Unlocking immunotherapies for patients with liver cancer

What are the molecular cues that determine how liver cancer patients respond to immunotherapies? Professor Helen Reeves, a gastroenterologist from Newcastle, tells us how a multidisciplinary team from across Europe is coming together via an Accelerator Award to advance research for one of the most lethal cancers affecting people today.

“Liver cancer – predominantly hepatocellular carcinoma (HCC) –  is one of the only cancer types where mortality is continuing to rise right now. It’s been traditionally very difficult to study. Most patients present with symptoms too advanced for treatment. Not only does this affect outcomes for them – it also means that biopsies are rarely collected, which reduces the resources available for research.

To overcome this, we’re tapping into the network of centres across the UK to collect samples from patients in Glasgow, London, Cambridge, Birmingham, Southampton and Newcastle. Using several locations at once will give us access to a critical number of tissue samples, which will speed up the pace of research.

Our goal is to understand the immunogenomic HCC microenvironment and know what it is that switches it off and allows cancer to progress. We’re looking at why some people respond to immune checkpoint inhibitors, and we hope that by the end of this award, we’ll be able to switch the immune system back on in patients with HCC.”

The key is really the molecular characterisation of liver cancers and looking at it with an immunotherapy hat on.

A ‘team science’ culture

“We’ve tried to bring in all the best people. There is a large team in Barcelona, seven UK sites and three in Italy.

It’s the first time that this type of programme is being carried out for liver cancer patients. Typically, centres either have the patients but insufficient scientific expertise, or they can produce translational models and high quality research, but have little exposure to liver cancer patients or their tissues. This programme gets everyone working together.

We will use the UK’s extensive Clinical Research Network to collect samples, alongside generating translational models. Josep Llovet’s team in Spain are leading on the molecular classification of liver cancers, while the Italian teams bring their impressive experience in immunology, which complements our own.

Training future leaders

“The funding will also help address the growing need for clinicians and scientists with expertise in liver cancer. Clinicians rarely choose liver cancer as a speciality, partially because there is a lack of options to offer to patients beyond palliative care. This Accelerator Award is changing that.

A group of 11 young scientists and clinical researchers will receive training in the UK, Italy and Spain, getting the opportunity to work with international experts and become the future leaders of liver cancer research.

By linking up enthusiastic early career clinicians and scientists with the exciting research coming out of the lab right now, we hope to convince more young researchers to make liver cancer their clinical speciality or area of special interest.”

Advice to future applicants: linking up with the experts in the field

“We applied for an Accelerator Award before but were unsuccessful. We thought we were ticking all the boxes: liver cancer is one of unmet need, we were seeking funding for infrastructure to help teams in different locations work together. But we were missing two key components. One was clearly defining the research questions our award would ultimately help to answer. The other was ensuring that we enlisted the right people to work on that specific area.

Following the initial rejection, Prof Tim Meyer, a liver cancer oncologist at UCL, and myself went back to revisit our application.  We agreed that our scientific focus should be on understanding the immune environment in which liver cancer develops and progresses, and that our co-investigators should strengthen that.

We had the patients and clinical expertise. To lead our basic science, we enlisted the help of Prof Derek Mann – an internationally recognised expert in the liver fibrosis field, with a developing and CRUK funded interest in the role of neutrophils in liver cancer. For translational modelling we recruited very strong teams in Newcastle, Glasgow and Cambridge. 

We didn’t have a track record in the molecular or immunogenomic characterisation of liver cancers, so we went where the experts are in that field – Barcelona. I had met Josep Llovet years before, as a researcher at Mount Sinai Medical School in New York and he had recently visited our CRUK Centre in Newcastle as a guest speaker. 

For the immunology expertise, we went to Mala Maini, a renowned liver immunologist from UCL and through her, to outstanding liver immunologists in Italy, Southampton and Birmingham.  I knew many of these people already, having met them while representing the UK on the governing board of the European Association for the Study of Liver.”

I strongly advise future hopefuls wishing to gain this type of funding to define clearly what you hope to achieve, alongside identifying and recruiting those best placed to help you deliver it. That’s what makes a successful application.