George Coukos: a temple from translational research

Switzerland wants a cancer centre that will promote “opportunity, integration and innovation”, focused tightly on delivering major benefits to patients. George Coukos is the man charged with making it happen.
by Simon Crompton

Within 15 years, says George Coukos, treatment advances in immunotherapy will mean that cancer cure rates could rise from 50% to 75%. “I’m quite optimistic about that,” says the recently installed director of the Oncology Department at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland.

Such hopeful predictions are viewed with caution by the cancer community. They raise too many questions. It’s all very well having promising research, but how do you build on early hope? How do you make fundamental science applicable in the clinic? How do you make innovation widespread, affordable, replicable? There have been false dawns before, particularly in the field of immunotherapy.

Coukos, a world-leading investigator in tumour immunology and ovarian cancer, is aware of all that. In fact, addressing those questions is central to the role he was specifically headhunted to perform at Lausanne – to build a comprehensive cancer centre for Switzerland, integrating research that will result in clinical advance. He has a recipe for progress, and it centres around a simple principle: bringing people together.

Coukos has a history of creating innovative translational research programmes within clinical services, having done just that at the University of Pennsylvania where he spent 22 years establishing the Penn Ovarian Cancer Research Center and directing it for seven years.

Appointed in Lausanne in July 2012 and put in charge of a multi-million euro budget, he has assembled a team of high-flyers from around the world to help him put in place a vision jointly agreed and funded by hospitals, universities, NGOs, Swiss government and philanthropic bodies to create something of global significance on the shores of Lake Geneva.

The Swiss Cancer Centre, federating research groups in oncology from CHUV, the University of Lausanne (UNIL), Ludwig Cancer Research, and the École Polytechnique Fédérale de Lausanne (EPFL) and others in nearby Geneva, is now a reality. At its core are Coukos’s beliefs about making things happen: maximise access, get people interacting together, combine data. With government and institutional commitment behind it, the big cancer project in Lausanne may indeed provide an antidote to the ‘silo’ culture that has slowed progress in cancer innovation for decades. In doing so, it could provide a model internationally.

Coukos has worked closely with Doug Hanahan, who directs EPFL’s cancer research institute (ISREC), to develop the partnerships.

“The vision is to create a vibrant environment that gives opportunity for wide communication and access – patient access to innovation, access of researchers to the clinical pathway, access of life scientists to cutting-edge technology and engineering. We want to totally integrate engineers, clinicians and life scientists. The principles are opportunity, innovation and integration.” What is striking in Lausanne is that these principles will have a very physical manifestation. George Coukos and I talk in the oncology administrative suite just across the road from the giant block of CHUV. Right behind us is the ghostly presence of a spectacular – but as yet unbuilt – translational cancer research centre.

The Agora Cancer Centre (named in reference to gathering places in Ancient Greece), a sweeping arc of glass and steel perched on the woody slopes surrounding CHUV and overlooking Lausanne and Lake Geneva, will bring together fundamental research and clinical practice. Coukos says it will be a “temple of true translational research” – an emblem for all that he is trying to achieve at Lausanne. It will cost 80 million francs (€67 million).

“Translational research is interpreted many ways, but true translational research has a direct impact on the way we manage patients. The key word is ‘impact’. It has the eyes really focused on a specific problem, and assembles teams and approaches to make a dent into this problem.”

But it has to be made to happen. That means taking account of the way people really behave. Despite good intentions, good research is often not translated into good clinical practice because clinicians feel too busy to spend time talking to researchers, or hospital budgets won’t stretch to allowing clinicians the luxury of research.

So the centre, which will house around 400 researchers, is located just 100 yards from the main hospital. “This is important because it has to be linked functionally with the clinical development programme at CHUV,” says Coukos. Equally important is that clinicians are being given protected time to be in this research environment – to think, read, talk and write.

The very design of the centre, which Coukos and Hanahan have been closely involved in, will “make people bump”. There will be offices and laboratory space for groups from CHUV, UNIL, Ludwig Cancer Research and EPFL concentrated at the two ends of each floor in the building – and between them will be spaces for sitting, talking, having coffee, creating ‘neighbourhoods’ on each floor.

Each laboratory will be without walls and doors. “That allows a continuous flow of information – people end up talking to each other and a culture of trust can develop,” says Coukos. “The experiments and the data are not locked behind doors, but resources are wide open for everyone to access. This design also creates flexibility because programmes can expand or shrink depending on the opportunity.”

To create vertical as well as horizontal interactions in the building, there will be plentiful open staircases creating a kind of ‘matrix organisation’. Large atria, with seating, vegetation and refreshments, will connect the centre with auditoria and other departments such as pathology.

“There will be a buzz. It’s the collective exchange of ideas that ultimately gets you somewhere and in these busy times where we don’t even have time to check our emails, bumping into people is critically important.

“In these times when we don’t even have time to check our emails, bumping into people is critically important”

“There’s a new top-down determination, a strategic reassignment at institutional level, to say we’re going to support physician scientists, we’re going to develop translational scientists, we’re going to build resources to allow them time.”

He acknowledges that money – and lots of it – is as important as change of culture. It’s particularly needed to bridge what Coukos calls the ‘Valley of Death’ between a laboratory idea and a phase I clinical programme.

“It’s absurdly expensive,” he says. “There are so many good ideas, but you can count on one hand the programmes that develop products for the clinic and take them into the clinic. A true translational programme must have – in addition to a critical mass of discovery labs – a very strong laboratory infrastructure for complex tissue ana-lyses, biobanks, a mouse hospital platform with sophisticated imaging, many supporting technology cores, and an advanced clinical research infrastructure with data management, interventional radiology capabilities, imaging, manufaturing cores, regulatory support, and nurses and doctors dedicated to phase I studies, for advancing the clinical protocols – so all of that means investing in people and structures.”

The commitment of the Swiss Cancer Centre’s funding partners was certainly one reason why coming to Lausanne seemed “the opportunity of a lifetime” to Coukos, even though it meant leaving a settled family life and successful career in the US. But then, Coukos’ globetrotting life so far hasn’t provided much indication that he’s one for settling with what he’s got.

Born and raised in Greece, he decided to go to medical school in Italy, having fallen in love with the country’s culture and sophistication during family visits. The medical school at Modena was “very didactic and comprehensive”, and he stayed on to complete a PhD in reproductive medicine and take up a residency in obstetrics and gynaecology at the University of Modena Hospital.

But it wasn’t enough: Coukos wanted more training, more hands-on work, so he went to the US in 1991 at the age of 29 to take more research training, then a second residency at the Department of Obstetrics and Gynecology at the University of Pennsylvania Medical Center. In 1999 he completed a fellowship in gynaecologic oncology, realising that it was the side of gynaecology which “needed most help”. The problems were complex, the patients were touching and rewarding – and in terms of ovarian cancer research, there was a big black hole to fill. Even today, Coukos laments that more progress hasn’t been made in ovarian cancer therapeutics.

“This seemed a very important area to spend energy and resources – mine in particular. I decided to spend the rest of my life working in cancer.” He stayed at Penn for the next 22 years.

He made his mark in the US as a researcher, clinician and administrator. By 2007 he had established the Ovarian Cancer Research Center, and become Penn’s Celso-Ramon Garcia Chair in Reproductive Biology and Associate Chief of the Division of Gynecologic Oncology. All the while his clinical practice offering innovative therapies like immunotherapy drew acclaim.

So it is hardly surprising that when a coalition of government, universities, leading hospital and the Swiss Institute for Experimental Cancer Research (ISREC) started searching for the right person to create a world-class comprehensive cancer centre in Switzerland, his name went on the shortlist. “I think it was my experience in building innovative translational programmes that were well integrated into the clinic that attracted them,” he says. But there was another factor that made the fit particularly good: Coukos’ passion for immunotherapy. Lausanne has a long history of expertise in cancer immunology, partly by virtue of the presence of Ludwig Cancer Research, which is today part of UNIL (Coukos, among his other posts, was appointed its director when he came to Lausanne). With so many Swiss cancer research bodies federating, there was a critical mass of immunotherapy researchers on the ground. Coukos was the man to take them forward.

His own interest in immunotherapy began in the late 1990s when he decided that the immune system was of key relevance in developing new treatments. Then Carl June’s arrival at Penn to start an immunotherapy programme provided inspiration. No one had seriously investigated immune responses in ovarian cancer before.

“It was a time when many had given up on tumour immunotherapy. At first, I found it hard to convince people that this area was of any importance, and many of my colleagues tried to dissuade me from going into this field because nothing would ever come of it. Many attempts with vaccines had failed. But I thought there were important opportunities, so we pursued them.”

The research programme that he developed at Penn discovered a spontaneous immune response in ovarian cancer – and that it had an impact on outcome. His paper in the New England Journal of Medicine in 2003 had an international impact, reviving the cancer community’s interest in anti-tumour immunity and its therapeutic potential.

“I think that it contributed to shifting the attention of the scientific community to spontaneous cancer immunity. Then additional papers started coming out about colon cancer and other tumours, and it became quite obvious that there is an immune response to most tumour types, and it has to mean something. It sparked additional investment in cancer immunotherapy, including efforts to mobilise endogenous immunity with the new antibody drugs that we have now.”

That work led to his team in Penn developing the first personalised vaccines for women with ovarian cancer based on dendritic cells, which elicit T-cell antibody responses against tumours. In addition, he built a programme studying T cells, especially tumour infiltrating lymphocytes (or TILs) extracted from patients’ own tumours. This work is now being built into an ambitious research and clinical programme in Lausanne.

Autologous TIL therapy has already proved successful in melanoma. US National Cancer Institute research on TILs, started ten years ago, showed that of 93 patients with metastatic melanoma treated with TILs, 20 had complete tumour regression and 19 had ongoing complete regressions beyond three years. The five-year survival rate for the responders was 93%. Coukos believes that similar results may be achieved with the majority of solid tumour types, so a comprehensive research plan for TIL therapy is being developed at Lausanne.

“We now know that about 50% of patients in all disease types have T cells in their tumours at time of diagnosis, and in some patients you can increase those T cells by therapies such as radiation – so you can then harvest the TILs when you surgically remove the tumour, identify those TILs that have activity against the tumour and then use them for therapy.”

CHUV is building a cellular manufacturing facility to produce several hundred vaccine or T-cell products a year, so that they can be “seriously tested” on all solid tumours.

“A patient will come to CHUV, have surgery to remove their tumour, then we will harvest the T cells, give them conventional chemotherapy and/or radiation as indicated by standard care, and then after that we can prescribe vaccine or T cells to boost the chance for long-term disease control. The expectation will be that the new therapy will eradicate the residual tumour and minimise the risk of recurrence. This is going to be a very important part of therapy in the future.”

With non-cell-based immunotherapy being pursued by the pharmaceutical industry – for example the highly effective immune checkpoint blocker drugs – he is confident that treatments modulating immune response could transform the prospects for curing cancers of all types within 10 years.

“There is the prospect of developing drugs that are universal to touch the majority of patients,” he says. “Immunotherapy is the only therapy that has long-term memory because it engages the patient’s own defences. So after surgery, radiation and targeted therapies have reduced or removed the tumour, the immune system can be activated to clear the residual cells which are always responsible for relapse. In a decade we could be in a position where, for the first time, we could see a drastic reduction in the relapse rate, and therefore a drastic increase in the cure rate.”

“Immunotherapy is the only therapy that has long-term memory, because it engages the patient’s own defences”

Unfortunately, highly promising personalised therapies such as TIL therapy hold little allure for the pharmaceutical industry. The only way personalised vaccines are going to get the considerable investment they need is through independent funding. Which is why the massive amounts being invested in the Swiss Cancer Centre is good news globally.

But is the model sustainable? I put it to Coukos that the world may well look on enviously at what is happening in Switzerland, but conclude that such a model of collaboration and research investment could only happen in wealthy countries. Will personalised immunotherapies ever go beyond high-income countries – or even high-income patients? The investment and running costs come from the usual sources open to everyone, he explains – grants, institutional support, contracts and philanthropy.

“Certainly, the fortunate aspect of being in Switzerland is that public funding is sufficient to allow us to start with our own research agenda. We want to partner with the pharmaceutical industry to bring our innovations to patients, but clearly there are aspects they would not support, and that’s where institutional support and fundraising matters a great deal.

“With T-cell therapy, once we have demonstrated success, we can hopefully convince insurance companies or the state to reimburse this kind of approach – this has already happened in some cases in Germany, UK and the United States.

“With the involvement of more and more medical centres, and growing success, one then brings in the engineers to help automate and simplify the process, which brings a reduction in cost and greater availability. This happened with bone marrow transplantation, which used to be only available in a few institutions but now every major hospital has a unit. So in a few years, we hope to be able to deliver a T-cell programme in an automated way so that we can really contribute to the health of the masses.”

Coukos hopes strong buy-in from university clinical teams and practising clinicians in the periphery will help ensure long-term sustainability. He is working with clinicians and administrators to create a regional cancer network, the cancer network of Suisse Romande (the name for French-speaking western Switzerland, a region of approximately two million people).

His confidence in the future is partly founded on an international team he has hand-picked from the US and Europe to take the Swiss Cancer Centre project forward. Eric Raymond, Head of Medical Oncology, came from the Bichat-Beaujon University Hospitals in Paris in 2013, and Jean Bourhis, Head of Radiation Oncology, came from the Institut Gustave Roussy in Paris in 2012. Coukos’ own arrival in 2012 followed a job-offer out of the blue and some soul-searching. His wife (a doctor) and two sons were settled in the US, his work was booming: “Nobody could believe I made the decision to move at this stage.”

Has he found it difficult parachuting in to take the helm in a health environment very different from the US? There has been a cultural transition, he acknowledges, but he quickly grew to appreciate the way that the Swiss value stability, meritocracy and equal opportunity, and take the long view in their decision-making. “They’re very important if you want to build solid programmes.” “In the United States planning is more on an individual basis, and it’s less long term. If you’re a good investigator or clinician, you have freedom to make a successful programme. But often there is no long-term vision from the institution about how to make it sustainable.”

Vision is a word Coukos uses a lot. Creating it, communicating it and empowering people so that the vision becomes theirs is the key to ending fragmentation and getting things done. So what’s the intended outcome?

“I always set myself five-year goals. So in five years’ time, we should have got some major advance in immunotherapy into the clinic, made major advance in radiation therapy and created opportunities for integrating immunotherapy with molecular targeted therapies or radiation therapies. And we should have a solid network of clinical and translational oncology in the French-speaking western Switzerland region. That’s my short-term goal, to bring important collaboration and innovation into the clinical space. I think it will happen.” Long term, who knows what may emerge. “The important thing is that a good idea will have a chance to make an impact.”

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