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New Oxford technology assesses cancer patient vulnerability to COVID-19

The web-based COVID risk prediction tool, QCovid, is the product of the latest research to emerge from the QResearch database co-founded by Prof Julia Hippisley-Cox based at the University of Oxford. The analysis of anonymised UK health records of more than 8 million adults using GP records, hospital records including intensive care data, mortality data, Cancer Registry data and COVID-19 testing data from late January 2020 to April 2020 allows clinicians to estimate someone’s  risk of COVID-19 infection as well as the risk of being admitted to hospital with serious illness due to the virus and the potential risk of COVID-19-related death. QCovid takes into account a range of risk factors such as age, gender ethnicity and medical conditions and enables the NHS to make evidenced based decisions when prioritising different patient groups for shielding and COVID-19 vaccination.

The work was commission by England’s Chief Medical Officer Chris Whitty, who involved the team led by clinical epidemiologist, Prof Julia Hippisley-Cox, at the University of Oxford as the group has acquired extensive experience in developing risk prediction tools for a range of diseases, including QCancer for the prediction of having  undiagnosed cancer, which are widely used in the NHS. QCovid has now been validated and published in the British Medical Journal, is accessible to the public at www.qcovid.org and has been adopted by NHS Digital as a way to assess the relative risk of COVID-19 for all members of the population, based on their medical history and other risk factors.

Based on the prediction tool, 1.7 million patients have been added to the shielding list, including many cancer patients. Those within the most ‘vulnerable’ group who are over 70 will have already been invited for vaccination and 820,000 adults between 19 and 69 years will now be prioritised for a vaccination.

CANCER & VULNERABILITY

Although previous studies from the University of Oxford have shown that blood cancer patients are at higher risk of COVID-19, until now no research or model had been published that assessed patients with different types of cancer, including their treatment history and backgrounds. The QCovid algorithm feeding into the prediction tool takes cancer factors such as diagnosis of blood, lung, oral or bone cancers and different cancer therapies into account.

Thus using the QCovid prediction tool, it has a been highlighted that those with blood (acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma) and respiratory (lung, laryngeal, nasopharyngeal and mouth) cancers are at increased COVID-19 risk.

In addition, those undergoing therapy (including recent bone marrow or stem cell transplant, chemotherapy, radiotherapy, immunotherapy or other antibody treatments for cancer and treatments that affect the immune system such as protein kinase inhibitors or PARP inhibitors), have also been identified at higher risk.

Thanks to the QCovid algorithm cancer patients now can be appropriately categorised and prioritised based on their type of cancer, current or previous cancer treatment and other factors such as corresponding health conditions that could make them more vulnerable to COVID-19.

The development of the QCovid model was led by the University of Oxford and involved researchers from Cambridge, Edinburgh, Swansea, Leicester, Nottingham, Liverpool, the London School of Hygiene & Tropical Medicine, Queen’s University Belfast, Queen Mary University of London and University College London. It was funded by the NIHR, NIHR Oxford Biomedical Research Centre, Wellcome Trust (ISSF) and John Fell Fund and supported by EMIS GP practices and the University of Nottingham.

Detecting for multiple cancers in one simple test

Biomarkers – or biological markers – are used in many areas of health and disease as measures of a biological or clinical state. In the context of cancer, identifying biomarkers of early stage cancer is crucial for being able to detect disease earlier and improving the outcomes of patients with cancer. However, biomarkers alone are not sufficient for earlier detection. We also need to develop cost-effective, non-invasive, simple-to-use technologies that can be used in the clinic to detect these biomarkers with high sensitivity, specificity and accuracy.

Professor Jason Davis in the Department of Chemistry at the University of Oxford is working on just that. Professor Davis’ research has focused on developing portable, handheld diagnostic tests that use a range of electroanalytical methods for biomarker detection. This includes recent work on using novel electrochemical impedance-based sensing technology to detect C-reactive protein, a marker of inflammation in the body.

These methods are advantageous for use in diagnostics since they generate results in a few minutes and are more sensitive than other commonly used techniques such as ELISA (enzyme-linked immunosorbent assay). They also do not require the sample to be processed before testing, meaning that a single drop of blood can be analysed directly, without needing further reagents or equipment. Multiple different biomarkers can be analysed simultaneously, potentially allowing multi-cancer blood tests in the future.

To further develop this technology into a clinically implementable assay, five years ago, Osler Diagnostics was spun out of Professor Davis’ lab. The ultimate aim is that this assay could be applied in GP surgeries to test for disease in asymptomatic individuals.

Professor Davis is currently looking at clinical applications within cardiac, cancer and neurological diseases and welcomes interest from researchers who would like to contribute their biomarker ideas and clinical problems.

About the researchers

The Davis Group runs an interdisciplinary research programme within the Department of Chemistry that develops and applies methods for the fabrication of advanced functional interfaces, and are actively engaged in the development of molecular detection, diagnostic, theranostic, and imaging methodologies.

Following the cancer metabolomic breadcrumb trail

By analysing the metabolic molecules that tumour cells leave behind, Dr James Larkin is investigating the applications of metabolomics in the early detection of many cancers.

New sequencing methods for distinguishing DNA modifications

Chemical modifications made to the DNA base cytosine play an important role in the regulation of gene expression across the genome. Cytosine can be chemically modified in four ways, with 5-methylcytosine (5mC) being the most common. Demethylation of 5mC by the TET family of enzymes results in the stable intermediates 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxycytosine (5caC). From what has been discovered so far, these modifications appear to have distinct functions. For example, 5mC is associated with repressed regions of the genome whereas 5hmC is present in active ones. However, to study these modifications further, robust sequencing methods are needed that can detect each of these four modifications specifically.

The traditional gold standard method for detecting DNA methylation is bisulphite sequencing. However, this relies on a harsh chemical treatment that degrades most of the DNA sample and is an indirect detection method, which decreases sequencing quality. Recently, a bisulphite-free method called TAPS has been developed by Ludwig Oxford’s Song lab, which has the advantage of preserving more of the DNA, increasing sensitivity, and directly detecting modified cytosines for improved DNA sequencing quality.

Despite its advantages, TAPS cannot distinguish between the different types of cytosine modifications. Other methods already exist that can do so but these use subtraction, for example, measuring 5mC and subtracting this signal from a combined measure of 5mC and 5hmC to obtain 5hmC levels. In addition to the disadvantages of using bisulphite and/or indirect detection strategies, these subtraction methods also need higher sequencing depths and generate very noisy data that can be difficult to interpret. New subtraction-free methods are therefore needed to specifically, directly and sensitively detect these four cytosine modifications in the genome.

In this paper published in Nature Communications, Dr Yibin Liu from Dr Chunxiao Song’s lab (Ludwig Oxford) and Dr Zhiyuan Hu from Professor Ahmed Ahmed’s lab (Weatherall Institute of Molecular Medicine and Nuffield Department of Women’s and Reproductive Health, University of Oxford) have developed a suite of TAPS-related whole genome sequencing methods for specifically detecting 5mC, 5hmC, 5fC and 5caC. They have named these TAPSβ (for 5mC), chemical-assisted pyridine borane sequencing (CAPS; for 5hmC), pyridine borane sequencing (PS; for 5caC and 5fC) and pyridine borane sequencing for 5caC (PS-c; for 5caC).

With these new methods, the research community is now armed to tackle more of the questions about the distinct and important functions of cytosine modifications in the genome and how their distribution is altered in diseases such as in cancer.

“The Oxford Classic” classification system uncovers new information about ovarian cancers

In 2020, using single cell RNA sequencing, Oxford cancer researchers made a breakthrough by identifying  new types of Fallopian tube cells that are the cells of origin for the majority of ovarian cancers. They showed that that the types of these newly-discovered non-cancer cells are “mirrored” into different ovarian cancer subtypes. These subtypes correlated well with survival.

Discovering the new subtypes of cells have allowed Oxford researchers to classify and categorise tumours based on their origin in the body, and determine which ones can lead to more severe cancer outcomes – an approach which has been dubbed the ‘Oxford Classification of Carcinoma of the Ovary’ or ‘Oxford Classic’ for short. The Oxford Classic will provide much more accurate predictions for disease outcome in patients, as well as helping researchers to develop targeted therapies for each type of cancer

Professor Ahmed Ahmed, Nuffield Department of Women’s and Reproductive Health and originator of the Oxford Classic, has how published a paper in collaboration with Imperial College, demonstrating the applications of the Oxford Classic approach. As well as shedding light on some previously unknown information about ovarian cancers.

Professor Ahmed says:

“Our group is very excited that we were able to confirm the predictive role of the Oxford Classic. This work highlights that it is now important to identify new personalised therapies for the Oxford Classic-defined EMT-high ovarian cancer subtype. The finding that there is a strong connection with abundant M2 Macrophages already offers a good hint as to where we could find good treatment options for patients with this type”.

Serous ovarian cancer (SOC) is the most common cancer subtype, but is challenging to classify and predict its prognosis. Using the Oxford Classic, researchers found that specific SOC subtypes, known as EMT-high types, were associated with a lower survival rate in serous ovarian cancer patients.

Professor Christina Fotopoulou of Imperial College London says:

“This has been a very fruitful collaboration between two major UK gynaecological cancer centres; Oxford and Imperial College. We have generated very promising results towards an individualisation of care of our ovarian cancer patients. Our data will help clinicians to stratify patients to the right treatment pathway based on features of tumour biology of their disease. I hope we can continue to work together on that basis and expand and validate our data further also on a larger scale.”

EMT stands for epithelial-mesenchymal transition, it is the process by which epithelial cells change and become more mobile. This mobility provides the cells with the opportunity to spread leading to cancer progression. EMT-high subtypes are tumours that have a high number of cancer cells with greater mobility.

Researchers also found that EMT-high subtypes were associated with abundance of a type of immune cells called M2 macrophage. M2 macrophages possess immunosuppressive properties, and can lead to poorer treatment responses if they are found in high quantities within a tumour. It has previously been observed that patients with high-EMT tumours had a poor immune response. This study confirms that the EMT-high subtypes are associated with an immunosuppressive environment (and so poor patient responses to treatment) due to their association with more M2 macrophages – a link that has not previously been identified.

Whether M2 macrophages induce the EMT level or the EMT level results in higher levels of M2 macrophages will be an important question to be addressed by Prof Ahmed’s future work. However, this study has demonstrated the Oxford Classic’s strong ability to predict a patient’s prognosis.

Classifying the EMT status of a tumour, using the Oxford Classic, could potentially become a valuable part of future cancer stratification methods. This will ensure that appropriate treatment methods and attention are given to patients with a poorer overall prognosis.

Ovarian Cancer Action’s CEO, Cary Wakefield, says

“While other cancers have achieved major improvements in treatment outcomes, ovarian cancer continues to go unrecognised, underfunded, and misdiagnosed. The Oxford classic is an exciting breakthrough that will help to identify new treatment options for ovarian cancers that have a lower chance of survival. Funding important research like this will bring us closer towards a shared goal of more women surviving ovarian cancer”.

About the study

This study was co-led by Prof Ahmed Ahmed of the University of Oxford and Prof Christina Fotopoulou of Imperial College. It was funded by Ovarian Cancer Action, CRUK Oxford Centre and the National Institute for Health Research (NIHR) Biomedical Research Centre.

This study has demonstrated the potential of the Oxford Classic to:

  1. Accurately classify types of serous ovarian cancers
  2. Identify populations of cancer cells that have poorer prognoses (such as EMT high cancers)

Ahmed Ahmed is a Professor of Gynaecological Oncology at the Nuffield Department of Women’s & Reproductive Health at the University of Oxford and a Consultant Gynaecological Oncology Surgeon at the Oxford Cancer and Haematology Centre. His work focuses on surgical, medical and fundamental research into ovarian cancer, its early detection, treatment and screening.

Read the fully study here: http://clincancerres.aacrjournals.org/content/early/2021/01/12/1078-0432.CCR-20-2782

Oxford spin out financed $6.8m for research into oncolytic therapies

Oxford spin out company, Theolytics, has raised $6.8 million in financing from Epidarex Capital and Taiho Ventures, to advance their work into viral derived cancer therapies. The closing of the recent Series A round resulted in participation from existing investor, Oxford Sciences Innovation (OSI) and new involvement from Epidarex Capital and Taiho Ventures LLC.

Theolytics is a biotechnology company founded from the University of Oxford, that harnesses the power of virus research to combat cancer. Originally launched in 2019, the company specialises in oncolytic viral therapy, developing a library of viral variants that can be used to produce new oncolytic viruses that selectively kill certain cancer cells. The in-house library at Theolytics hosts thousands of viral variants upon which researchers can draw candidates for new therapies, akin to phage display libraries used for antibody development.

The company was spun out of Len Seymour’s lab at the University of Oxford with the idea of applying external pressures to viruses to force the emergence of a variant with a set of desired characteristics, such as attacking specific cancers. Their most recent project will focus on ovarian cancer and ‘arming’ viruses with therapeutic agents for a localised, potent expression at the tumour site.

Len Seymour, Co-Founder and Professor of Gene Therapies within the Department of Oncology at the University of Oxford, says:

Bio selection represents a clever strategy to develop therapeutics that exploit scientific mechanisms that are not yet fully understood. By applying the correct selection pressure it is possible to identify oncolytic viruses that could not be designed on the basis of existing knowledge. The most exciting aspects of Theolytics approach are the huge diversity of the viral libraries they have produced using sophisticated molecular shuffling, thereby harnessing the therapeutic power of many diverse adenovirus serotypes, and the clinically relevant model systems they have developed. By combining these two strategic innovations, the Theolytics scientists have developed some truly exciting and world class therapeutic candidates.

In the long run, the company are working to transform the way in which viral therapies for cancer are discovered and developed. Read more about the technology here.

Oxford Cancer alumni’s biotech success

Scenic Biotech was founded in March 2017 as a spin-out of the University of Oxford and the Netherlands Cancer Institute. The company is based on the Cell-seq technology developed by co-founders Sebastian Nijman and Thijn Brummelkamp in their academic labs.

Cell-seq is a large-scale genetic screening platform that allows the identification of genetic modifiers – or disease suppressors – that act to decrease the severity of a disease. These disease-specific genetic modifiers are difficult to identify by more traditional population genetics approaches, especially in the case of rare genetic diseases. By mapping all the genetic modifiers that can influence the severity of a particular disease, Cell-seq unveils a new class of potential drug targets that can be taken forward for drug development.

In a deal worth $375m, Scenic Biotech has recently entered into a strategic collaboration with Genentech, a member of the Roche Group. This will enable discovery, development and commercialisation of novel therapeutics that target genetic modifiers.

Detecting pancreatic cancer through blood tests

Pancreatic ductal adenocarcinoma (PDAC) makes up 95% of all pancreatic cancer cases and has the lowest survival rate, and early diagnostic methods have yet to be developed. As a result, diagnosis often comes at a later stage when treatment options are limited and prognosis is poor.

Diagnosis at this stage often comes from imaging techniques followed by tissue biopsies, which are not appropriate options to use as standardised, early screening methods. New ways to diagnose PDAC at an earlier stage are needed, without the use of invasive procedures.

Liquid biopsies are becoming a more popular option to fill this demand. Taking a blood sample is minimally invasive, quick, and can tell us a lot of information about a person from their cfDNA (cell free DNA). cfDNA is released from cells and circulates in the blood, containing information about the cell they come from.

Methylation on cfDNA often appears in cancer patients, making it an effective biomarker that can be used to diagnose the presence of cancer with high accuracy and specificity about the cancer (such as location). The concept has many applications, including in the earlier diagnosis of PDAC.

The identification of these biomarkers in blood is often limited to the technology used, with DNA being damaged by the harsh chemicals that are used in the processing. The recent development of TAPS technology at the University of Oxford has helped to overcome this, using a bisulphate-free method, and making it a perfect method for PDAC biomarker identification.

DPhil students Paulina Siejka-Zielinska and Felix Jackson and Postdoctoral Researcher Jingfei Chang from Dr Chunxiao Song’s lab in collaboration with Dr Shivan Sivakumar (consultant medical oncologist) have been investigating TAPS as a method to identify PDAC biomarkers. Using blood samples from PDAC patients and healthy individuals, they are applying TAPS technology to prove that it can be used to accurately detect pancreatic cancer biomarkers in cfDNA.

Preliminary results from this study suggest that cfDNA methylation can be used for the identification of PDAC, as well as being able to accurately distinguish between pancreatic cancer and other pancreatic disorders that effect the DNA, such as pancreatitis.

If this is the case, then the results from this study will make for solid grounds for the application of TAPS in the earlier screening for pancreatic cancer.

About the Song Lab

The Song Lab combine various chemical biology and genome technologies to develop novel tools to analyse the epigenome. The lab apply these tools to two main research areas: the use of epigenetic modifications in circulating cell-free DNA from the blood for non-invasive disease diagnostics including early detection of cancer, and understanding the contribution of epigenetic heterogeneity in cancer development.

Most recently, the TAPS technology developed at the Song Lab has led to the creation of the start up Base Genomics, which has been launched to set a new gold standard in DNA methylation detection using this TAPS technology. Base Genomics will initially focus on developing a blood test for early-stage cancer and minimal residual disease. You can read more about it here.

Innovative drug delivery techniques show promise in clinical trials

Pancreatic cancer has a limited response to chemotherapy treatment, due to the movement of anti-cancer drugs from the blood into tumour cells being limited by cellular mechanisms such as poor perfusion, high stromal content and raised interstitial pressure. One way to overcome these challenges and increase the toxic effect of chemotherapy treatment on a tumour would be to increase drug dosage. However, this would result in the damage of healthy non-tumour cells, and would likely result in unacceptable toxicity to patients.

The aim of Professor Constantin Coussios and his team in the Institute Biomedical Engineering is to develop of drug delivery system capable of enhancing drug penetration into and around a tumour, whilst minimising toxicity to the patient. The team has so far found a successful approach, by increasing drug uptake into tumours through warming of the body, which causes vasodilation.

By using focused ultrasound (FUS) to generate heat, only defined areas (approximately the size of a grain of rice) are targeted for treatment. In combination, chemotherapy drugs such as doxorubicin can be encapsulated in a heat-sensitive lipids (ThermoDox®), so that the active drug is only released when a specific temperature is reached at a specified location, as defined by the position of the FUS beam.

Research fellows Dr Michael Gray (Dept of Engineering) and Dr Laura Spiers (Dept of Oncology) have been working with the Department of Pathology in the Oxford University Hospitals NHS Foundation Trust, to help characterise the efficacy of this approach, by assessing thermal and acoustic ultrasound properties of the ex vivo pancreas.

This new knowledge will be directly applied to patients in the new early phase clinical trial, PanDox (targeting pancreatic cancers with focused ultrasound and doxorubicin chemotherapy). This builds on the successful TarDox trial, which already demonstrated FUS-induced heating resulted in improved delivery of the ThermoDox® encapsulated chemotherapy drugs to liver metastases from various primary cancers.

The effect in the TarDox trial was such that a positive response to therapy from the tumour was seen after only a single treatment cycle in 4 out of 7 patients, even in cancers as colorectal adenocarcinoma (which is not known to respond to conventionally administered doxorubicin). These results suggest that if the cytotoxic threshold needed to successfully treat a tumour can be reached, then a positive response may be achieved without unacceptable toxic consequences on the patient.

The upcoming PanDox trial translates this approach to patients with non-resectable pancreatic adenocarcinomas. It will combine focused ultrasound to generate heat with ThermoDox® delivered into the blood.

The main aim of PanDox is to determine whether this novel approach to treating pancreatic cancer can enhance the amount of drug delivered to tumours that cannot be surgically removed. Secondary aims will assess tumour response and procedural safety. The first patients will be recruited from early 2021.

About the PanDox Team

Prof Constantin Coussios, PanDox Priniciple Investigator, is the Director of the Institute of Biomedical Engineering. His area of interest is in the study of drug delivery systems and improvement of delivery into tumours.  He founded and heads the Biomedical Ultrasonics, Biotherapy and Biopharmaceuticals Laboratory (BUBBL), a research group of 4 faculty and some 45 researchers working on a wide array of therapeutic applications. He is also serves as the Director of the Oxford Centre for Drug Delivery Devices.

Dr Laura Spiers is a doctor of Medical Oncology. She is currently undertaking a DPhil in Oncology with the Institute of Biomedical Engineering, investigating ultrasound-enhanced drug delivery.

Dr Michael Gray is a Senior Research Fellow, interested in the clinical therapeutic potential of ultrasound.

$410 million buy out for Oxford cancer detection technology

Biotechnology company, Base Genomics, launched in June 2020 based on Oxford’s Dr Chunxiao Song’s innovative TET-assisted pyridine borane sequencing (TAPS) technology. This week, Base Genomics was bought out by Exact Sciences for $410 million.

TAPS is a new method for measuring DNA methylation, a chemical modification on cytosine bases. DNA methylation is frequently altered in cancer and these altered DNA methylation levels are preserved in the small amounts of DNA that are released into the blood from cancer cells. With its enhanced sensitivity over the standard methodology for measuring DNA methylation, TAPS has great potential as the basis for a multi-cancer blood test.

“This acquisition by Exact Sciences will enable us to accelerate the clinical and commercial development of Base Genomics and unlock a new era for early cancer detection. This is a big step forwards”

says Base Genomics co-founder and chemistry lead, Dr Yibin Liu, who co-invented the technology while a post-doc at the Ludwig Institute for Cancer Research, Oxford Branch.

Exact Sciences will continue to build on the Base Genomics team in Oxford, creating a world-leading research centre for early stage cancer detection.

“I am thrilled that the TAPS technology developed in my lab has received this level of investment. We can now proceed much more rapidly to fully leverage the power of this technology for cancer detection and patient benefit”

says Dr Chunxiao Song, Assistant Member of the Ludwig Institute for Cancer Research, Oxford Branch and Base Genomics co-founder.

Chunxiao Song’s research has received funding from the Ludwig Institute for Cancer Research, Cancer Research UK and the NIHR Oxford Biomedical Research Centre. TAPS is continuing to be developed in Chunxiao’s lab, for example it was recently adapted for long-read sequencing, to further its application to other fields of biomedical research.