{"entity":{"id":"idea-immunotherapy-mss-crc","kind":"idea","name":"Making microsatellite-stable colorectal cancer immunotherapy-responsive","aka":[],"tldr":"Ninety-five percent of bowel cancers ignore immunotherapy. Combinations that heat the tumour up (targeted drugs, radiation, new checkpoints) are the main hope.","summary":"MSS CRC has few neoantigens, TGF-beta-rich stroma, and liver metastases that induce systemic tolerance. Approaches: botensilimab + balstilimab (Fc-enhanced anti-CTLA-4; 17% ORR in the phase 1, 21% in the later cohort selected for the absence of liver metastases), KRAS G12C inhibitor + PD-1, anti-EGFR + PD-1 in RAS wild-type (AVETUX), radiation to liver metastases, CEA-directed T-cell engagers.","asOf":"2026-09-07","links":[{"label":"Bullock et al., Botensilimab plus balstilimab in relapsed or refractory microsatellite-stable colorectal cancer (Nature Medicine 2024)","url":"https://doi.org/10.1038/s41591-024-03083-7"}],"tags":[],"related":["colorectal-roadmap","idea-crc-mss-immunotherapy-by-biomarker-not-by-line"],"cancers":["colorectal"],"sections":[],"technologies":["checkpoint-inhibitor","kras-inhibitors"],"targets":["ctla4","pd1","kras"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["cold-vs-hot","msi"],"trials":["checkmate-8hw","codebreak-300","keynote-177","nct05855200","nct05890742"],"people":[],"bottlenecks":[],"keyPapers":["paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024","paper-topalian-anti-pd1-nejm-2012","paper-le-mmr-deficiency-pd1-nejm-2015","paper-ctla-4-colorectal-j-exp-clin-cancer-res-2019"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Fc-enhanced CTLA-4 blockade plus PD-1 blockade, restricted to MSS CRC without active liver metastases, will show an OS benefit over trifluridine/tipiracil-based therapy in third line.","rationale":"Liver metastases deplete tumour-specific CD8 T cells; excluding them enriches for responders, as seen in the botensilimab expansion cohorts.","test":"Randomised phase 3 in third-line MSS CRC without liver metastases (BATTMAN-style), OS primary; ctDNA and TGF-β signatures as stratifiers.","maturity":"early-clinical"},"route":"/ideas/idea-immunotherapy-mss-crc/","neighbours":{"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/"}],"idea":[{"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-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/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"}],"target":[{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"}],"trial":[{"id":"nct05890742","kind":"trial","name":"A Clinical Trial Evaluating the Efficacy and Safety of IBI310 in Combination With Sintilimab, for Neoadjuvant Treatment of MSI-H/dMMR Resectable Colon Cancer","route":"/trials/nct05890742/"},{"id":"checkmate-8hw","kind":"trial","name":"CheckMate 8HW","route":"/trials/checkmate-8hw/"},{"id":"codebreak-300","kind":"trial","name":"CodeBreaK 300","route":"/trials/codebreak-300/"},{"id":"keynote-177","kind":"trial","name":"KEYNOTE-177","route":"/trials/keynote-177/"},{"id":"nct05855200","kind":"trial","name":"Study of Perioperative Dostarlimab in Participants With Untreated T4N0 or Stage III dMMR/MSI-H Resectable Colon Cancer","route":"/trials/nct05855200/"}],"paper":[{"id":"paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024","kind":"paper","name":"Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial","route":"/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/"},{"id":"paper-ctla-4-colorectal-j-exp-clin-cancer-res-2019","kind":"paper","name":"Combination of CTLA-4 and PD-1 blockers for treatment of cancer","route":"/key-papers/paper-ctla-4-colorectal-j-exp-clin-cancer-res-2019/"},{"id":"paper-le-mmr-deficiency-pd1-nejm-2015","kind":"paper","name":"Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ","route":"/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/"},{"id":"paper-topalian-anti-pd1-nejm-2012","kind":"paper","name":"Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer","route":"/key-papers/paper-topalian-anti-pd1-nejm-2012/"}],"bottleneck":[{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"}]}}