CARINA clinical trial aims to find better treatments for children whose Acute Myeloid Leukaemia does not respond to standard treatment (refractory disease) or whose disease returns after initial treatment (relapsed disease).

Acute Myeloid Leukaemia (AML) is a type of blood cancer that starts in the bone marrow – the soft tissue inside bones where blood cells are made. In AML, the bone marrow produces too many immature white blood cells. These abnormal cells do not work properly and crowd out healthy blood cells, preventing them from performing their normal functions. Although AML is more common in adults, it can also affect children – about 600 are diagnosed with the disease each year in Europe. Many children do not respond to treatments or relapse, and in these cases the therapeutic options are very scarce.

The phase I (first-in-human) CARINA clinical trial will test a novel form of immunotherapy called CAR T-cell therapy. In this approach, a patient’s T cells – a type of white blood cell that normally eliminates infections and abnormal cells – are taken from the blood and genetically modified in the laboratory with a “molecular radar” that helps them recognise and attack leukaemia cells.

These therapies are usually made from the patient’s own blood cells, so there is a waiting period before treatment can start. A major innovation of this study is the use of an “off-the-shelf” CAR T-cell product, meaning the therapy is not custom-made for each patient but instead uses T cells obtained from healthy donors. This approach allows for faster treatment, avoiding dangerous delays that can occur while waiting for personalised cell manufacturing. Moreover, donor-derived T cells are often stronger and more effective than those taken from patients who have already undergone intensive chemotherapy.

Building on promising early results, the researchers aim to further enhance how these modified T cells recognise AML cells – a key challenge that has limited the effectiveness of CAR T therapy in this disease. If successful, this study could bring new hope not only for children with relapsed or refractory AML but also for other paediatric cancers being treated with CAR T therapy.

The goal of the INTERB-NHL-2025 clinical trial is to reduce treatment-related toxicities in children with B-cell non-Hodgkin lymphoma.

B-cell non-Hodgkin lymphoma (B-NHL) is a cancer that occurs when certain white blood cells, called B cells, which normally fight infections, start growing out of control. These abnormal cells can form lumps (tumors) in the lymph nodes (in the neck, armpits, or groin) and other blood-forming organs such as the spleen, bone marrow, or even other parts of the body. Doctors classify the disease as high-risk or standard-risk. High-risk B-NHL spreads quickly and is harder to treat, while standard-risk grows more slowly and usually responds well to therapy. Around 40% of children with B-NHL have the standard-risk type, and survival rates reach 96–98% with chemotherapy alone. However, the main drug used, doxorubicin, often causes severe side effects such as mouth sores, fever, and infections in more than 70% of patients.

The INTERB-NHL-2025 clinical trial aims to reduce these toxic side effects without lowering treatment success. Researchers will test whether new drug, rituximab, can safely replace some or all of doxorubicin. Rituximab works like a guided missile – it binds specifically to B cells and helps the immune system identify and destroy them, limiting damage to other healthy cells. To ensure that treatment effectiveness is not compromised, doctors will first check if a child’s cancer has a particular genetic mutation that makes it harder to treat. If the mutation is present, the doxorubicin dose will be cut in half. If not, it will be omitted entirely.

If successful, this study could change routine treatment for standard-risk B-NHL, helping children avoid severe side effects while keeping excellent survival rates.

The goal of the INTER-EWING-1 clinical trial is to improve survival and reduce treatment-related toxicities in Ewing Sarcoma patients.

 Ewing Sarcoma (ES) is a rare cancer that usually starts in bones or the soft tissues around bones, like muscles or cartilage. It most often affects children, teenagers, and young adults.

In about one in four patients, the disease has already spread to the lungs by the time it is diagnosed. When this happens, the chances of survival drop to around 30–36%, compared with much higher rates for patients whose cancer has not spread (85% survival). The standard treatment includes chemotherapy, surgery, and sometimes radiotherapy. The INTER-EWING-1 clinical trial is open to patients aged two years and older in Europe, Australia, and New Zealand, making it possible to recruit enough participants for what is a very rare type of cancer. Doctors will test whether adding an extra drug called regorafenib to the standard chemotherapy can improve survival for patients whose disease has spread. Regorafenib targets a weak point in certain tumour cells, helping to block their growth and spread.

Additionally, researchers will perform lab studies on biological samples (blood or tumour tissue) collected from these patients, to predict which patients are likely to respond to this new treatment scheme.

If this approach is proven to help, it could become the new standard treatment for the the patients with advanced form of ES who are likely to benefit from it, providing individually-tailored treatment plans for children and young adults with this rare challenging disease.

The goal of the CRYSTAL-Immune project is to have better immunotherapy treatments for childhood leukaemia in the brain.

 Acute Lymphoblastic Leukaemia (ALL) is a type of cancer of the blood and bone marrow – the soft tissue inside the bones where blood cells are made. ALL starts when the bone marrow is making too many immature white blood cells called lymphoblasts. These cells don’t work properly and crowd out healthy blood cells that body needs. ALL is most common in children between 2 and 10 years old, and is the most common childhood cancer.

ALL cancer cells can spread to the brain and spinal cord, also called the central nervous system (CNS). To prevent the disease from coming back, all children with ALL receive several spinal injections of chemotherapyto eliminate any leukemia cells “hiding” in the CNS. This treatment is very effective – about 9 out of 10 children are cured – but it can also cause serious side effects. Around 4 out of 10 children develop learning and memory problems due to the effect of chemotherapy on the brain. New immunotherapy treatments that help the body’s immune system destroy leukaemia cells in the bone marrow have shown great success and fewer side effects. However, they don’t work well in the CNS, and researchers still don’t fully understand why.

The CRYSTAL-Immune project aims to find out how the immune cells and immunotherapies function in the CNS. Researchers will study spinal fluid samples routinely collected from children treated for ALL. Using advanced laser and imaging technologies, they will create a detailed “atlas” of immune cells in the CNS, showing their types, numbers, and locations. The team will also test how low nutrient levels in the CNS affect immune cells and explore ways to boost their cancer-eliminating power.

By the end of the project, researchers aim to develop new prototype treatments that could make CNS therapy for ALL more effective and gentler, improving both survival and quality of life for children.

The EurATRT project aims to shed light on Atypical Teratoid Rhabdoid Tumors (ATRT) – a very rare and aggressive childhood cancer that remains poorly characterised due to the lack of comprehensive research and limited availability of patient samples.

Atypical Teratoid Rhabdoid Tumors (ATRT) are very rare and aggressive cancers of the brain and spinal cord, representing only 1–2% of all childhood cancers. They most often occur in children under the age of three. Even with the strongest treatments – a combination of surgery, chemotherapy, radiotherapy, and sometimes a stem cell transplant – only about 4 in 10 children survive. Sadly, many survivors live with serious long-term side effects caused by these treatments.

Because ATRT is so rare, doctors and researchers still don’t fully understand why some children respond well to treatment while others don’t, or how to spot when the cancer is coming back (relapses) early enough to act quickly. The EurATRT research project is based on the largest international ATRT clinical trial, which collects samples, such as blood and  tumour fragments, from children around the world. Given how rare this cancer is, building a collection of samples like this is exceptionally valuable and challenging. Using these samples, scientists will look for biological clues (biomarkers) that can predict how a child will respond to therapy and help detect relapses sooner. Researchers will also grow tumor cells from patients in the lab, so they can test new drugs safely and quickly outside the body before trying them in children.

The results of this project could help doctors adapt treatments to each child, reduce harmful side effects, detect relapses earlier, and discover new therapies for those who don’t respond to current treatments.

The SIGBMRRI project uses state-of-the-art technologies to reveal why some of the most aggressive brain tumours resist radiotherapy and immunotherapy, and how this resistance might be overcome.

Brain tumours are the most common type of cancer in children under 19 years old and cause more deaths than any other childhood cancer. About half of all childhood brain tumours are gliomas or ependymomas. Gliomas develop from the brain’s support cells, called glial cells, while ependymomas start in the cells that line the fluid-filled spaces around the brain and spinal cord. The most aggressive forms of these cancers have very poor survival rates and, sadly, few or no effective treatment options.

A tumour is not made up of cancer cells alone — these cells live in a complex “neighbourhood”, called the tumour microenvironment (TME). This environment includes blood vessels that feed the tumour, immune cells that could destroy cancer but are sometimes “tricked” into helping it grow, support cells and fluids that form the structure around it, and chemical signals that help the cancer cells communicate.

Researchers working on the SIGBMRRI project believe that TME plays a key role in helping aggressive, treatment-resistant tumours survive. In this project, scientists will study tumour samples from patients and advanced laboratory animal models to map how tumour cells interact with their surroundings. Using cutting-edge technologies, they aim to find weak points in these interactions that could be targeted by treatments relying on the patient’s own immune system (immunotherapy) and to understand how the TME changes during this type of therapy. Researchers also aim to discover which elements of the tumour’s surroundings help it resist radiotherapy and immunotherapy, and explore how these barriers can be overcome.

This research could open the door to more effective, targeted treatments for children with aggressive and treatment-resistant brain tumours.