Scientists have equipped a virus that kills carcinoma cells with a protein so it can also target and kill adjacent cells that are tricked into shielding the cancer from the immune system.
It is the first time that cancer-associated fibroblasts within solid tumours – healthy cells that are tricked into protecting the cancer from the immune system and supplying it with growth factors and nutrients – have been specifically targeted in this way.
The researchers, who were primarily funded by the MRC and Cancer Research UK, say that if further safety testing is successful, the dual-action virus – which they have tested in human cancer samples and in mice – could be tested in humans with carcinomas as early as next year.
Currently, any therapy that kills the ‘tricked’ fibroblast cells may also kill fibroblasts throughout the body – for example in the bone marrow and skin – causing toxicity.
In this study, published in the journal Cancer Research, the researchers used a virus called enadenotucirev, which is already in clinical trials for treating carcinomas. It has been bred to infect only cancer cells, leaving healthy cells alone.
They added genetic instructions into the virus that caused infected cancer cells to produce a protein called a bispecific T-cell engager.
The protein was designed to bind to two types of cells and stick them together. In this case, one end was targeted to bind to fibroblasts. The other end specifically stuck to T cells – a type of immune cell that is responsible for killing defective cells. This triggered the T cells to kill the attached fibroblasts.
Dr Joshua Freedman, from the Department of Oncology at the University of Oxford, who was first author on the study said: “We hijacked the virus’s machinery so the T-cell engager would be made only in infected cancer cells and nowhere else in the body. The T-cell engager molecule is so powerful that it can activate immune cells inside the tumour, which are being supressed by the cancer, to attack the fibroblasts.”
Dr Kerry Fisher, from the Department of Oncology at the University of Oxford, who led the research said: “Even when most of the cancer cells in a carcinoma are killed, fibroblasts can protect the residual cancer cells and help them to recover and flourish. Until now, there has not been any way to kill both cancer cells and the fibroblasts protecting them at the same time, without harming the rest of the body.
“Our new technique to simultaneously target the fibroblasts while killing cancer cells with the virus could be an important step towards reducing immune system suppression within carcinomas and should kick-start the normal immune process.
“These viruses are already undergoing trials in people, so we hope our modified virus will be moving towards clinical trials as early as next year to find out if it is safe and effective in people with cancer.”
The scientists successfully tested the therapy on fresh human cancer samples collected from consenting patients, including solid prostate cancer tumours which reflect the complex make-up of real tumours. They also tested the virus on samples of healthy human bone marrow and found it did not cause toxicity or inappropriate T cell activation.
Dr Nathan Richardson, head of molecular and cellular medicine at the MRC said: “Immunotherapy is emerging as an exciting new approach to treating cancers. This innovative viral delivery system, which targets both the cancer and surrounding protective tissue, could improve outcomes for patients whose cancers are resistant to current treatments. Further clinical studies will be crucial to determine that the stimulation of the patient’s immune system does not produce unintended consequences”.
Dr Michelle Lockley, Cancer Research UK’s expert on immunotherapy, said: “Using the power of the body’s own immune system to tackle cancer is a growing area of research. This work in human tumour samples is encouraging, but can be complicated – one of the biggest challenges of immunotherapies is predicting how well they will work with the patient’s immune system, and understanding what the side effects could be. The next stage will be using clinical trials to test whether this is both a safe and effective way to treat the disease in people.”
The virus targets carcinomas, which are the most common type of cancer and start in cells in the skin or in tissues that line or cover internal organs, such as the pancreas, colon, lungs, breasts, ovaries and prostate.
The study was funded by Cancer Research UK, the Medical Research Council, the Kay Kendall Leukaemia Fund and the Oxford NIHR Biomedical Research Centre. Materials were provided by PsiOxus Therapeutics Ltd.
Content adapted from the MRC website.
Oxford researcher Chunxiao Song, who is a group leader and chemist at the Ludwig Institute for Cancer Research, recently gave an interview to CRUK speaking about his work recently funded by the CRUK-OHSU Project Award. The Award is jointly funded by CRUK and Oregon Health and Science University (OHSU).
In collaboration with Dr Thuy Ngo (OHSU) Chunxiao is developing novel tools to analyse liquid biopsies for pancreatic and oesophageal cancer. The aim is to use epigenetic and transcriptome technology to detect cancer earlier and provide information on where the cancer originated from. The researchers plan to use machine learning to create classification models that distinguish cancer patients from healthy controls.
The collaborating researchers believe that a combination of those two technologies will generate a fuller picture than a focus on just one technology. Chunxiao explains: “Our project uses liquid biopsies – a test that looks for DNA and RNA shed by tumours (and in fact all cells) in a patient’s blood sample. I have developed new measuring technologies that use less harsh chemicals than the standard approach. This causes less DNA degradation, which makes it easier to measure small quantities of cell -free DNA. Thuy has focused her research on measuring cell-free RNA. This is even more difficult than measuring cell-free DNA – but she has developed a special protocol that’s really gentle and doesn’t cause degradation of the RNA.”
Chunxiao also speaks about his experiences with applying for CRUK funded grants. He emphasises how uncomplicated the process is, and how well CRUK supports applicants: “My advice to anyone thinking of putting in an application is to contact the CRUK funding managers early on because they can help guide you through the process from the beginning.”
The full interview can be found via this link.
(Content adapted from www.cancerresearchuk.org)
October 4th and 5th 2018 saw the first Marseille-Oxford Cancer Centres Collaboration (MOC3) meeting, held in the beautiful location of Villa Gaby, Marseille. The meeting was held to initiate a new partnership between the Cancer Research UK Oxford Centre, the Cancer Research Centre of Marseille and the Institut Paoli-Calmettes.
The objectives of these cancer centres are closely aligned, across both basic and clinical activities. The aim of MOC3 is to benefit from the complementary state-of the-art expertise and experimental and clinical infrastructures of the two sites to tackle major clinical challenges faced by those treating cancer patients.
The first meeting focussed on genome stability and the DNA damage response, based upon the respective strengths in these fields of both centres, from basic through translational research and in clinical practice. Thirty-five Oxford scientists and sixty-five Marseille scientists including students, post-doctoral fellows and group leaders attended the meeting which consisted of talks, posters sessions and a workshop – the latter proving very successful in identifying new collaborative projects that will be up-and-running in the next few months.
A follow-up meeting will take place in 2019 in Oxford and will be aimed at identifying collaborative projects centred around the DNA damage response and the maintenance of genome stability in relationship to leukemias and pancreatic cancer.
(B)(extract): Static PET-CT images in coronal plane pre- and post-metformin are from an individual with an
increase in KFDG-2cpt following metformin;note increased uptake in axillary lymph nodes (circled).
An international collaborative team of medical oncologists, radiologists, cell biologists and bioinformaticians led from Oxford by Simon Lord and Adrian Harris, have identified different metabolic response to metformin in breast tumours that link to change in a transcriptomic proliferation signature.
Published last week in Cell Metabolism, the team integrated tumour metabolomic and transcriptomic signatures with dynamic FDG PET imaging to profile the bioactivity of metformin in primary breast cancer.
Simon Lord stated: “This study shows how the integrated study of dynamic response to a short window of treatment can inform our understanding of drug bioactivity including mechanism of action and resistance. Further work will look to identify how mutations in mitochondria may define the metabolic response of tumours.”
The group demonstrated that metformin reduces the levels of several mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumours.
The paper “Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer” defines two distinct metabolic signatures after metformin treatment, linked to mitochondrial metabolism. These differential metabolic signatures apparent in tumour biopsy samples, did not link to changes in systemic metabolic blood markers including insulin and glucose, suggesting metformin has a predominant direct effect on tumour cells. Analysis of the dynamic FDG-PET-CT data showed that this novel imaging technique may have potential to identify early response to treatment that is not apparent using standard static clinical FDG-PET-CT.
Key point summary of the study:
- There is great interest in repurposing metformin, a diabetes drug, as a cancer treatment
- Two distinct metabolic responses to metformin seen in primary breast cancer
- Increased 18-FDG flux, a surrogate marker of glucose uptake, observed in primary breast tumours following metformin treatment
- Multiple pathways associated with mitochondrial metabolism activated at the transcriptomic level
- Further evidence that metformin’s predominant effects in breast cancer are driven by direct interaction with tumour mitochondria rather than its effects on ‘host’ glucose/insulin metabolism
The study has been funded by Cancer Research UK, the Engineering and Physical Sciences Research Council, the Medical Research Council, and the Breast Cancer Research Foundation.
The published paper can be found at:
Content adapted from the original paper by Simon Lord et al.
AstraZeneca – Oxford Cancer Symposium (AZOCS)
Thursday 13th September 2018 | Keble College, Oxford
On Thursday 13th June, Keble College in Oxford hosted the
inaugural AstraZeneca – Oxford Cancer Symposium (AZOCS).
Over 125 researchers from Oxford and 90 cancer scientists from AstraZeneca and MedImmune attended to develop and establish a series of collaborative cancer research projects.
Almost 100 posters and 27 presentations showcased current
projects across all organisations, covering DNA Damage
Response, Early-Phase Clinical Trials, Enabling Technologies,
Epigenetics, Immuno-Oncology, and Radiation Oncology.
David Andrews from AstraZeneca in Cambridge commented:
“The feedback I have had from AstraZeneca and Medimmune colleagues has been overwhelmingly positive and it is clear there are many opportunities for us to collaborate – from target identification and validation all the way through to patient studies. We are very excited by the prospect of deploying our disease know-how, target knowledge and
portfolio of drugs in development alongside Oxford’s excellent
access to patients and patient-derived models.
Oxford’s specific disease and biological knowledge should also
enable us to more deeply understand biological targets
and bring benefit to patients.”
Chris Schofield from the Department of Chemistry in Oxford
emphasised: “The AZ-Oxford meeting showcased brilliant
science from both organisations aimed at enabling breakthrough treatments for cancer. The truly impressive research ranged from fundamental work on the origins of tumorigenesis to clinical studies. There is clearly enormous potential for industry and academic to work synergistically to cement the UK’s leading position in cancer research.”
Poster winners for the AZOCS Poster Prizes 2018 are:
A Fluorescent Reporter of Base Editing
Activity Reveals Editing Characteristics of APOBEC3A
– Matthew Coelho, AstraZeneca
A gene signature associated with PTEN activation defines good outcomes in intermediate-risk prostate cancer cases
– Chee Wee Ong, University of Oxford
If you attended the Symposium and would like to find out any more information about any of the presentations you saw, any of the posters, or further information on the CRUK Oxford Centre or AstraZeneca/MedImmune then please contact email@example.com .
If you would like further information on how to download the Networking Meeting App ATTENDIFY, please contact firstname.lastname@example.org .
We are delighted to announce a partnership symposium between AstraZeneca and the Cancer Research UK Oxford Centre, which will take place on September 13th 2018 at Keble College.
The primary aim of the event is to provide an opportunity for researchers from both organisations to get a better understanding of the research activities of the other, in order to establish a series of collaborative cancer research projects. Through the Centre Development Fund, financial support for projects emerging from the event will be available.
The event will include presentations on 4 core topics, DNA damage repair, radiation oncology, epigenetics and immunoncology and posters covering target identification and validation, CRISPR capabilities, early phase clinical trials, biophysics, structural biology, biochemistry/cellular assays and chemical probes.
There will be a range of speakers from both Oxford and AstraZeneca (see draft schedule below), and numerous opportunities for individual networking during breaks and at the drinks reception. We will be opening our next round of development funding at the event in order to support collaborations emerging from the event.
If you are interested in attending this free event, (open to group leaders, and post-doc’s across the University and Trust) and presenting a poster to showcase your research to AZ (and making yourself eligible for the poster prize) please register your interest here by Tuesday June 19th. Places are limited to 150 attendees and will be prioritised to those researchers presenting posters and those who register sooner.
Please note, all information included in the above application and presented at the conference will be considered pre-competitive, so bear this in mind when choosing which details to disclose.
We are delighted to congratulate Professor Chris Holmes, member of the Centre Management Group, on his new joint role for the Alan Turing Institute and Health Data Research UK (HDR UK).
Chris, who is Professor in Biostatistics at the University of Oxford, has considerable expertise in data science and artificial intelligence methodologies, specifically statistics and machine learning and its application to health and biomedical science problems. He has been employing computational statistics and machine learning approaches to integrate the multi-omics data (DNA sequence, methylation, transcriptome and patient records) generated by the S-CORT consortium to provide a greater biological understanding of colorectal cancer.
In his new role, Chris will facilitate direct scientific collaboration and leadership between the two national centres. He will develop and coordinate a programme of research involving collaboration across The Alan Turing Institute’s growing university network, creating opportunities with HDR UK’s six substantive sites and the broader health and data science sector. His programme will build on an already established set of health projects underway at the Turing, including partnerships with Cystic Fibrosis Trust applying machine learning to improve treatment plans, a set of interdisciplinary projects awarded jointly with the British Heart Foundation through the BHF-Turing Cardiovascular Data Science Awards and cross-cutting foundational research looking into data security and privacy.
Commenting on his appointment, Chris remarked:
“Already we are seeing data science and AI innovation bear fruit in the health sector; with areas like medical imaging now opening up to machine learning algorithms. There are many other areas of opportunity; including using data to inform adaptive clinical drug trials, personalised medicine, addressing operational challenges within the health service and using theoretical mathematics and statistics to help connect and understand the algorithms that can extract information from large datasets.”
“I am delighted to join with the Turing and HDR UK and look forward to working with these two national centres to improve human health and the scientific understanding of biomedical systems.”
Oxford University researchers have identified a protein used by tumours to help them detect food supplies. Initial studies show that targeting the protein could restrict cancerous cells’ ability to grow.
A team from Oxford University’s Department of Physiology, Anatomy and Genetics led by CRUK Oxford Centre Member Dr Deborah Goberdhan worked with oncologist and researcher, Professor Adrian Harris, to understand the effects of this protein called PAT4.
Dr Goberdhan said: ‘We found that aggressive cancer cells manufacture more PAT4, which enables them to make better use of available nutrients than the cells around them – including healthy tissue.’
Cancer cells often have restricted access to the body’s nutrient-rich blood supply. The ability to sense and acquire nutrients is critical for a cancer to grow.
Dr Goberdhan’s and Prof Harris’s groups collaborated to develop an antibody that could be used to highlight PAT4 in human tissue samples. This was then used to study anonymous tumour samples taken from patients with colorectal cancer, a common form of the disease.
The results were compared to the known outcomes for the patients. Those who had higher levels of PAT4 in their tumours did less well than those with lower levels – being more likely to relapse and die.
The researchers then looked at what happened when PAT4 levels were reduced. They showed that by reducing PAT4 levels, cancerous tumours grew more slowly.
Dr Goberdhan said: ‘These findings support each other. Not only do higher levels of PAT4 mean a worse outcome, but lowering levels improves the situation. This means that we have identified a mechanism which cancer cells prefer to use and which we might be able to target as part of a combination treatment.’
The research, funded by Cancer Research UK, the Wellcome Trust and the Biotechnology and Biological Sciences Research Council was published in the science journal Oncogene on 5 October 2015. It continues and may eventually provide a way of increasing survival from cancer.