Neuroblastoma is the most common extracranial paediatric solid tumour, and it accounts for over 15% of cancer childhood deaths. High-risk patients undergo extensive multimodal treatment, but relapse/progression rates remain over 70%. In the last decade, the use of cell immunotherapy has resulted in a significant increase in survival for haematological cancers, but solid tumours remain a challenge. This problem is enhanced in paediatric solid tumours due to the low mutational burden, the high heterogeneity, and the strongly immunosuppressive tumour microenvironment. This project aims to combine two novel therapeutic approaches to overcome these challenges.
Ferroptosis is a recently described type of programmed cell death that depends on iron accumulation and lipid peroxidation. Ferroptosis not only is immunogenic, being able to reverse the immunosuppressive tumour microenvironment, but can also be triggered by multiple drugs with different mechanism of action, opening the door to personalized therapy. Our main goal is to combine ferroptosis-inducing agents with natural killer (NK) cell immunotherapy. We hypothesize ferroptosis induction will promote NK cell infiltration in the tumours. Meanwhile, once the immunosuppressive environment has been overcome, the NK cells will be able to target neuroblastoma cells better than other immunotherapies, as they don´t depend on specific targets/mutations.
Furthermore, the high heterogeneity of neuroblastoma, along with the variety of ferroptosis induction mechanism, might complicate the personalized matching of patient and treatment. In the later years, mathematical oncology modelling has risen as a powerful tool to predict tumour response and improve personalized medicine.
The main objectives we expect to achieve with this project are:
1) To characterise the immune response triggered by ferroptosis in neuroblastoma
2) To identify and validate at least one combination of ferroptosis-inducing agents and NK cells
3) To generate a mathematical model that can assist combination selection based on tumour characteristics and mechanism of action of the drugs
On top of these scientific objectives, we also aim to achieve training and career development achievements and communication goals, both to the scientific community and the general society.
