Scientists at the Centre for Cancer Immunology have made a breakthrough in understanding why some cancers don’t respond to immunotherapy treatment, bringing fresh hope that many more people could survive the disease.
A study, published Cancer Research, identified a key cell protein that prevents the treatment from working and crucially, have found a drug that can overcome it.
Immunotherapy works by triggering the body’s own immune system or ‘T-cells’ to recognise and attack cancer cells and has been successful in treating many types of cancer.
But for a large number of patients, the treatment is ineffective due to a protective barrier of cells called cancer assisted fibroblasts (CAFs) sitting around the tumour that our T-cells cannot penetrate.
The six-year study, led by Professor Gareth Thomas and funded by CRUK, revealed that the CAFs are regulated by a protein called ATM which normally controls DNA repair in cells. Blocking the ATM protein, prevents the protective CAF barrier forming and therefore gives the patient’s immune system a better chance of attacking the cancer cells while undergoing immunotherapy.
Gareth Thomas, Professor of Experimental Pathology said: “Immunotherapy for cancer has been a very exciting development but still doesn’t work in most patients. Our results suggest that in many cases, treatment resistance is caused by CAFs and this can be overcome by targeting ATM.
“Many patients have tumours that contain high levels of CAFS, which are preventing the T-cells from reaching the tumours. This includes around 50% of head and neck cancers, 95% of pancreatic cancers and 60-70% of oesophageal and colorectal cancers.
“If we can prevent this CAF formation by blocking the ATM protein then we can overcome immunotherapy resistance and we are very excited that this could be effective in a large group of patients across different cancer types.”
What makes this latest study even more significant is the fact researchers have already designed a drug that can block the ATM protein. ATM inhibitors have been developed for another purpose – to sensitise cancer cells to radiotherapy and are currently being evaluated in clinical trials for their potential to improve radiotherapy response in people with brain cancer.
Professor Thomas added: “What’s really exciting about this is that we’ve been using a drug that already exists, so we don’t need to spend time developing a drug and could take this straight to testing.
“It is very effective at getting T-cells into the tumour by targeting CAF, which is a completely novel use for the drug. We’ve shown in our mouse models that we can inhibit CAF formation, overcome immunotherapy resistance and significantly improve the response to this type of treatment. It is really very striking.”
The team’s next step will be to develop a clinical trial that will see the research translate from bench to bedside.
This latest research was led by scientists from the Faculty of Medicine at the University of Southampton, working with colleagues at the universities of Leicester, Liverpool and Centre Médical Universitaire, Switzerland, together with AstraZeneca in Cambridge.