The BEACON 2 trial aim to test two promising treatments that combine chemotherapy with new anti-cancer medicines (respectively bevacizumab and dintutuximab beta) to cure children with relapsed neuroblastoma with fewer side effects. 

Despite intensive treatments, the chances of survival for children with neuroblastoma that has come back remain unacceptably low, with less than 20% of children achieving long term cure. Only one type of drug has ever been developed specifically for neuroblastoma and it is critical to develop new medicines for this aggressive cancer. 

The two promising treatments that combine chemotherapy with new anti-cancer medicines that will be tested in the BEACON 2 trial are respectively targeting the blood vessels that help the tumours grow and directly the tumour cells via an antibody that binds on a molecule found on the surface of neuroblastoma cells. In the latest, it will allow the child’s own immune system to recognise and kill the tumours cells. 

The Beacon2 trial will confirm which of these two treatments is better in a larger group of patients. This is an essential step to change practice, so that the treatment can be given by doctors widely across Europe after the trial. It will also develop new combinations of drugs that improve the efficacy of immunotherapy, curing more children with fewer side effects. 

Despite the current intensive treatments, the chances of survival for children with neuroblastoma that has come back (in relapse) remain unacceptably low, with less than 20% of children achieving a long-term cure while the treatment causes severe long-term side effects for survivors.As a result, today’s challenge is to reduce the side effects of the treatment while retaining and improving its efficacy to cure more patients.

An international team of computer scientists, biologists, and clinicians will collaborate to build computer models of patients (Digital Twins), which will allow the design of personalised therapies that are more efficient and less toxic than the current therapies.

The technique of digital Twins is already successfully used in engineering, where engineers build, test, and improve a computer model so that they can build the best version of the real machine.

The team will start by building “DigiTwins” of mouse models with neuroblastoma. These mouse models are very similar to the human disease and have been successfully used to develop and test new drugs for neuroblastoma. They allow to perform a comprehensive molecular analysis, where changes in the genome, in the expression of genes (epigenetics), in the production of proteins and of metabolites (which supply building blocks for the body) will be measured. The team will then use advanced computational methods to combine these molecular data and construct the Digital Twin models. Every neuroblastoma mouse will have a corresponding DigiTwin computer model, which can be used to try out different treatments virtually on the computer so that the best possible individual treatment can be identified. These treatments then will be tested in the mice.

Once the accuracy of the DigiTwin models in mice is ascertained, it will be translated to humans. The accuracy of these human DigiTwin models will be evaluated against the treatment outcomes of these patients.

The final objective of DigiTwins project is to pave the way for future clinical studies, where DigiTwins can provide better and more personalised treatments for neuroblastoma patients.

Leukaemia and lymphoma are the most common haematological malignancies in children and constitute almost half of all paediatric cancer cases. High-risk patients, who do not respond to standard therapy or suffer from relapse (when the disease comes back), only have a 27% survival rate.The HEM-iSMART is a personalised medicine trial in which children with relapsed leukaemia or lymphoma will receive a treatment corresponding to the specific genetic alteration(s) present in their tumour. It aims at recruiting sixty patients in total.

Continuous research in cancer genetics and rapid development of new techniques to analyse tumour material have facilitated the development of drugs that specifically target mutations found in cancer cells.
When tumour cells are mutated, they produce mutated proteins that, in turn, promote cancer development and progression, and can lead to resistance of the tumour cells to standard treatment.

Targeted drugs could revert the activity of altered proteins, stop cancer growth or induce tumour cell death. As a result, such drugs could increase the chances of survival for children with relapsed leukaemia or lymphoma.

The HEM-iSMART trial aims at testing four new therapies, each one matching a specific genetic alteration present in the tumour of the patients. This new approach, the first to tackle this issue at a European level, will be carried out in collaboration with the International Leukaemia Target Board (ILTB).

Leukaemia is a cancer of the blood where the patient’s own system turns malignant: the white blood cells grow anarchically and surpass the red blood cells in the blood stream – causing extreme fatigue, bruising and ultimately, the patient’s death.Acute lymphoblastic leukaemia or ALL is the most common type of blood cancer – lymphoblastic refers to the type of white blood cells that has mutated. Today, about 90% of the children with ALL will survive. As a result, childhood ALL can almost be considered as a curable disease. Unfortunately, this is not true for all patients diagnosed with ALL, especially not for infants, i.e., children under 1 year of age.

This project pursues two objectives. First of all, it aims at understanding the mechanisms which make infant ALL so aggressive. It has already been demonstrated that most of the babies diagnosed with ALL carry a leukaemia-specific mutation in the MLL gene. Understanding the MLL gene is thus the key to better treatments.

Second, it will attempt to identify new treatment options by targeting these mechanisms and providing evidence to show that these newly identified treatments could be efficient when applied to patients in the clinic.

The findings of this project will be discussed with the clinical trial groups that set up clinical studies in ALL: the INTERFANT/UKALL consortium.

The project’s findings could be used to improve the risk stratification between the patients and test the identified treatments in an international clinical setting. This could allow more personalised, effective, and kind treatments for infants with ALL in the future.

The aim of this project is to address the urgent clinical challenge in neuroblastoma that is the relapses. In a majority of patients, the tumor comes back in the next five years after initial treatments. These so called ‘relapses ‘are resistant to therapy and have a fatal outcome.

It was found that the cells at the origin of these relapses are resembling to immature cell type and it was suggest that they can escape chemotherapy and seed their lethal relapses in neuroblastoma. A drug that kills the immature neuroblastoma cells was identified but its use was not suitable for patients. This project aims to test a new generation of drug, called GEN1029, on a mouse xenograft relapse model for neuroblastoma to see if this drug inhibits the developments of relapses.

In parallel, the project aims as well whether the immature tumor cells are present in human neuroblastoma tumors and can escape chemotherapy. The results of this project will thus provide all information required to decide on testing in patients. In such future tests, the new drug can be added to current therapy to learn whether relapses are inhibited and outcome for neuroblastoma patients improves.

Today, when a child with cancer runs out of standard treatment options, they will seek treatment in the framework of a clinical trial in the hope to cure or at least to extend their life.In the framework of a clinical trial, all the data about the effect of the tested drug are recorded with the specific intent to determine whether the tested drug is effective and its toxicity is acceptable. Unfortunately, today, there are not enough relevant clinical trials for most of the children for which the current treatments are not effective.

More often than not, as a result, those children with cancer will be treated with a novel drug off-label, in the framework of a compassionate use or medical need programme. In such a case, the clinical data of the patients are lost, when in fact we would need to detect unnecessary toxicity or remarkable efficacy.

This is exactly what the SACHA international registry will do: collect real-life data about innovative therapies administered outside clinical trials to children, adolescents and young adults with paediatric malignancies. These real-life data will help to: 1) recommend the halt of the prescription of the drugs that show to be ineffective or have an unacceptable toxicity, 2) support the development of paediatric clinical trials when new anti-tumour activity is observed.

SACHA international is built on the previous experience of the SACHA France pilot initiated by the French Society of Paediatric Oncology (SFCE) that has included more than 280 patients since March 2020, confirming the feasibility of this type of registry. SACHA International is an initiative from the Innovative Therapies for Children with Cancer (ITCC) Consortium and plans to include 500 patients per year over three years in several European countries, as well as Australia and New Zealand.

This project aims to improve therapy for acute myeloid leukemia (AML), the second most common blood cancer after acute lymphoblastic leukemia (ALL). While 9 out of 10 children with ALL are cured, only 6 out of 10 children with AML are cured, often with much more toxic therapies. Hence, we need to improve therapy for AML. The fantastic improvements in cure of childhood ALL is due to development of highly sensitive genomic technologies to monitor the response of leukemia to therapy and personalized adjustments of therapy.

One of the big challenges of pediatric AML is the lack of highly sensitive methodologies to detect the response of the leukemia to therapy by similar genomic approaches as in ALL. This project propose a novel genomic based methodology to overcome this challenge. This project will utilize this novel approach to not only determine response to therapy but also to characterize the leukemic cells that remain resistant to therapy. This could lead to identification of novel drugs that may overcome this resistance. Connected to ITCC, the methodologies developed in this project will be translated and disseminated fast among the leukemia community as critically important tools to determine the effectivity of novel drugs for AML. The existence of such tools is likely to enhance the precise adjustment of therapy to each child with AML and, consequently, to improve the chances for cure.

Liver cancer in children is rare but can have serious consequences. The most common type of liver cancer can be treated relatively well. However, more than 40% of survivors develop serious late effects as a result of their treatment. Examples of these late effects are heart failure, deafness and other tumours later in life. One in 5 children with a liver tumour has an aggressive variant. They often do not survive the disease. Either because current treatments do not work or because the tumour returns after treatment.

The aim of this project is to discover more effective treatments for patients with aggressive liver tumours as well as identify patients with less aggressive liver tumours to reduce drug doses and their associated late effects.

BT4ChildLC will benefit from the ongoing Paediatric Hepatic International Tumour Trial (PHITT) and the associated collection of biological samples of this rare disease that was established from PHITT patients. In particular, this project will study the differences between aggressive and less aggressive tumours to identify new and more efficient drugs against childhood liver cancer and use new experimental models to determine the most appropriate drug for each patient. In addition, this project seeks to identify indicators within the individual tumours of aggressiveness, likelihood of response to treatment and outcomes. This will help clinicians to predict in advance patients with less aggressive tumours that could benefit of lower doses of chemotherapy to reduce the current treatment toxicity.

The treatment of childhood liver cancer over the past decades has not changed much; with this research, we expect to significantly move forward to an individualized approach to treatment of this disease, thereby improving survival and quality of life of childhood liver cancer patients. Finally yet importantly, these findings are expected to be implemented in the next clinical trial, PHITT-2, which is set to open in 2024-25.

Lead Institution : Germans Trias i Pujol research Institute, Universitat Autònoma de Barcelona (Spain)

Ewing sarcoma is an aggressive bone tumour. While chances for survival for patients without metastases at diagnosis nowadays reach 85%, the chances for survival dramatically drop to 20-30% in case of lung metastases, and to less than 5% in case of bone metastases. Giving more of the current treatments does not improve the chance of survival but does cause more side effects. Therefore, innovative, new treatments are urgently needed.

This project aims to enable novel therapies for children, adolescents and young adults affected by Ewing sarcoma (EwS). Despite improvements of treatment protocols over past decades, one third of patients succumb due to relapsed disease that cannot be controlled by conventional therapies. Maximizing treatment intensity did not improve survival but instead increased toxicity and led to mutilating surgeries, such as amputation of affected extremities. Innovative, more efficient, and in particular less toxic treatment options are needed for these patients.
This project will investigate how many EwS neoproteins (unusual proteins that exist exclusively in tumor cells) exist, what their functions in EwS might be, and which of them may serve as target structures for specific therapies and particularly immunotherapy. EwS-specific neoproteins would constitute exceptional targets as they are exquisitely specific to tumor cells and not found in any normal tissue of the body. In case of success, and owing to the ongoing close collaboration with immuno-oncologists at Princess Máxima Center, the findings of this project could be immediately transferred into clinical trial. Moreover, researchers anticipate that this approach could also serve as a template for identification of other immunotargets in additional pediatric cancers, which is why we expect this project to have a far broader outreach than EwS.

Lead Institution : Princess Máxima Center for Pediatric Oncology (the Netherlands)

This project aims to identify genetic biomarkers to improve risk-stratified treatment in retinoblastoma. The survival rate is high due to early diagnosis, but metastatic retinoblastoma has a poor prognosis. Children with advanced retinoblastoma are treated with enucleation and some of them with adjuvant chemo-and radiotherapy to reduce the risk of relapse. The main challenge is to identify children at risk for metastasis. Risk stratification is essential for treatment to be reduced and late toxicity minimised in children with lower risk whilst allowing intensification of treatment for children with higher risk.
In this project, the genetic and genomic features of retinoblastoma subtypes will be characterized to identify biomarkers for tumours with high or lower metastatic risk. The results will be correlated with the clinical course. These biomarkers could contribute to identify patients at risk for metastasis to reduce the late effects of treatment in others. CoBioRB builds the foundation for a pan-European clinical trial “EURBG2” on biomarkers for risk stratification of adjuvant treatment for retinoblastoma.