Dr Lennard Lee awarded ACP McElwain Prize for contributions to medical oncology

Dr Lennard Lee, Academic Clinical Lecturer at the University of Oxford, has been awarded the 2020 Association of Cancer Physicians (ACP) McElwain Prize for his contribution to the development of Medical Oncology in the UK.

During the COVID-19 pandemic, Dr Lee’s contributions were best reflected in his creation and implementation of a national prospective observational cohort study of cancer patients during the COVID-19 pandemic, the UK Coronavirus Cancer Monitoring Project (UK CCMP). This was one of the largest global registries and the first to identify that cancer treatments can be safely delivered during a COVID-19 pandemic.

The initial phase of the project has been successfully achieved with the roll out and implementation of the UK CCMP emergency observational response network, as well as studies to determine those in our population who are most at risk – such as blood cancer patients.

Thanks to this project, the UK oncology community now has the tools and the mechanism to learn from each case of COVID-19 in cancer patients and the evidence required to bring about clinical management/service/treatment decision changes to improve the outcomes of cancer patients. The data from this project has helped form the guidelines which have been published from NHS England about the resumption of cancer services and led to the return of near-normal chemotherapy prescribing levels.

Building on the success of this work, Lennard is now leading on further studies to understand and better safeguard cancer patients during the pandemic. He has co-launched projects on COVID-19 vaccine efficacy, understanding how this is impacted by cancer treatments, and studies to identify other effective COVID-19 risk reduction interventions.

Lennard Lee said

“I am honoured to receive this award on behalf of all the clinicians and researchers who took part in the UKCCMP. The work by the UK oncology community had global impact, demonstrating that cancer patients can be treated safely during the pandemic. No one should be denied appropriate cancer treatments and it is important that we continue to deliver research excellence in order to protect the vulnerable during this pandemic”.

For more information about the UK CCMP see here.

Two clinical academic research partnerships awarded to Oxford researchers

Dr Karthik Ramasamy and Dr John Jacob are both Oxford clinical researchers that have been awarded a Clinical Academic Research Partnership (CARP) by the MRC. Both have been awarded upwards of £200,000 to fund projects investigating myeloma early detection & brain cancer modelling, respectively. Find out more about the projects being funded with this award below.

Dr Karthik Ramasamy

Earlier diagnosis of the bone marrow cancer myeloma is a high priority for patients since it can both improve survival and allow for better control of symptoms. Every case of myeloma is preceded by a condition called Monoclonal Gammopathy of Undetermined Significance (MGUS) and individuals with MGUS are regularly monitored so that progression to myeloma can be caught early.

While this approach is benefitting some patients, there are two main issues that still need to be overcome to improve earlier myeloma diagnosis:

  1. MGUS is largely symptomless and often undiagnosed, meaning that 80-90% of myeloma patients are diagnosed without first receiving an MGUS diagnosis that would have prompted monitoring for myeloma.
  2. Only 1% of patients with MGUS progress to myeloma every year and the risk of progression is not well defined, placing a large resource burden for monitoring on healthcare providers and creating anxiety for patients.

In this MRC CARP award, Dr Karthik Ramasamy will address both of these challenges. Firstly, working with Professor Kassim Javaid, Professor Daniel Prieto-Alhambra, Dr Constantinos Koshiaris and data from primary care health records, Dr Ramasamy will identify specific clinical signs/symptom clusters associated with MGUS to enable a greater proportion of individuals with MGUS to be diagnosed and monitored. Secondly, additionally collaborating with Dr Ross Sadler, Professor Chris Schofield and Professor James McCullagh, Dr Ramasamy will seek to identify routinely recorded clinical characteristics and additional protein biomarkers that improve prediction of progression from MGUS to myeloma in a cohort of patients undergoing monitoring at Oxford University Hospitals NHS Trust. This latter work is bolstered by a recently awarded CRUK Oxford Centre Development Fund award, which will enable the research team additionally to pilot protein glycosylation analysis in blood samples collected as part of a current study investigating serological markers in plasma cell dyscrasias (BLOOM).

Dr Karthik Ramasamy is Lead Clinician for myeloma and other plasma dyscrasias in Thames Valley Strategic Clinical Network and Divisional Lead of Cancer Research across Thames Valley and South Midlands Research Network.

Learn more about myeloma early detection research in Oxford.

Dr John Jacob

Brain cells that originate in the cerebellum give rise to the most common childhood brain tumour, known as medulloblastoma, which can also affect adults. Although it can be cured, it is often a devastating disease, with common treatment options resulting in an increased risk of adverse side effects such as strokes and seizures.

Like most cancers, the development of new treatment options that improve survival rate and reduce side effects is reliant on researchers establishing models that reflect the human tumours, in order to test the efficacy of new therapeutics before these are tested in patients. Existing models for medulloblastoma have shortcomings making the discovery of new treatment options slow. This is due to:

  1. Growing medulloblastoma cells outside of a patient is hard, due to the change in environmental factors. Growing cells outside the body usually does not accurately reflect the microenvironment that cells are derived from, and so the cells will behave differently and unlike a real tumour. As a result, only a few cell lines from medulloblastoma patients have been successfully grown ex vivo.
  2. Models can be costly, and these include mouse-based models, which pose limitations due to the difference in species
  3. Medullobastoma tumours are genetically different between patients – there is no ‘one size fits all’ model and there is a need to develop more treatment options that target specific genetic subtypes in order to improve survival.

In this CARP award, Dr John Jacob (Nuffield Department of Clinical Neurosciences) aims to investigate a specific genetic subtype of medulloblastoma (known as sonic hedgehog medulloblastoma) – and test if the presence of the tumour microenvironment, which consists of non-cancerous cerebellar tissue, is necessary to better simulate the typical tumour growth conditions.

Working alongside Associate Professor Esther Becker (Nuffield Department of Clinical Neurosciences) and Dr Benjamin Schuster-Boeckler (Big Data Institute & Oxford Ludwig Cancer Institute), the team hope to recreate the in vivo tumour microenvironment more accurately compared to existing models. The Becker group previously established a methodology to grow human cerebellar neurons from human induced pluripotent stem cells (hiPSC). By using hiPSCs to form miniature cerebellar structures, termed cerebellar organoids, the tumour microenvironment can be recreated in a dish.

The team hope to overcome the existing modelling difficulties by growing medulloblastoma cells on these organoids. Dr Jacob, aided by the computational biology expertise of Dr Schuster-Boeckler will then investigate the growth of individual tumour cells, in a more physiological context. The resulting outcomes could mean the development of a new model to test patient-specific therapies on, in order to assess their toxicities and efficacy more accurately.

Dr John Jacob is a consultant neurologist who is interested in better understanding the genetic complexity of cancer and what it means for personalised treatment. Through this award and collaboration, Dr Jacob hopes to improve the success of therapy development and ultimately improve the repertoire of therapies of this cancer.

The Medical Research Council Clinical Academic Research Partnership scheme allows NHS consultants with a PhD or MD to participate in collaborative high-quality research partnerships with established leading biomedical researchers.

 

Potential for radiotherapy and VTP multimodality therapy for prostate cancer

Each year in the UK around 48,500 men are diagnosed with prostate cancer, and 11,900 die from this malignancy. The most common radical treatments for prostate cancer are surgical removal of the prostate gland (prostatectomy), or radiotherapy (usually combined with hormone treatment).

However, there is a need to improve the overall patient outcomes from radical treatment, as many cases of high-risk prostate cancer recur. Moreover, there is an unmet clinical need to reduce radical treatment side effects.

Vascular targeted photodynamic therapy (VTP) is a novel minimally invasive precision surgery technique that has been developed to focally treat prostate cancer. VTP destroys the vasculature supply of blood to the tumour, thereby providing tumour control.

To date, VTP has been investigated in clinical trials as a monotherapy for low-volume, low-risk prostate cancer. Whilst VTP has been combined with other treatments such as hormone therapy in pre-clinical models, to date it has not been investigated alongside external beam radiotherapy to assess the effects of combined treatment on prostate cancer tumour control.

A recent study from Richard Bryant and Freddie Hamdy of the Nuffield Department of Surgical Sciences, alongside collaborators in the Institute of Biomedical Engineering & Department of Oncology, and collaborators from the Weizmann Institute of Science (Israel) and the National Cancer Institute (National Institutes of Health, USA), has investigated the impact of combining VTP with external beam radiotherapy treatment, and the potential improvement to treatment outcomes.

In a recent publication in the British Journal of Cancer, the team used a multi-modality treatment approach to test the sequential combination of fractionated radiotherapy and VTP – which have previously not been used together.

They found that, whilst fractionated radiotherapy or VTP alone can help delay tumour growth, combination therapy using fractionated radiotherapy followed by VTP suppressed tumour growth to a greater extent than either treatment alone. Radiotherapy induced changes to the blood vessels within the tumour, which may be a contributing factor to the increased effectiveness of subsequent VTP as part of combination therapy. Ongoing studies are now investigating the immunological effects of the combined treatment.

This is the first time that VTP has been evaluated in combination with external beam radiotherapy treatment, either for prostate cancer or any other solid-organ tumour. This pre-clinical study provides the proof-of-concept necessary to go on and test this multi-modality approach in first-in-man early phase clinical trials. Following future testing of safety and efficacy in patients, this combined radiotherapy and VTP approach could help to redefine best practice for treating certain prostate cancer patients in a more effective way.

About the study

This study was a collaboration between Richard Bryant (Nuffield Department of Surgical Sciences), Freddie Hamdy (Nuffield Department of Surgical Sciences), Ruth Muschel (Department of Oncology) and Avigdor Scherz (The Weizmann Institute of Science, Israel). It was funded by a Cancer Research UK & Royal College of Surgeons of England Clinician Scientist Fellowship (reference C39297/A22748) and by a research grant from The Urology Foundation.

AI endoscopy enables 3D surface measurements of pre-cancerous conditions in oesophagus

Clinicians and engineers in Oxford have begun using artificial intelligence alongside endoscopy to get more accurate readings of the pre-cancerous condition Barrett’s oesophagus and so determine patients most at risk of developing cancer.

In a research paper published in the journal Gastroenterology, the researchers said the new AI-driven 3D reconstruction of Barrett’s oesophagus achieved 97.2 % accuracy in measuring the extent of this pre-cancerous condition in the oesophagus in real time, which would enable clinicians to assess the risk, the best surveillance interval and the response to treatment more quickly and confidently.

Barrett’s is a pre-malignant condition that develops in the lower oesophagus in response to acid reflux. There is a less than 0.1-0.4% risk per year of developing cancer with normal Barrett’s oesophagus – or one in 200 patients. However, that risk increases with the extent of Barrett’s lining.

Clinicians use a system called the Prague C&M criteria to give a standardised measure of Barrett’s oesophagus. This uses the circumferential length of the Barrett’s section and the maximum extent of the affected area. This score roughly determines the level of risk of developing cancer and how often the patient needs to be surveyed by an endoscopist, usually every five years for low-risk cases and two to three years for longer Barrett’s segments.

Oxford University Hospitals (OUH) NHS Foundation Trust has a cohort of around 800 patients with Barrett’s who have periodic endoscopic surveillance.

OUH Consultant Gastroenterologist Professor Barbara Braden, together with Dr Adam Bailey, oversees a large endoscopic surveillance programme for Barrett’s patients at OUH. She says the quality of the endoscopy is very dependent on the skill and expertise of the person carrying out the procedure.

“Until now, we have not had any accurate ways of measuring and quantifying the Barrett’s oesophagus. Currently, we insert the scope and then we estimate the length by pulling it back,” said Prof Braden.

“We asked colleagues from the Department of Engineering Science – Prof Jens Rittscher and Dr Sharib Ali – whether they could find a way to measure distances and areas from endoscopic videos to give us a more accurate picture of the Barrett’s area and they came up with the brilliant idea of three-dimensional surface reconstruction.”

Prof Braden, of the University of Oxford’s Translational Gastroenterology Unit, based at the John Radcliffe Hospital, added:

“Currently, you have to have a great deal of experience to know how to spot the subtle changes which indicate early neoplastic alterations in Barrett’s oesophagus. Most endoscopists don’t encounter an early Barrett’s cancer that often. So, instead of teaching thousands of endoscopists, by applying deep learning techniques to endoscopic videos you can teach a programme.”

The Oxford study is using technology to reconstruct the surface of the Barrett’s area in 3D from the endoscopy video, giving a C&M score automatically. This 3D reconstruction allows the clinician to quantify precisely the Barrett’s area including patches or ‘islands’ not connected to the main Barrett’s area.

Dr Sharib Ali, the first author of the paper and the main contributor of this innovative technology, is part of the team working on AI solutions for endoscopy at the University of Oxford’s Department of Engineering Science. He said:

“Automated segmentation of these Barrett’s areas and projecting them in 3D allows the clinician to not only report very accurately the extent of the Barrett’s area, but to pinpoint precisely the location of any dysplasia or tumour, which has not been possible up to now.”

The technique was tested on a purpose-built 3D printed oesophagus phantom and high-definition videos from 131 patients scored by expert endoscopists. The endoscopic phantom video data demonstrated a 97.2 % accuracy for the C&M score measuring the length, while the measurements for the whole Barrett’s oesophagus area achieved nearly 98.4 % accuracy. On patient data, the automated C&M measurements corresponded with the endoscopy expert scores.

“With this new AI technology, the reporting system will be much more rigorous and accurate than before. It makes it much easier when the clinician sees the patient again – they know exactly where to target biopsies or therapy. And the quicker and more efficient it is, the better the experience for the patient,” Dr Sharib Ali explained.

The research was supported by the NIHR Oxford Biomedical Research Centre (BRC), through its cancer and imaging themes.

Groundbreaking FOCUS4 clinical trials report their findings at ASCO

As FOCUS4 prepares to report findings at the ASCO (American Society of Clinical Oncology) Annual Meeting on 4-8 June 2021, the NIHR have taken a historical look at how this groundbreaking trial has helped shape the future of clinical trial delivery in the UK. Professor Tim Maughan of the Department of Oncology at the University of Oxford and co-Principal Investigator of the FOCUS4 studies, explores how experience gained from delivering FOCUS4 has helped the UK to rapidly answer questions of global importance about the treatment of COVID-19.

FOCUS4, one of the UK’s flagship precision medicine cancer trials, opened back in 2014. It is a randomised trial investigating treatments for colorectal cancer using a complex adaptive methodology which is known as Multi-Arm, Multi-Stage (MAMS) design. Such trials, also called umbrella or platform trials, allow for multiple treatments to be tested simultaneously against the standard of care (the control). However, FOCUS4 has the added complexity of stratified medicine, which requires that all eligible patients undergo genome sequencing to identify genetic biomarkers relating to their cancer. Patients are then matched to the trial arm/treatment to which they are most likely to respond.

This new way of working emerged following a rapid increase in the number of new cancer treatments being developed by life science companies which needed a systematic approach to quickly understand which treatments worked against which cancers. Professor Maughan explains:

“The adaptive, multi-arm, multi-stage approach was pioneered by the MRC Clinical Trials Unit at UCL and it provides a more efficient way of working compared to traditional back-to-back randomised clinical trials which only test one treatment at a time. Not only does it avoid the delays and costs of setting up a new trial for each new drug candidate, it also makes the screening process more efficient. Patients are screened for a match to all the drugs being trialled and have a higher probability of being able to join the trial and access a cutting-edge treatment. But more importantly – and this is where the adaptive bit comes in – new arms can be added to the trial platform as new drugs become available. Equally, where drugs are showing no benefit, that arm of the trial can be closed and another trial can be opened in the part of the trial.”

The FOCUS4 trial design was considered groundbreaking when it opened in 2014 as it was one of the first large-scale, molecularly stratified, MAMS cancer trials in the UK. It successfully enrolled 1,434 patients from 88 hospitals. Prior to this the FOCUS3 study, opening in February 2010, sought to establish the feasibility of this approach, recruiting 240 patients at 24 centres.

However, the UK’s experience of MAMS trials can be tracked back further to the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) Trial which opened in the UK in 2005. This trial is ongoing, has recruited almost 12,000 participants, and has produced practice-changing results in the treatment of prostate cancer. Although STAMPEDE commenced much earlier than FOCUS3 or FOCUS4, Professor Maughan says it is important to note:

“Although very challenging in other ways, STAMPEDE does not currently involve molecular stratification and this is a significant difference in the complexity of the trial delivery and why trials like FOCUS4 and the National Lung Matrix are world-renowned, despite opening a number of years after STAMPEDE.”

Fast forward to 2020 and the COVID-19 pandemic. The emergency situation necessitated a systematic approach to quickly understand which treatments worked against the novel coronavirus. Sound familiar?

Collaborative research culture

Speed and agility are imperative in a pandemic situation. This caused a seismic shift in attitudes towards developing new ways of working in areas such as streamlining the trial approval process.

Rapid trial set-up and delivery are also crucial. Thankfully, as we’ve established, the UK already had experience and understanding of implementing large scale, adaptive multi-arm, multi-stage clinical trials. This existing knowledge and ability to collaborate on a national scale certainly seems to have underpinned our rapid COVID-19 research response seen in trials like RECOVERY (Randomised Evaluation of COVID-19 Therapy). Professor Maughan said:

“FOCUS4 lies in this historic development of complex innovative designs. It builds first of all on the establishment of the research infrastructure through the Clinical Research Network, which is integral to the support of all these major UK national trials. Secondly, it builds on the adaptive statistical methodology, which was first developed in STAMPEDE – the multi-arm, multi-stage design approach.

“The RECOVERY trial is built on the same adaptive statistical model and also the fact that there was this fantastic research delivery infrastructure in the UK, which enabled it to move very fast and recruit these huge numbers of patients in a very short period of time. The success of RECOVERY and other MAMS trials in recent years is testament to the 20 years of investment in clinical research delivery culture in the NHS and the collaborative working across the industry in the UK.”

The world-leading RECOVERY trial does, indeed, use the MAMS trial design to test emerging treatments for the novel coronavirus and was established during the early stage of the pandemic when there were no proven treatments available. Within three months, it generated clinical evidence resulting in dexamethasone becoming the world’s first proven drug to reduce mortality for the most seriously ill patients. It also showed that hydroxychloroquine, once considered a promising therapeutic candidate for COVID-19, has no clinical benefit for hospitalised patients and this arm of the trial ceased immediately.

The PRINCIPLE (Platform Randomised trial of INterventions against Covid-19 In older peoPLE) and REMAP-CAP (A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia) trials also utilise an adaptive platform approach. These flagship trials, building on the foundations of STAMPEDE, FOCUS4 and Lung Matrix, are likely to accelerate uptake and acceptance of the adaptive platform approach in clinical trial delivery in future years as the global drive for faster and more efficient clinical trials intensifies.

Forthcoming findings

It seems quite pertinent then for FOCUS4 to be on the cusp of publishing new findings in the wake of the pandemic. Professor Maughan looks back at some of the previously published results of the trial:

“Our first molecular cohort showed comprehensive negative results, and we were able to close it after only 32 patients had been accrued to FOCUS4-D – one arm of the FOCUS4 trial. That was published back in 2017 and you’ll see in many platform designs that a number of negative results come out. That’s important because we’re showing that things don’t work as well as the things that do work.

“The trial has now closed to recruitment in October 2020, after conducting three molecularly targeted sub-trials and one non-molecularly stratified trial in six years, and has generated some interesting results. Prof Richard Adams will be presenting some of these at the ASCO (American Society of Clinical Oncology) Annual Meeting on 4-8 June 2021 and we are in conversation with journals about publications.

“When we embarked on FOCUS4 we knew it would be a challenge, and we have learnt a huge amount along the way. It’s really important now that we share this learning and continue to improve the way we do clinical trials in the future.”

Professor Maughan also recognises that complex trials like FOCUS4 require the right ingredients to enable successful delivery. He emphasises the importance of the UK’s unique clinical research landscape:

“The whole complex research ecosystem of the UK presents an unparalleled opportunity for complex and innovative trials. We have the NHS as a single health care provider, the NIHR Clinical Research Network as a coordinated research delivery organisation, collaborative laboratory scientists delivering the sequencing, the collective work of the funders, forward-thinking regulators, and the National Cancer Research Institute. All this facilitates a really collaborative clinical research culture within the UK where organisations don’t have to compete with each other for patients, for example. Not a lot of countries in the world that can replicate that same environment.

“We have also shown that our research infrastructure can be adapted to an emergency situation and this is thanks to the NIHR Clinical Research Network and the trained research workforce who are based in every hospital and primary care setting in the UK. I think the real challenge now is ensuring that we learn from the COVID-19 crisis to improve the way we do things normally, in the clinical research setting, outside of the pandemic.”

 

Eoghan Mullholland awarded colorectal cancer fellowship

As part of UK Pride month, we are spotlighting the work of cancer researcher and University LGBTQ+ Representative Dr Eoghan Mulholland