University of Leuven/Belgium: CANCER IMMUNOLOGISTS JAMES P. ALLISON AND CARL H. JUNE: “SOON, WE’LL BE ABLE TO BEAT MANY CANCERS”

For over thirty years, American immunologists James Allison (68) and Carl June (63) were met with disbelief and even ridicule. But in the past years they have cured cancer patients in such a miraculous way that there’s no denying it anymore: they have revolutionized the fight against the disease. “Never underestimate the power of our own immune system.”

Let’s rewind to 2012. Emily Whitehead is seven years old and doomed to die of persistent leukaemia. Looking for a miracle, her parents agree to an experimental T-cell treatment developed by Carl June. At first, Emily gets very sick and almost dies. “But after 17 days, she woke up and there was no trace of the leukaemia – an amazing moment,” says June, speaking with great emotion. “Four years later Emily is still in top form. It’s hard to imagine many other jobs that come with this kind of reward.”

His colleague James Allison has equally moving stories. “I recently ran into a woman I helped fifteen years ago: her skin cancer had spread, and I made it disappear. At the time, she was 24 and newly married. Today, we cried tears of relief together.”

Your work must be very rewarding.

“Absolutely. A recent study showed that 22% of the 5,000 skin cancer patients whom we treated with experimental CTLA-4 ten years ago are now considered permanently cured. Before we started with our trials, this type of metastatic cancer was a death sentence: half the people were dead within eleven months after diagnosis. The combination of the molecules CTLA-4 and PD-1, too, has the potential to cure more than half of these skin cancer patients.”

SPEAKING FROM EXPERIENCE

Allison knows what he’s talking about. “My mother died of lymphoma when I was eleven, I lost two uncles, and later my brother and several friends. I’ve survived both prostate cancer and melanoma myself. So I’ve always wanted to do something about cancer but I felt that, first and foremost, I had to understand the basic mechanisms. I don’t think I would ever have made my discoveries if I had just dived into looking for a cure. That’s what I try to tell my students: start with basic science. Translational research is obviously important but if everybody were to do only translational work there’d be nothing left to translate after a while. Making big leaps and discovering something completely new takes basic research. This is what makes it so rewarding.”

Was your spark purely scientific as well, Professor June?

“Definitely. When I saw the first bone marrow transplants in the early eighties, I understood the potential of so-called T-cells. These are crucial for our immune system because they recognize and attack intruders. Through basic research, I wanted to find out all about them. But I didn’t start spending 100% of my effort on T-cell treatments until cancer became part of my personal life as well. It was 1996 and my wife Cindy, the mother of my eldest three children, was diagnosed with ovarian cancer. She was 41. I tried treatments that, at the time, showed promise in mice – but to no avail. She died five years later. It was very hard, but I learned a lot and many patients are now reaping the benefits of these insights. I still spend a day each week on ovarian cancer, to turn a very negative experience into something positive. My new wife and I now have two more children, and I have four grandchildren.”

SERIAL KILLERS

The general public only learned about T-cells when HIV started to spread. This virus kills T-cells. When that happens, the entire immune system fails to work and patients succumb to infections. But June managed to make T-cells genetically resistant to HIV, so that the virus can no longer kill them. He also succeeded in reprogramming the T-cells to recognize and destroy cancer cells. “We collect millions of T-cells from the patient, infect these cells with a genetically modified virus in the lab, and reinject them into the bloodstream.”

With good results?

“These reprogrammed CAR T-cells behave like serial killers: a single one of these cells can destroy up to 100,000 cancer cells and they are more powerful than chemotherapy and radiation. What is more, the first patients we treated in 1997 still have these ‘serial killer cells’. The intriguing part is that our immune system has a memory. Unlike other treatments, therefore, our treatment remains effective, it stays in the body like a kind of vaccine. If the cancer comes back, the CAR T-cells attack again. It’s a living drug.”  

Is it already on the market?

“For our leukaemia treatment, we’re expecting approval by the FDA (Food and Drug Administration, ed.) sometime this year and not too long after that by the EMA (the European Medicine Agency, ed.). These will be milestones. Together with this honorary doctorate – my first – it will make 2017 a very big year.”

Are you expecting similar breakthroughs, Professor Allison?

“In 2014, the FDA approved my CTLA-4 treatment for metastatic melanoma. Since then, they’ve also approved CTLA-4, PD-1, and the combination of these two to treat early-stage melanoma, Hodgkin’s lymphoma, and lung, kidney, bladder, neck and head cancer. And it won’t end there.”

CHAMPAIGN

A well-deserved honorary doctorate, in other words, which both gentlemen are happy to share. “I’ve never considered Carl to be a competitor,” says Allison. “Our approaches are very complementary. Carl’s main focus is on leukaemia, and I work mostly on solid tumours. He developed a way to collect T-cells from the patients’ body, I came up with immune checkpoint therapy as a way to manipulate the signals that control T-cells.”

Could you explain this to a layman in your field?

“In the late eighties, my team was the first to identify the T-cell receptor, the ignition lock of the T-cell, so to speak. Later we discovered the gas pedal: CD28, a molecule that can activate the immune system. It makes the T-cells divide hundred thousands of times and attack the enemy cells like soldiers. But the immune system also needs a brake if you want to prevent it from going into overdrive and eventually killing you. We identified this brake in 1995: the CTLA-4 molecule. Later PD-1 was discovered. Today, we use antibodies that temporarily block the brake response of CTLA-4 and PD-1 so that the soldiers keep attacking the cancer.”

What is unique about your approach?

“T-cells can recognize an almost infinite number of different molecules and therefore, they can effectively target almost any form of cancer. Other treatments often target one specific mutation, and if the tumour doesn’t have this one particular mutation, it escapes. In the near future we will move towards a combination of treatments, but immunotherapy will always be one of them.”

You must be proud.

“It’s funny because, for decades, immunologists were thought of as what we in the US used to call snake oil salesmen – people who claim to have some magical potion that in reality does absolutely nothing. A revealing anecdote: in 2006, I was at the Cold Spring Harbor Meeting, the pinnacle of cancer biology, to address an audience of traditional oncologists. These people hated immunotherapy. But after my lecture, I received what is perhaps the highest accolade in my career: Nobel Prize winner James Watson came up to me and said that I had almost made him believe that immunotherapy had some potential. Almost. Watson has come around now. When I attended the same meeting in 2014 and received an email announcing that the FDA had approved my treatment, he broke up the champaign.”

WILLIE NELSON

The story sounds all too familiar to Doctor June. “It’s only in the last seven years that we’re no longer met with disbelief and scepticism. Up to then, I felt like a beggar. I came very close to having to quit for lack of funding. It’s a night-and-day difference with today. After we’d cured Emily, I received a phone call from the National Cancer Institute. They hadn’t supported me until then but this time they came across generously. Now I get to spend less time on funding applications and more time in the lab. That is very rewarding. There are also more scientists working in our field now, so it’s advancing much more rapidly.”

What kept you going all this time?

“The clinical results were disappointing, but I’ve always been convinced of the potential of immunotherapy. At times, my conviction was almost like religion rather than science. In any case, I’m very persistent. I run ultramarathons (marathons longer than the traditional 42.195 km, ed.) in my spare time. As a scientist, you have to be very patient, bounce back after every setback – and there are plenty – and of course have some luck. I’m grateful that all this was the case in my career. Science is also delightfully international. In my lab, I had PhD students from all over the world. Peter Vandenberghe (head of the haematology unit of University Hospitals Leuven, ed.) was one of my first students. I look forward to seeing him and his wife again soon.”

Do you know Leuven as well, Professor Allison?

“I’ve been there a couple of times, as a tourist too. I wanted to stay a little longer this time, but it didn’t work out. There’s also less and less time for my great passion: music. I sing and play the harmonica in The Checkpoints, a blues band of immunologists and oncologists. I was lucky enough this year to play with country legend Willie Nelson, for 70,000 people. I can assure you it was quite nerve-racking. But it was one of my big personal dreams, because Nelson has been an idol of mine since I was a student.”

Do you still have professional dreams as well?

“Finding a successful treatment for prostate cancer. A very large trial has recently started, led by my wife (Padmanee Sharma, oncologist at the same university, ed.), and I am optimistic that we will get good results with a combination of CTLA-4 and PD-1.”

Will we beat cancer one day?

“Some cancers: yes. Prostate cancer and pancreatic cancer are more difficult to beat because they offer the immune system only a few mutated molecules, so that our current treatments have little effect on them. But many other types with more mutations, including skin, bladder, kidney and lung cancer, will disappear in the next years.”

June: “I am confident about it, but I also have to caution that we don’t know exactly how long it will take to develop drugs that we can actually use on patients. Furthermore, my CAR T-cell therapy is still patient-specific, which makes it difficult and expensive. We’re working hard to find a kind of universal donor, similar to the blood transfusion system. Fortunately, the pharmaceutical industry is keeping pace. It’s a new, flourishing industry.”

Allison: “I definitely want to keep contributing to it. Our work is too exciting to even think about retirement.”

Who is James P. Allison? 

° 1948 in Alice, Texas

• obtains his PhD in Biological Sciences at the University of Texas in 1973 and starts working at Berkeley and in New York
• has been an immunology professor at the University of Texas MD Anderson Cancer Center since 2012
• is the first to discover the immune checkpoint blockade as a pioneering cancer treatment
• shares the Paul Ehrlich and Ludwig Darmstaedter Prize – a kind of Nobel Prize for physiology or medicine – with Carl June in 2015

Who is Carl H. June? 

°1953 in Denver, Colorado

• graduates from the United States Naval Academy as a biologist in 1975. Obtains his Doctor of Medicine degree from the Baylor College of Medicine in Houston in 1979
• has been Richard W. Vague Professor in Immunotherapy at the University of Pennsylvania since 1996
• becomes world-famous when he is the first to use genetically modified T-cells to successfully cure cancer
• sees his insights and Doctor Allison’s declared the most important scientific breakthrough of 2013 in Science