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New drug could unlock benefits of immunotherapy for more patients

A scientist wearing a mask and blue gloves holds a red pill in focus.

     Image: Scientist holding a pill. Credit: scanrail/Getty Images/iStockphoto

A new drug could offer a powerful way to sensitise tumours to immunotherapy, a new trial suggests.

Ceralasertib showed promise for patients no longer responding to current cancer treatments in an early clinical trial. Given on its own, the drug stabilised the growth of tumours in more than half of patients who received it, with one patient seeing benefits for more than five years.

Prime tumours to be more responsive to immunotherapy

Researchers found that ceralasertib, a drug which targets cancer's ability to repair its DNA by blocking a key protein called ATR, also profoundly increased immune activity in some patient's tumours – changes which could leave them much more susceptible to immunotherapy treatments.

The study opens exciting new avenues for future trials which would use ceralasertib to prime tumours to be more responsive to immunotherapies, potentially unlocking their benefits for a wider group of patients.

A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust led the phase I PATRIOT trial.

Researchers treated 67 patients with very advanced solid tumours with ceralasertib on its own. For these patients, other treatments had stopped working and their tumours were continuing to grow.

The study was funded by AstraZeneca, Cancer Research UK and the Rosetrees Trust, and it has been published in the Journal of Clinical Investigation.

Tumour biopsies showed immune response

Ceralasertib, which can be taken as a pill, stopped tumours growing in more than half of patients – 34 out of 66 patients whose treatment response could be measured. In five patients, the drug shrank their tumours. Of the 39 patients who benefited from the drug, 68 per cent saw no progression of their disease for at least four months. 

One patient with advanced ovarian cancer, whose tumour had faults in the key DNA repair gene ARID1A, responded remarkably well to ceralasertib, seeing their tumour continue to shrink over a period of more than five years. Researchers at The Institute of Cancer Research (ICR) previously identified the ARID1A gene as a marker of sensitivity to ATR inhibitors such as ceralasertib.

In the current study, the scientists compared tumour biopsies taken before and after treatment with ceralasertib to understand the underlying biology behind the drug's effects.

They were excited to observe that the drug on its own caused profound changes in patients’ immune systems, both in their blood and within their tumours, in addition to its impact on DNA repair.

Giving ceralasertib led to increases in a type of immune cell that seeks out and kills cancer cells in the blood, alongside increased infiltration of immune cells into the tumours. These are signs that tumours are under attack and would be responsive to a range of immunotherapies – drugs which harness the body’s own immune system to fight cancer.

Critical biological insights

Clinical trials have already shown that ceralasertib is effective when used in combination with the most common type of immunotherapy, known as PDL-1 inhibitors, but the current study is the first to prove that ceralasertib modulates the immune system in its own right.

The researchers have gained critical insight into the way in which the drug primes tumours to respond to immunotherapies. They hope this will lead to even better combinations of the drug with immunotherapy – a cutting-edge class of drugs which currently only works for a minority of patients. 

Since the PATRIOT trial launched, other clinical trials led by the ICR and The Royal Marsden have begun – investigating the use of ceralasertib in combination with other drugs which prevent DNA from repairing itself, such as the PARP inhibitor olaparib.

Study leader Dr Magnus Dillon, Clinician Scientist at The Institute of Cancer Research, London, and Clinical Consultant at The Royal Marsden NHS Foundation Trust, said: 

“This is the largest clinical trial of an ATR inhibitor, and it’s encouraging to see that on its own ceralasertib can keep cancer from progressing and even shrink patients’ tumours for an impressive time, giving some patients precious extra years of living well. It has also given us a clue as to the biological markers which may predict who could benefit from this drug in future.

“Excitingly, this trial provides us with the biological insights for how best to combine this drug with an immunotherapy and generate an even more powerful cancer treatment for people who have exhausted other options.”

George Pieri, 70, from Great Yarmouth, was diagnosed with skin cancer on his lower lip in 2017, which was first picked up by his dentist. He was referred to The Royal Marsden and later joined the PATRIOT trial. George said:

“My cancer has been very difficult to treat, and the disease spread to both my mouth and neck. Treatment has included chemotherapy and radiotherapy, an operation to replace the bone in my lower jaw, and I also had a tracheostomy. I joined a trial which I initially responded well too, but when it stopped working I was really running out of options.

"That’s when I heard about this PATRIOT trial, and since taking ceralasertib my cancer has remained stable. I’m really happy and incredibly grateful, it’s saved my life and has allowed me to spend precious time with my grandchildren.”

George with his wife and grandchildren.

Image: George with his wife and grandchildren. Credit: George Pieri. 

Dr Anna Kinsella, Science Engagement Manager at Cancer Research UK:

"This is the largest study to date showing the potential of a class of drugs called ATR inhibitors in treating cancer when used alone. While there is still a long way to go before ceralasertib can be used in the clinic, it’s always exciting to see new approaches showing potential in early-stage clinical trials. These promising results lay the foundations for future clinical trials and offer scientists and doctors new avenues of research. We look forward to seeing how this work drives further progress."

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Kevin Harrington ceralasertib skin cancer Magnus Dillon
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