{"entity":{"id":"paper-ribas-wolchok-checkpoint-blockade-science-2018","kind":"paper","name":"Ribas and Wolchok 2018: cancer immunotherapy using checkpoint blockade","aka":[],"tldr":"A review by two of the field's leading trialists, written as checkpoint inhibitors reached a dozen cancers, explaining how CTLA-4 and PD-1 blockade work, why only some patients respond, and how resistance arises.","summary":"Ribas and Wolchok summarised the science and clinical results of checkpoint blockade at the point where PD-1 pathway antibodies had been approved across many cancers. They described CTLA-4 blockade as broadening the T cell repertoire and PD-1 blockade as reinvigorating exhausted T cells already in the tumour; reviewed the features of responding tumours, including mutational burden, pre-existing T cell infiltration and interferon-gamma signalling; and catalogued primary and acquired resistance mechanisms such as loss of antigen presentation and interferon signalling defects. They argued for rational combinations based on these mechanisms.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.aar4060"}],"tags":[],"related":["paper-pardoll-immune-checkpoint-blockade-nrc-2012","paper-tumeh-pd1-adaptive-immune-resistance-nature-2014"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["ctla4","pd1","pdl1"],"drugs":[],"companies":[],"institutions":["ucla-jonsson","mskcc"],"pathways":[],"terms":["immune-checkpoint","tmb","irae"],"trials":[],"people":["antoni-ribas","jedd-wolchok"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":2018,"doi":"10.1126/science.aar4060","authors":"Ribas A, Wolchok JD.","paperType":"review","findings":["CTLA-4 blockade acts mainly at T cell priming and broadens the repertoire; PD-1 blockade reinvigorates antigen-experienced T cells in the tumour.","Response is associated with mutational burden, pre-existing T cell infiltration and intact interferon-gamma signalling.","Resistance arises through loss of antigen presentation (for example beta-2-microglobulin), JAK-STAT defects and immunosuppressive microenvironments."],"whatItMeans":"This is the standard overview of checkpoint immunotherapy for clinicians and scientists, tying together the trial results and the biology of response and resistance that guide today's combination trials.","caveats":["A review; the field has moved on with LAG-3 blockade, neoadjuvant use and new biomarkers.","Both authors led many of the trials discussed."],"changedPractice":false},"route":"/key-papers/paper-ribas-wolchok-checkpoint-blockade-science-2018/","neighbours":{"paper":[{"id":"paper-pardoll-immune-checkpoint-blockade-nrc-2012","kind":"paper","name":"Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy","route":"/key-papers/paper-pardoll-immune-checkpoint-blockade-nrc-2012/"},{"id":"paper-tumeh-pd1-adaptive-immune-resistance-nature-2014","kind":"paper","name":"Tumeh 2014: PD-1 blockade works by releasing T cells already present at the tumour edge","route":"/key-papers/paper-tumeh-pd1-adaptive-immune-resistance-nature-2014/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"ucla-jonsson","kind":"institution","name":"UCLA Jonsson Comprehensive Cancer Center","route":"/institutions/ucla-jonsson/"}],"term":[{"id":"immune-checkpoint","kind":"term","name":"Immune checkpoint","route":"/terms/immune-checkpoint/"},{"id":"irae","kind":"term","name":"Immune-related adverse events (irAEs)","route":"/terms/irae/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"person":[{"id":"antoni-ribas","kind":"person","name":"Antoni Ribas","route":"/people/antoni-ribas/"},{"id":"jedd-wolchok","kind":"person","name":"Jedd D. Wolchok","route":"/people/jedd-wolchok/"}]}}