Project title: Enhancing CAR T-cell expansion and prolonged persistence for the effective treatment of paediatric medulloblastoma
Lead investigator: Dr Laura Donovan
Institution: Institute of Child Health
Award: Approx. £120,000 (funded by The Little Princess Trust and administered by CCLG)
Medulloblastomas are the most common malignant brain tumours in children, and Group 3 medulloblastomas are the most aggressive group. These tumours often spread throughout the brain and spinal cord before a child is even diagnosed (called metastatic disease), and survival is strongly linked to whether the cancer has spread.
Our research project emerged from a clear clinical need: to find safe, targeted therapies that can treat both primary and metastatic disease while minimising long-term toxicity. Current treatments, surgery, radiotherapy and high-dose chemotherapy, can save lives but are extremely harsh. Many children experience long-term neurological and developmental side effects because these treatments are non-specific and often more intensive than necessary. Immunotherapies like CAR T-cell therapy, which train a patient's own immune cells to recognise and attack cancer cells based on specific markers on their surface, have revolutionised the treatment landscape for some cancers. However, many patients with medulloblastoma eventually develop resistance.
Our group’s previous work showed that CAR T-cell therapy could be effective for medulloblastoma. We identified a molecule found on medulloblastoma cells, both from the initial cancer and metastatic disease, called IL13RA2. CAR T-cells that target IL13RA2 have already produced extraordinary results in adult brain tumours, so we wanted to see if we could redesign IL13RA2 CAR T-cells to overcome treatment resistance for childhood Group 3 medulloblastoma.
We set out to re-engineer IL13RA2 targeted CAR T-cells to reverse the process of T-cell exhaustion, one of the main reasons immunotherapies lose effectiveness over time. In aggressive and metastatic cancers such as Group 3 medulloblastoma, CAR T-cells are repeatedly stimulated by tumour antigens and gradually become ‘exhausted’, losing their ability to fight the cancer. To prevent T-cell exhaustion, we had to activate a protein called ß-catenin that can affect T-cells’ behaviour. ß-catenin helps enable the T-cells to endure for longer periods and mount a strong response when they encounter tumour cells.
By enhancing ß-catenin activity, we effectively counteracted T-cell exhaustion. The engineered CAR T-cells are more able to self-renew, survive for longer, and resist suppression. As a result, they retain their ability to seek out and destroy tumour cells over a much longer period than standard CAR T-cell designs.
In the lab, we found this combination treatment has improved persistence, reduced exhaustion, and enhanced anti-tumour activity. This work lays the foundation for next generation engineered immunotherapies for childhood brain tumours. If our strategies prove effective, they could be extended to other resistant or metastatic paediatric cancers.
With more research, this approach could transform the treatment of Group 3 medulloblastoma by offering a highly targeted therapy that avoids the long-term harm caused by chemotherapy and radiotherapy. By redesigning immunotherapy at the molecular level to target metastatic disease while sparing healthy tissue, we aim to bring safer, more effective, and more durable treatments to the children who need them most.
From Contact magazine issue 110 | Spring 2026
