Van Loghem laureate Ton Schumacher: “Immunotherapy is a plea for fundamental research”

Friday December 09 2016

After a long period of disillusionments, the breakthrough of cancer immunotherapy has come with the speed of lightning. After experimental successes with melanoma a few years ago, this therapy is now applied to more and more patients, in earlier disease stages and against a wider range of cancers.“I regard the present breakthrough as a victory for fundamental research”, professor of Immunology at the Netherlands Cancer Institute Ton Schumacher remarks.

tonschumacher-35-45mm.jpgWith his study of Medical Biology at the University of Amsterdam, Ton Schumacher chose a field that was relatively remote from his family's tradition in medical professions. “Only more recently my work brought me closer to the clinic. I started out as a classical scientist, just wanting to know how things work. That is what still drives me.” Schumacher was only eight when his mother developed cancer; she died from it when he was seventeen. “This has undoubtedly also played a role in where I am today, but subconsciously rather than consciously.”
His fundamental inclination put Schumacher on the track of immunology, being inspired by work from people such as Frank Miedema, Kees Melief and Hidde Ploegh. “At the time, our understanding of T-cell immunology was still too fragmented to be of much use in oncology”, Schumacher remembers. “It is amazing what has been accomplished since then on the basis of the fundamental study of immune recognition.” As a flip side of the same coin: he is bothered by the current call for an ever increasing amount of translational research. “Certainly, translational research is immensely valuable to bring new findings to clinical practice. However, in the end translation cannot exist without fundamental research. The flow in the innovation pipeline will dry up, there is still so much more to learn.”

Science buzz
Schumacher got his PhD in Ploegh's group in 1992, where he closely collaborated with last year's laureate Sjaak Neefjes. “A molecular understanding of antigen presentation was at point lacking. It was known that T-cells recognize infected cells, but how exactly they detect pieces of virus was unknown. At that time, Alain Townsend just showed that HLA molecules can present stretches from intracellular proteins to T-cells and Don Wiley unraveled the crystal structure of an HLA molecule, showing what we now know as the peptide binding groove with electron density in between, possibly a mix of peptides. I elaborated on this: what peptides are these? How do HLA molecule present these peptides? I started developing an assay to show which peptides HLA molecules can bind. It turned out that bound peptides are essential for the stability of HLA molecules. We also showed that in an immune response against viruses, HLA molecules only binds peptide stretches of an accurately defined length.”

Next, we aimed to answer how cells get such peptides from their cytoplasm to the compartment where they can bind to HLA. In parallel with work from Sjaak, who at that time had become an independent PI, we showed that this process is mediated by the TAP transporter, and also showed which peptides this transporter prefers to handle. “This solved another question in the field of antigen presentation”, Schumacher concludes.
When Hidde Ploegh went to MIT, he asked Schumacher to join him. “Not an easy decision”, says Schumacher, “as I have difficulty with the social inequality at the other side of the ocean. But in the end, the extremely fascinating scientific environment of the Boston area won me over. The continuous science buzz over there is very stimulating indeed.”

Technology and content
During his post-doc period within the US, Schumacher joined Peter Kim's lab at the Whitehead Institute. Schumacher: “It was a major leap. I had the feeling I could be quite good at developing novel technologies, and that this would allow me to answer novel questions. However, my knowledge of the area was still very limited, and it felt like I was starting from scratch when I entered the Whitehead. I learned a lot, for instance how chemists carry out research in a quite different manner than most immunologists. Immunologists generally tend to explore unmapped territory. Chemists, however, plan a route towards a specific goal.”
In 1996, Schumacher returned as group leader in the Immunology Department at the NKI. His group continues the focus on technology development to support their research goals, which now mostly focuses on understanding T-cell recognition of human cancers. “At some point, we conclude that it would be useful to have an assay to measure some aspect of an immune response. We define this goal, work our way towards that, and then use it in our research. Technology and biological research questions are entangled in our work.”

Value chain
At the NKI, Schumacher set up a collaboration with John Haanen, who had just started as a medical oncologist. “Two decades of collaboration so far showcase the added value of multidisciplinary co-operation”, says Schumacher. “I should say that there was no master plan here, basically we started to collaborate because we happened to share an office”, Schumacher reveals. “There is a lot more serendipity in science than people often realize. Both our careers would have been entirely different if we hadn't simply shared a room. Together, we started forming an extremely short but quite complete development chain from fundamental science to clinical application.”
Schumacher is presently involved in two lines of research. “One focuses more on the creativity of basic science, the other on the practicality of applied work.” The fundamental part aims at unraveling how T-cell responses work. In animal models, individual T-cells are for instance followed over generations to study how different T-cell subsets develop from one another. “For this, we developed a trick to provide individual T cells with unique stretches of DNA, something we like to think of as a paternity test for T-cells”, Schumacher summarizes. “Using this, we for instance showed how an immune response is an average of the extremely different behavior of individual cells.”
In his applied research, Schumacher focuses on cancer-specific immune responses in patients. Schumacher: “In collaboration with Huib Ovaa's group we developed technology to measure the immune response against tumour antigens in a sensitive way for many different antigens. In recent years, we have used this technology to show that in many patients with tumors with high amounts of DNA damage, the immune system detects the neo-antigens that are created as a consequence of this DNA damage. This makes it very attractive to try and stimulate this fully tumor-specific immune response further.

Juggling act
In recent years, cancer immunotherapy has become mainstream in oncology. One of the consequences is that the pressure on people within the field has risen enormously, Schumacher notices. A busy schedule is a downside to an otherwise major blessing. “It is of course great to do research in this era and to witness how what used to be just a promising idea  now has such huge clinical impact.” But still, you have to cope with that: “It has become a juggling act to keep something of a private life.”

The book 'Busy' helped him with that by presenting a few simple tricks. “On simple trick is for instance not to decide how nice or important an activity is by itself, but how valuable it is in the context of what you want to accomplish. Then the difference between 'nice' and 'really valuable' becomes rapidly clear.”
Schumacher rates his involvement in the establishment of three companies under 'really valuable'. “In AIMM Therapeutics, which was started around work from Hergen Spits, I only played a minor role. T-Cell Factory was a company that we started to exploit a number of our technologies, and that has now been taken over by Kite Pharma. Neon Therapeutics was set up in 2015 in the Boston area to exploit the recent understanding of the role of cancer neo-antigens to develop therapies to enhance immune responses against them. In all three cases the underlying rationale was the same, when a field reaches the point where application opportunities arise that cannot be accomplished at the same level in academia, I think one shouldn't hesitate. Development of your findings into a therapeutic or diagnostic is the ultimate value test.” 

Cancer Immunogram
In this respect, the fact that immunotherapy has become a top priority for large pharma is telling. Schumacher: “In the next decade we are heading towards more personalized forms of cancer immunotherapy based on the interaction between the patient's immune system and tumor. Insight into this process tells us why the patient's immune system cannot deal with the tumor and how we may enable it to do so.”
Together with colleague Christian Blank, Schumacher recently presented a framework to describe this interaction as a 'cancer immunogram': scoring patients on a seven axis chart, asking questions such as Is the tumor sufficiently 'non-self' to induce an immune response? Is the patient's immune system capable enough to fight cancer? Can T-cells penetrate the tumor? Are they allowed to function there…” Schumacher: “The concept will certainly be further refined, but the basis for mapping the interaction between tumor and immune system has been laid. The bottom line is that for each individual patient we need to understand what goes wrong and what we should do to solve it, and at least for part of the patient population we are getting there.”

Tekst: Bureau Lorient

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