For years, a patient diagnosed with cancer had a few options in order to get rid of a progressing tumor: chemotherapy, surgery or radiation therapy. Since a few years, immunotherapy has been added to these treatment options. Cancer immunotherapies do not directly kill the tumor cells, but do give your own body the ammunition to fight cancer cells. “The concept of immunotherapy has existed for quite some years, but many colleagues didn’t take it very serious as a potential treatment. That has changed now”, says Ton Schumacher, Oncode Investigator at the Netherlands Cancer Institute. During his studies he became fascinated with the ability of the human body to spot foreign intruders and to get rid of these. “Your immune system knows how to spot aberrant cells and decide: I should do something with these cells and leave those ones alone. It is quite ingenious.”

In order to find out how the human immune system works, you only need to cross the department of Schumacher at the NKI. On the toilet door you’ll see a full-figure T-cell with explanation of the different compartments of these soldiers of the human body. When a virus enters the body or a tumor starts to grow, the T-cells can – in at least some cases – respond to these potential dangers. On the walls of the board room you can find wine corks as trophies for the articles that were published in prestigious academic magazines these past years. The research of Ton Schumacher and his colleagues is no longer an interesting hobby in the world of cancer research. It’s a hot topic with impressive results.

“I hope you know how to handle confronting images”, Schumacher says when he shows some pictures on his computer screen. The image shows the upper leg of a patient with huge yellow and black abscesses. It is a melanoma. Patients with metastatic melanoma used to have an average life expectancy of only a couple of months. But the person on this picture didn’t die. On later images the bumps disappear, leaving only scar tissue. “When we saw the results of this study in a few patients of my colleague John Haanen, we knew immunotherapy had the potential to become a really important strategy to treat cancer.”

Schumacher shows another picture of an infusion bag that contains a thick, white liquid. These are the T-cells of a patient that were grown in the lab to improve their ability to attack the tumor cells. A more broadly used immunotherapy that has also been developed over the past years is the use of so-called checkpoint inhibitors. Frequently, cancer cells use an inhibitory signal that impairs the function of T-cells. It helps them not to get killed by these T-cells. A checkpoint inhibitor blocks this signal. It gives the little white soldiers that you can also see in the infusion bag the opportunity to do their job: killing the growing tumors.

It is great news that someone with late stage melanoma may now live for years and in some cases even have a chance to be cured. But Schumacher is mindful about unrealistic expectations. Although many people with melanoma and lung cancer have a higher chance of survival after being treated with immunotherapy, these therapies do not work for every patient with these diseases. And many other forms of cancer are still much harder to tackle with this form of therapy.

“The fact that we now use these immunotherapies in the clinic is not due to a single Eureka moment, but is a prime example of the value of fundamental research. It’s the effect of the many little steps that the field has taken over many years”, Schumacher stresses. “Having an open mind and exploring novel ideas is really the only way to make progress and discover new things.” The immune system is highly complex and many pieces of the puzzle remain unknown, much is still to be discovered.

As an example: Why does one person with melanoma benefit from immunotherapy while the same immunotherapy does not seem to be able to push the immune system into action in another body? The poster at the toilet of the life-size T-cell speaks to our imagination, but it is a very simple rendition of the reality, Schumacher explains. At his department researchers therefore reflect, weigh up, puzzle and look endlessly at T-cells and other immune cells, to understand their tiniest details. “It is the only way to fully understand the finesses of the immune system. Otherwise you won’t be able to come up with new strategies and therapies that hopefully cure more people of cancer.”

Anne van der Leun, PhD student within the Schumacher Research Group is one of these people that tries to find new answers. She wants to know why T-cells that are normally programmed to attack aberrant cells don’t succeed in that task in the case of cancer cells. “For a long time, scientists assumed they didn’t attack because those cells were exhausted. But my research, together with work from others, shows this is not the case. Instead, these cells have changed their function. Sometimes they recognise cancer cells, but they simply don’t attack them. When we’ll better understand why we can reactivate T-cells to fight the tumor in certain patients and not in others, we should be able to personalise the therapy for every patient.”

The research of van der Leun rests heavily on team work inside the NKI and beyond. Clinical oncologists ask their patients whether their tissues may be used for research. In cooperation with two Israeli labs, van der Leun prepared the available tissues for further analysis. In the end she vetted more than 30,000 T-cells, one by one.

For much of her time, she has looked at the data from all these individual cells, trying to understand which genes were on and which ones were off. “It’s the only way to analyse what happens at the cellular level and to check what those different T-cells have in common. And also, how they differ from one another.” It’s important to understand how T-cells in cancer lesions are altered relative to normal T-cells, she stresses. “Follow-up research will hopefully determine how to get those T-cells that lost their fighting function fully active again.”

For the future development of cancer immunotherapy it is important to not only focus on T-cells. The inhibitory function of tumors needs to be better understood as well. Meike Logtenberg, PhD student within the Schumacher Research Group wanted to discover how the protein on tumor cells that is responsible for the ‘do-not-eat me signal’ that cancer cells broadcast is being regulated. “When we identified a second protein that helps with the broadcasting of this signal this was really exciting.” Especially because they may be able to use this therapeutically.

Exciting times lie ahead, with immunotherapy likely becoming increasingly important for cancer treatment. “But to make this happen we will need to continue to invest in doing research”, says Schumacher. “It is all about taking these little steps.” But these little steps have been important before as they have given hope to people in a dire situation. “Hopefully we will be able to make additional progress in the coming years, for many forms of cancer.”

Martine Zeijlstra