Researchers have identified a new potential target in the fight against cancer. When the immune system is trained to recognise this target, tumours vanish completely. The treatment could be used against numerous solid tumours, says a researcher.
For decades, cancer researchers have focused on one of the biggest challenges in oncology: solid tumours. Blood cancer such as leukaemia has been conquered with new, targeted immunotherapies, but solid tumours have proved much more difficult to defeat.
Solid tumours, however, act like fortresses: they build walls of support cells and signalling molecules that protect the cancer from attack. And most importantly, cancer cells are composed of building blocks (proteins) that are almost identical to those of the healthy cells from which they develop, such as normal lung tissue in the case of lung cancer. This makes it very difficult to find therapeutic targets that are unique to the cancer cells. Treatment should not destroy essential normal tissues.
After many years of searching, researchers in Oslo, Norway have found a possible breakthrough. They identified a mutation that is shared across several different types of cancer, and the immune system can be trained to recognise it. In mice, it made the difference between life and death: the tumours disappeared without a trace.
“Mutations that are shared between people with the same type of cancer and between different types of cancer are among the most attractive targets, but there are not many of them. Ninety-nine per cent of all mutations are unique to each individual,” explains Johanna Olweus, Professor at Oslo University Hospital the University of Oslo, Norway.
What is special about their discovery is that they developed therapy directed at a mutation that is among the 1% that is shared among many patients – a treatment that could work for many people.
The research has been published in Nature Immunology.
The CAR-T revolution
About 15 years ago, a revolution in cancer treatment began when researchers discovered that immunotherapy could target the CD19 molecule on the surface of B-cell cancer.
The researchers learned to reprogramme the body’s T cells to function as guided missiles. When these cells were equipped to recognise CD19, they sought out the cancer cells directly and destroyed them: chimeric antigen receptor T-cell (CAR-T) therapy.
“During CAR-T therapy, normal B cells are also destroyed. But since we can live without B cells, this is not a major problem,” says Johanna Olweus.
Today, CAR-T therapy is standard for several types of leukaemia and lymphoma and saves thousands of lives every year.
Why solid tumours are more difficult
The success of CAR-T therapy has also led researchers to search for more potent targets over the past 15 years. But solid tumours build walls of support cells and signalling substances to protect the cancer.
“The biggest challenge is that many of the most obvious targets are also found on cells we cannot do without – for example, in the lungs or pancreas. That is why finding good, safe points of attack has been so difficult,” notes Johanna Olweus.
Johanna Olweus and colleagues have developed a new type of immunotherapy that targets a mutation in the gene that produces the molecule beta-catenin. Beta-catenin acts like a traffic light for cell division. When the signal stays green for too long, the cells grow uncontrollably – and cancer develops. The mutation makes the traffic light stay on constantly, givng the cancer cells an advantage.
“For decades, researchers have dreamed of being able to switch off this protein. But it has been like trying to unlock a door with the wrong key. The fact that we can now use the immune system to target mutations in beta-catenin makes the discovery even more remarkable,” she says.
Cancer’s weakness found
Johanna Olweus explains that mutations in beta-catenin are especially promising targets for cancer therapy because these mutations help to drive cancer development.
This means that the mutations often arise early in cancer development and therefore represent targets present in all daughter cells derived from the original cancer cell.
Researchers have long tried to develop treatments that inhibit the function of beta-catenin but with little success.
Johanna Olweus and colleagues identified two T-cell receptors that can recognise a frequent cancer mutation in beta-catenin – each in a different way.
According to Olweus, these receptors can be used to direct immune cells specifically against the mutated cancer cells.
A needle in a haystack – and a new advantage
The researchers found the T-cell receptors in the blood of healthy individuals. They combed through millions of immune cells to find the very few that could recognise the mutation – like looking for a needle in a haystack. Only a few laboratories worldwide have the technology to perform this kind of large-scale search.
In future treatments, the immune cells of people with cancer will be genetically modified to express the therapeutic T-cell receptors. These modified cells will then be returned to these people and activated by cancer cells carrying the mutations – and destroy them.
Olweus explains that using T-cell receptors offers an advantage that CAR-T therapy has never been able to overcome.
“In CAR-T therapy, the therapeutic target – CD19 – must be located on the surface of the cells before we can target them. Our T-cell receptors do not have this limitation. They can also identify targets inside the cells,” says Johanna Olweus.
Since 80–90% of a cell’s proteins are located inside the cell, using T-cell receptors provides far more potential targets.
Mouse tumours disappeared completely
To test their new therapy, the researchers aimed to cure mice of cancer.
The mice, whose immune systems had been disabled, were implanted with human cancer cells so the researchers could specifically test the treatment on human tumours.
They then treated the mice with T cells engineered to recognise the two mutated peptides and watched what happened to the tumours.
“To our delight, something happened that is rarely seen in cancer research: the tumours did not just shrink – they disappeared completely. And this happened in a demanding mouse model in which the mice carry naturally diverse tumor tissue from patients, not just cancer cell lines.”
However, the researchers emphasise that results in mice cannot always be directly translated to humans although the model provides strong evidence and an important indication that the treatment works as intended.
“No one else has managed to do this with T-cell receptor therapy targeting a single mutation in a disease-relevant mouse model. That is why it is so exciting,” says Johanna Olweus.
She emphasises that the study is the result of a tremendous team effort by members of her own and Fridtjof Lund-Johansen´s research groups, praising in particular first author Maria Stadheim Eggebø and co-corresponding author Morten M. Nielsen for outstanding work.
Already thinking about human clinical trials
Johanna Olweus explains that the researchers have estimated how many people this therapy could potentially help: initially about 3,000 people in the United States per year. This may seem like a small number but is only the beginning. If the strategy proves effective it could be extended to include more patients with lung, pancreatic, prostate and endometrial cancer having this mutation. Moreover, the concept could also be extended to other shared mutations.
“First and foremost, we want to explore the potential to cure several types of human cancer having this mutation in model systems, using our recently awarded Pioneer grant from Novo Nordisk Foundation. However, the results are so promising that we later also will explore the possibility to move on to human clinical studies. We are very grateful to the funding organizations that made this breakthrough possible” concludes Johanna Olweus.
