Grant: Operating Grant: SickKids-CIHR-IHDCYH New Investigator Grants

High-grade glioma is a highly fatal and devastating pediatric brain cancer, in part due to the inability to completely resect the tumour from the intertwined normal brain tissue and the development of chemoresistance. Hence, new and effective therapies are urgently needed for this type of refractory brain cancer. Effective cancer immunotherapies have been recently developed that employ antibodybased drugs to overcome the ability of tumour cells to suppress a host immune-mediated attack. These biologics, called immune checkpoint inhibitors (ICIs), are demonstrating efficacy in a remarkable number of different cancers and are being tested in adult and pediatric patients with brain tumours. I postulate that ICI treatment in combination with a class of small molecules called Smac mimetic compounds (SMCs) have the potential to target gliomas by allowing the body to attack and kill cancer cells in situ. My data demonstrate that I can cure the majority of mice with brain gliomas using this therapeutic strategy. In this proposal, I will decipher the immunomodulatory properties of SMCs that potentiate ICI function and identify the mechanisms of resistance to immunotherapies. Overall, my proposed study will add insight into the importance of cytokine production and immune cell responses to enhance the efficacy of anti-cancer immunotherapies. Moreover, I expect that the data will provide the justification to undertake a combination approach for the treatment of pediatric gliomas.