Tag Archive for: Immunity Inflammation and Transplantation

Treating newly-diagnosed Crohn’s patients with advanced therapy leads to dramatic improvements in outcomes



A large-scale clinical trial of treatment strategies for Crohn’s disease has shown that offering early advanced therapy to all patients straight after diagnosis can drastically improve outcomes, including by reducing the number of people requiring urgent abdominal surgery for treatment of their disease by ten-fold.

The PROFILE trial, led by researchers at the University of Cambridge, involved 386 patients with newly-diagnosed active Crohn’s disease. Recruiting from 40 hospitals across the UK, and supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre and NIHR Clinical Research Network, it sought to test whether a biomarker – a genetic signature – could predict which patients were at greatest risk of relapses of their condition, and to test two different approaches to treating the disease.

Crohn’s disease is a life-long condition characterised by inflammation of the digestive tract. It affects around one in 350 people in the UK. Even at its mildest, it can cause symptoms that have a major impact on quality of life including: stomach pain, diarrhoea, weight loss and fatigue. Typically patients experience ‘flares’ of inflammation, where their condition worsens for a time, producing more symptoms and progressive bowel damage. As many as one in 10 patients will require urgent abdominal surgery to treat their condition within their first year of diagnosis.

The findings of the PROFILE trial, sponsored by Cambridge University Hospitals (CUH) NHS Foundation Trust and the University of Cambridge, are published today (22 February) in The Lancet Gastroenterology and Hepatology. While the biomarker did not prove useful in selecting treatments for individual patients, a ‘top-down’ treatment strategy involving use of the drug infliximab straight after diagnosis, showed dramatic results.

Infliximab works by blocking a protein found in the body’s immune system, TNF (tumour necrosis factor)-alpha, which plays an important role in inflammation. The drug is administered through regular intravenous infusions directly into the bloodstream or injections under the skin. However, due to historical concerns about cost and side-effects – including an increased risk of infection related to immunosuppression – it is currently only offered when patients experience regular flare-ups that do not respond to less potent treatments.

In the PROFILE trial, patients were assigned at random to one of two treatment groups. Each group was given a different treatment strategy and patients were followed up over the course of a year.

The first group was treated using an ‘accelerated step-up’ approach, which is the conventional treatment strategy used in the UK and across most countries around the world. In this group, patients only started on infliximab if their disease was progressing and not responding to other simpler treatments.

The second group, however, was treated using ‘top-down’ therapy – that is, they were provided with infliximab as soon as possible after their diagnosis, regardless of the severity of their symptoms.

The results were dramatic: 80% of people receiving the top-down therapy had both symptoms and inflammatory markers controlled throughout the course of the entire year compared to only 15% of people receiving the accelerated step-up therapy.

Two-thirds (67%) of patients in the ‘top-down’ group had no ulcers seen on their endoscopy camera test at the end of the trial – something known as endoscopic remission. Endoscopic remission is considered very important as this has been consistently associated with decreased risk of later complications in Crohn’s disease. Most previous clinical trials of therapies have been considered highly successful based on getting 20 to 30% of patients into endoscopic remission.

As well as these findings, patients in the top-down arm also had higher quality of life scores, less use of steroid medication and lower number of hospitalisations.

Strikingly, while around one in 20 patients (5%) in the conventional treatment arm of the trial required urgent abdominal surgery for their Crohn’s disease, only one in 193 (0.5%) receiving the ‘top-down’ therapy required such surgery.

Dr Nuru Noor from the Department of Medicine at the University of Cambridge, one of the study’s lead researchers and first author of the trial, said: “Historically, treatment with an advanced therapy like infliximab within two years of diagnosis has been considered ‘early’ and an ‘accelerated step-up’ approach therefore ‘good enough’. But our findings redefine what should be considered early treatment.

“As soon as a patient is diagnosed with Crohn’s disease, the clock is ticking – and has likely been ticking for some time – in terms of damage happening to the bowel, so there’s a need to start on an advanced therapy such as infliximab as soon as possible. We’ve shown that by treating earlier, we can achieve better outcomes for patients than have previously been reported.”

In fact, say the researchers, the improvements seen among the trial patients receiving ‘top-down’ therapy might be even more stark compared to usual clinical care. Few patients with Crohn’s disease in standard clinical care receive the rapid, ‘accelerated step-up’ approach provided by the trial protocol, and so the benefits of implementing a ‘top-down’ approach in standard clinical care might be even more pronounced.

Crucially, the team found no difference in risk of serious infection between treatment strategies, suggesting that infliximab straight after diagnosis was well tolerated, contrary to previous concerns about its safety. In addition, the cost of the drug, which is now an off-patent, generic and ‘biosimilar’ medicine, has fallen considerably from around £15,000 to around £3,000 per patient per year.

Chief Investigator of the PROFILE trial Professor Miles Parkes, Director of the NIHR Cambridge Biomedical Research Centre, said:  “Up until now, the view has been ‘Why would you use a more expensive treatment strategy and potentially over-treat people if there’s a chance they might do fine anyway?’

“As we’ve shown, and as previous studies have demonstrated, there’s actually a pretty high risk that an individual with Crohn’s disease will experience disease flares and complications even in the first year after diagnosis.

“We now know we can prevent the majority of adverse outcomes, including need for urgent surgery, by providing a treatment strategy that is safe and becoming increasingly affordable. If you take a holistic view of safety, including the need for hospitalisations and urgent surgery, then the safest thing from a patient point of view is to offer ‘top-down’ therapy straight after diagnosis rather than having to wait and use ‘step-up’ treatment.”

The PROFILE team are now actively working on an analysis of the health economics to see whether the benefits of the therapy outweigh its cost.

Professor Parkes added: “It’s not just those five per cent of people requiring surgery that we need to think about. In the ‘step-up’ arm lots of people experienced disease flares without necessarily needing surgery. And every time somebody flares, they require several consultations with specialist doctors and nurses, clinical investigations such as scans and colonoscopies, time off work, time out of education and so on – all leading to major impacts on quality of life for individuals.”

While there are other anti-TNF drugs, such as adalimumab, that work in a similar manner to infliximab and are significantly cheaper, more research is required to understand if it would be as clinically effective.

Ruth Wakeman, Director of Services, Advocacy & Evidence at Crohn’s & Colitis UK said: “Crohn’s Disease affects over 200,000 people in the UK and we know that many of them have symptoms for a long time before they are diagnosed. But diagnosis is not the end of their journey, and the trial and error involved in finding the right treatment can be challenging and distressing.

“This study shows what a dramatic difference early treatment with advanced therapy can make to newly-diagnosed patients. People with Crohn’s don’t want to be stuck in hospital or having surgery, they want to be out in the world, living their lives. Anything that speeds up the path to remission can only be a good thing.”

The research was funded by Wellcome and PredictImmune Ltd and supported by the NIHR Cambridge Biomedical Research Centre.

“If the drug had been offered in the first place, things could have been very different.”

Toby Moore, 28, was just ten years old when it became clear there was something wrong.

“I was at primary school at the time and was getting lots of abdominal pain, lots of going to the toilet and vomiting, low energy levels – I was effectively unable to consume any food or drink without some kind of problem. It was just terrible.”

He visited the GP repeatedly over six months, where among other things he was told it was due to the stress of Year Six exams. He says that for his mother and father, it was probably the most challenging time of their lives as parents.

“I was eventually referred to a paediatric gastroenterologist specialist who within 30 seconds of looking at me said, ‘Right. I think you have Crohn’s disease. I’d like to do these tests,’ and off we went.”

The specialist was correct. He put Toby on an ‘elemental diet’ to manage his condition, which meant that for six weeks he could eat no food or drinks (other than water), only prescription shakes aimed at allowing his digestive system to heal. Toby then had to reintroduce different foods into his diet to see if they could identify what triggered his condition.

Not long afterwards, he had a ‘flare up’, with his symptoms worsening significantly. His local Peterborough hospital was unable to help and so he was referred to the Royal Free Hospital in London. There, his parents had to make the difficult decision of whether he should receive abdominal surgery or go onto biologic medication. They chose the latter, and Toby was put on infliximab.

“If you asked my parents now, they’d call it a light switch drug. I was infused with it on a Thursday and by the Sunday I was a different person. I was eating, drinking, my symptoms had stopped. It was unbelievable. Arguably, if that had been offered in the first place instead of the lighter approach, things could have been very different.”

Toby was on infliximab for several years, but was taken off the drug in late secondary school when he became unwell – “not in a Crohn’s disease way, something else was going on”. He was taken into hospital, where the doctors immediately stopped the treatment, concerned it was a trigger.

Toby was transferred to Addenbrooke’s Hospital, where Dr Miles Parkes took over his treatment. It turned out that Toby also had large vessel vasculitis, another autoimmune condition. Whereas Crohn’s affects your digestive system, this affects blood vessels. It causes the aorta, the main blood vessel in your body, to become narrowed, which causes symptoms including weight loss, unexplained lower back pain and fatigue.

Since then, Toby has been on a number of different biologic treatments, each working for a while before their effects wear off, he experiences another flare up, and is prescribed a different drug. Were it not for the drugs, he says his life would be very different.

“It can be quite debilitating, especially when it’s flaring up, as I’m sure you can imagine, when you have minimal control over certain bodily functions. It’s not the most pleasant.”

His current medication, upadacitinib, involves taking a daily pill. It has helped him manage his condition – flare ups aside – allowing him to live a relatively normal life, hold down a steady job as a chef in a local hospice , close to where he lives, and start a family. But he still has to be very careful.

“Where possible I try to avoid stressful situations that life throws at you. When you live at your mum and dad’s life’s a bit more simple, you’ve got a few less responsibilities, so stress is slightly less, but when you go out into the big wide world – and I’ve got a two-and-a-half year old daughter now – that obviously adds a new dynamic to your life!”

Toby has nothing but praise for the NHS. “They’ve been just phenomenal. Miles is very good at nipping things in the bud straight away. He always actions things, he doesn’t just say, ‘Well, we’ll see how you are in a month’. So it never gets too out of control. My opinion of the NHS is really, really high. They’ve been a lifeline for me.”

Paper Reference

Noor NM, Lee JC, Bond S, et al. PROFILE: a multi-centre, randomised, open-label, biomarker-stratified clinical trial of treatment strategies for patients with newly-diagnosed Crohn’s disease. Lancet Gastroenterol Hepatol; 23 Feb 2024; DOI: 10.1016/S2468-1253(24)00034-7

Underactive immune response may explain obesity link to COVID-19 severity

Individuals who are obese may be more susceptible to severe COVID-19 because of a poorer inflammatory immune response, say Cambridge scientists.

Scientists at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) and Wellcome Sanger Institute showed that following SARS-CoV-2 infection, cells in the lining of the lungs, nasal cells, and immune cells in the blood show a blunted inflammatory response in obese patients, producing suboptimal levels of molecules needed to fight the infection.

Since the start of the pandemic, there have been almost 760 million confirmed cases of SARS-CoV-2 infection, with almost 6.9 million deaths. While some people have very mild – or even no – symptoms, others have much more severe symptoms, including acute respiratory distress syndrome requiring ventilator support.

One of the major risk factors for severe COVID-19 is obesity, which is defined as a body mass index (BMI) of over 30. More than 40% of US adults and 28% of adults in England are classed as obese.

While this link has been shown in numerous epidemiological studies, until now, it has not been clear why obesity should increase an individual’s risk of severe COVID-19. One possible explanation was thought to be that obesity is linked to inflammation: studies have shown that people who are obese already have higher levels of key molecules associated with inflammation in their blood. Could an overactive inflammatory response explain the connection?

Professor Menna Clatworthy
Professor Menna Clatworthy

Professor Menna Clatworthy, pictured right, is the Immunity, Inflammation and Transplantation theme lead at NIHR Cambridge BRC and a clinician scientist at the University of Cambridge, studying tissue immune cells at CITIID alongside caring for patients at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust. She said: “During the pandemic, the majority of younger patients I saw on the COVID wards were obese. Given what we know about obesity, if you’d asked me why this was the case, I would have said that it was most likely due to excessive inflammation. What we found was the absolute opposite.”

The team analysed blood and lung samples taken from 13 obese patients with severe COVID-19 requiring mechanical ventilation and intensive care treatment, and 20 controls (non-obese COVID-19 patients and ventilated non-COVID-19 patients). These included patients admitted to the Intensive Care Unit at Addenbrooke’s Hospital.

Her team used a technique known as transcriptomics, which looks at RNA molecules produced by our DNA, to study activity of cells in these key tissues. Their results are published in the American Journal of Respiratory and Critical Care Medicine.

Contrary to expectations, the researchers found that the obese patients had underactive immune and inflammatory responses in their lungs.  In particular, when compared to non-obese patients, cells in the lining of their lungs and some of their immune cells had lower levels of activity among genes responsible for the production of two molecules known as interferons (INF) – interferon-alpha and interferon-gamma – which help control the response of the immune system, and of tumour necrosis factor (TNF), which causes inflammation.

When they looked at immune cells in the blood of 42 adults from an independent cohort, they found a similar, but less marked, reduction in the activity of interferon-producing genes as well as lower levels of IFN-alpha in the blood.

Professor Clatworthy said: “This was really surprising and unexpected. Across every cell type we looked at, we found that that the genes responsible for the classical antiviral response were less active. They were completely muted.”

The team was able to replicate its findings in nasal immune cells taken from obese children with COVID-19, where they again found lower levels of activity among the genes that produce IFN-alpha and IFN-gamma. This is important because the nose is one of the entry points for the virus – a robust immune response there could prevent the infection spreading further into the body, while a poorer response would be less effective.

One possible explanation for the finding involves leptin, a hormone produced in fat cells that controls appetite. Leptin also plays a role in the immune response: in individuals who are normal weight, levels of the hormone increase in response to infection and it directly stimulates immune cells. But obese people already have chronically higher levels of leptin, and Clatworthy says it is possible that they no longer produce sufficient additional leptin in response to infection, or are insensitive to it, leading to inadequate stimulation of their immune cells.

The findings could have important implications both for the treatment of COVID-19 and in the design of clinical trials to test new treatments.

Because an overactive immune and inflammatory response can be associated with severe COVID-19 in some patients, doctors have turned to anti-inflammatory drugs to dampen this response. But anti-inflammatory drugs may not be appropriate for obese patients.

Co-author Dr Andrew Conway Morris from the Department of Medicine at the University of Cambridge and Honorary Consultant on the intensive care unit at Addenbrooke’s Hospital said: “What we’ve shown is that not all patients are the same, so we might need to tailor treatments. Obese subjects might need less anti-inflammatory treatments and potentially more help for their immune system.”

Clinical trials for potential new treatments would need to involve stratifying patients rather than including both severe and normal weight patients, whose immune responses differ.

The research was largely supported by Wellcome, the Medical Research Council and the National Institute for Health and Care Research (NIHR), including via the NIHR Cambridge Biomedical Research Centre.

Paper Reference

Guo, SA, Bowyer, GS, Ferdinand, JR, Maes, M & Tuong, ZK et al. Obesity associated with attenuated tissue immune cell responses in COVID-19. Am J Resp Critical Care Med; 1 Mar 2023; DOI: 10.1164/rccm.202204-0751OC 

Off-patent liver disease drug could prevent COVID-19 infection

Cambridge scientists have identified an off-patent drug that can be repurposed to prevent COVID-19 – and may be capable of protecting against future variants of the virus – in research part-funded by the NIHR Cambridge BRC.

The research, published in Nature, showed that an existing drug used to treat a type of liver disease is able to ‘lock’ the doorway by which SARS-CoV-2 enters our cells, a receptor on the cell surface known as ACE2. Because this drug targets the host cells and not the virus, it should protect against future new variants of the virus as well as other coronaviruses that might emerge.

If confirmed in larger clinical trials, this could provide a vital drug for protecting those individuals for whom vaccines are ineffective or inaccessible as well as individuals at increased risk of infection.

Dr Fotios Sampaziotis, from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge and Addenbrooke’s Hospital, led the research in collaboration with Professor Ludovic Vallier from the Berlin Institute of Health at Charité.

Dr Sampaziotis said: “Vaccines protect us by boosting our immune system so that it can recognise the virus and clear it, or at least weaken it. But vaccines don’t work for everyone – for example patients with a weak immune system – and not everyone have access to them. Also, the virus can mutate to new vaccine-resistant variants.

“We’re interested in finding alternative ways to protect us from SARS-CoV-2 infection that are not dependent on the immune system and could complement vaccination. We’ve discovered a way to close the door to the virus, preventing it from getting into our cells in the first place and protecting us from infection.”

Work on organoids

Dr Sampaziotis had previously been working with organoids – ‘mini-bile ducts’ – to study diseases of the bile ducts. Organoids are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same functions as the part of the organ being studied.

Using these, the researchers found that a molecule known as FXR, which is present in large amounts in these bile duct organoids, directly regulates the viral ‘doorway’ ACE2, effectively opening and closing it. They went on to show that ursodeoxycholic acid (UDCA), an off-patent drug used to treat a form of liver disease known as primary biliary cholangitis, ‘turns down’ FXR and closes the ACE2 doorway.

In this new study, his team showed that they could use the same approach to close the ACE2 doorway in ‘mini-lungs’ and ‘mini-guts’ – representing the two main targets of SARS-CoV-2 – and prevent viral infection.

The next step was to show that the drug could prevent infection not only in lab-grown cells but also in living organisms. For this, they teamed by up with Professor Andrew Owen from the University of Liverpool to show that the drug prevented infection in hamsters exposed to the virus, which are used as the ‘gold-standard’ model for pre-clinical testing of drugs against SARS-CoV-2. Importantly, the hamsters treated with UDCA were protected from the -new at the time- delta variant of the virus, which was new at the time and , which was -at least partially- resistant to existing vaccines.

Professor Owen said: “Although we will need properly-controlled randomised trials to confirm these findings, the data provide compelling evidence that UDCA could work as a drug to protect against COVID-19 and complement vaccination programmes, particularly in vulnerable population groups. As it targets the ACE2 receptor directly, we hope it may be more resilient to changes resulting from the evolution of the SARS-CoV-2 spike, which result in the rapid emergence of new variants.”

Testing using donated lungs not suitable for transplantation

Next, the researchers worked with Professor Andrew Fisher from Newcastle University and Professor Chris Watson from Addenbrooke’s hospital to see if their findings in hamsters held true in human lungs exposed to the virus.

The team took a pair of donated lungs not suitable for transplantation, keeping them breathing outside the body with a ventilator and using a pump to circulate blood-like fluid through them to keep the organs functioning while they could be studied. One lung was given the drug, but both were exposed to SARS-CoV-2. Sure enough, the lung that received the drug did not become infected, while the other lung did.

Professor Fisher said: “This is one of the first studies to test the effect of a drug in a whole human organ while it’s being perfused. This could prove important for organ transplantation – given the risks of passing on COVID-19 through transplanted organs, it could open up the possibility of treating organs with drugs to clear the virus before transplantation.”

Testing on healthy volunteers

Moving next to human volunteers, the Cambridge team collaborated with Professor Ansgar Lohse from the University Medical Centre Hamburg-Eppendorf in Germany.

Professor Lohse explained: “We recruited eight healthy volunteers to receive the drug. When we swabbed the noses of these volunteers, we found lower levels of ACE2, suggesting that the virus would have fewer opportunities to break into and infect their nasal cells – the main gateway for the virus.”.

While it wasn’t possible to run a full-scale clinical trial, the researchers did the next best thing: looking at data on COVID-19 outcomes from two independent cohorts of patients, comparing those individuals who were already taking UDCA for their liver conditions against patients not receiving the drug. They found that patients receiving UDCA were less likely to develop severe COVID-19 and be hospitalised.

A safe, affordable variant-proof drug

First author and PhD candidate Teresa Brevini from the University of Cambridge said: “This unique study gave us the opportunity to do really translational science, using a laboratory finding to directly address a clinical need.

“Using almost every approach at our fingertips we showed that an existing drug shuts the door on the virus and can protect us from COVID-19. Importantly, because this drug works on our cells, it is not affected by mutations in the virus and should be effective even as new variants emerge.”

Dr Sampaziotis said the drug could be an affordable and effective way of protecting those for whom the COVID-19 vaccine is ineffective or inaccessible. “We have used UDCA in clinic for many years, so we know it’s safe and very well tolerated, which makes administering it to individuals with high COVID-19 risk straightforward.

“This tablet costs little, can be produced in large quantities fast and easily stored or shipped, which makes it easy to rapidly deploy during outbreaks – especially against vaccine-resistant variants, when it might be the only line of protection while waiting for new vaccines to be developed. We are optimistic that this drug could become an important weapon in our fight against COVID-19.”

The research was largely funded by UK Research & Innovation, the European Association for the Study of the Liver, the NIHR Cambridge Biomedical Research Centre and the Evelyn Trust.

  • Watch a video of Dr Sampaziotis explaining the implications of this research:

World-first trial to transfuse lab-grown red blood cells is underway in Cambridge



Red blood cells that have been grown in a laboratory have now been transfused into another person at the NIHR Cambridge Clinical Research Facility in a world first clinical trial.

The manufactured blood cells were grown from stem cells from donors. The red cells were then transfused into volunteers in the RESTORE randomised controlled clinical trial.

This is the first time in the world that red blood cells that have been grown in a laboratory have been given to another person as part of a trial into blood transfusion.

If proved safe and effective, manufactured blood cells could in time revolutionise treatments for people with blood disorders such as sickle cell and rare blood types. It can be difficult to find enough well-matched donated blood for some people with these disorders.

The RESTORE trial is a joint research initiative by NHS Blood and Transplant and the University of Bristol, working with the University of Cambridge, Guy’s and St Thomas’ NHS Foundation Trust, NIHR Cambridge Clinical Research Facility, and Cambridge University Hospitals NHS Foundation Trust. It is part-funded by a NIHRH grant and supported by NIHR Cambridge BRC.

The trial is studying the lifespan of the lab grown cells compared with infusions of standard red blood cells from the same donor. The lab-grown blood cells are all fresh, so the trial team expect them to perform better than a similar transfusion of standard donated red cells, which contains cells of varying ages.

Additionally, if manufactured cells last longer in the body, patients who regularly need blood may not need transfusions as often. That would reduce iron overload from frequent blood transfusions, which can lead to serious complications.

The trial is the first step towards making lab grown red blood cells available as a future clinical product. For the foreseeable future, manufactured cells could only be used for a very small number of patients with very complex transfusions needs. NHSBT continues to rely on the generosity of donors.

Two people have so far been transfused with the lab grown red cells in Cambridge. They were closely monitored and no untoward side effects were reported. They are well and healthy. The identities of participants infused so far are not currently being released, to help keep the trial ‘blinded’.

The amount of lab grown cells being infused varies but is around 5-10mls – about one to two teaspoons.

Donors were recruited from NHSBT’s blood donor base. They donated blood to the trial and stem cells were separated out from their blood. These stem cells were then grown to produce red blood cells in a laboratory at NHS Blood and Transplant’s Advanced Therapies Unit in Bristol. The recipients of the blood were recruited from healthy members of the NIHR BioResource.

A minimum of 10 participants will receive two mini transfusions at least four months apart, one of standard donated red cells and one of lab grown red cells, to find out if the young red blood cells made in the laboratory last longer than cells made in the body.

Further trials are needed before clinical use, but this research marks a significant step in using lab grown red blood cells to improve treatment for patients with rare blood types or people with complex transfusion needs.

Chief Investigator Professor Cedric Ghevaert, Professor in Transfusion Medicine and Consultant Haematologist the University of Cambridge and NHS Blood and Transplant, pictured right, said: “We hope our lab grown red blood cells will last longer than those that come from blood donors. If our trial, the first such in the world, is successful, it will mean that patients who currently require regular long-term blood transfusions will need fewer transfusions in future, helping transform their care.”

Co-Chief Investigator Dr Rebecca Cardigan, Head of Component Development NHS Blood and Transplant and Affiliated Lecturer at the University of Cambridge said: “It’s really fantastic that we are now able to grow enough red cells to medical grade to allow this trial to commence, we are really looking forward to seeing the results and whether they perform better than standard red cells.”

New cohort created to help further research in Paediatric Inflammatory Bowel Disease

Cambridge researchers studying Inflammatory Bowel Disease (IBD) in children will now have access to a panel of young volunteers with IBD, thanks to a new research cohort from the NIHR BioResource.

The Paediatric Inflammatory Bowel Disease (PIBD) BioResource offers children and young people (0-15 years of age) living with the condition to take part in research. Researchers investigating IBD in the immune system as well as genetic or environmental factors, will be able to apply to the NIHR BioResource panel to find suitable volunteers to study the disease further and find new treatments.

Addenbrooke’s Hospital at Cambridge University Hospitals, is one of nine NHS Trusts so far in the UK that will be recruiting patients to the new arm of the NIHR BioResource. Clinicians will offer newly diagnosed IBD patients or patients already living with the disease a chance to take part in research.

Children sign up to the NIHR BioResource by providing blood, biopsy and stool samples as well as details about their health and lifestyle data, which is then anonymised and ready to be used for the purposes of research.

This new PIBD cohort led by Professor Holm Uhlig, from the University of Oxford and in collaboration with Cambridge University Hospitals and the NIHR BioResource, aims to establish a resource of more than 5,000 young patients with IBD to help researchers with their investigations and find much-needed treatments.

Treating IBD through research

Inflammatory Bowel Disease (IBD) is a term used to describe two conditions, Crohn’s disease and Ulcerative Colitis. These lifelong illnesses flare at intervals, producing debilitating symptoms including cramping abdominal pains, anaemia, weight loss and diarrhoea. They require on-going drug therapy, and many patients also require major surgery. The exact causes of Crohn’s disease and Ulcerative Colitis are unclear, but yet the number of people diagnosed with the condition is rising, especially in children.    

In the UK, more than 500,000 people are affected, and despite major advances in characterising the genetic and some of the environmental factors, much work remains to be done to fully understand the disease.

It can take many years just to find the right group of patients who can participate in a particular research trial, and the aim of the NIHR BioResource is to speed up research, by bringing people and researchers together.

People can volunteer to join the NIHR BioResource by providing a blood/ saliva sample and complete a health data questionnaire. This data is then anonymised and stored securely. 

When a study is accepted by the NIHR BioResource, researchers are able to select a unique cohort of samples and/or data, based on genotype (genetic makeup) and/or phenotype (a person’s traits such as age, gender, height, blood group etc.). Researchers can also invite participants to attend one of the 13 centres in England, including Cambridge, to collect more data or additional biological samples. 

More than 200,000 people with and without health conditions have signed up to the NIHR BioResource and are ready to take part in research.

As well as supporting hundreds of studies, the NIHR BioResource also run their own core of research programmes within their centres in conditions such as inflammatory bowel disease, immune mediated inflammatory diseases, mental health, non-alcoholic fatty liver disease and rare genetic diseases. Adding a new cohort of people will allow researchers investigating IBD, particularly in children, to access a greater resource of volunteers and health data.  

Professor Holm Uhlig, Lead Researcher for the PIBD BioResource said: “Inflammatory bowel diseases in children are increasing in numbers in the UK and worldwide. The PIBD BioResource research network provides the scientific research community with a resource of data and samples to study mechanisms of paediatric onset IBD required to develop better diagnostics and medicines.

“This collaborative project will support both UK and international research towards more personalised medicine in PIBD.”

Professor Miles Parkes, Chief Investigator for the IBD BioResource and NIHR Cambridge BRC director said: “I am delighted to see the launch of the Paediatric IBD BioResource led by Holm Uhlig and supported by key opinion leaders in paediatric IBD across the UK. There is an enormous amount to learn from studying children with IBD, of potential benefit to their future care but also impacting how we understand IBD in adults – both the similarities and the differences can be instructive.

“The opportunity to extend the highly successful IBD BioResource to support children, their families and their clinical researchers is one that we welcome, and we look forward to seeing this collaboration bear fruit in the years ahead as we research together and work towards improved treatments in IBD, and maybe one day a cure.”

Dr Nathalie Kingston, Director of the NIHR BioResource said: “NIHR BioResource is excited to be opening the Paediatric IBD BioResource with the support of our valued partners. Such a new initiative will nicely complement the recent launch of our Young People’s BioResource, which recruits young individuals through schools.

“Paediatric IBD is the first dedicated paediatric BioResource programme recruiting through NHS hospitals and Trusts, with the hope of further advancing health research in diseases appearing in both childhood and adulthood.”

First NHS Trusts who will enrol patients to the PIBD BioResource

  • Oxford Children’s Hospital and University of Oxford
  • Addenbrooke’s Hospital and University of Cambridge
  • Alder Hey Children’s Hospital, Liverpool
  • Birmingham Women’s and Children’s Hospital
  • Barts and the London School of Medicine and Dentistry, London
  • Royal Hospital for Children and Young People Edinburgh and University of Edinburgh
  • Evelina Hospital, London
  • Royal Hospital for Children Glasgow, University of Glasgow
  • Great Ormond Street Hospital, London

Cambridge University Hospitals hosts one of the 13 NIHR BioResource centres, on the Cambridge Biomedical Campus, close to Addenbrooke’s Hospital. It is supported by the NIHR Cambridge BRC. You can contact the NIHR BioResource Cambridge centre team by emailing: cbr@bioresource.nihr.ac.uk or phoning: 0800 090 1212

Find out more information about the NIHR BioResource

Cambridge recruits first patient to national inflammation study

A new trial taking place in UK to look at the best treatment for vasculitis has recruited its first patient– a child aged 10

A national trial led by chief investigator Professor David Jayne, NIHR Cambridge Biomedical Research Centre researcher and supported by the NIHR Cambridge Clinical Research Facility (CRF), is testing which biologic drugs – those that directly target the immune system – are most effective to treat vasculitis in all ages.

Vasculitis is a rare disease where inflammation occurs in the blood vessels. The immune system attacks the vessels, which become swollen, limiting or blocking blood supply to organs in the body.

Biologic drugs are licensed medicines and have been used to treat vasculitis and are expensive. Currently, there is not enough data to help clinicians choose which licenced drugs are most effective for patients, which is what the Cambridge team are investigating.

National trial begins

Vasculitis is potentially a life-threatening condition, yet the causes are unknown. Symptoms can range from fatigue and weight loss to numbness, pain and shortness of breath. Steroids are commonly used to help treat the disease, however, many people experience side effects or find no relief at all.

Cambridge researchers have now begun recruiting 140 adults and children around the UK with a rare vasculitis known as ANCA negative, who have not responded well to current treatments and cannot reduce their steroid dose to a safe level.

Patients will be randomised to either one of three biologic drugs or a placebo as well as answer questionnaires on their symptoms or if they have noticed any changes. They will then be monitored through follow-up appointments over a course of four to six months. The hope is to show which biologic medication is more effective.

Eliska, pictured top right with her mother, is the first child in the UK to take part in the trial at the NIHR Cambridge CRF at Addenbrooke’s Hospital. She said: “I’m hoping it will help me and also other children with vasculitis. I enjoy spending the time with the research nurses and Dr Armon.”

Kamila, Eliska’s mum, said: “I’m pleased that Eliska has a very special and experienced research team, and also good care here. I’m pleased they can help her and we hope she will be healthy soon.”

Dr Kate Armon

Dr Kate Armon, a paediatric rheumatologist, pictured left, who is overseeing the paediatric part of the trial in Cambridge said: “Vasculitis can be life-threatening and currently we don’t have enough information which medication is the most suitable. When we try to bring the steroid dose down for children and young people with vasculitis, the condition can flare, causing a fever, a rash and pain and stopping them from living a normal life.

“Our team agreed that the best option is to trial a biologic medication to see if it can control the disease better. On this trial, patients like Eliska will be randomised to a biologic drug as well as steroids and immune suppressive medication to control the illness, we will then monitor any changes to their condition.

“We hope to understand further how the biologic treatments affect patients like Eliska and find out which have better outcomes on the patient’s health and quality of life.

“I am delighted that Eliska has been able to participate in this important study to potentially treat her very rare disease. To have access to this trial in the NIHR Cambridge CRF has been perfect for the family and for the study.”

Cancer drug gives hope in treating heart attacks

Cambridge researchers have found a drug used to treat cancer could help with heart attack recovery.

Funded by the British Heart Foundation, NIHR Cambridge BRC and supported by the NIHR Cambridge Clinical Research Facility, researchers from Cambridge University Hospitals and the University of Cambridge found that a low dose of the cancer drug, aldesleukin, could harness the power of the immune system to improve recovery after a heart attack. Published in the New England Journal of Medicine – Evidence, researchers have said it has the potential to become the first treatment of its kind available for patients.

A heart attack is where the supply of blood is blocked to the heart, it can be life-threatening, requiring urgent treatment as it could potentially cause serious damage to the heart.

When a heart attack occurs it triggers the body’s immune cells to rush to the damaged heart and surrounding blood vessels. However, instead of having a healing effect, this can cause further harm, increasing the risk of future heart attack, stroke, and heart failure. Right now, there are no treatments available to counter this damaging immune response.   

Cambridge researchers launched a 2a clinical trial at NIHR Cambridge Clinical Research Facility, where they tested aldesleukin, a drug used to treat cancer, to see if it could help the immune system and heart attack recovery.

High doses of aldesleukin stimulate the immune system to attack cancer cells. Researchers investigated whether using doses a thousand times lower than those used in cancer treatment could selectively target and boost anti-inflammatory cells in patients’ immune systems. 

They found that low doses could improve recovery after a heart attack by stopping the harmful feedback loop. Researchers will now carry out larger clinical trials, in the hope it could be used to treat patients within the next 5 years. 

Repurposing cancer medication

The study involved 16 patients admitted to hospital with a heart attack who were given one of two doses of aldesleukin or a placebo. The drug was injected under the skin in their abdomen once a day for five days, and they were then followed up again a week after they’d received the final dose of the drug. 

Researchers found patients that received aldesleukin had a significantly greater increase in the number of regulatory T cells, a type of white blood cell that calms inflammation, a week after their last dose of aldesleukin compared to those who received a placebo. 

Further analysis revealed that not only were the numbers of regulatory T cells increasing, but the cells themselves had features that suggested that they were also becoming more anti-inflammatory.  

Low doses of aldesleukin also decreased the levels of other types of immune cells that can have damaging effects on inflammation and recovery after a heart attack. The team thinks this is another way that the drug could promote healing.

Researchers were encouraged with the results and are currently halfway through a larger clinical trial to investigate whether low doses of aldesleukin after a heart attack can reduce inflammation in patients’ blood vessels, which could potentially provide even more treatment to patients.    

Dr Tian Zhao, British Heart Foundation Clinical Lecturer in Cardiovascular Medicine at the University of Cambridge, said: “It’s only in the past decade that we’ve begun to understand the considerable role that the immune system plays in heart attack recovery. 

“In this study we’ve shown, for the first time, that low doses of aldesleukin given to heart attack patients can enhance the number of anti-inflammatory cells in the immune system. Previous research has suggested that this can reduce inflammation in blood vessels and improve heart healing. 

“Our ongoing study will give us the first signs of whether this is having clinical benefits for patients. We hope these results will bring us one step closer to the first treatment that can stop the damaging immune response that follows a heart attack.” 

Professor James Leiper, Associate Medical Director at the British Heart Foundation, said: “In the UK one person is admitted to hospital with a heart attack every five minutes. Thankfully, more people than ever are surviving heart attacks, but some will be left with long-term health problems such as heart failure. We urgently need new treatments that can help people to make a better recovery after a heart attack and reduce their risk of future ill health. 

“Treatments that can unlock the anti-inflammatory power of the immune system have the potential to become a new treatment option for heart attack patients. This research is an important step towards making this type of treatment a reality.” 

This research was also funded by the Medical Research Council.

Adapted from BHF press release

Could a cancer drug be key to helping patients recover from a heart attack?

A stage 2 trial is underway in Cambridge to investigate whether a cancer drug could improve the recovery of heart attack patients, by targeting the immune system.

The study led by researchers at Cambridge University Hospitals (CUH), the University of Cambridge and supported by the NIHR Cambridge Clinical Research Facility, has found that a low dose of the cancer drug, known as aldesleukin, injected into the skin of patients who have had an acute heart attack, increased the activation of immune cells shown to protect the heart.

In a previous study, the drug activates a rare white blood cell called innate type 2 lymphocyte (ILC2). ILC2 has previously been shown to decrease the harmful inflammation that promotes the build-up of fatty deposits in arteries.

By targeting the inflammation caused by the body’s immune response to a heart attack the researchers also hope to reduce a person’s chances of having a second heart attack. The Cambridge team are now conducting a Phase 2 clinical trial to test the drug.

Julian Hough - patient

Julian Hough (pictured right), had a heart attack in July despite having an active and healthy lifestyle. He’s on the road to recovery and wanted to take part in the trial. He said: “This trial is important because if this drug works, which is the results the doctors expect, it’s going to benefit so many people. 

“For me personally it’s helped me get my confidence back. I can see the results of scans and blood tests at each stage of the trial as the weeks go by. I can see how things are progressing as I start to get back to normal life.”

Dr Rouchelle Sriranjan

Dr Rouchelle Sriranjan, honorary cardiology registrar and clinical research associate at CUH (pictured left), said: “Some patients who have heart attacks, have an imbalance in the cells of their immune system. These patients are at a higher risk of second heart attacks or strokes and have more damage done to the heart. 

“The hope is a low dose of aldesleukin, will re-calibrate the imbalance in the immune system and promote healing of the heart muscle and lower inflammation in the blood vessels. We hope this drug will reduce a person’s chances of having a second heart attack.”

Dr Tian Zhao, BHF clinical lecturer in cardiovascular medicine at the University of Cambridge said: “Right now, there is no way to stop the immune system, which gets activated after a heart attack, from mistakenly damaging the heart.

“If our clinical trial shows that aldesleukin works by harnessing the ‘good cops’ of our immune system, we may have found a way to help the heart heal after a heart attack.”

Dr Joseph Cheriyan, CUH consultant clinical pharmacologist and chief investigator of the Phase 1b clinical trial added: “The findings represent very early positive signals but there’s still a long way to go. Work is currently ongoing in Phase 2 trials, which will hopefully lead to large scale Phase 3 trials in the next year or so.”

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, who funded the study said: “Every five minutes someone is admitted to a UK hospital due to a heart attack. Thanks to research, heart attacks are now treatable, and seven out of ten people will survive. However, many heart attack survivors will still be left with damaged hearts.

“This research reveals a new approach that has the potential to both help heal hearts damaged by a heart attack and reduce the risk of a further heart attack.

“If clinical trials results confirm these early research findings, drugs that activate ILC2 could revolutionise heart attack treatment.” 

The research is supported by NIHR Cambridge BRC and the Medical Research Council and featured on BBC Look East in October 2021.

Adapted from the British Heart Foundation press release

How is research helping with life-saving liver transplants?

As part of Organ Donation week, Professor Ludovic Vallier, theme lead for transplantation and regenerative medicine at the NIHR Cambridge BRC, talks about his team’s cutting edge liver research, why we need donated livers and the importance of collaborative working.

Professor Vallier explains that no donated livers are wasted even if they are not suitable for transplantation as researchers can use them to learn more about the liver and improve treatments to ultimately benefit patients.

Watch the short video below to find out about the latest research happening in Cambridge.

World first for AI and machine learning to treat Covid patients worldwide

In a groundbreaking study, Addenbrooke’s Hospital in Cambridge along with 20 other hospitals from across the world and healthcare technology leader, NVIDIA, have used artificial intelligence (AI) to predict Covid patients’ oxygen needs on a global scale.

The research was sparked by the pandemic and set out to build an AI tool to predict how much extra oxygen a Covid-19 patient may need in the first days of hospital care, using data from across four continents. 

The technique, known as federated learning, used an algorithm to analyse chest x-rays and electronic health data from hospital patients with Covid symptoms. 

To maintain strict patient confidentiality, the patient data was fully anonymised and an algorithm was sent to each hospital so no data was shared or left its location.  

Once the algorithm had ‘learned’ from the data, the analysis was brought together to build an AI tool which could predict the oxygen needs of hospital Covid patients anywhere in the world.

Published today (15 September) in Nature Medicine, the study dubbed EXAM (for EMR CXR AI Model), is one of the largest, most diverse clinical federated learning studies to date. 

To check the accuracy of EXAM, it was tested out in a number of hospitals across five continents, including Addenbrooke’s Hospital.  The results showed it predicted the oxygen needed within 24 hours of a patient’s arrival in the emergency department, with a sensitivity of 95 per cent and a specificity of over 88 per cent. 

“Federated learning has transformative power to bring AI innovation to the clinical workflow,” said Professor Fiona Gilbert (pictured right), NIHR Cambridge BRC Imaging theme lead, who led the study in Cambridge and is honorary consultant radiologist at Addenbrooke’s Hospital and chair of radiology at the University of Cambridge School of Clinical Medicine. 

“Our continued work with EXAM demonstrates that these kinds of global collaborations are repeatable and more efficient, so that we can meet clinicians’ needs to tackle complex health challenges and future epidemics.”

Professor Fiona Gilbert - Imaging theme lead

First author on the study, Dr Ittai Dayan, from Mass General Bingham in the US where the EXAM algorithm was developed said: “Usually in AI development, when you create an algorithm on one hospital’s data, it doesn’t work well at any other hospital. By developing the EXAM model using federated learning and objective, multimodal data from different continents, we were able to build a generalizable model that can help frontline physicians worldwide.”

Bringing together collaborators across North and South America, Europe and Asia, the EXAM study took just two weeks of AI ‘learning’  to achieve high-quality predictions.

“Federated Learning allowed researchers to collaborate and set a new standard for what we can do globally, using the power of AI, ” said Dr. Mona G. Flores, Global Head for Medical AI at NVIDIA. “This will advance AI not just for healthcare but across all industries looking to build robust models without sacrificing privacy.”

The outcomes of around 10,000 Covid patients from across the world were analysed in the study, including 250 who came to Addenbrooke’s Hospital in the first wave of the pandemic in March/April 2020. 

The research was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC). 

Work on the EXAM model has continued. Mass General Brigham and the NIHR Cambridge BRC are working with NVIDIA Inception startup Rhino Health, cofounded by Dr. Dayan, to run prospective studies using EXAM. 

Professor Gilbert added: “Creating software to match the performance of our best radiologists is complex, but a truly transformative aspiration. The more we can securely integrate data from different sources using federated learning and collaboration, and have the space needed to innovate, the faster academics can make those transformative goals a reality.”

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