{"entity":{"id":"idea-bio1-immunopeptidome-timing","kind":"idea","name":"Time immunotherapy to the moment targeted drugs make tumours visible","aka":[],"tldr":"Targeted drugs briefly make cancer cells easier for the immune system to spot. Giving immunotherapy exactly in that window, rather than at the same time, may work better.","summary":"MAPK and CDK4/6 inhibition transiently increase MHC class I expression, antigen presentation and interferon signalling, then this fades as resistance develops. Concurrent combinations have often been toxic and no more effective. Mass spectrometry immunopeptidomics and MHC imaging could define the window in patients, and immunotherapy could be scheduled to coincide with peak presentation rather than dosed continuously alongside.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Acquired resistance to every therapy): Soria et al., Osimertinib in untreated EGFR-mutated NSCLC (FLAURA, NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1713137"}],"tags":[],"related":[],"cancers":["melanoma","breast-hr-positive"],"sections":[],"technologies":["checkpoint-inhibitor","proteomics","cdk46-inhibitor"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["ras-mapk","pd1-checkpoint"],"terms":[],"trials":[],"people":[],"bottlenecks":["b-resistance","b-immunotherapy-response","b-combination-space"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Immunotherapy administered during the measured peak of antigen presentation after targeted therapy produces greater T-cell infiltration and deeper responses than concurrent continuous combination, with less toxicity.","rationale":"The immunomodulatory effect of targeted agents is transient and dose-dependent; scheduling is a free variable that combination trials have almost never explored systematically.","test":"Serial biopsy window study mapping MHC class I and immunopeptidome dynamics over the first weeks of targeted therapy, then a randomised schedule comparison in the tumour type with the clearest window.","maturity":"preclinical-evidence","actor":"research","cost":"medium","horizonYears":5},"route":"/ideas/idea-bio1-immunopeptidome-timing/","neighbours":{"cancer":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"}],"technology":[{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"proteomics","kind":"technology","name":"Proteomics & phosphoproteomics","route":"/technologies/proteomics/"}],"pathway":[{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"}]}}