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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.

Being a part of cancer drug discoveries

Last month, the biotech company Immunocore announced results from its phase 3 clinical trial investigating the efficacy of Tebentafusp (a new anti-tumour immunotherapy), in the treatment of patients with metastatic melanoma. If it is given regulatory approval, it is likely that the drug will enter wider clinical use next year. If it does, it will give those living with uveal melanoma (UM), a rare cancer, a new treatment option and would be the first new therapy to improve the overall survival of this group of patients in over 40 years. Susan was one of the first patients to receive the drug when it was in its early stages of development.

Susan’s Clinical Trial Experience

In 2008, what appeared to be a small spot on the top of my head turned out to be melanoma. After surgery at the John Radcliffe Hospital in Oxford to remove the tumour there was no sign of recurrence, until 2012 when the melanoma had apparently spread to my lungs. It was at then that I was invited to enrol on a clinical study at Oxford’s Early Phase Clinical Trials Unit (EPCTU).

I met Professor Middleton, head of the trials unit, in 2012 following the appearance of cancer metastases in my lungs when he informed me of a new clinical trial he was leading,  investigating a drug called IMCgp100, now known as Tebentafusp. At the time, there was no way to know if the drug would help in any way. Early-stage clinical trials for a new drug are not tried and tested, the side effects are not always clear and the outcomes not always sure.

For me, in the first 30 days of the trial I experienced rashes, headaches and lethargy. Common for many undergoing cancer treatments, but unpleasant none-the-less. Throughout the whole time I was on the trial the doctors and nurses were completely honest with me.  There were no promises.  They were on a learning curve themselves and if they didn’t know the answer to a question, they said so.

However, gradually these side effects subsided, and it became clear on my scans that the tumour had begun to shrink. Later on, it had stopped shrinking, but had not grown either. After 14 drug cycles on the trial, I attended my last scan. The tumour in my lung had shrunk to an operable size, and after another operation in 2015, the cancer was removed.

I cannot tell you how wonderful it felt when I was told that there was no sign of any tumour in the left lung and that the right one was continuing its downward trend. All of this was because of an experimental drug in an ever-evolving trial that I was part of.

At the time it didn’t occur to me that my experience was laying the ground work for the introduction of a new drug into common use.

From being told I had 18 months left to live in 2012, to being cancer free in 2015, I think my case exemplifies why clinical trials are important. It was fortunate that I qualified to be part of a first stage clinical trial in Oxford, and one that went on to help me. But even more, it is fantastic to hear that the same drug I was treated with has now gone on to complete a phase 3 trial, and have the potential to give people like me a new lease on life.

Whist clinical trial drugs are experimental until rigorously tested, the knowledge and resources of the staff at the University of Oxford is what contributed to the early identification of Tebentafusp as a potential therapy, so that it may go on to be translated into the clinic to help me and other melanoma patients.

Sometimes in life, something is so important that you have to make a decision without any knowledge of where it will lead you.

I made that decision and underwent a clinical trial that was administered under rigorously strict guidelines, with the patient’s safety as paramount

I don’t know whether the cancer will return, as I believe melanoma is a tricky devil, but I feel as if I have been given a second chance and my remission wouldn’t have been possible without the researchers and staff at Oxford involved in the development of new drugs.

About the clinical trial

Tebentafusp was tested in a phase 1 and 2 clinical trial by researchers at the University of Oxford and Immunocore, hosted at the EPCTU. The success of those trials has allowed the drug to be tested in stage 3 trials which were recently reported on by Immunocore.

The detailed results of the phase 3 trial will be submitted for publication in a peer-reviewed journal later next year. All the information about the drug will be submitted to the regulator, the MHRA, for their assessment after which it is hoped that the drug will enter the clinic.

The phase 1 and 2 trials were led by Prof Mark Middleton at the Department of Oncology.

 

New melanoma drug a step closer to the clinic

Previous phase 1 and 2 clinical trials have been conducted into Tebentafusp, a new anti-tumour immune response drug for patients with metastatic melanoma. The results from Immunocore and the University of Oxford, found that this first-of-its-kind treatment showed great promise in helping the immune system fight off melanoma cancers of both the eye and skin. The phase 3 clinical trial for this drug is the first for an affinity optimised T-cell receptor drug, making it the first of its kind.

Today, Immunocore the company behind the drug have announced trial results showing tebentafusp works better for patients with untreated metastatic uveal melanoma, when compared to other treatment choices.

“A positive survival benefit for tebentafusp represents a major step towards bringing a potential new treatment for cancer patients with a high unmet need. If approved, it would be the first new therapy to improve the overall survival in 40 years and to be specifically used in the treatment of metastatic uveal melanoma, a disease with poor survival where new therapies are urgently needed”

– Bahija Jallal, CEO of Immunocore

Tebentafusp comes out of clinical trials led by Prof Mark Middleton (Department of Oncology). Now, we see the potential for this drug coming into the clinic, subject to regulatory approval, as early as next year.

“It is very exciting that our observations in the first trial of tebentafusp, that it could make some uveal melanomas shrink, have now been borne out in larger studies. There’s still a way to go but there is every hope that this will prove an option for the treatment of this difficult cancer quite soon.”

– Prof Mark Middleton, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre.

Uveal melanoma is a rare and aggressive form of cancer that affects the eye, and typically has a poor prognosis and has no accepted optimal treatment and management. After the cancer metastases, 50% of patients have life expectancy of less than a year. Tebentafusp has the potential to be the first new therapy to improve the life expectancy of patients in over 40 years.

About the researchers

This research was funded by Immunocore.

Prof Mark Middleton is the Head of the Department of Oncology at the University of Oxford. He has overseen the development of internationally leading melanoma and upper GI clinical research groups and establishment of portfolios of early phase radiotherapy and haemato-oncology trials in Oxford. He is involved in the evaluation of novel immunotherapeutics, including pre-clinical development, trial design, proof of mechanism and proof of concept.

Immunocore, is a pioneering, clinical-stage T cell receptor biotechnology company working to develop and commercialise a new generation of transformative medicines to address unmet needs in cancer, infection and autoimmune diseases.  The Company’s most advanced programs are in oncology and it has a rich pipeline of programs in infectious and autoimmune diseases. Immunocore’s lead program, tebentafusp (IMCgp100), has entered pivotal clinical studies as a treatment for patients with metastatic uveal melanoma. Collaboration partners across the Immunocore pipeline include Genentech, GlaxoSmithKline, AstraZeneca, Eli Lilly and Company, and the Bill and Melinda Gates Foundation. Immunocore is headquartered at Milton Park, Oxfordshire, UK, with offices in Conshohocken, Pennsylvania and Rockville, Maryland in the US. For more information, please visit www.immunocore.com.

The National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) is based at the Oxford University Hospitals NHS Foundation Trust and run in partnership with the University of Oxford.

The NIHR is the nation’s largest funder of health and care research. The NIHR:

  • Funds, supports and delivers high quality research that benefits the NHS, public health and social care
  • Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
  • Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
  • Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
  • Partners with other public funders, charities and industry to maximise the value of research to patients and the economy

The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.

This work uses data provided by patients and collected by the NHS as part of their care and support and would not have been possible without access to this data. The NIHR recognises and values the role of patient data, securely accessed and stored, both in underpinning and leading to improvements in research and care. www.nihr.ac.uk/patientdata

 

What we can learn from cancer survivors

Understanding how an individual survives cancer, and why they respond well to therapy, can be vital in identifying new therapeutic targets. A new project seeks to see why some advanced pancreatic cancer patients overcome the odds and respond positively to treatment.

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.

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.

New hydrogel technology has promise in breast cancer modelling

In science, a model is used as a representation of something in the real world, so that ideas and concepts may be tested out. Models have a variety uses, but in cancer biology they are often popular as they can help to mimic the complex environment seen in human   disease. Models are used to explore the effects of new drugs, understand genetic or cellular pathways on tumour development or predict the potential response of a patients cancer.

It’s in a researcher’s best interest to create a model that is as faithful to the real world as possible, so that the outcomes are accurate and can translate successfully into humans. However, the go-to models to recapitulate human cells in a lab use, a protein matrix extracted from mouse tumours, which is used to resemble the extracellular environment found human tumours. But the extent to which mouse matrix can be used is limited by its fixed extracellular matrix components, which are often not representative of the human tissue, and the inability to add or remove the individual extracellular components to explore the influence these on tumour growth.

Dr Gillian Farnie, Nuffield Department of Orthopaedics, Rheumatology and Musculorskeletal Sciences, has focused her work on developing new models that allow human breast cancer cells to be grown and researched, whilst overcoming these limitations.

A recent publication in Matrix Biology, funded by the NC3Rs, outlines a new peptide hydrogel developed by the Farnie group in collaboration with Prof Merry (University of Nottingham).  This new peptide hydrogel offers the added benefit of being customisable, by incorporating or removing specific extracellular matrix components that researchers want to test, to better understand their influence on cancer cells. It therefore allows full control over the biochemical and physical properties of the model, providing researchers with the opportunity to more accurately adapt the model to the real-life environment of human breast tumour.

The new technology’s applications are incredibly widespread and promising. For example, certain extracellular matrix proteins, when found in high quantities in a tumour, can often be associated with a poorer prognosis for a patient. Researchers may want to understand if this is a simple correlation, or if the proteins are assisting the cancer in some way, such as promoting treatment resistance. The ability to remove these proteins from a cancer model and test the response, whilst remaining faithful and accurate to human cells, is incredibly useful and can allow us to discover therapeutic targets.

Dr Gillian Farnie is currently working with the breast cancer research community to apply this new technology in multiple breast tumour research projects. The hydrogel’s applications are not limited to just matrix biology, but also in investigating areas such as the biological significance of blood vessel supply to tumours or even other cancer types outside the breast.

This new hydrogel provides an opportunity to better understand the individual influences of the extracellular matrix, mechanical properties and cell-cell interactions on breast cancer and other disease. It is an open and reproducible model that Dr Farnie is currently publishing a detailed methodology in JOVE, so that more cancer researchers can have access to the new technology.

About this research

Dr Gillian Farnie is based in the Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences.  Her research focuses on the development of patient derived pre-clinical breast cancer models that are used to examine mechanisms of inherent and induced therapy resistance, interrogating both intra-tumour heterogeneity (cancer stem cells) and the tumour microenvironment (ECM, Stroma, Immune cells).

New melanoma cancer drug in development shows promise

University of Oxford and Immunocore Ltd have investigated Tebentafusp, a new anti-tumor immune response drug for patients with metastatic melanoma

Focussed ultrasound and nanomedicine offer new hope for improving effects of cancer drugs

Researchers have made a breakthrough in more precisely targeting drugs to cancers.

A number of Centre members were part of a multi-disciplinary team of biomedical engineers, oncologists, radiologists and anaesthetists that have used ultrasound and lipid drug carriers (liposomes) to improve the targeting of cancer drugs to a tumour. The new technology has been used in humans for the very first time, with ultrasound remotely triggering and enhancing the delivery of a cancer drug to the tumour.

“Reaching therapeutic levels of cancer drugs within a tumour, while avoiding side effects for the rest of the body is a challenge for all cancer drugs, including small molecules, antibodies and viruses” says Professor Constantin Coussios, Director of the Oxford Centre for Drug Delivery Devices and of the Institute of Biomedical Engineering at the University of Oxford. “Our study is the first to trial this new technique in humans, and finds that it is possible to safely trigger and target the delivery of chemotherapy deep within the body from outside the body using focussed ultrasound. Once inside the tumour, the drug is released from the carrier, supplying a higher dose of chemotherapy directly to the tumour, which may help to treat tumours more effectively for the same or a lower systemic dose of the drug.”

The 10-patient phase 1 clinical trial, supported by the Oncology Clinical Trials Office, used focused ultrasound from outside the body to selectively heat liver tumours and trigger drug release from heat-sensitive carriers, known as thermosensitive liposomes. Building on over a decade of preclinical studies, the study demonstrated the ultrasound technique to be feasible, safe, and capable of increasing drug delivery to the tumour between two-fold and ten-fold in the majority of patients. Ongoing research worldwide is investigating the applicability of this technique to other tumour types, and future research could explore the combination of ultrasound with other drugs.

All 10 patients treated had inoperable primary or secondary tumours in the liver and had previously received chemotherapy. The procedure was carried out under general anaesthesia and patients received a single intravenous dose of 50 mg/m2 of doxorubicin encapsulated within low-temperature-sensitive liposomes (ThermoDox®, Celsion Corporation, USA). The target tumour was selectively heated to over 39.5° C using an approved ultrasound-guided focussed ultrasound device (JC200, Chongqing HAIFU, China) at the Churchill Hospital in Oxford. In six out of ten patients, the temperature at the target tumour was monitored using a temporarily implanted probe, whilst in the remaining four patients ultrasonic heating was carried out non-invasively.

Before ultrasound exposure, the amount of drug reaching the tumour passively was low and estimated to be below therapeutic levels. In seven out of 10 patients, chemotherapy concentrations within the liver tumour following focussed ultrasound were between two and ten times higher, with an average increase of 3.7 times across all patients.

“Only low levels of chemotherapy entered the tumour passively. The combined thermal and mechanical effects of ultrasound not only significantly enhanced the amount of doxorubicin that enters the tumour, but also greatly improved its distribution, enabling increased intercalation of the drug with the nucleus of cancer cells ” says Dr Paul Lyon, lead author of the study.

“This trial offers strong evidence of the rapidly evolving role of radiology in not only diagnosing disease but also guiding and monitoring therapy. The treatment was delivered under ultrasound guidance and patients were subsequently followed up by CT, MRI and PET-CT, evidencing local changes in tumours exposed to focussed ultrasound” commented Professor Fergus Gleeson, radiology lead co-investigator for the trial.

“A key finding of the trial is that the tumour response to the same drug was different in regions treated with ultrasound compared to those treated without, including in tumours that do not conventionally respond to doxorubicin” adds Professor Mark Middleton, principal investigator of the study. “The ability of ultrasound to increase the dose and distribution of drug within those regions raises the possibility of eliciting a response in several difficult-to-treat solid tumours in the liver. This opens the way not only to making more of current drugs, but also targeting new agents where they need to be most effective”.

The study was published in The Lancet Oncology journal.

Anti-malaria drug could make tumours easier to treat

An anti-malaria drug could help radiotherapy destroy tumours according to a Cancer Research UK-funded study published in Nature Communications.

The study, carried out at the CRUK/MRC Oxford Institute for Radiation Oncology in Oxford, looked at the effect of the drug, called atovaquone, on tumours with low oxygen levels in mice to see if it could be repurposed to treat cancer.

Radiotherapy works by damaging the DNA in cells. A good supply of oxygen reduces the ability of cancer cells to repair broken DNA. So when a tumour has low levels of oxygen, it can repair itself more easily after radiotherapy.

This means that tumours with low oxygen levels are more difficult to treat successfully with radiotherapy. They are also more likely to spread to other parts of the body.

This research showed for the first time that an anti-malaria drug slows down the rate at which cancer cells use oxygen by targeting the mitochondria, the powerhouses of the cell that make energy, a process that uses oxygen.

By slowing down the use of oxygen, this drug reverses the low-oxygen levels in nearly all of the tumours. The fully-oxygenated tumours are more easily destroyed by radiotherapy.

The drug was shown to be effective in a wide range of cancers, including lung, bowel, brain, and head and neck cancer. This older medicine is no longer patented and is readily and cheaply available from generic medicines manufacturers.

Professor Gillies McKenna, Cancer Research UK Oxford Centre Director and joint lead author alongside Dr Geoff Higgins, said: “This is an exciting result. We have now started a clinical trial in Oxford to see if we can show the same results in cancer patients. We hope that this existing low cost drug will mean that resistant tumours can be re-sensitised to radiotherapy. And we’re using a drug that we already know is safe.”

Dr Emma Smith, Cancer Research UK’s science information manager, said: “The types of cancer that tend to have oxygen deprived regions are often more difficult to treat – such as lung, bowel, brain and head and neck cancer. Looking at the cancer-fighting properties of existing medicines is a very important area of research where medical charities can make a big impact and is a priority for Cancer Research UK. Clinical trials will tell us whether this drug could help improve treatment options for patients with these types of tumour.”