UMC Utrecht well rewarded by KWF

In what ways can immunotherapy be used more effectively against head and neck cancer, liver cancer, multiple myeloma and other tumor types? And how do we prevent the overtreatment of children with thyroid cancer? These questions are central to four new, cutting-edge studies at UMC Utrecht. KWF Kankerbestrijding is funding these projects, about which we tell you more below, with a total of over three million euros.

1. Strengthened army of immune cells

Our body is one big battlefield: it continuously fights all kinds of invaders, often without us even realizing it. Think of viruses, bacteria, fungi but also cancer cells: our army of T-cells (a special type of white blood cells) waits for them and clears them away. Our ingenious self-defense mechanism serves as the basis for designing immunotherapy. This treatment activates and strengthens our immune system. Doctors are now successfully using immunotherapy for a variety of conditions.

There are several ways to strengthen the immune system in this way in the fight against cancer. For example, researchers can multiply the body's own T cells. But researchers can also modify the body's own immune cells genetically, allowing them to fight more effectively. The latter is the case with TEG therapy, for example, which is the focus of one of the new studies.

TEGs are genetically engineered T cells that combine the best of two types of T cells (alpha-beta and gamma-delta). A patient's own immune cells are taken from a patient, modified and then returned to the patient. The enhanced army of T cells can thus recognize and eliminate cancer cells more quickly and effectively. The TEGs were developed at UMC Utrecht by Jürgen Kuball (professor of hematology UMC Utrecht) and his research group.

First and second generation

In their earlier experiments at the cellular level and in mice, the researchers have shown that treatment with this form of immunotherapy is safe and effective. The application in humans is now also being tested: this year, the first complete remission was observed in a leukemia patient during a clinical trial. This gives great hope for further application in humans.

On the basis of these initial results, Jürgen will now start work on the second generation of TEGs. For this, KWF is giving him over 775,000 euros. He is going to build TEGs differently, with different and more proteins. This will make them even more effective. The new generation will be able to recognize more types of cancer. Some tumors are in fact protected by a powerful 'firewall' of their own. This is especially the case with solid tumors (cancer in organs and tissues).

Jürgen and his team also want the second generation to remain active longer and in greater quantity, to control the tumor better and to stimulate other immune cells. In mice, the first positive results have already been achieved: tumors became smaller, and healthy cells were not at risk.

Jürgen is now focusing on developing a treatment for patients with head and neck tumors. This type of cancer is uncommon, often detected at a late stage and therefore difficult to treat. He hopes that with this more powerful TEG, he will be able to initiate clinical trials for patients with head and neck cancer more quickly. In addition, he expects that this improved therapy can also be used in other types of cancer.

"We are now developing T cells that are more resistant to the defense mechanisms of cancer cells. This is currently a major challenge in treating cancer with immunotherapy," Jürgen says. "Research on the first generation of TEGs is certainly continuing, because we have found that they seem to be effective. The next generation is a good addition, but of course we will first thoroughly investigate whether our ideas really work and are safe before testing them in patients."

2. CAR-T with extra boost

Associate Professor Victor Peperzak' s new research seeks to improve CAR T cell therapy for multiple myeloma patients. To that end, KWF and funding partner Alpe d'HuZes are giving him more than 850,000 euros.

Like TEGs, CAR T-cell therapy is a form of immunotherapy in which T cells are genetically modified. In this treatment, T cells are taken from patients, genetically altered into CAR T cells and put back into them. The genetically modified immune cells are equipped with a special protein that acts like an antenna: as soon as it recognizes the cancer cell, it immediately sounds the alarm. CAR T cells can thus clear the tumors better and provide protection longer than the patient's non-adapted T cells.

CAR T-cell therapy has now been used successfully in a number of blood cancers. But recurrence after treatment remains a problem. This is especially true for people with multiple myeloma, a rare form of bone marrow cancer in which plasma cells proliferate. Plasma cells are a special type of white blood cells that produce antibodies.

Toxic molecule decides battle

Victor and his research group now want to improve the way CAR T cells kill cancer cells. They have already shown in a previous study that genetically modified immune cells can be additionally armed with NOXA. This is a toxic molecule that is specifically released into myeloma cells and kills tumor cells there.

In the new research project, Victor and his team want to determine how to produce and apply the enhanced CAR T-cell therapy as efficiently as possible. Furthermore, they want to see if the new therapy in multiple myeloma works better than existing CAR T-cell treatment. Finally, they also want to rule out damaging healthy tissue by adding NOXA. To this end, they will test the new treatment at the cellular level, in mice and in 3D culture models with bone marrow cells from myeloma patients.

This study should serve as the basis for a new clinical trial to be set up in myeloma patients.

"CAR T-cell therapy directed against myeloma cells initially gave tremendously encouraging clinical results. In almost all patients, the cancer cells were cleared up and seemed to be gone, but unfortunately they returned over time," Victor said. "Therefore, we developed a method to allow CAR T cells to also clear the more resistant myeloma cells. We expect CAR T cell therapy with this technology to work more efficiently and prevent or delay cancer recurrence."

3. Proteins at work

Assistant Professor Dennis Beringer, who is part of Jürgen Kuball's research group, focuses on so-called GABs. These are therapeutic proteins that bring T cells into contact with tumor cells, allowing the cancer to be detected and addressed more quickly. Dennis will receive over 790,000 euros for this from KWF.

GABs can be produced faster, easier and cheaper than the aforementioned TEGs. Those genetically modified cells are obviously promising but they are still more difficult and expensive to make. TEGs must be developed per patient, which is time-consuming and makes large-scale application difficult.

GABs, on the other hand, can be produced more easily and more cheaply in multiples. As a result, more patients can be treated more quickly at a lower cost. During previous research focused on leukemia, Dennis and his colleagues have already developed GABs with promising results: cancer cells were recognized faster, and tumor growth in mice was slowed.

In gear

Now Dennis is going to improve these GABs so that they help T cells signal and eliminate a wider range of cancer cells. In doing so, he is working primarily with liver tumor organoids. Organoids are miniature organs or tumors that have been grown in a laboratory. The organoids in this study were made available by the research group of principal investigator Weng Chuan Peng at the Princess Máxima Center for Pediatric Oncology.

Dennis' goal is to use the improved GABs to develop immunotherapy for various types of cancer, both solid and non-solid types, not just liver cancer.

Dennis will now first determine how to get the GABs to bind to tumor cells as well as possible, so that fewer are needed for the same effect. Next, he is going to add another protein to the GABs that will make the T cells even more active.

"For many cancers, immunotherapy does not yet work optimally. So developing new strategies and improvements to existing concepts is very important to eventually be able to treat a large group of patients with immunotherapy," Dennis says. "We hope that the improved GABs will eventually be tested in patients. First we are going to prove that they are safe and effective. After that, preparations for a clinical trial can begin."

4. Stop over-treatment of thyroid cancer

Thyroid cancer in children is very rare, affecting 10 to 15 children annually in the Netherlands. Fortunately, with current treatments, children with this form of cancer have a good survival rate of more than 98 percent.

Standard treatment includes removal of the thyroid gland and subsequent administration of radioactive iodine. Unfortunately, over 40 percent of children subsequently experience adverse effects from the given treatment, such as parathyroid, salivary gland and tear duct damage. They may also have an increased risk of developing second tumors.

The good prognosis of 98 percent combined with many side effects suggests that many children are now being over-treated. Some children may be able to be treated less intensively, leaving them with fewer side effects. But who can be treated less intensely, and in whom, on the contrary, should everything be thrown into battle? That question Sarah Clement (pediatrician and postdoctoral researcher in pediatric endocrinology) hopes to answer with her research project for the Thyroid Cancer Center of Expertise. For this, KWF has awarded her the Young Investigator Grant of over 760,000 euros.

International collaboration

The solution can be found in developing reliable prediction models. With these, the risk of recurrence (return of the disease) can already be determined at diagnosis. Drawing up these models requires a lot of data from patients. And that is difficult because the disease is so rare in the Netherlands.

That's why Sarah, together with Hanneke van Santen (associate professor of pediatric endocrinology at both UMC Utrecht and Prinses Máxima Centrum), set up a unique European registry for children with thyroid cancer last year: the ped-DTC registry. With KWF's money, the first predictive study (ped-DTC STRATIFY) within this registry can now be conducted.

Over a two-year period, 200 children with recently diagnosed thyroid cancer will be added to the study. Among other things, the researchers will record thyroid cancer characteristics and treatments given. They will also track notable genetic changes in the thyroid tissue removed.

Patients are followed for 24 months after their diagnosis. By comparing all the data collected with those who eventually experience a recurrence, Sarah and her colleagues aim to determine the factors that determine the eventual recurrence of the disease. In this way, it will be possible to determine, for each child, whether the risk of recurrence is high even at diagnosis. This helps doctors decide to which patients they do need to give more aggressive treatment and in which they would be better off opting for less intense therapy. In the latter case, surgery may be less extensive or treatment with radioactive iodine may be omitted.

"Due to the lack of prospective studies, all children with thyroid cancer have been treated pretty much the same for decades," Sarah said. "With the grant from KWF and our unique European collaboration, we are now able for the first time to develop an adequate model to estimate the risk of recurrence at diagnosis. The ultimate goal is to use this model to be able to more personalize the current unified treatment strategy so that children with and after thyroid cancer have a better quality of life."

Source: UMC Utrecht