« Brain tumours, especially malignant gliomas, are the main killers in paediatric and adolescent oncology. We can estimate that more than 500 such young patients in Europe die each year for these cancers due to the lack of effective treatments.

The Immuno-Oncology (IO) approaches have brought spectacular improvement in adult and paediatric blood cancers but these treatment approaches are at an early stage of development for brain tumours. Preliminary results in early phase studies (case reports and phase I studies) with immunotherapies have shown encouraging results. However, taking the next step into larger scale clinical studies required to carefully test if these immunotherapies can be effective has been challenging.

FKC funds the set-up of the platform (first 2 years of the project), which is designed to fill the gap between early results and clinical implementation at a larger scale by providing appropriate phase II data with appropriate controls to convince industry and legislator to allow their use in patients and marketing authorization.

The ELICIT platform will contribute to develop the strategy to introduce the most promising immunotherapy agents into phase II trial aiming at demonstrating their efficacy.

The ELICIT platform will implement an aligned approach to study design, and selection of patients for a given study. Further it will set up harmonized methods used to assess clinical, imaging and immune responses in patients enrolled on the study to ensure data from different studies are comparable and provide us with the maximum amount of information. To this end, we need also to set up standard operating procedures to select patients for each trial, to evaluate the efficacy from the clinical, immunological and radiological standpoints across studies.

The ELICIT platform will implement an aligned approach to study design, and selection of patients for a given study. Further it will set up harmonized methods (standard operating procedures) used to assess clinical, imaging and immune responses in patients enrolled on study.

This approach will ensure that data from different clinical trials are comparable and provide us with the maximum amount of information. » : Project summary from the PI

« Brain tumour and their treatment in children are often associated with loss of vision. Depending on the type of brain tumour, thirty to ninety percent of the children have vision loss including decreased visual acuity and contrast sensitivity, loss of colour vision, and visual field loss (hemianopia) profoundly impacting their learning, development, independence and quality of life. No visual rehabilitation procedures currently existing for children with visual field loss consecutive to brain tumour. There is a need for visual rehabilitation procedures to stimulate and restore visual perception in children, adolescents and young adults with hemianopia.

This pilot results suggest that patients with hemianopia improve visual perception in the damaged visual field after an audiovisual stimulation procedure.

This promising telerehabilitation approach uses high-technology devices to provide audiovisual stimulation with better ecological validity due to immersive virtual reality, greater flexibility due to home-based programs and improved efficiency due to patient-tailored protocols.

In this multicentric study, the team seek to investigate the effectiveness of an 8-weeks audiovisual telerehabilitation program on visual perception in 100 children/adolescents/young adults aged 10-25 years old with visual field loss consecutive to a brain tumour.

Participants will be recruited in paediatric neuro-oncology programs in 8 centres accross 7 European countries. They will follow the audiovisual telerehabilitation program from home with remote control of the device from our laboratory.

Visual assessments will be performed remotely at 4 weeks and at their hospital ophthalmology clinic at baseline, and end-of-intervention with follow-ups at 1 and 6 months.

Primary outcomes will be visual field restoration.

Secondary outcomes will correspond functional vision and quality of life.

Exploratory outcomes will be head/eye movement, brain activity in primary visual area V1 and retinal cells integrity.

The team anticipate increased visual perception in the blind visual field ultimately improving development, independence and quality of life. Their visual telerehabilitation program represents a paradigmatic shift in the conceptualization of healthcare, embracing a more comprehensive vision and facilitating the delivery of personalized care. It ensures equitable access, providing the capability to receive supportive therapy at home independently, without direct supervision by healthcare professionals. This empowers children and adolescents residing outside urban areas to access specialized therapies. » : Project summary from the PI

« Paediatric High-Grade Gliomas are the most common cause of tumour-related death in children. Of them, diffuse midline glioma (DMG) is associated with extremely poor survival, as less than 10% of patients survive two years post-diagnosis. Despite multiple advances in the biology of these tumours, preclinical research is struggling to discover new targets that can be incorporated into clinical trials for these patients.

In this context, one of the most promising therapeutic approaches is immunotherapy. However, although microglia and macrophages are the most abundant immune cells in the brain tumour microenvironment and are often associated with treatment resistance and cancer progression, they are not integrated into current preclinical models.

Understanding the complex interaction between macrophages/microglia and glioma cells could lead to a decisive breakthrough. With this aim, establishing adequate preclinical models that replicate the glioma microenvironment coupled with a multidisciplinary approach, integrating insights from immunology, metabolism, cancer biology, and drug development is needed.

Florent Ginhoux’s team has already established a neural organoid model with microglia/macrophages, recapitulating the interactions among different cell types in a developing brain. These results have been recently published in Nature. Based on this previous expertise in microglia-sufficient neural organoids, they decided to move forward and use this unique tool to study DMG development.

This research is performed within the frame of the institutional study “Immune-Organoids” (Sponsor: Gustave Roussy), approved by the French Ethical Committee.

Since the beginning of the project, they have already collected tumour and skin samples from six paediatric patients with H3K27M DMG treated at Necker Enfant Malades Hospital (Paris) and Gustave Roussy. They have already generated tumoroids from patients’ tumour samples for all six patients.

So far, they have reprogrammed fibroblasts into induced pluripotent stem cells (iPSC), generated iPSC-derived macrophages(iMacs) for all of them and iPSC-derived neural organoids for three patients. For these three patients, they added tumoroids to their autologous microglia-sufficient neural organoids, generating what we call a “patient avatar”, allowing us to analyse the impact of microglia in glioma invasion and progression. The “Immune-Organoids” study is still ongoing, with an expected total number of 10 patients with H3K27M DMG. Funding for this part of the project (sample collection, model generation, and characterisation of the model) has already been secured.

However, this project was born as a cognitive approach, and funding for translational studies is needed. They propose to use two autologous 3D models (immuno-tumoroids and microglia-sufficient neural organoids) as a tool to test and validate new immunotherapies and combinations with the purpose of eliciting an efficient immune response against glioma cells.

Indeed, the purpose of the project  is to use these unique patient avatars to select the most promising immunotherapies, provide biomarkers predictive of treatment response and better understand the mechanisms of treatment resistance, thus enhancing the success of translating promising therapies from the lab to the clinic. For paediatric patients with H3K27M DMG, their aim is to identify the most promising new immune-related targets and combinations by their testing in 10 patient-derived autologous 3D models (patient avatar).

This project has 3 objectives to achieve this aim:
1) Testing in the autologous 3D models of currently available treatments targeting tumour-host interactions to boost immune response and validation of new non-currently druggable targets by gene modification techniques based on in-house data from patient-derived 3D models;
2) In-depth characterisation of these treated preclinical models to identify biomarkers of response or resistance and elucidate mechanisms responsible for tumour evasion and immunosuppression specific teach tested treatment.
3) Testing in patient-derived 3D models of new combinations developed from the previous two objectives to enhance the immune anti-tumour response.

In this interdisciplinary project, as a joint effort, immunologists, metabolism experts and paediatric oncologists will work together in areas of common interest, such as immune dysregulation in paediatric patients with brain cancer.
The team’s strategy, consisting of the establishment of an innovative preclinical model based on autologous patient-derived neural organoids with macrophages and tumour cells (patient avatar), will provide essential resources for a better understanding of macrophage-glioma crosstalk.

In H3K27M DMG, this knowledge will guide the identification and validation of immune/metabolism-related therapies. We truly believe that this approach will identify new therapeutic avenues for paediatric patients with currently no effective treatment option, which can be translated to clinical trials to improve survival rates.

This will lead to:
-Drug repositioning in a paediatric phase I/II trial if the targeted treatment is already available. This drug, alone or in combination, could be part of a new arm in the program AcSé/eSMART (« European Proof -of-concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed of Refractory Tumours in Children ») or in the BIOMEDE trial, both trials being sponsored by Gustave Roussy.
-A collaboration with start-ups within Paris Saclay Cancer Cluster (PSCC) to create new drugs if a treatment specific to the newly discovered macrophage-glioma pathway is unavailable. Once the new molecule is developed, it will be tested on these patient avatars to accelerate its translation into clinical practice.

The ultimate goal is to make these new preclinical models available to the scientific community, create a powerful platform upon which to build studies on the immune system and glioma cells, and more efficiently discover and test new drugs to increase the survival of paediatric patients with brain tumours. » : Project summary from the PI

« Medulloblastomas are the most common malignant brain cancers affecting children. Radiotherapy is commonly used to treat this disease. While it can lead to remission in some patients, some do not respond to radiotherapy and others relapse after an initial response. Furthermore, the vast majority of survivors will suffer life-long toxic side effects from radio therapy to the brain, often resulting in learning difficulties as well as motor, speech and/or memory deficits. There is therefore an urgent need to improve the current radiotherapy protocols in order to increase efficacy while reducing the doses used so as to decrease toxicity and long-term side effects.

In this project, called RADIO-MEDSCREEN, the team will combine two complementary approaches involving high-throughput screening technology. It is based on automated systems that allow the rapid testing of hundreds of perturbators, to identify ways to increase the efficacy of radiotherapy against medulloblastomas. They will thus screen in parallel a library of 220 approved drugs and molecules in clinical development and a library of more than 77,000 small DNA fragments that can individually silence all the genes of the genome.

The two libraries will be screened alone and in combination with radiotherapy to reveal:
1- drugs that can increase the effect of radiotherapy
2- genes that play a key role in radio resistance in medulloblastomas.

They will then use several clinically relevant models of the disease to validate these results and demonstrate the therapeutic potential of the novel combinatory treatments. The RADIO-MEDSCREEN project will not only improve our knowledge of the mechanisms of resistance to radiotherapy in medulloblastomas but also open major therapeutic avenues for the patients. The team’s strong network of paediatric oncologists highly involved in clinical trials will facilitate the transfer of our results to the bedside and hopefully improve the outcome of medulloblastoma patients while decreasing the life-long side effects. » : Project summary from the PI

« Our understanding of childhood cancer biology has been completely transformed over recent decades, with the widespread application of cutting-edge technologies leading to huge advances in disease understanding, diagnostics and sub-classification. Sadly, however, this improved knowledge has largely failed to result in new treatments.

There is a clear bottleneck in the process of converting scientific findings into new therapies for young patients, which urgently needs to be addressed. This is particularly true for brain tumours, where unique factors such as the natural barrier protecting the brain from chemicals in the blood (‘blood-brain barrier’) make treatment delivery even more challenging. Almost 2,000 new brain tumours are diagnosed per year in the EU27countries, with about half of those representing ‘high-risk’ groups and an even high proportion experiencing disease relapse.

Across all tumours, overall survival at 10 years after diagnosis is around 75%. For many high-risk tumours, however, even 5-year survival is sadly close to 0%. Of those who do survive, many experience lifelong problems and poor quality of life due to side effects of their treatment.

The proposed project aims to address these problems in three ways.

Firstly, together with the experts within the ITCC Brain tumour-specific working groups, the team will generate and continuously update a survey of promising treatment targets across all paediatric brain tumours. This will help to prioritize candidates for further investigation and ensure that promising targets are not lost due to poor communication.

Secondly, they will establish a robust pipeline for performing and analysing high-quality pre-clinical experiments exploiting selected targets, investigating the effects of new treatments on multiple tumour models, and providing the pre-clinical data essential to progress towards clinical trials. Here, they will utilize the infrastructure and models available through the ITCC-P4 pre-clinical platform.

Finally, strong links will be forged with the ITCC Sponsor Committee, to ensure that targets with a strong rationale are pushed forward in a meaningful way, by identifying bespoke investigator teams leading clinical trial design in negotiation with pharmaceutical companies.

The team believe that this comprehensive approach can have a substantial impact on bridging the disappointing gap that currently exists between basic research findings and clinical advances. It offers a way to systematically identify and test promising new treatments, which will lead to an increased number of clinical trials to provide young patients with accelerated access to innovative new drugs. » : Project summary from the PI

« In 2022 more than 1800 children aged 0-19 have been diagnosed with a brain or spinal cord (summarized as central nervous system) tumour within the EU-27. CNS tumours are still the leading cancer-related cause of death in the paediatric population.

Prognosis very much depends on the type of cancer and long -term survival ranges between 0 and almost 100%. There are many burdens patients and their families face during the disease: surgery with its associated risks, waiting time for the diagnosis and the associated anxiety: “Will I/my child need additional therapy?”, if post-operative therapy is needed, “Does the tumour response?”, at the end of treatment, “Is it completely gone”, “will it come back?” and in the case of recurrence “is there any additional treatment option?”

This project aims to set the groundwork for tackling these questions by advancing liquid biopsies (LB). LBs describe the usage of blood, urine or, especially in the case of brain tumours, cerebrospinal fluid (CSF), the water-like fluid that surrounds the brain. It has been shown recently that tumours shed their unique genetic pattern into the CSF.

The team plan to use this shed DNA, called cell-free tumour DNA and analyse it by various methods.

The goals are:
1) to allow for diagnosis at the time of or even before surgery
2), to allow the surgeon to optimally plan the tumour resection minimizing neurological deficits and reduce the waiting time for diagnosis and treatment initiation,
3) to allow for response monitoring throughout treatment deciphering changes in the tumour not being visible on radiological images,
4) to evaluate if the produced data allows for risk stratification, so that each patients receives as much therapy as they need, but not more, thereby minimizing long-term side effects;
5) to use LBs as an additional tool for recurrence monitoring, allowing for early detection and finally to analyse tumour evolution throughout treatment, allowing for an informed choice of targeted therapy in the case of recurrence. Moreover, the project is designed to develop the resources that these methods will be widely applied for patients leading to improved therapies in the near future. » : Project summary from the PI

« Ependymoma is the third most-common cancerous brain tumour in children and adolescents. Each year, between 200 and 300 children in Europe are diagnosed with ependymoma, and 50 to 60% of them will die from their disease. To date, the treatment for ependymoma mainly consists of brain surgery and radiation therapy since standard chemotherapies do not work well against this type of tumour. Even in the case of a cure, these treatment options often cause severe, life-long side effects, like severe cognitive impairment or hormone and growth deficiencies. The main challenge in the treatment of these tumours is that there are no effective treatment options for ependymomas that recur after initial therapy.

This project EUROPE aims at finding new cures for ependymoma by studying the tumour cells that survive the initial therapy and cause a disease recurrence.

To this end, the team will systematically compare the genetic information of cells isolated from pairs of primary and recurrent tumours from the same patient.

This way, they seek to understand which form of genetic changes enable cells to survive current treatment strategies and render them resistant against chemotherapy.

In addition, they will analyse which kind of cells communicate with each other within the tumour, and how normal cells influence the tumour growth. By combining all this aiming to identify biological vulnerabilities that could be used to design new drugs against recurring ependymoma.

In the next step, they will analyse how current treatment options used in the clinic are influencing the growth of ependymoma in mouse models. By integrating data from our analysis of human tumours and treatment trials in mice, they seek to understand how changes in the genetic code of resistant cells arise during cancer treatment.

In the last work package, this new knowledge will be applied to choose drugs that specifically target the cells which are causing a disease recurrence and that are resistant to our current therapeutic options.

In order to make sure that these drugs have a realistic chance to be translated into the clinic, they will also consider drugs that are not yet on the market but developed in cooperating laboratories.

By the end of this project, the team envision to have identified specific drug candidates that can then undergo intensive investigations to establish a new clinical trial for recurring ependymoma across Europe.

Lastly, all data from this project will be freely shared with the scientific community to enable as much progress as possible on the way to better treatments for children suffering from this devastating disease. »: Project summary from the PI

« Medulloblastoma represents around 60% of all paediatric brain tumours, accounting for approximately 650 newly diagnosed patients per year in Europe.

Group 4 medulloblastoma (G4MB) is the most common subgroup, comprising 40% of medulloblastoma cases.

Despite the high frequency of this malignant tumour, G4MB’s biology is not well understood, and specific treatments have not yet been developed.

Radiotherapy followed by chemotherapy is the standard treatment for G4MB patients, but results are poor: around 40% of patients experience cancer relapse, which is almost always fatal.

Therefore, there is an urgent need to develop specific treatments for those young patients, and in order to develop those treatments it is essential to understand the biology of G4MB.The biology of G4MB is not well understood in part due to the lack of preclinical mouse models and in vitro cell models.

This project, FIGHT4MB, aims at addressing this gap.

Successful generation of preclinical cancer models relies on the activation of specific genetic mutations in cells that will then form cancers: they are known as the cancer cells of origin. The genetic alterations that lead to G4MB were identified only within the last five years, and scientific evidence points at a specific type of neuron, called Unipolar Brush Cells, as the cell type from which G4MB arises.

In FIGHT4MB, the team aim to take the next step and develop the first preclinical models of G4MB.

To this end, they will generate new genetically engineered mouse models and in vitro cell-based models to test whether alterations in Unipolar Brush Cells leads to G4MB formation.

Next, they will validate that the generated models mimic human disease.

Finally, we will use these models to test therapy response to the current treatment regimen and identify which genes to target to avoid relapse following standard treatment.

Altogether, FIGHT4MB will develop the first models of G4MB, both serving as platforms to better understand the disease and as preclinical models to assess drug response prior to the start of clinical trials. FIGHT4MB will open the door to new therapeutic avenues for the young patients suffering from G4MB and ultimately improve their quality of life and life expectancy. »: Project summary from the PI