ideasIdea
Reprogramme the liver's own immune cells to refuse metastases
The liver is where bowel cancer most often spreads. Drugs delivered straight into the liver's blood supply could retrain its resident immune cells to reject arriving cancer cells.
Kupffer cells and liver sinusoidal endothelium determine whether arriving colorectal cells die or seed, and hepatic arterial infusion is an established delivery route with dedicated pumps and an experienced clinical community. Combining regional delivery with a myeloid agonist — CD40 agonist, TLR9 agonist or STING agonist — targets the niche rather than the tumour, at doses that would be intolerable systemically.
Hypothesis
Regional hepatic delivery of a myeloid-agonist regimen after resection of colorectal liver metastases reduces the new-hepatic-lesion rate at 18 months compared with systemic therapy alone.
Rationale
Regional floxuridine infusion already improves liver-specific outcomes, proving the route matters. CD40 agonism converts liver macrophages to an anti-tumour state in murine colorectal liver metastasis models, and systemic CD40 agonists are limited mainly by hepatotoxicity and cytokine release.
What would test it
Dose-finding regional infusion study with paired liver biopsies for myeloid phenotype, then a randomised trial with new-hepatic-lesion-free survival as primary endpoint.
Maturity
preclinical evidence
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
7
Bottlenecks it attacks
- Metastasis is understood least and studied last · Metastasis causes about nine in ten cancer deaths but gets a small fraction of research money and almost no trials of its own.
- Cold tumours and the immunosuppressive microenvironment · Most tumours keep the immune system out or asleep, so immunotherapy helps only a minority.