/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"person":[{"id":"f-stephen-hodi","kind":"person","name":"F. Stephen Hodi","route":"/people/f-stephen-hodi/"},{"id":"georgina-long","kind":"person","name":"Georgina V. Long","route":"/people/georgina-long/"},{"id":"ghassan-abou-alfa","kind":"person","name":"Ghassan K. Abou-Alfa","route":"/people/ghassan-abou-alfa/"},{"id":"heinz-josef-lenz","kind":"person","name":"Heinz-Josef Lenz","route":"/people/heinz-josef-lenz/"},{"id":"james-allison","kind":"person","name":"James P. Allison","route":"/people/james-allison/"},{"id":"jedd-wolchok","kind":"person","name":"Jedd D. Wolchok","route":"/people/jedd-wolchok/"},{"id":"jeffrey-bluestone","kind":"person","name":"Jeffrey A. Bluestone","route":"/people/jeffrey-bluestone/"},{"id":"michael-postow","kind":"person","name":"Michael A. Postow","route":"/people/michael-postow/"},{"id":"padmanee-sharma","kind":"person","name":"Padmanee Sharma","route":"/people/padmanee-sharma/"},{"id":"paul-baas","kind":"person","name":"Paul Baas","route":"/people/paul-baas/"},{"id":"robert-motzer","kind":"person","name":"Robert J. Motzer","route":"/people/robert-motzer/"},{"id":"sharon-belvin","kind":"person","name":"Sharon Belvin","route":"/people/sharon-belvin/"},{"id":"tak-mak","kind":"person","name":"Tak W. Mak","route":"/people/tak-mak/"},{"id":"thierry-andre","kind":"person","name":"Thierry André","route":"/people/thierry-andre/"}],"bottleneck":[{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"}],"term":[{"id":"checkpoint","kind":"term","name":"Checkpoint (two meanings)","route":"/terms/checkpoint/"},{"id":"avoiding-immune-destruction","kind":"term","name":"Hallmark: avoiding immune destruction","route":"/terms/avoiding-immune-destruction/"},{"id":"immune-checkpoint","kind":"term","name":"Immune checkpoint","route":"/terms/immune-checkpoint/"},{"id":"immune-surveillance-immunoediting","kind":"term","name":"Immune surveillance and cancer immunoediting","route":"/terms/immune-surveillance-immunoediting/"},{"id":"t-cell","kind":"term","name":"T cell","route":"/terms/t-cell/"}],"target":[{"id":"cd28","kind":"target","name":"CD28","route":"/targets/cd28/"},{"id":"cd80","kind":"target","name":"CD80 (B7-1)","route":"/targets/cd80/"},{"id":"cd86","kind":"target","name":"CD86 (B7-2)","route":"/targets/cd86/"},{"id":"vista","kind":"target","name":"VISTA","route":"/targets/vista/"}],"institution":[{"id":"dartmouth-cancer-center","kind":"institution","name":"Dartmouth Cancer Center","route":"/institutions/dartmouth-cancer-center/"},{"id":"pascale-naples","kind":"institution","name":"Istituto Nazionale Tumori IRCCS Fondazione G. Pascale","route":"/institutions/pascale-naples/"}]}}