Neuroblastoma is an aggressive tumor that develops in the nervous system. In the Netherlands, about 25 to 30 children are diagnosed with this form of cancer each year. Children whose cancer returns after treatment or whose tumor has spread have a poor prognosis. New, improved treatments for high-risk neuroblastoma are therefore urgently needed.
Mixed results
One of the potential new treatments is CAR T-cell therapy, a form of immunotherapy. In CAR-T therapy, a child’s own immune cells are modified to recognize and attack the tumor. This approach works well in children with certain types of blood cancer.
However, results for neuroblastoma have been mixed. Josephine Strijker, a PhD candidate in the Molenaar group at the Princess Máxima Center, wanted to understand why. ‘Previous studies showed that CAR T-cells work on small tumors, but less effectively on larger ones. That led us to think: the tumor is probably suppressing the immune system, and thus the CAR T-cells,’ she explains.
Immune suppression
Dr. Judith Wienke, then a postdoctoral researcher in the Molenaar group, delved into the biology of neuroblastoma tumors. She examined how tumor cells and immune cells influence each other. It turned out that some tumor cells secrete substances that suppress immune cells. One substance stood out: MIF.
‘That’s when everything clicked,’ says Strijker. ‘In my experiments, I saw that neuroblastoma cells secrete a lot of MIF. It turned out that MIF really does make immune cells less active.’
Bypassing tumor defenses
The researchers tested whether blocking MIF would help. Colleagues at the University of Groningen developed a prototype drug that breaks down the MIF protein. In the lab and in mice, Wienke, Strijker, and colleagues observed that CAR T-cells performed much better without MIF and were able to attack the tumor cells again.
‘With this approach, we bypass the tumor’s defenses and make it vulnerable again to the immune system’s attack,’ explains Wienke, who is set to become a research group leader at the Máxima. ‘This increases the chances that CAR T-cells will also work well in children with high-risk neuroblastoma.’
Foundation for clinical trials
The next step is to further test this combined treatment—CAR T-cells with a MIF inhibitor—and to refine the prototype drug, a so-called PROTAC. This follow-up research could lay the foundation for new clinical trials in children with high-risk neuroblastoma.
Wienke hopes the research will soon contribute to better treatments: ‘CAR T-cell therapy is very promising, but it doesn’t yet work well for neuroblastoma. Much research focuses on improving the CAR T-cells themselves. We approached the problem from the other side: how do you make the tumor more sensitive to CAR-T? With our research, we’re bringing CAR-T for children with neuroblastoma one step closer.’
The research was an international project, with contributions from groups in Philadelphia, London, and Singapore, and was made possible in part by support from organizations including Villa Joep and the Royal Netherlands Academy of Arts and Sciences (KNAW). The study was published in the European Journal of Cancer.