Nobel Prize 2018: How Allison and Honjo turned immune cells against cancer

Using a patient’s immune system to fight cancer seems like a gloriously simple solution to a horribly complex disease. The reality is far harder than it sounds, but this type of treatment, called immunotherapy, has begun transforming the way we treat certain cancers.

Today, two scientists who laid the ground work for a suite of new cancer drugs have been recognised.

Dr James Allison, from The University of Texas MD Anderson Cancer Center, and Professor Tasuku Honjo, from Kyoto University, have been awarded the Nobel Prize for Physiology or Medicine “for their discovery of cancer therapy by inhibition of negative immune regulation.”

But what does this mean?

The duo’s discoveries have revolutionised our understanding of how the immune system sees cancer. And at the heart of this revolution is a tiny but extremely powerful immune cell called a T cell. 

The mighty T cell

T cells live in our bodies and protect us from foreign invaders, such as bacteria and viruses. And, under the right conditions, they can also destroy cancer cells.

T cells circulate our bodies scanning for molecular flags that signal ‘danger’. And they’re constantly making decisions about how to react to what they’re inspecting. They can either do nothing, or alert other immune cells to start an attack.

T cells carry an array of molecular machinery on their surface that helps them make this choice. And thanks to Allison and Honjo, we now know the inner workings of two key components – called CTLA-4 and PD-1 – make T cells tick, or rather, stay quiet.

Targets for immune-boosting drugs: Allison’s work on CTLA-4

In 1996, Allison and his team found that CTLA-4 works like a silencing switch on T cells – preventing them from assembling an army of supporting immune cells to attack foreign invaders. And in landmark work, the team showed early signs of how this knowledge could transform cancer treatment. They gave mice with cancer a molecule that blocks CTLA-4, freeing T cells to build the immune response – the tumours started to shrink.

Dr Sergio Quezada, a Cancer Research UK-funded immunologist from University College London, worked in Allison’s lab shortly after this seminal work was unveiled. 

“Allison was trying to understand what actually makes T cells active and during these investigations he worked out how T cells were made inactive,” he says.

According to Quezada, Allison realised immediately that this knowledge could inform new cancer treatments. He started talking to pharmaceutical companies and spread the word that CTLA-4 could be a promising new drug target. 

“This Nobel Prize really shows that basic science can have a huge impact on medicine,” says Quezada. “He was always out at conferences, but he let the data do the talking.”

Targets for immune-boosting drugs: Honjo’s work on PD-1

The surface of T cells now seemed like the best place to look for new molecules that controlled these immune cells. Only a few years later Professor Tasuku Honjo and his team identified another molecule that influences T cell activity, called PD-1.

PD-1 sticks to a molecule on cancer cells called PD-L1. This interaction causes the immune cells to ignore the tumour cell. And drugs stopping this molecular ‘handshake’ help reveal tumour cells to the immune system, allowing T cells to attack and kill the cancer cells.

Watch this video to see how these drugs work.

Both CTLA-4 and PD-1 can be manipulated by drugs called checkpoint inhibitors. If we didn’t know how these molecules worked then the immune-boosting drugs of today, and the future, would never exist.

Where are we now?

Thanks to these two scientists, and the teams of researchers involved, many companies are now developing drugs that block CTLA-4, PD-1 and PD-L1. And the hunt for other similar molecules continues.

Ipilimumab (Yervoy) was the first of its kind to emerge from Allison’s discovery.

It’s designed to block CTLA-4 so that the T cells stay switched on, freeing them to coordinate an attack on cancer cells.

Immunotherapy is literally a life-saver: I’m here today thanks to drugs developed from these researchers’ work.

– Jolene Dyke, melanoma patient

Pembrolizumab (Keytruda) and Nivolumab (Opdivo) target the PD-1 molecules on the surface of T cells. And in doing so, it releases the ‘brakes’ on the immune cells so they can find and kill cancer cells.

In many cases these drugs are still being tested in clinical trials. But for some advanced cancers they have already saved lives.

Jolene Dyke, 31, was diagnosed with melanoma in her teens. By her twenties, the disease had spread to her lungs, brain and bowel, and she was told she would have months to live.

Thanks to immunotherapy her cancer is now stable. And she offers her tribute to all the scientists behind today’s prize-winning discoveries. “Immunotherapy is literally a life-saver: I’m here today thanks to drugs developed from these researchers’ work. It’s just fantastic that they’ve been recognised with a Nobel Prize.”

Jolene says she hopes this prize inspires researchers to redouble their efforts to uncover the next generation of treatments.

What’s left to do?

Despite great progress, responses to immunotherapy like Jolene’s are the exception, rather than the rule. But Quezada is feeling good about the future. “If you think CTLA-4 and PD-1 have revolutionised the way we think about cancer therapy in the last eight years, imagine what the drugs in the pipeline could do,” he says. “There’s a huge amount of potential.”

Now, Quezada says, scientists must build their understanding of how these drugs work in patients, either alone or together, so we know the best ways to boost response rates.

“That’s why we need to keep funding research in this area and engaging patients, so we can understand why drugs work and more importantly what’s going on when they don’t work, and how can we fix that.”

While many were looking at the inner workings of cancer cells in the hunt for new drugs, these immunologists asked how the body sees cancer.

And in doing so, Allison, Honjo and their teams thrust the immune system into the spotlight as a powerful tool in treating cancer.

Gabi