Every year in the Netherlands, 25 children are diagnosed with neuroblastoma; a malignant tumor of the sympathetic nervous system. Eight of the children whose disease recurs after standard treatment die within five years of diagnosis. Better treatment is therefore desperately needed.
Immunotherapy is a promising new type of treatment that targets your child’s immune system against cancer cells. In recent years, the so-called anti-GD2 immunotherapy has increased the chances of survival of children with neuroblastoma by 15%. But immunotherapy still doesn’t work well enough, and not yet in all children.
High resolution
To better understand why immunotherapy doesn’t always work, researchers at the Princess Máxima Center mapped the tumors of children with neuroblastoma at very high resolution. Using single cell RNA sequencing they analyzed 24 tumors from 19 children who had been treated at Máxima. Single-cell RNA sequencing is a technique for studying the cells of a tumor – including both tumor and immune cells – at an individual level. The research was published today (Thursday) in the leading specialist journal Cancer cell. The research was co-financed by NWO, KiKa and Villa Joep.
The researchers analyzed more than 22,000 individual cells. They saw that one type of immune cell, T cells, did not function properly in neuroblastoma tumors. These dysfunctional T cells also often had a protein on their surface called TIGIT. This protein inhibits the activity of T cells so that they do not attack the cancer cell. An existing class of immunotherapies can block this inhibition. This type of medicine, so-called checkpoint inhibitors, activates the immune system. This allows it to work to eliminate cancer cells.
Combination
In 3D mini-tumors, also called organoids, and in mice, the researchers saw that a combination of checkpoint inhibitors against TIGIT and another protein called PD-L1 successfully killed neuroblastoma cells. The researchers were also able to simulate recurrent neuroblastoma in mice, an aggressive form of the disease that is treated with chemotherapy and anti-GD2 immunotherapy. In this experiment they also saw that the new combination with checkpoint inhibitors led to longer survival.
The drugs that block TIGIT and PD-L1 and activate the immune system, tiragolumab and atezolizumab, are already used, among other things, in studies on lung and liver cancer in adults. The researchers are now working with the pharmaceutical company Roche to launch a clinical trial in children with neuroblastoma in Europe and the United States.
New starting points
Dr. Judith Wienke, senior researcher in the Molenaar group at the Princess Máxima Pediatric Oncology Center and who co-led the research, says: “In our new study we have mapped the immune landscape of neuroblastoma in high resolution. This gives us insight unique insight into how different immune cells function differently in the tumor.The Neuroblastoma Immune Atlas offers important new starting points for improving immunotherapy for this type of childhood cancer.
‘Our research is still at an early stage, but the results of the new immunotherapy combination in the laboratory are very encouraging. The next step is to test this experimental treatment in a clinical trial. We will study the safety and possible effect of the combined treatment in children with metastatic or recurrent neuroblastoma.’
Fast translation
the professor. Dr Jan Molenaar, research team leader at the Princess Máxima Pediatric Oncology Center and who co-led the research, says: “It is fantastic to be able to immediately translate the results of basic research on the biology of neuroblastoma into the clinic – I have not I had never done this before and experienced that the translation happened so quickly. I can’t wait to start the clinical trial to ultimately see if children with neuroblastoma actually benefit from this new combination of immunotherapies.”
‘Immunotherapy is being offered to more and more children with cancer, both as an experimental treatment and as part of standard treatment. Basic research into the immune landscape of tumors is essential to improve the efficacy of immunotherapy and reduce side effects. Our research helps further fulfill the promise of immunotherapy for children with neuroblastoma.”
Clinical study
the professor. Dr Max van Noesel, pediatric oncologist and clinical director of solid tumors at the Princess Máxima Pediatric Oncology Centre, who was also involved in the research, says: “In adults, checkpoint blockers – therapies that curb the body’s immune system – have the potential to treat, for example, melanoma and lung cancer have improved enormously.But the best-known checkpoint blockers, which target the PD-L1 protein, have not yet shown any effect in children.
‘Thanks to single cell In our study, in addition to PD-L1, another target also emerged, TIGIT. We are already well advanced in preparing a clinical study on the effects of a combination of TIGIT and PD-L1 blockers. I look forward to seeing whether this approach, based on basic biological research, can make a difference for children with high-risk or relapsed neuroblastoma.”
Leontine Heisen, founder and member of the board of directors of Villa Joep, which co-financed the research, says:
‘Villa Joep has been sponsoring very targeted research for 20 years that can increase the low survival rate of neuroblastoma. We are very pleased with this promising development and will follow it with great interest.’
2024-01-04 16:00:00
#Immune #Atlas #points #immunotherapy #neuroblastoma #Princess #Máxima #Center