In total, through this funding round, KWF is enabling the start of 23 fundamental research projects. With the two projects, including a Young Investigator Grant, KWF supports the Máxima in working towards the mission to cure every child with cancer with optimal quality of life.
Unraveling mechanisms and drug testing
T-cell lymphoblastic lymphoma (T-LBL) is diagnosed annually in about ten children in the Netherlands. It is a form of cancer that arises from “young” T cells, a particular type of immune cells. The standard treatment usually works well. But children in whom the disease subsequently recurs often have a poor prognosis.
Researchers from the Kuiper group found that children in whom T-LBL has recurred and for whom treatment has failed often have specific genetic abnormalities, so-called NOTCH1 fusions. Dr. Jan Loeffen, a pediatric oncologist involved in this study, says: 'We don't know now why NOTCH1 fusions in children with T-LBL lead to a poor chance of cure and how we can improve this.' Prof. Dr. Roland Kuiper, research group leader, adds: 'That's what we want to find out: what happens at the cell and gene level that causes treatment in NOTCH1 fusion-positive T-LBL to not work well? Together with Dr. Frank van Leeuwen's research group, we are going to unravel these mechanisms.'
With the new knowledge, the researchers will then search for better-acting drugs. To this end, they will test existing and new drugs on tumor cells with NOTCH1 fusions. Kuiper is looking forward to starting the new research: 'We have a great team of researchers and closely involved pediatric oncologists, and with the KWF funding we want to increase the cure rate and quality of life of children with T-LBL and NOTCH-1 gene fusions.'
Remove brake on CAR T cells in solid tumors
CAR-T cell therapy is a form of immunotherapy in which a child's immune cells are modified to attack cancer cells. For some children with leukemia, it has already proven to be a successful treatment. But in solid tumors, such as neuroblastoma, this approach does not currently work as well. That’s because the tumor produces so-called ‘neuronal factors’ – signaling molecules that inhibit the activity of CAR T-cells. Some neuronal factors, normally used for communication between nerve cells, can also suppress immune cells. Tumors exploit this to escape detection by the immune system.
Dr. Judith Wienke, upcoming research group leader at the Máxima, wants to address this with her KWF Young Investigator Grant by turning off the neuronal factors, and thus making CAR-T therapy work better. She says: 'I’m incredibly excited that, with support from KWF, I can now develop two strategies in the lab to make CAR T-cell therapy more effective against solid tumors. I will combine CAR T-cells with existing drugs that block neuronal factors, and I’ll modify the CAR T-cells to make them resistant to this suppression. I call these modified cells NasCAR T-cells.'
Wienke will then test the most promising approach in mice. 'If this works in neuroblastoma, it could potentially be benificial for other childhood cancers as well.'
KWF is awarding a total of €1.7 million in support for pediatric cancer research at the Máxima with these two projects.