University of Birmingham’s genial Professor of Medical Oncology, Gary Middleton

Professor of Medical Oncology, Gary Middleton

Scientists talking science

Birmingham has a global reputation for stratified medicine; allowing patients to receive treatments as personalised as their conditions. Ian Halstead talked to two specialists at the University of Birmingham who are tackling the scourge of lung cancer.

To those unfamiliar with the arcane jargon of cutting-edge medical research, Mastering the Matrix could be the long-awaited reboot of the dystopian sci-fi classic. Instead, it’s the catchy phrase which the University of Birmingham’s genial Professor of Medical Oncology, Gary Middleton, uses to describe the challenge which he faces, as the national lead of the personalised lung cancer treatment programme, known as MATRIX.

Until a decade or so ago, the same drugs were given to all victims of lung cancer, although it exists in many forms, and the chemotherapy used to tackle the most common form had multiple side-effects because of its toxic nature.

However, MATRIX is an innovative and hugely ambitious attempt to precisely match sub-groups of patients to new or existing treatment regimes, which address the cancers more effectively and accurately, and also reduce or remove the painful side-effects.

Middleton is certainly not alone in this Herculean task, and modestly makes the point on several occasions that a host of clinicians, researchers, data specialists and PhD students, in Birmingham and throughout the UK, are also working on these trials.

He arrived in Birmingham to take up his current role in January 2012, within the Department of Immunology and Immunotherapy at the University of Birmingham (UoB) and started on his present project as a joint initiative with Cancer Research UK.

MATRIX itself follows the second phase of the UK’s Stratified Medicine Platform, known in the healthcare world as SMP2.

“One element which gives Birmingham a huge advantage in healthcare is our ability to do large-scale screening, then to carry out accelerated clinical trials, and this initiative has now become the largest lung cancer research programme in Western Europe, and quite likely, in the world,” says Middleton. “Essentially, we take tissue which has been left over from earlier biopsies on patients, and use it to identify changes in their DNA which related to their cancers. We’re looking at 28 separate genes, because we think these are the most important ones in the evolution of lung cancer.

“We then match up a drug to a particular gene - which has mutated to allow the cancer to grow - and use targeted drug therapies to ‘switch off’ that molecule. Next, we take what data we have discovered, from a small number of individual patients, to look at the generality of lung cancer treatment.

“Once we have discovered which therapies work best on particular genetic structures, we can then really start to evolve our approach to treatment by carrying out tests in a real-world context.

“Each stage naturally takes a great deal of time and effort, so everyone in the MATRIX team is also constantly looking for ways to make the research process and the trials quicker and more efficient, so we can deliver these new treatments more quickly to patients.”

The MATRIX programme is led by Middleton and his Birmingham-based team, but they also work with researchers, data analysts and principal investigators at 18 Experimental Cancer Medicine (ECM) centres across the country. “Everyone involved in the SMP2 platform meets very regularly,” says Middleton. “It is a complex process, but it operates very efficiently. In recent years, the UK has been behind the game in addressing lung cancer, but the presence of the NHS enables us to work in ways which wouldn’t be possible in the US, for example.

“It isn’t simply academic research, the programme is deeply embedded in the day-to-day workings of the NHS, which is a huge advantage. It’s also a tribute to the great reputation which Birmingham has acquired for taking an outward-looking approach, that MATRIX is led from here.”

Although some of the trials use existing drugs, there is an intense focus on using existing drugs in new ways, and in developing novel and experimental immunotherapies, which are tested on patients who have the specific genetic condition (bio-markers) for that particular treatment.

An ever-present challenge is the need to recruit new patients for the trial stages, as some of the current patient cohorts are very small.

“At the moment, we’re screening around 1,200 patients with lung cancer every year, but we’d like to get that up to around 2,000 to ensure all the data can be validated,” says Middleton. “We’d like to open some more ECD centres in the UK, and I’d hope that this time next year, they’d be operating and the patient numbers would be rising. By then, we’d also expect to have published our top-end clinical data so the benefits of MATRIX become clear.”

The research is sponsored by UoB, and although AstraZeneca, the giant British-Swedish corporation, is the biggest external partner, it is very much Middleton, and not Big Pharma, who is in charge. “This is our study, and its foundation is academic research which was initiated by us. We have funding up to mid-2018, and we’re thinking about internationalising the programme, once we can fully demonstrate that these studies can deliver valuable data.”

BagnallAs Middleton stressed, a pyramid of talented researchers, data analysts and clinicians underpins the MATRIX programme, and one such is Chris Bagnall, an immunotherapeutics support officer, within the UoB’s Human Biomaterials Resource Centre. He qualified as a biomedical scientist, then trained at Birmingham’s City Hospital, and worked there, specialising in histology, for 15 years, before joining the UoB team.

Bagnall works with the tissue bank, analysing samples and looking for different types of tumour, with the aid of some seriously clever software and expensive hardware.

“I help people speed up their research, and our Vectra 3.0 pathology imaging system is a tremendous benefit,” he says. “In a routine laboratory, a pathologist can look for one type of cell via a microscope, but this machine allows you to look for six types simultaneously.

“As it’s digital, it can count millions of cells, rather than the pathologist having to laboriously take notes, so although it won’t replace pathologists, it speeds up the process enormously. Gary comes with ideas about which direction the research should take, then we aim to identify what is happening to certain cells.

“We are looking for biomarkers, which allow us to monitor and predict the health ‘states’ of individuals, or patient groups. Essentially, it’s about identifying which cells are impacted by different forms of lung cancer, and what happens to different patients when they are given different treatments.

“We have a database of archived material, so we can learn what happened to patients in the past and see what the outcomes were. At the moment, our work is mainly about discovering what is happening within tumours, but we’re also starting clinical trials with patients, using biopsies from before and after surgery.

“We’ve probably got 200 patients on early-stage trials, and as the programme progresses, we discover new avenues, and can take the research in new directions.”

Bagnall also had a notable ‘Eureka’ moment a year ago, when he developed a new protocol for the Vectra system - allowing it to analyse ‘stained’ tissue samples at far quicker speed than previously. “It used to take us a week to run the six colour slides through, but we’ve since got that down to a day, and sometimes even less,” he says.

Now, it takes a lot to make the US company which designs and manufactures the Vectra equipment take note. PerkinElmer Inc. did around US$2bn of business in 2016, and they’ve been devising industry-leading detection systems for more than 80 years. However, when they heard of Bagnall’s breakthrough, he was awarded its much-prized ‘Key Opinion Leader’ status, of which he is understandably proud.

“Since joining in 2015 I have been able to use my expertise as a biomedical scientist to help increase the quality and speed of work in a research setting, to make it easier to ‘reproduce’ the work, as well as developing new and exciting protocols,” he says. “I really enjoy the challenges, the direction in which my career has taken me, and am very appreciative that the QEHB charity has funded my post, as without them UoB might not be advancing as quickly as it is.”