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Stephen P. Cobbold, MA, PhD, Professor of Cellular Immunology “A personal approach to translational research”

doi: 10.1097/TP.0000000000002633
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You have trained as a Biochemist. What motivated you to join The Sir William Dunn School of Pathology in Oxford?

PROFESSOR STEPHEN P. COBBOLD: I read Biochemistry as an undergraduate at Oxford, where I became interested in immunology before starting my PhD with Herman Waldmann in Cambridge on the project that would eventually lead to the development of Alemtuzumab, then known as Cambridge Pathology (CAMPATH). The move to the Sir William Dunn School of Pathology was for many reasons. Herman Waldmann became head of the Dunn School, and there was an opportunity to build the Therapeutic Antibody Centre, headed by Geoff Hale. This meant that we could produce good manufacturing process-grade antibodies, including CAMPATH, for academic clinical trials, at a time when there was little interest from the pharmaceutical industry.

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Your involvement has been critical in developing CAMPATH. What were true “Eureka” moments during the adventure of developing this new immunosuppressant?

STEVE COBBOLD: For me, the first “Eureka” moment came toward the end of my PhD project, where I tested a whole series of rat monoclonal antibodies for their ability to deplete T cells in vivo in various mouse models and found that only the rat IgG2b isotypes were effective. This proved to be true for the rat antibody variants of CAMPATH too, and led to a further surprise that depletion depended on fragment crystallizable receptor cell-mediated killing and not complement activation as was thought at the time. These discoveries later drove similar studies showing that humanized IgG1 CAMPATH was the most effective in patients.

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You have experienced symptoms of your kidney disease early on. Had you envisioned that the very drug that you were developing could be helpful for yourself?

STEVE COBBOLD: When I first experienced symptoms (hematuria) in my mid-20s, I was sent to the urologists, who after some investigations dismissed my symptoms as trivial. My rheumatologist friends suggested it could be IgA nephropathy (at that time a little known kidney disease—“Berger’s Disease”—assumed to be mostly benign), so I never envisioned I might need a kidney transplant at that time. It was only 20 years or so later that a chance high blood pressure reading led to a biopsy and confirmation of stage III chronic renal failure. Even then my renal function stabilized for more than 10 years, so although transplantation had been discussed as an option, the possible use of CAMPATH was not forefront in my mind. Issues such as having no matched living donor, what type of dialysis to choose, and keeping up with the constantly changing medications tended to dominate at this stage.

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Your kidney disease advanced in 2014 and you received a kidney transplant in 2015 as a paired kidney exchange. How was your experience of the paired donation process?

STEVE COBBOLD: My wife had always said she would donate, but she was a blood group and ethnic mismatch, so a paired or pooled exchange was considered the only realistic option. We were very lucky in that as she successfully completed all her health and ethical checks, and we then found a paired match at the first attempt, all in <6 months. This allowed me to avoid dialysis and receive my kidney transplant just in time (with <4% function remaining).

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I assume that you have been involved in the discussion on the “best” immunosuppression. What was the rationale to treat with CAMPATH and how did it feel to be treated with the very drug that you had developed?

STEVE COBBOLD: The paired exchange standard protocol was to use Basiliximab conditioning rather than CAMPATH, with tacrolimus plus mycophenolate maintenance and tapered steroids. However, Professor Peter Friend, now head of the Oxford Transplant Unit, had helped us develop CAMPATH for kidney transplantation ever since he did his MD thesis in our Cambridge laboratory. He had recently published the 3C study that showed that CAMPATH allowed lower tacrolimus and mycophenolate maintenance, avoided steroids while still reducing the risk of acute rejection by about half compared to basiliximab. As my donor kidney was a 2:1:1 mismatch, we decided that could be the best option for me. My wife had also previously worked as Peter Friend’s research assistant, and then on much of the clinical testing of CAMPATH, so Peter also performed both our operations. Because of these close connections, nearly all the staff on the transplant ward knew the situation, so the first words I heard in recovery were “The CAMPATH’s going in now,” and I was treated as a minor celebrity during my stay on the ward.

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You are in a unique position of representing the roles of a patient advocate and researcher. What is your advice for patients? For the scientist in transplantation: Where do you see the most relevant need for progress?

STEPHEN COBBOLD: I would suggest that patients should ask as many questions as possible and to try and understand their disease and the treatments being offered by their doctors. I think this helps the patient understand the complexity of renal failure, and why it is important to try and be proactive and compliant in taking all the different and constantly changing drugs and treatments both during chronic renal failure and after transplantation. I believe it is also important to try and keep as fit and healthy as possible—I kept trying to play competitive squash right up to the transplant despite feeling totally exhausted when it would have been so much easier to just take it easy.

As a scientist, I think major breakthroughs that might make immune regulation and tolerance a practical and reliable clinical approach are probably still quite a long way off. One area where rapid progress could be made, however, is in patient compliance—making medications as easy and convenient (and cheap) to take as possible. Smaller tablets and less frequent dosing (perhaps slow release patches) and technological solutions to provide convenient checking of compliance and blood levels might have a considerable impact on patient and graft survival in the longer term.

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Transplantation offers unique treatment options, yet there are many shortcomings. Where do you see the most relevant progress in the next decade?

STEVE COBBOLD: For transplantation, we still need to understand how immune regulation and tolerance works—I don’t think just adding in more regulatory T cells will be a long-term solution. We need to better understand what regulates the homeostasis between effector and regulatory T cells in vivo and how this interacts with different immunosuppressive combinations. But there will never be enough organ donors. Perhaps the ultimate solution will be some form of artificial replacement organs—over recent years, we have been able to miniaturize all sorts of technology—electronics and microfluidics—could we do something similar to make a fully automatic dialysis machine that would fit in the abdomen?

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You have had many cooperations with the industry. How can the cooperation between industry and academia work in an optimal way?

STEVE COBBOLD: We still need much more basic and pretranslational research as taking new science to industry too early can kill it. We had to take CAMPATH back from industry (when the industrial development stalled) and then do more basic research many times before it was eventually licensed (a process that took 30 y). Even then, CAMPATH has only been licensed for leukemia and multiple sclerosis and has never been licensed for transplantation (not profitable enough). We need to find new and cheaper ways to fund the development of drugs for the less profitable disease indications.

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You are an emeritus now but stay involved in research. What is your current academic interest?

STEVE COBBOLD: I am still working on debunking some of the myths that seem to be building up around regulatory T cells, immune homeostasis, and metabolism. For example, many major publications had been claiming that T-cell differentiation and cell fates were binary and determined by an initial asymmetric cell division. We recently published data to show that most of the evidence for any asymmetric divisions was likely artefactual, and that differentiation could be initiated before T cells entered mitosis.

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You have a very active life outside of your academic profession. Are there any limitations since your transplant? Activities that you enjoy in a different way after the transplant?

STEVE COBBOLD: I don’t really notice any major limitations (and no obvious side effects) since the transplant. It is a slight inconvenience to remember to take my twice daily immunosuppression on time, particularly in the evening when we may be out or busy. I do seem to take longer to fight off colds and chest infection in the winter than my wife. Mostly, I notice the significant improvements compared to the 10 years or so pretransplant. I am a keen skier, and doing so at altitude with a low blood hemoglobin was a challenge pretransplant, but now I feel fully fit on the most challenging black runs.

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