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Author: Louise Stanley

World-first trial to assess ‘life-extending’ cannabis-based drug for thousands with aggressive brain tumours

BHP founder member the University of Birmingham will co-ordinate a major UK trial to analyse the efficacy of cannabis-based drug Sativex in treating the most aggressive form of brain tumours.

The new phase II trial, to be funded by The Brain Tumour Charity, is to launch at 15 NHS hospitals and follows promising results from a phase I study in 27 patients. The phase II trial will assess whether adding Sativex (an oral spray containing cannabinoids THC and CBD) to chemotherapy could extend life for thousands diagnosed with a recurrent glioblastoma, which currently has an average survival of less than 10 months*.

In a phase I trial in glioblastomas earlier this year**, the drug — already used in treating multiple sclerosis — was found to be tolerable in combination with chemotherapy, with the potential to extend survival.

While the phase I study observed that more patients were alive after one year in the Sativex arm compared to the placebo arm, the study was not sufficiently powered to show survival impact.

The new three-year phase II trial (called ARISTOCRAT), led by Professor Susan Short at the University of Leeds and co-ordinated by the Cancer Research UK Clinical Trials Unit at the University of Birmingham, is due to begin recruiting over 230 patients across all UK nations in early 2022, subject to sufficient funds being raised.

Having seen its income drop by over 25% last year due to the pandemic and been forced to pause its regular research grant funding programme, The Brain Tumour Charity has today launched an appeal to raise the £450,000 needed to open the trial as soon as possible.

Experts hope that, should the trial prove successful, Sativex could represent one of the first additions to NHS treatment for glioblastoma patients since temozolomide chemotherapy in 2007.

Glioblastomas are the most common and most aggressive form of brain cancer, with around 2,200 people diagnosed each year in England alone***. They are usually fast-growing and diffuse, with poorly-defined boundaries and thread-like tendrils that extend into other parts of the brain.

Almost all glioblastomas recur even after intensive treatment including surgery, radiotherapy and chemotherapy, and average survival is just 12-18 months from first diagnosis****.

Over the last decade, there has been significant global interest within both patient and scientific communities about the activity of cannabinoids in brain tumours, with the view that cannabinoid-based products may not only help relieve symptoms but could also have a positive impact on survival.

Several pre-clinical laboratory studies***** have suggested that cannabinoids THC and CBD may reduce brain tumour cell growth and could disrupt the blood supply to tumours – however, to date, clinical evidence that they could treat brain tumours has been limited.

In this new phase II trial, researchers will assess whether adding Sativex to the current standard chemotherapy treatment (temozolomide) could offer extra time to live for adults diagnosed with a recurrence of their glioblastoma after initial treatment.

The trial plans to recruit 232 participants across a minimum of 15 hospitals******: two thirds of the participants will be given temozolomide plus Sativex, while one third will be given temozolomide plus placebo*******.

Sativex, manufactured by GW Pharma, is an oromucosal spray containing 1:1 THC (Delta-9-tetrahydrocannabinol) and CBD (cannabidiol), with the active ingredients being absorbed in the lining of the mouth, either under the tongue or inside the cheek.

Participants will be asked to administer up to 12 sprays per day (or to the maximum dose they can tolerate if fewer than 12) of Sativex or placebo oral sprays. Participants will then undergo regular follow-up including clinical assessment (every four weeks), blood tests, MRI scans (every eight weeks), and they will complete quality of life questionnaires. This will also be one of the first trials to integrate with The Brain Tumour Charity’s app BRIAN.

The trial will measure whether adding Sativex to chemotherapy extends the overall length of patients’ lives (overall survival), delays the progression of their disease (progression-free survival) or improves quality of life.

Professor Pam Kearns, Director of the Cancer Research UK Clinical Trials Unit (CRCTU) at the University of Birmingham, which is co-ordinating the trial, said: “Our mission at the CRCTU is to translate cutting-edge science and research into improved patient care by identifying novel therapies that will save lives. It is vital that trials like this, investigating the role cannabis or the chemicals in it can play treat cancer, are carried out.”

Principal Investigator, Professor Susan Short, Professor of Clinical Oncology and Neuro-Oncology at the University of Leeds, said: “The treatment of glioblastomas remains extremely challenging. Even with surgery, radiotherapy and chemotherapy, nearly all of these brain tumours re-grow within a year, and unfortunately there are very few options for patients once this occurs.

“Cannabinoids have well-described effects in the brain and there has been a lot of interest in their use across different cancers for a long time now. Glioblastoma brain tumours have been shown to have receptors to cannabinoids on their cell surfaces, and laboratory studies on glioblastoma cells have shown these drugs may slow tumour growth and work particularly well when used with temozolomide.

“It’s really exciting that we’re now at the point where we can run a definitive, well-designed study that will tell us the answer to whether these agents could help treat the most aggressive form of brain tumour. Having recently shown that a specific cannabinoid combination given by oral spray could be safely added to temozolomide chemotherapy, we’re really excited to build on these findings to assess whether this drug could help glioblastoma patients live longer in a major randomised trial.”

Dr David Jenkinson, Interim CEO at The Brain Tumour Charity, which is funding the trial, said: “We hope this trial could pave the way for a long-awaited new lifeline that could help offer glioblastoma patients precious extra months to live and make memories with their loved ones.

“With so few treatments available and average survival still so heartbreakingly short, thousands affected by a glioblastoma in the UK each year are in urgent need of new options and new hope.

“We know there is significant interest among our community about the potential activity of cannabinoids in treating glioblastomas, and we’re really excited that this world-first trial here in the UK could help accelerate these answers. The recent early-stage findings were really promising and we now look forward to understanding whether adding Sativex to chemotherapy could help offer life-extension and improved quality of life, which would be a major step forward in our ability to treat this devastating disease.

“But we also know that for many, this trial won’t come soon enough. In the meantime, while other cannabis-based products may help alleviate symptoms, there is insufficient evidence to recommend their use to help treat brain tumours. For anyone considering using cannabis-based products or other complementary therapies, it’s vital that you discuss these with your medical team first, as they could interact with other treatments such as anti-epileptic medicines or steroids.”

Stephen Lee, 62 from Leyland in Lancashire, took part in the phase I trial of Sativex in 2015 after his glioblastoma returned following initial treatment. Stephen was first diagnosed in 2010, just a few months after he had very sadly lost his older brother to the same disease. Stephen said: “My diagnosis was very sudden and was one of those days you never forget. Having had to leave work early with a severe headache and a stabbing pain in my right eye, my wife insisted that we go straight to hospital after what my brother had experienced.

“I was admitted that same day, had a scan and that’s when they identified it was a brain tumour. I had the operation the following week, and beforehand my wife and I agreed that we wanted to stay positive, to keep living our lives and to enjoy however much time we had together.

“I joined the early trial of Sativex in the hope that it could improve my quality of life, but I also thought it was important to do so as the chemotherapy and radiotherapy I was having had all been trialled by other people before it could be used safely. I thought it only right and proper that I followed in their footsteps and joined a trial to help prove a new drug which could benefit so many people in the future with a recurring glioblastoma.

“I took the oral spray 10 times a day, and it was easy as I could take it wherever we were going, even while out for dinner. While I don’t know whether I had Sativex or the placebo, since the trial finished in 2016, all my MRI scans have been clear.

“This new trial is so important as it will give people hope that there could be life beyond a glioblastoma diagnosis and that there are other treatments being trialled to support them to live their lives.”
Anyone affected by a glioblastoma can speak to The Brain Tumour Charity on 0808 800 0004.

References:

*Twelves et al. A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma. Br J Cancer 124, 1379–1387 (2021).

**The initial phase 1b trial, led by the same authors, was published in the British Journal of Cancer in February 2021. The study assessed the safety and potential effectiveness of adding Sativex to temozolomide for patients with a newly recurrent glioblastoma (GBM) – finding it could be tolerated, did not appear to interfere with temozolomide treatment and had the potential to improve survival. In the first part of the study, 6 patients received a personalised regime of Sativex of up to 12 sprays per day, alongside their temozolomide therapy – and the side-effects were recorded and reviewed. In the second part of the study, 21 patients were randomised to receive either Sativex with temozolomide (12 patients) or placebo with temozolomide (9 patients) for a total duration of 12 months. 10 out of 12 (83.3%) patients receiving Sativex were still alive after one year, compared to 4 out of 9 (44.4%) patients in the placebo arm.

***Greenberg et al. Incidence and outcomes for cerebral glioblastoma in England, Public Health England; Brodbelt, A., Greenberg, D., Winters, T., Williams, M., Vernon, S. and Collins, V.P. Glioblastoma in England: 2007–2011. Eur. J. Cancer 2015, 51, 533–542.

****The prior figure (‘less than 10 months’) is the average survival from the point of tumour recurrence following initial treatment, whereas the ‘12-18 months’ figure is the average survival from first diagnosis.

****Rocha et al. Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J Neurooncol, 2014. 116(1): p. 11-24; Dumitru, C.A., I.E. Sandalcioglu, and M. Karsak, Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs. Front Mol Neurosci, 2018. 11: p. 159; Torres, S., et al., A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther, 2011. 10(1): p. 90-103.

******The recruiting centres include: Leeds General Infirmary; Guy’s and St Thomas’, London; Queen Elizabeth Hospital, Birmingham; Addenbrooke’s Hospital, Cambridge; Western General Hospital, Edinburgh; The Beatson, Glasgow; The Clatterbridge Cancer Centre, Liverpool; The Christie, Manchester; Queen’s Medical Centre, Nottingham; John Radcliffe Hospital, Oxford; Southampton General Hospital; Southmead Hospital, Bristol; Charing Cross Hospital, London; Velindre Cancer Centre, Cardiff, and the Royal Victoria Hospital, Belfast.

*******Both Sativex and the placebo are being provided free-of-charge for the duration of the trial by GW Pharma.

Rheumatology Research Group awarded five year EULAR Centre of Excellence Status

The Rheumatology Research Group (RRG) at BHP founder-member the University of Birmingham has been awarded five-year EULAR Centre of Excellence status for the second time in a row.

EULAR (European League Against Rheumatism) represents people with arthritis/rheumatism as well as health professionals in rheumatology and scientific societies across Europe.

The application reflects extensive collaboration across rheumatology departments at the University of Birmingham, Sandwell and West Birmingham NHS Trust and fellow BHP member University Hospitals Birmingham NHS Foundation Trust. The RRG was first awarded Centre of Excellence status in 2016.

Professor Karim Raza, RRG lead said, “The whole of the Birmingham Rheumatology Research Group is immensely proud that our EULAR Centre of Excellence has been renewed. This award is testament to the outstanding research carried out in Birmingham in the fields of rheumatoid arthritis, systemic lupus erythematosus and Sjögren’s syndrome with research programmes spanning the full spectrum from discovery science to experimental medicine to applied health research. Collaboration with other EULAR centres of excellence in the UK and across mainland Europe has been critical to our ability to deliver high quality Rheumatology research and we look forward to continuing and expanding those collaborations.”

The Centre of Excellence status will be valid until June 2026.

New study aims to improve healthcare for pregnant women with multiple health conditions

BHP founder-member the University of Birmingham is leading a new three-year UK-wide study aimed at improving healthcare and outcomes for pregnant women who have two or more active long-term health conditions.

Currently, one in five pregnant women in the UK have two or more active long-term health conditions. These can be both physical conditions (like diabetes or raised blood pressure), and mental health conditions (such as depression or anxiety). Often women also have to take several medications to manage their different health needs.

The new study, called Multimorbidity and Pregnancy: Determinants, Clusters, Consequences and Trajectories (MuM-PreDiCT), aims to use data-driven research to characterise and understand what makes having two or more long-term conditions more likely for pregnant women and the consequences for mother and child; and to predict and prevent adverse outcomes.

MuM-PreDiCT will be divided into five research work packages:

      1. Examining how health conditions accumulate over time and identifying what makes a woman more at risk of developing two or more long-term health conditions before pregnancy.
      2. Exploring women’s experiences of care during pregnancy, birth and after birth, working together with families and health professionals to establish how care could be improved.
      3. Deeper delve into how having two or more long-term health conditions may affect pregnant women and their children by identifying outcomes that women, health professionals and researchers feel should be reported in research; examining how often women experience pregnancy complications; and exploring how frequently women and their children develop additional long-term ill health
      4. Investigating how taking combinations of medication may affect pregnant women with two or more long-term health conditions and their babies.
      5. Building a prediction model to help identify how likely a previously healthy pregnant woman will develop multiple long-term conditions after pregnancy.

Professor Krish Nirantharakumar, of the University of Birmingham’s Institute of Applied Health Research and Principal Investigator of MuM-PreDiCT, said: “Having two or more health conditions is becoming more common in pregnant women as women are increasingly older when they start having a family and as obesity and mental health conditions are on the rise in general.

“However, we don’t really understand what the consequences are of multiple health conditions or medications for mothers and babies.

“This can make pregnancy, healthcare and managing medications more complicated. Without deeper understanding of the problem, women with several long-term health conditions may not have the best and safest experience of care before, during and after pregnancy because services have not been designed with their health needs in mind.”

Dr Beck Taylor, Clinical Senior Lecturer at the University of Birmingham and Co-Investigator of MuM-PreDiCT, said: “Our research will provide valuable information to help women and clinicians make informed decisions and identify points for prevention and intervention. We will also explore the experiences of maternity care for women with two or more long-term conditions and work with families and health and social care professionals to produce recommendations on how to plan and design services that meet the needs of women and their families before, during and after pregnancy.”

MuM-PreDiCT is being funded via the £20M UK Research and Innovation’s (UKRI) Strategic Priorities Fund (SPF) initiative ‘Tackling multi-morbidity at scale: Understanding disease clusters, determinants & biological pathways’. SPF is delivered by the Medical Research Council and National Institute for Health Research in partnership with the Economic and Social Research Council, and in collaboration with the Engineering and Physical Sciences Research Council. It is jointly funded by UKRI and the Department of Health and Social Care, through the NIHR.

MuM-PreDiCT is being led by the University of Birmingham in collaboration with the University of Aberdeen, University of St Andrews, Swansea University, Queen’s University of Belfast, University of Ulster, The University of Manchester, Keele University, University Hospitals Bristol & Weston NHS Foundation Trust, Bradford Teaching Hospitals NHS Foundation Trust, and Guy’s & St Thomas’ NHS Foundation Trust.

Siang Ing Lee, Academic Clinical Fellow at the University of Birmingham and MuM-PreDiCT, added: “We would like to extend our heartfelt gratitude to our amazing patient and public involvement (PPI) advisory group and PPI co-investigators who will play an integral part in MuM-PreDiCT.”

UHB and Cambridge University Hospitals win government funding for ground-breaking AI in radiotherapy

A machine learning technology that helps cut the time patients wait for life-saving cancer treatment has been successful in the latest round of the Artificial Intelligence (AI) in Health and Care Award.

BHP founder member University Hospitals Birmingham, working in partnership with Addenbrooke’s Hospital, part of Cambridge University Hospitals (CUH) is one of 38 organisations singled out for funding.

The AI Award is making £140 million available over four years to accelerate the testing and evaluation of artificial intelligence technologies which meet the aims set out in the NHS Long Term Plan.

Over the next year, UHB will work with CUH to leverage Microsoft Project InnerEye’s open-source AI toolkit to differentiate tumour and healthy tissue on cancer scans (called ‘segmenting’), prior to radiotherapy treatment. The aim of this AI Award project is to evaluate how this could save clinicians’ time, reduce the time between the scan and commencing treatment, and scale this to four NHS Trusts.

Dr Kal Natarajan, UHB consultant clinical scientist, said: “I’m really looking forward to working with colleagues in Birmingham and Cambridge on this project.

“The technology has tremendous potential to transform radiotherapy care, helping patients to be treated quicker and ensure clinicians spend their time as effectively as possible.”

Dr Raj Jena, CUH oncologist and project lead, said: “I am so pleased that our project has been awarded government funding to take it to the next level. AI has the capacity to deliver so much behind-the-scenes routine work, enabling doctors to spend more time face-to-face with patients, and shortening the time that patients have to wait for treatment.

“We believe this is first time an NHS hospital has trained its own medical imaging AI for its own patients and our aim is to assist other radiotherapy departments to use the models for their patients.”

Up to half of the UK population will be diagnosed with cancer at some point in their lives. Of those, half will be treated with radiotherapy, often in combination with other treatments such as surgery, chemotherapy, and increasingly immunotherapy.

Radiotherapy involves focusing high-intensity radiation beams to damage the DNA of hard cancerous tumours while avoiding surrounding healthy organs. This is a critical tool in the fight against cancer, with around 40% of cured patients undergoing precision radiotherapy.

Radiotherapy is most effective when treatment takes place as soon as possible. However, segmenting the tumour targets and healthy tissue on image scans is a key step that is currently performed manually by doctors, taking several hours per patient.

Microsoft’s recent peer-reviewed research paper in JAMA Network Open shows that clinicians could segment prostate and head & neck cancer images up to 13 times faster when using InnerEye machine learning assistance, with an accuracy similar to that of human experts.

Javier Alvarez-Valle, from Microsoft Research Cambridge, said: “We are delighted that CUH and UHB are able to use our open-source software to build their own AI models, for the benefit of their patients. This NHSX AI Award paves the way for more NHS Trusts to reduce cancer treatment times using assistive AI, and to help alleviate the workload of clinicians.”

Already, over 17,000 stroke patients and over 25,000 patients with diabetes or high blood pressure have benefited from the first round of the AI in Health and Care Award since September, where £50 million was given to 42 AI technologies.

The AI Award is one of the programmes that make up the NHS AI Lab, led by NHSX and delivered in partnership with the Accelerated Access Collaborative (AAC) and National Institute for Health Research (NIHR).

£1.5m funding for youth mental health research

The Institute for Mental Health at BHP founder member the University of Birmingham has been awarded £1.5M from the Wolfson Foundation to fund a research centre focused on supporting youth mental health.

The research team at the Institute for Mental Health work with NHS partners to understand the causes of poor mental health and to develop effective treatments, preventative strategies and services. The Institute draws upon expertise from across the University as well as from local, national, and international partners. This award from the Wolfson Foundation will help to create a physical space for individuals and groups from across the university and externally to come together and collaborate in a new purposely designed, shared place.

Professor Matthew Broome, Director of the Institute for Mental Health comments; “We are extremely grateful to the Wolfson Foundation for supporting our work through this new centre at the University of Birmingham. It will create a new space for researchers, postgraduate students, NHS colleagues and our youth advisory group to come together more effectively. We hope that this will provide the scientific environment and conditions that the Institute for Mental Health needs to accelerate our work to support and treat young people with mental ill health.”

Members of the Institute represent a breadth of academic fields including psychology, psychiatry, philosophy, health economics, epidemiology, geography, neuroscience, public health, sport and exercise science, and social policy. Collectively our researchers have developed new methodological approaches, drawing on different disciplines, and shared ideas across new groupings. These include validating machine-learning tools to predict outcome in early psychosis, pioneering approaches to examine immune mechanisms in mental ill health, and developing novel mixed-methods strategies, including social media data, to study self-harm.

Paul Ramsbottom, CEO of the Wolfson Foundation, said, “The Wolfson Foundation is delighted to be funding this crucial area of research. We were impressed by the quality of the proposed research and by its dynamic leadership. A real hallmark of the centre will be collaborative working: with partners across the UK and globally – but, perhaps even more important, with young people and civil society across Birmingham. We hope the research will have a significant impact in Birmingham – the city with the UK’s youngest demographic – and beyond.”

The Wolfson Foundation is an independent, grant-making charity with a focus on research and education. Its aim is to support civil society by investing in excellent projects in science, health, heritage, humanities and the arts across the UK. Find out more about the Wolfson Foundation –  https://www.wolfson.org.uk/

Urine test for bladder cancer to be developed by University of Birmingham and Nonacus

BHP founder-member the University of Birmingham and Nonacus, a provider of genetic testing products for precision medicine and liquid biopsy, have partnered to develop a non-invasive test for bladder cancer. The test, which is expected to be available by mid-2022, will use highly sensitive liquid biopsy technology developed by Nonacus, and a panel of biomarkers validated by Dr Rik Bryan and Dr Douglas Ward from the University’s Bladder Cancer Research Centre, to diagnose the disease from urine samples.

Bladder cancer is the seventh most common cancer in the developed world1. In the UK, over 100,000 people a year are referred to hospital clinics that investigate for bladder cancer, usually after passing blood in their urine (haematuria).  The first stage of investigation is usually cystoscopy, which involves inserting a camera into the bladder.   Of these 100,000 patients, around 12% are subsequently diagnosed with bladder cancer, normally after a second invasive procedure to extract a biopsy.

Dr Bryan, Director of the Bladder Cancer Research Centre,  commented: “While blood visible in the urine should always be investigated, over 80% of people who have a cystoscopy at a haematuria clinic are diagnosed with non-malignant conditions or have no abnormality.  Unfortunately, the remaining 20% will need a further invasive procedure to confirm diagnosis.  What is required is a highly sensitive and specific, non-invasive test that can rapidly determine those who need a biopsy and those who do not, and a urine test is the obvious place to start.”

While the ‘liquid biopsy’ approach is attractive, the low levels of tumour DNA in a background of DNA from normal tissues requires highly sensitive analytical techniques to obtain accurate results.  However, researchers at the University started their work in the knowledge that Nonacus had successfully pioneered commercial non-invasive prenatal tests to identify low-levels of fetal DNA in maternal blood samples.  Moreover, the company was developing methods to allow confident and sensitive calling of mutations from as little as 10ng of DNA.

The researchers used ‘deep sequencing’ of tumour DNA to identify mutations that are present in the majority of urothelial bladder cancers (UBCs).  Their work, which was funded by Cancer Research UK and an MRC Confidence in Concept grant, involved sequencing 23 genes from tumour samples collected from 956 newly diagnosed, treatment-naïve patients.  This deep sequencing of genes identified 451 unique mutations that were present in over 96% of tumours.  The researchers also demonstrated that these mutations were identifiable in urine samples collected at the same time as tumour sampling2.

As the researchers have shown, mutated DNA in a urine sample can be extracted from cancer cells shed into the urine from the lining of the urinary tract, or can be found as cell-free DNA fragments. However, extracting DNA from the cancer cells provides more reliable amounts of DNA for the test, especially when only small volumes of urine may be available. Coupling the mutation panel with the unique molecular identifiers and the proprietary target capture technology provided by the Nonacus Cell3 Target™ will provide a much more sensitive test than the existing PCR-based approach. The researchers are already working on validating this combination in a further 600 cases (including non-cancer cases) and they expect to publish data on sensitivity and specificity within six months.

Nonacus intends to launch the new bladder cancer test within 12 months, and the final product will include access to bioinformatics software to help with analysis.  The company expects the test will provide high sensitivity for all stages and grades of disease, and will ensure the test is available worldwide to laboratories, hospitals and clinics.

Promisingly, the original research also determined the influence of the mutations on cancer progression, time to recurrence, and overall and disease-specific survival in patients with non-muscle-invasive bladder cancer (NMIBC), and disease-specific survival in patients with muscle-invasive bladder cancer (MIBC), raising the possibility that the test could be used to stratify patients according to risk.

Chris Sale, CEO of Nonacus Ltd, commented:  “We expect this partnership to deliver better care and outcomes for patients by reducing the number of invasive procedures, providing earlier diagnosis and speeding up access to treatment for people with bladder cancer.”

Tony Hickson, Chief Business Officer at Cancer Research UK, said: “As funders of much of the world-class, cutting-edge cancer research happening in the UK, we offer unique opportunities to commercial partners looking for early involvement in new discoveries. Having Nonacus on board to help transform promising findings in the lab into a new non-invasive test to diagnosis bladder cancer is a testament to how commercial collaborations have the potential to transform the lives of patients. We are looking forward to seeing the next steps as the test is developed and rolled out to the UK and beyond.”

Allen Knight, Chair of Trustees, Action Bladder Cancer UK, said:  “This really is very exciting and has the potential to make an incredible difference for patients and for Bladder Cancer treatment. Currently urine tests do not ​accurately pick up bladder cancer, and invasive tests are required to confirm a diagnosis.  A urine test that can rapidly determine who needs these tests will be a very welcome development.  Many patients, myself included, find cystoscopies very uncomfortable at best, and they can have lasting side effects.  This research could pave the way for routine screening, common in other cancers, but unavailable at present for Bladder Cancer.”