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.

 

Investigating the effects of co-morbidities on liver cancer risk

Hepatitis B virus (HBV) infection is one of the world’s leading causes of infection-related death and levels are increasing. A large proportion viral of hepatitis-associated deaths are due to liver cancer and cirrhosis. However, because not everyone with chronic HBV will develop liver cancer, more needs to be understood about the additional risk factors for liver cancer in people with chronic HBV infection. This will allow improved risk prediction for liver cancer, which, in addition to more sensitive diagnostic technologies, is an important part of the strategy for monitoring, to support earlier liver cancer detection and improved survival.

In this review published in the Journal of Viral Hepatitis, Cori Campbell and colleagues from Dr Philippa Matthews’ and Professor Ellie Barnes’ groups (Nuffield Department of Medicine) performed a literature review and meta-analysis to look for evidence of risk factors linked to HBV-associated liver cancer. Given the increasing prevalence of co-morbidities such as diabetes, high blood pressure and kidney disease, and metabolic risk factors such as obesity and dyslipidaemia (abnormal lipid blood profiles), the focus of this review was placed on these risk factors.

The researchers identified 40 studies that showed an association between liver cancer risk in the presence of chronic HBV infection and diabetes, high blood pressure, dyslipidaemia and obesity. Out of all these associated co-morbidities, only diabetes had enough published studies on it to be able to perform further analysis.

The risk of liver cancer was over 25% higher in individuals with chronic HBV infection and diabetes compared to those without diabetes, although there was some variation between the effect of diabetes seen in different studies. This suggests that it may be worth increasing liver cancer screening in individuals with both chronic HBV infection and diabetes. Interestingly, in studies where metformin was given as a treatment for diabetes, the association of diabetes with risk of liver cancer was weakened, warranting further investigation.

The full review article can be accessed on the Journal of Viral Hepatitis website.

For more information about liver cancer early detection research in Oxford, see the liver cancer research showcase.

Potential of DNA-based blood tests for detecting pancreatic cancer earlier

Pancreatic cancer is sadly a disease with very poor outcomes and only 7.3% of people survive this cancer for 5 years or longer in England (Cancer Research UK). The majority of patients with pancreatic cancer are diagnosed too late for potentially curable treatment to be applied and so there is an urgent need to detect pancreatic cancers earlier with the aim of improving outcomes from this disease.

One strategy for earlier detection is to screen people before they experience any symptoms using a minimally invasive test such as a blood test to look for indicators of pancreatic cancer. Published in the journal Cancers, Dr Shivan Sivakumar (Department of Oncology and Oxford University Hospitals NHS Trust) and colleagues Dr Jedrzej Jaworski (University of Oxford) and Dr Robert Morgan (University of Manchester and Christie NHS Foundation Trust) review the potential of cancer DNA in the blood as an effective and reliable indicator of pancreatic cancer.

DNA from cancer cells can be distinguished from DNA from healthy tissue using either genetic or epigenetic methods (or a combination of both). In the genetic method, cancer can be detected by looking at the DNA sequence, with the presence of cancer-associated DNA sequence changes called mutations or altered fragmentation patterns indicating cancer. In the epigenetic method, chemical modifications to the DNA called methylation are measured that have been shown to change in cancer.

In this review, the authors discuss the potential for DNA-based blood tests for pancreatic cancer earlier detection, the challenges that still need to be overcome and the future perspectives.

Read the full review article on the Cancers journal website.

Pancreatic cancer blood test research in Oxford

In Oxford, we have a couple of research projects underway to study both the genetic and epigenetic methods for detecting pancreatic cancer-derived DNA in the blood.

Dr Siim Pauklin (Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences) is working to identify a pancreatic cancer-specific DNA signature. In the long-term, it is hoped that this can be used as the basis of a simple blood test to detect the presence of pancreatic cancer earlier. This project is funded by the Pancreatic Cancer UK Research Innovation Fund. Read more about Siim’s project here.

Dr Chunxiao Song (Ludwig Institute for Cancer Research) is collaborating with Dr Shivan Sivakumar to apply his TAPS technology to pancreatic cancer. TAPS is a new, more sensitive method for detecting methylation on DNA, which gives it an advantage over other detection methods for measuring the very small levels of circulating tumour DNA in the blood. The team are working to identify patterns of DNA methylation that are specific for pancreatic cancer with the aim of developing this into a diagnostic test. Read more about Chunxiao’s and Shivan’s project on the CRUK Oxford Centre website.

Research projects to detect pancreatic cancer in the blood through non-DNA markers are also in progress in Oxford.

Bioengineering the human gut

The ability to grow human tissue in the lab has progressed rapidly over recent years, promising a new frontier for regenerative medicine and experimental modelling of human diseases, including for early detection research. The in vitro culture of the gastrointestinal (GI) tract is particularly attractive due to the prevalence of disorders of this tissue, including irritable bowel disease and cancer, and the need for replacement tissue for transplantation. However, the number of different cell types and the precise arrangement required to form a functional tubular GI tract makes this tissue challenging to grow in the lab.

A common strategy for constructing GI tracts is to use a scaffold material to establish the tissue structure, which is then seeded with human cells that stick to the structure and grow. Various different scaffold materials have been tested but there is still room for improvement.

To generate GI tracts that are representative of those in the body, Dr Linna Zhou and Dr Carlos Ruiz Puig from Professor Xin Lu’s (Ludwig Institute for Cancer Research) and Professor Hagan Bayley’s (Department of Chemistry) labs have researched the use of collagen protein as a scaffold. In their paper published in the journal Advanced Functional Materials, the researchers developed a new and simple method to construct tubular GI tracts from collagen without some of the additional steps that have been used by others previously.

Their method uses precise 3D printing of droplets containing cells and collagen, which then form into continuous tubes. Importantly, the complex tubular shape was produced by controlling the density of the fibroblasts – cells that produce the structural framework for animal tissues – seeded at different sections of the GI tracts.

They generated different types of GI tract (intestine and stomach) by seeding the collagen structures with human cells from different tissues and were able to demonstrate the important layered structural features found in the natural GI tract. The engineered stomach tissues were susceptible to infection with the cancer-associated bacteria Helicobacter pylori, providing a valuable early disease model.

These advanced bioengineered GI tracts therefore show great potential both for use as a disease model in biological research and for regenerative medicine. Future plans include using these engineered GI tracts to study GI cancer development and progression. Understanding more about the biology of early cancer will assist with strategies for early detection. This model will also be used to test therapeutic agents.

Full article on the OxCODE website.