Gottardo N (Perth Children’s Hospital), Kotecha R (Perth Children’s Hospital), Robinson BWS, Creaney J, Redwood A.
Funding: Perth Children’s Hospital Foundation
Lay synopsis: Although immunotherapy is rapidly changing clinical management of adult cancers, these exciting new treatments are largely ineffective in childhood cancers. Two of Western Australia’s leading cancer clinician-researchers—Prof Nick Gottardo (recently awarded the 2022 Cancer Council WA Cancer Researcher of the Year) and Prof Bruce Robinson (2022 Cancer Council WA Researcher Career Achievement Award)—are partnering to crack one of the most important mysteries in cancer: why childhood cancers don’t respond to immunotherapy and how to change that.
Cancer is a leading cause of illness and death in Australian children. This project focuses on the two most common childhood cancers: acute leukaemias and brain tumours, which together account for more than half of childhood cancer cases. Despite improvements in survival rates, many aggressive and relapsed cancers remain difficult to treat, and current therapies cause severe side effects that impact survivors throughout their lives.
Part of the immune system’s regular function is to detect and destroy cancer cells. Cancer cells carry unique mutations that can be recognised by the immune system as foreign, called neoantigens. This collaborative team will study paediatric leukaemia and brain cancer samples to identify which neoantigens the immune system can potentially attack, determine how each child’s immune system responds (or fails to respond) to these neoantigens over time, and, excitingly, draft a clinical trial protocol based upon their discoveries.
This research could lead to entirely new therapeutic approaches that are more effective and less toxic than current treatments. By understanding why immunotherapies that work in adults fail in children, this platform study has the potential to transform how we monitor and treat childhood cancer.
Scientific synopsis: Immunotherapies that unleash or initiate immune responses have transformed treatment for some adult cancers, with immune checkpoint inhibitors showing remarkable success in advanced melanoma and neoantigen vaccines extending survival in deadly brain cancers.
However, clinical trials in children have not demonstrated the same efficacy outside of Hodgkin’s lymphoma. The reasons for this difference are not well understood.
This collaborative project establishes a discovery platform to characterise neoantigen profiles and immune responses in paediatric acute lymphoblastic leukaemia (ALL) and brain tumours. The team leverages established ZERO Childhood Cancer genomic data and NCARD’s Antigen Targeted Therapy Against Cancer (ATTAC) program, which employs state-of-the-art antigen discovery (ATTAC-MAP) calibrated to identify simple and complex neoantigens, including antigenic “dark-matter” missed by conventional mapping studies.
The project will study existing and approved samples and data from up to 100 children aged 6-16 years diagnosed with acute leukaemia or brain cancer. Advanced genomic, immunoproteomic, bioinformatic and immunoassay capabilities will be used to: (1) characterise neoantigen profiles including structural variants and peptide splice-variants; (2) determine the extent and type of T-cell recognition; (3) evaluate changes in immune responses over time; and (4) identify response patterns that correlate with clinical outcomes.
By discovering which neoantigens are present, which are loaded onto tumour cell surfaces, and which trigger immune responses, this platform will enable improved immune monitoring during therapy and inform the design of future immunotherapy clinical trials. The iterative approach ensures findings can be rapidly translated into clinical protocols, potentially enabling neoantigen vaccines, adoptive cell therapies, or improved CAR-T cell approaches for childhood cancers.