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Immunotherapy for brain tumours

The long-term goal is clear: a treatment against glioblastoma, the most aggressive type of cancer that originates in the brain. But the road to the goal is long and winding. It goes through several loops - and exploits some surprising similarities between humans and dogs.

Johannes vom Berg and Barbara Zimmermann at the Institute of Laboratory Animal Science at the University of Zurich.

It takes stamina - and perseverance. In the laboratory at the Institute of Laboratory Animal Science at the University of Zurich, the focus is on cells that communicate with each other. And which (at least to laymen) all look exactly the same. As they work, the scientists look deeply through their microscopes - but without losing sight of their clear goal: "In our work, we always have the patients in mind," says Johannes vom Berg.


Suppressing the immune response

Together with his group, the neuroimmunologist is researching new treatment options for glioblastomas, the most common and aggressive form of brain tumors, for which medicine has unfortunately not yet found a suitable answer. Medicine has placed great hopes in immunotherapies, which are not directed against the cancer cells themselves, but rather strengthen the body's own defense system and direct it to fight the cancer cells. The fact that these hopes have not yet been fulfilled in the case of glioblastomas is also due to the fact that "in the brain, there is a suppression of the immune response against the tumor," says vom Berg.

His work, which is funded by Swiss Cancer Research, centers on a molecule interleukin-12, or IL-12 for short, which activates resting immune cells and plays a crucial role in the defense against intracellular pathogens (such as viruses). "If IL-12 is missing, an infection with such pathogens gets out of control," says vom Berg.


Causing inflammation

In this context, infected cells have one thing in particular in common with cancer cells: "They must be killed off by the immune system as quickly as possible," explains the researcher. As initial studies on mouse models have shown, IL-12 is indeed capable of causing inflammation in brain tumors - and thus initiating the desired destruction of the cancer cells, which would otherwise be suppressed, i.e. without IL-12.

These promising results also paved the way for the first clinical trials with this molecule in the 1990s. However, the trials had to be stopped early due to severe side effects, which even led to death in two patients. In these early studies, the IL-12 was injected into a vein - and therefore triggered inflammatory reactions throughout the body.

But vom Berg and his team want to limit the molecule's effect to the area around the tumor. They therefore modified it "so that it remains in the brain and is rapidly degraded when it crosses into the blood," vom Berg writes in the final report of his recently completed project.


Helping dogs with cancer

Vom Berg and his team have patented their new IL-12, which is optimized for the treatment of glioblastomas. But before they can administer it to humans for the first time in a clinical trial, they must first test their genetically modified molecule on animals. If you think of mice or rats, you're wrong about this project. The team led by vom Berg is trying to help dogs with cancer with their compound. "That is a great feeling," vom Berg says.

"Unlike farm animals, dogs - as four-legged companions of humans - are allowed to grow old," he continues. And as they age, their risk of developing cancer increases, too, he adds. With their study on dogs suffering from brain tumors, vom Berg and his team want to kill two birds with one stone: By paving the way for a possible treatment option for dogs, they want to simultaneously "enable a prediction of efficacy in humans," vom Berg explains.


Throw a spanner in the works

The veterinary study was supposed to take place in the United Kingdom, but Brexit and later the coronavirus threw a wrench in the works. But the team around vom Berg was not discouraged by this and continued research in another direction for the time being. The researchers used the time to test which of the seven immunotherapeutic drugs already available and approved for the treatment of cancer patients also work in dogs. Surprisingly, one of these checkpoint blockers also unleashes canine immune cells.

"This means we have identified a drug that is suitable for combination therapy with our modified IL-12," vom Berg says. In the last two years, he has founded a spin-off company and also established contacts with people at the Animal Hospital Zurich, as well as with researchers in Italy, Spain and the United States, to further develop immunotherapies against brain tumors - for both dogs and humans.


Project ID: KFS-4146-02-2017