{"entity":{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","aka":[],"tldr":"Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating.","summary":"PD-L1 immunohistochemistry, tumour mutational burden and mismatch-repair deficiency are the approved selection biomarkers for checkpoint inhibitors, and all are imperfect: PD-L1-negative patients respond, PD-L1-high patients progress, TMB thresholds vary by tumour type and assay, and only dMMR/MSI-high is a strong discriminator. As a result checkpoint inhibitors are given to nearly half of US patients with cancer while an estimated one in eight benefits, at a cost of tens of billions of dollars and a burden of immune-related adverse events in non-responders. Better predictors will need to integrate the tumour (antigenicity, interferon signalling, antigen presentation), the microenvironment (T-cell infiltration, myeloid state), the host (HLA genotype, microbiome) and early on-treatment dynamics (ctDNA clearance, CD8 PET, radiomics). The regulatory and reimbursement systems also need to accept biomarkers that deselect patients, which no sponsor is motivated to develop.","asOf":"2026-09-08","links":[{"label":"Haslam & Prasad (JAMA Network Open 2019)","url":"https://doi.org/10.1001/jamanetworkopen.2019.2535"},{"label":"Cristescu et al., Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy (Science 2018)","url":"https://doi.org/10.1126/science.aar3593"},{"label":"Hirsch et al., Blueprint PD-L1 IHC assay comparison project (JTO 2017)","url":"https://doi.org/10.1016/j.jtho.2016.11.2228"}],"tags":[],"related":["idea-cd8-pet-io","idea-multimodal-foundation-model","immunotherapy-roadmap","idea-bio2-tcr-repertoire-early-readout","idea-bio2-spatial-signature-cdx","idea-bio2-ctdna-six-week-io-switch","idea-bio2-io-biomarker-data-commons","idea-bio2-til-reactivity-selection","idea-bio2-antigen-presentation-triage","idea-bio2-epigenetic-priming-cold-tumours","idea-bio2-neoadjuvant-biomarker-engine","idea-bio2-steroid-sparing-irae"],"cancers":["nsclc","melanoma","head-and-neck","urothelial","gastric","colorectal"],"sections":[],"technologies":["checkpoint-inhibitor","immuno-pet","liquid-biopsy","pathology-foundation-model","digital-pathology-ai","cgp"],"targets":["pd1","pdl1"],"drugs":["pembrolizumab","nivolumab","atezolizumab","durvalumab"],"companies":["owkin","tempus","paige","foundation-medicine"],"institutions":[],"pathways":[],"terms":["tps","cps","tmb","msi","tils","cold-vs-hot","irae","ctdna"],"trials":["keynote-024-189","keynote-048","checkmate-067","keynote-177"],"people":[],"bottlenecks":[],"keyPapers":["paper-haslam-jama-netw-open","paper-hirsch-j-thorac-oncol","paper-cristescu-science"],"journals":[],"dependsOn":[],"notes":[],"stage":"biology","severity":"major","metrics":[{"label":"US patients with cancer eligible for checkpoint inhibitors vs estimated responders (2018)","value":"43.6% eligible, 12.5% respond","source":"Haslam & Prasad, JAMA Network Open 2019","url":"https://doi.org/10.1001/jamanetworkopen.2019.2535"},{"label":"Objective response rate to pembrolizumab vs chemotherapy in untreated NSCLC selected by PD-L1 TPS 50% or more (KEYNOTE-024): even the best-selected group has a majority of non-responders","value":"44.8% vs 27.8%","source":"Reck et al., NEJM 2016","url":"https://doi.org/10.1056/NEJMoa1606774"}],"causes":["Response depends on several partly independent axes (antigenicity, T-cell infiltration, antigen presentation, host factors) that no single marker captures.","PD-L1 expression is heterogeneous, dynamic and measured with several non-interchangeable assays and cut-offs.","TMB is a proxy for neoantigen load that ignores immunogenicity and antigen presentation.","Sponsors are not rewarded for developing biomarkers that shrink the eligible population.","Early on-treatment signals (ctDNA, imaging) are rarely used to stop ineffective therapy."],"currentEfforts":["The Friends of Cancer Research TMB Harmonization Project and the Blueprint PD-L1 IHC Comparison Project have standardised assay reporting.","Immuno-PET tracers such as 89Zr-labelled CD8 minibodies are in trials as early pharmacodynamic readouts of T-cell infiltration.","ctDNA dynamics in the first weeks of checkpoint therapy are being validated as an early marker of benefit in lung cancer and melanoma.","Multimodal foundation models trained on pathology, genomics and radiology (Owkin, Tempus, Paige) aim to predict immunotherapy benefit from routine data.","FDA approval of pembrolizumab for TMB-high solid tumours (2020) and dMMR tumours (2017) established tumour-agnostic immune biomarkers."],"successLooksLike":"A validated pre-treatment or early on-treatment test identifies the large majority of non-responders before they are exposed to months of ineffective immunotherapy, and the share of treated patients who benefit at least doubles."},"route":"/bottlenecks/b-immunotherapy-response/","neighbours":{"idea":[{"id":"idea-tr2-tmb-calibration-standard","kind":"idea","name":"A single calibrated tumour mutational burden across all sequencing panels","route":"/ideas/idea-tr2-tmb-calibration-standard/"},{"id":"idea-bio1-pmhc-bispecifics-public-drivers","kind":"idea","name":"Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface","route":"/ideas/idea-bio1-pmhc-bispecifics-public-drivers/"},{"id":"idea-nl-diet-covariates-io-trials","kind":"idea","name":"Capture diet, fibre and antibiotic exposure in every immunotherapy pivotal trial","route":"/ideas/idea-nl-diet-covariates-io-trials/"},{"id":"idea-cd8-pet-io","kind":"idea","name":"CD8 PET to stop or switch immunotherapy early","route":"/ideas/idea-cd8-pet-io/"},{"id":"idea-bio2-antigen-presentation-triage","kind":"idea","name":"Check whether a tumour can still show itself to the immune system","route":"/ideas/idea-bio2-antigen-presentation-triage/"},{"id":"idea-bio2-cxcr2-neutrophil-blockade","kind":"idea","name":"Clear the suppressive neutrophils out of pancreatic tumours first","route":"/ideas/idea-bio2-cxcr2-neutrophil-blockade/"},{"id":"idea-bio2-lactate-acid-axis","kind":"idea","name":"De-acidify the tumour so T cells can work in it","route":"/ideas/idea-bio2-lactate-acid-axis/"},{"id":"idea-bio2-tertiary-lymphoid-induction","kind":"idea","name":"Grow immune command posts inside tumours","route":"/ideas/idea-bio2-tertiary-lymphoid-induction/"},{"id":"idea-bio1-organoid-immune-coculture","kind":"idea","name":"Grow tumour organoids together with the patient's own immune cells","route":"/ideas/idea-bio1-organoid-immune-coculture/"},{"id":"idea-bio1-immune-matched-humanised-mice","kind":"idea","name":"Humanised mice with an immune system matched to the tumour donor","route":"/ideas/idea-bio1-immune-matched-humanised-mice/"},{"id":"idea-moon-cold-to-hot-programme","kind":"idea","name":"Make every cold tumour hot: a coordinated programme to reprogramme immune-excluded tumours","route":"/ideas/idea-moon-cold-to-hot-programme/"},{"id":"idea-bio1-spatial-clone-immune-map","kind":"idea","name":"Map which tumour clones sit next to which immune cells before choosing therapy","route":"/ideas/idea-bio1-spatial-clone-immune-map/"},{"id":"idea-tr2-pdl1-digital-calibration","kind":"idea","name":"One digital PD-L1 scale that maps across all the competing assays","route":"/ideas/idea-tr2-pdl1-digital-calibration/"},{"id":"idea-multimodal-foundation-model","kind":"idea","name":"Patient-level multimodal foundation models for treatment selection","route":"/ideas/idea-multimodal-foundation-model/"},{"id":"idea-moon-neoantigen-vaccines-at-scale","kind":"idea","name":"Personalised cancer vaccines at commodity cost through fully automated manufacturing","route":"/ideas/idea-moon-neoantigen-vaccines-at-scale/"},{"id":"idea-bio2-radiotherapy-sting-fractionation","kind":"idea","name":"Pick the radiation dose that switches the immune alarm on, not off","route":"/ideas/idea-bio2-radiotherapy-sting-fractionation/"},{"id":"idea-bio2-io-biomarker-data-commons","kind":"idea","name":"Pool every immunotherapy trial's biomarker data into one commons","route":"/ideas/idea-bio2-io-biomarker-data-commons/"},{"id":"idea-moon-irae-prediction-and-prevention","kind":"idea","name":"Predict immune side-effects before they happen and pre-empt them","route":"/ideas/idea-moon-irae-prediction-and-prevention/"},{"id":"idea-bio2-antibiotic-stewardship-io","kind":"idea","name":"Protect the gut flora of patients about to start immunotherapy","route":"/ideas/idea-bio2-antibiotic-stewardship-io/"},{"id":"idea-reg-antihistamine-plus-io-trial","kind":"idea","name":"Randomise a cheap antihistamine alongside immunotherapy","route":"/ideas/idea-reg-antihistamine-plus-io-trial/"},{"id":"idea-tr2-biomarker-negative-arms","kind":"idea","name":"Randomised trials to test whether biomarker-negative patients really do not benefit","route":"/ideas/idea-tr2-biomarker-negative-arms/"},{"id":"idea-bio2-trem2-myeloid-reprogramming","kind":"idea","name":"Reprogramme suppressive macrophages instead of trying to delete them","route":"/ideas/idea-bio2-trem2-myeloid-reprogramming/"},{"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/"},{"id":"idea-bio2-til-reactivity-selection","kind":"idea","name":"Select patients for cell therapy by whether their tumour holds reactive T cells","route":"/ideas/idea-bio2-til-reactivity-selection/"},{"id":"idea-tr2-spatial-biomarker-standards","kind":"idea","name":"Standards for spatial and multiplex tissue biomarkers before they reach the clinic","route":"/ideas/idea-tr2-spatial-biomarker-standards/"},{"id":"idea-bio2-fmt-plus-checkpoint-phase3","kind":"idea","name":"Take faecal transplant plus immunotherapy to a definitive trial","route":"/ideas/idea-bio2-fmt-plus-checkpoint-phase3/"},{"id":"idea-bio2-fibre-diet-io-trial","kind":"idea","name":"Test a high-fibre diet as an immunotherapy adjunct","route":"/ideas/idea-bio2-fibre-diet-io-trial/"},{"id":"idea-bio2-protein-plus-training-during-io","kind":"idea","name":"Test protein and resistance training during immunotherapy","route":"/ideas/idea-bio2-protein-plus-training-during-io/"},{"id":"idea-bio1-immunopeptidome-timing","kind":"idea","name":"Time immunotherapy to the moment targeted drugs make tumours visible","route":"/ideas/idea-bio1-immunopeptidome-timing/"},{"id":"idea-bio2-steroid-sparing-irae","kind":"idea","name":"Treat immunotherapy side-effects without wiping out the response","route":"/ideas/idea-bio2-steroid-sparing-irae/"},{"id":"idea-bio2-in-situ-vaccination-solid","kind":"idea","name":"Turn one tumour into a vaccine to treat all the others","route":"/ideas/idea-bio2-in-situ-vaccination-solid/"},{"id":"idea-bio2-spatial-signature-cdx","kind":"idea","name":"Turn the map of immune cells inside a tumour into a standardised test","route":"/ideas/idea-bio2-spatial-signature-cdx/"},{"id":"idea-bio2-epigenetic-priming-cold-tumours","kind":"idea","name":"Unmask hidden antigens with a short epigenetic course before immunotherapy","route":"/ideas/idea-bio2-epigenetic-priming-cold-tumours/"},{"id":"idea-bio2-ctdna-six-week-io-switch","kind":"idea","name":"Use a blood test at six weeks to decide whether to keep 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(TILs)","route":"/terms/tils/"}],"trial":[{"id":"checkmate-067","kind":"trial","name":"CheckMate 067","route":"/trials/checkmate-067/"},{"id":"fmt-pd1-refractory-melanoma-pitt","kind":"trial","name":"FMT plus pembrolizumab in anti-PD-1-refractory melanoma (Pittsburgh)","route":"/trials/fmt-pd1-refractory-melanoma-pitt/"},{"id":"keynote-024-189","kind":"trial","name":"KEYNOTE-024 & KEYNOTE-189","route":"/trials/keynote-024-189/"},{"id":"keynote-048","kind":"trial","name":"KEYNOTE-048","route":"/trials/keynote-048/"},{"id":"keynote-177","kind":"trial","name":"KEYNOTE-177","route":"/trials/keynote-177/"},{"id":"mimic-01","kind":"trial","name":"MIMic-01: healthy-donor FMT plus anti-PD-1, first-line melanoma","route":"/trials/mimic-01/"}],"paper":[{"id":"paper-felip-impower010-adjuvant-atezolizumab-lancet-2021","kind":"paper","name":"Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer 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