# Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed

Source: https://onco.cc/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/  
OnCo record `idea-crc-mss-immunotherapy-by-biomarker-not-by-line` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Ninety-five percent of advanced bowel cancers ignore immunotherapy, and the only real signal so far came in patients without active liver secondaries. Trials keep enrolling by treatment line rather than by immune biology, which guarantees the responders are diluted away.

## Summary

Le's original study set the boundary: 40 percent response in mismatch repair-deficient colorectal cancer, 0 of 18 in proficient disease, with 1,782 against 73 somatic mutations per tumour. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with balstilimab gave the first credible microsatellite stable signal: 17 percent response and 61 percent disease control in 101 evaluable heavily pre-treated patients, with responses concentrated in those without active liver metastases.

The field has two measurable handles it does not use for enrolment. Galon's immune contexture showed in 2006 that the type, density and location of T cells in a colorectal tumour predicts outcome better than stage, and the consensus molecular subtypes separate the immune-infiltrated CMS1 and the mesenchymal, TGF-beta-driven CMS4 that excludes T cells. A trial that enrolled by Immunoscore band, CMS class and liver-metastasis status would test the combination in the population where the mechanism predicts it can work, rather than in whoever has exhausted chemotherapy.

## Fields

- Kind: Idea
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Hypothesis: In microsatellite stable metastatic colorectal cancer selected by an immune-exclusion biomarker (high Immunoscore or CMS1-like signature, no active liver metastases), Fc-enhanced CTLA-4 blockade with PD-1 blockade produces an objective response rate above 30 percent and an overall survival benefit against standard refractory-line treatment, where an unselected population shows neither.
- Rationale: The one positive signal in this population is already concentrated in a biologically defined subgroup, liver-metastasis-free disease, discovered after the fact; enrolment by line of therapy mixes that subgroup with patients whose tumours have no T cells to release.
- Proposed test: A randomised trial stratified prospectively by Immunoscore band, consensus molecular subtype and liver-metastasis status, with overall survival as the primary endpoint in the biomarker-selected stratum and the unselected stratum reported separately; paired biopsies to confirm that responders convert from excluded to inflamed. Kill the hypothesis if response in the selected stratum does not exceed the 17 percent seen unselected.
- Maturity: early-clinical
- Actor: research

## Sources

- Bullock et al.: botensilimab plus balstilimab in MSS colorectal cancer (Nat Med 2024): https://europepmc.org/article/MED/38871975
- Le et al.: PD-1 blockade in mismatch-repair deficiency (N Engl J Med 2015): https://europepmc.org/article/MED/26028255
- ClinicalTrials.gov NCT05608044: https://clinicaltrials.gov/study/NCT05608044

## 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/), [Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity](https://onco.cc/roadmaps/immunotherapy-roadmap/)
- ideas: [Making microsatellite-stable colorectal cancer immunotherapy-responsive](https://onco.cc/ideas/idea-immunotherapy-mss-crc/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- fronts: [Immunotherapy](https://onco.cc/fronts/immunotherapy/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [CTLA-4](https://onco.cc/targets/ctla4/), [PD-1](https://onco.cc/targets/pd1/)
- pathways: [TGF-β signalling](https://onco.cc/pathways/tgf-beta/)
- drugs: [Balstilimab](https://onco.cc/drugs/balstilimab/), [Botensilimab](https://onco.cc/drugs/botensilimab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Agenus](https://onco.cc/companies/agenus/)
- terms: [Consensus molecular subtypes (CMS1-4)](https://onco.cc/terms/cms-subtypes/), [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Neoantigen](https://onco.cc/terms/neoantigen/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- 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/), [Galon 2006: the type, density and location of immune cells in colorectal tumours predict outcome](https://onco.cc/key-papers/paper-galon-immune-contexture-colorectal-science-2006/), [PD-1 blockade in tumors with mismatch-repair deficiency](https://onco.cc/key-papers/paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015/), [The consensus molecular subtypes of colorectal cancer](https://onco.cc/key-papers/paper-cms-guinney-nat-med-2015/)

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