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

The five-year survival of pediatric patients with high-grade gliomas is ~25% in children and glioma deaths account for the largest proportion of pediatric cancer deaths under the age of 4. The long-term goal of this study is to develop new and effective immunotherapy for pediatric glioblastoma (GBM). We have significantly contributed to the concept that certain types of immunogenic cancer cell death (ICD) modalities can emit biomolecules to reinstate multiple aspects of the anticancer immunity cycle. However, many human tumors, including GBM, down-regulate as well as mutate cell death effector proteins to hide from natural and chemo-radiotherapy induced immune attacks. We postulate that reconstituting selective ICD modalities by expressing central drivers of immune-stimulatory cell death from a cancer-killing (oncolytic) virus (OV) can bypass tumor evasion strategies to exploit the full potential of ICD, resulting in a much higher therapeutic efficacy by converting non-T cell inflamed pediatric GBM into de novo vaccines. Supporting this hypothesis, we have data showing inducible activation of selective ICD modalities can prevent tumors in up to 85% of treated mice. In addition, inducible activation of selective ICD modalities in OV infected human and murine GBM permits the emission of immunomodulatory secretomes. In this project we will define how selective induction of ICD in OV infected GBM dictates the early intra-tumoral inflamed state (Aim 1) to shape the magnitude and functionality of T cells and their anticancer effect (Aim 2). Overall, this study will develop a new approach to attack pediatric GBM that often lacks intra-tumoral T cell infiltrate. We have cutting-edge technologies, human and mouse GBM model systems, as well as a team of excellent scientists and pediatric neuro-oncologists to successfully complete this project and translate the findings. In addition, the new knowledge will be disseminated to the knowledge users through publications and lectures.