# Making microsatellite-stable colorectal cancer immunotherapy-responsive

Source: https://onco.cc/ideas/idea-immunotherapy-mss-crc/  
OnCo record `idea-immunotherapy-mss-crc` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-07
- 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.
- Proposed 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

## Sources

- Bullock et al., Botensilimab plus balstilimab in relapsed or refractory microsatellite-stable colorectal cancer (Nature Medicine 2024): https://doi.org/10.1038/s41591-024-03083-7

## Connected records

- roadmaps: [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](https://onco.cc/roadmaps/colorectal-roadmap/)
- ideas: [Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed](https://onco.cc/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/), [Unmask hidden antigens with a short epigenetic course before immunotherapy](https://onco.cc/ideas/idea-bio2-epigenetic-priming-cold-tumours/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/)
- targets: [CTLA-4](https://onco.cc/targets/ctla4/), [KRAS](https://onco.cc/targets/kras/), [PD-1](https://onco.cc/targets/pd1/)
- terms: [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/)
- trials: [A Clinical Trial Evaluating the Efficacy and Safety of IBI310 in Combination With Sintilimab, for Neoadjuvant Treatment of MSI-H/dMMR Resectable Colon Cancer](https://onco.cc/trials/nct05890742/), [CheckMate 8HW](https://onco.cc/trials/checkmate-8hw/), [CodeBreaK 300](https://onco.cc/trials/codebreak-300/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/), [Study of Perioperative Dostarlimab in Participants With Untreated T4N0 or Stage III dMMR/MSI-H Resectable Colon Cancer](https://onco.cc/trials/nct05855200/)
- key papers: [Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial](https://onco.cc/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/), [Combination of CTLA-4 and PD-1 blockers for treatment of cancer](https://onco.cc/key-papers/paper-ctla-4-colorectal-j-exp-clin-cancer-res-2019/), [Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ](https://onco.cc/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/), [Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer](https://onco.cc/key-papers/paper-topalian-anti-pd1-nejm-2012/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/)

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