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Advanced bowel cancer patients who have stopped responding to one of the main drugs used to treat it could be helped by immunotherapy, researchers have found.
Researchers at the Institute of Cancer Research (ICR) in London, and The Royal Marsden NHS Foundation Trust, have been exploring how tumours become resistant to cetuximab.
They looked at 35 people with advanced bowel cancer and found that cancer-killing immune cells were on average six times more active in tumours that had become resistant to cetuximab than those that had not responded to the drug at all.
Cetuximab only works in about half of patients, and most will eventually stop responding as their cancer becomes drug resistant.
Once this happens, patients have very limited treatment options, and researchers say new therapies are “desperately needed”.
Their study, published in Cancer Cell, could help pave the way for new treatments and also show which cancer sufferers are most likely to become resistant to the drug.
A trial has begun to test how immunotherapy could benefit patients who have stopped responding to the drug.
Dr Marco Gerlinger, consultant medical oncologist at the Royal Marsden NHS Foundation Trust, said: “In our new study, we have shone a light on the complex biology that lies behind the ability of bowel cancers to evade treatment with the targeted drug, cetuximab.
“Most bowel cancers are ‘immune deserts’ – so it’s enormously exciting to see that cetuximab attracts immune cells into these tumours.
“At the ICR and the Royal Marsden, we have already started a clinical trial of immunotherapy in people whose bowel tumours have become resistant to cetuximab and chemotherapy.
“I’m eager to see if immunotherapy can unleash the immune cells and shrink these tumours.
“Our findings could also lead to better tests so that people with changes in their tumours that mean they’re unlikely to respond to cetuximab – or likely to stop responding – could be spared unnecessary treatment.”
Tumours often adopt genetic strategies or change their environment to evade treatment.
The researchers were surprised to find that genetic changes could explain the development of drug resistance in only 36% of the tumours.
In contrast, in five out of seven patients who had stopped responding to treatment, tumours were heavily infiltrated by non-cancerous cells from surrounding supportive tissue.
These nurtured the cancer cells and helped them to grow during treatment
The team examined different immune cells in tumour samples before and after treatment with cetuximab.
They found that cancer-killing immune cells were on average six times more active in tumours that had become resistant to cetuximab than those that had never responded to the drug.
The researchers believe that cetuximab kills cancer cells in a way that sends signals that attract immune cells to the tumour.
This suggests that immunotherapies designed to “take the brakes off” the immune system could be effective in treatment.
A trial is now looking at how a combination of immunotherapy drugs, nivolumab and relatlimab, could potentially help patients whose tumours have stopped responding to a combination of cetuximab and chemotherapy.
The study also identified six ways where tumours were genetically evolving to become resistant to cetuximab.
The authors believe this will help doctors develop better tests to pick out patients unlikely to respond to it so they can be given alternative treatments.
The new research forms part of the ICR’s “Darwinian” drug discovery programme to overcome cancer evolution and drug resistance.
