New discovery could help combat side effects of cancer immunotherapy

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Researchers in Liverpool and the US have made a breakthrough that could lead to improved immunotherapy treatments for some cancer patients.

Their findings, which have been published in Nature, provide critical clues to why many immunotherapies trigger dangerous side effects - and point to a better strategy for treating patients with solid tumours, such as head and neck cancers.

The work was led by Professor Christian Ottensmeier, Professor of Immuno-Oncology at the University of Liverpool and a Consultant Medical Oncologist at The Clatterbridge Cancer Centre, and Professor Pandurangan Vijayanand at the La Jolla Institute for Immunology in California.

Immunotherapy side effects

While immunotherapy has revolutionised the world of cancer treatment, long term disease control is achieved in only around 20 to 30 percent of patients with solid cancers. Immunotherapy can also come at a cost as many patients develop serious problems in their lungs, bowel, and even skin during treatment. These side effects can be debilitating and may force physicians to stop the immunotherapy.

When head and neck patients started showing adverse side effects during an immunotherapy trial sponsored and funded by Cancer Research UK's Centre for Drug Development in a number of cancer centres across the UK, the researchers went back through the data and worked with patient samples to see what went wrong.

The patients had been given an oral cancer immunotherapy called a PI3Kδ inhibitor, which are new to the cancer immunotherapy scene, but hold promise for their ability to inhibit "regulatory" T cells (Tregs).

At the time of the trial, PI3Kδ inhibitors had proven effective for B cell lymphomas but had not yet been tested in solid tumours. Unfortunately, 12 of the 21 patients in the trial had to discontinue treatment early because they developed inflammation in the colon, a condition called colitis.

Using cutting edge single-cell genomic sequencing on human and mouse tissue, the researchers showed that in the process of increasing tumour-fighting T cells, the PI3Kδ inhibitor, also blocked a specific Treg cell subset from protecting the colon. Without Tregs on the job, pathogenic T cells, called Th17 and Tc17 cells, moved into the bowel and caused bowel inflammation.

It was clear to the researchers that the cancer trial patients had been given a larger PI3Kδ inhibitor dose than they needed, and the immunotherapy had thrown the delicate composition of immune cells in the gut out of balance.

New dosing strategy

Using a mouse model, the team found that intermittent dosing was a promising treatment strategy that combines sustained anti-tumour immunity with reduced toxicity.

The researchers are now designing a human clinical trial to test the intermittent dosing strategy in humans.

Professors Ottensmeier said: “Our data show clearly how removal of a particular type of T cells can enable both the good (immune attack on the cancer cells) and the bad by causing side effects. Our data suggest a way in which we can disentangle these from each other. We are very excited that we may be on the way to making immunotherapy useful to a larger group of patients without extra side effects.”

Collaborative effort

The international study also involved Liverpool-based researchers and clinicians from the Liverpool Head and Neck Centre, the Liverpool Experimental Cancer Medicine Centre and Liverpool University Hospitals NHS Foundation Trust.

Professor Ottensmeier added: "This study has been an extraordinary collaborative effort. It's taken groups of medical oncologists, surgeons, research nurses, our patients, and scientists—all working together on two sides of the pond.”

The paper ‘Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs’ is published in the journal Nature, DOI:10.1038/s41586-022-04685-2.

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