Funded by The Little Princess Trust and administered by CCLG
Lead investigator: Dr Laura Donovan, Institute of Child Health
Award: £118,148.93
Awarded December 2020
Medulloblastomas (MBs) are the most common cancerous brain tumours of children.
Group3 MBs are the most aggressive type as they have the ability to spread through the brain and spinal cord. By time of diagnosis, group3 MBs have frequently metastasized, with overall survival depending heavily on the presence/absence of metastatic disease.
Conventional treatment regimens include surgery, radiotherapy (in children aged 3 or over) and high-dose chemotherapy, and as a result many children are over-treated with non-specific therapies causing long-term developmental and neurological side-effects.
Chimeric antigen receptor T-cells (CARTs) are a branch of immunotherapy which involves reprogramming the patient’s own immune cells to fight a specific cancer. The lead supervisor’s research has shown CARTs are a successful therapy against cerebellar brain tumours. Immunotherapeutic strategies are now at the forefront of anti-cancer therapy, especially in leukaemia.
However, with the majority of patients developing a resistance to the immunotherapy over time, enhancing sensitivity and persistence to these therapies is crucial to improve patient outcomes.
IL13RA2 is a molecule found on the surface of MB primary tumours and tumour metastases. As a target for CART therapies, IL13RA2 has shown extraordinary results for the treatment of adult brain tumours. We hypothesise that IL13RA2 CARTs can be leveraged as a safe and effective therapy against group3 MB.
Using novel genetic modification techniques, we will re-engineer patient’s IL13RA2 CARTs, reversing T-cell exhaustion, thereby enhancing persistence. Persistence of CART cell activity will be further increased by addition of a well-tolerated drug that both increases survival of T-cells whilst also being toxic to tumour cells.
High-throughput biological and molecular characterisation of these combination strategies will be evaluated in tissue culture and in animal models using patient-derived group3 MB cells. The project addresses the two major obstacles for MB treatment, the toxicity of current standard of care, and the lethality of the metastatic disease.