In both adults and children, aggressive primary brain tumours have an almost uniformly fatal outcome. These patients face abysmal 1-5% five-year survival rates that have shown little improvement over the last 30 years. CAR-T cell immunotherapy has achieved significant breakthroughs in the treatment of hematological malignancies, but are as yet unproven in the solid cancer setting. Nevertheless, the recent report of a complete remission lasting 8 months in a glioblastoma (GBM) patient receiving CAR-T therapy has ignited interested in CAR-T cells for the treatment of brain cancer. We are currently developing 3rd-generation, GD2-specific CAR-T cells for the treatment of both adult glioblastoma and childhood diffuse midline glioma (DMG). We have previously successfully translated this CAR-T cell platform into a phase I clinical trial in melanoma and other solid cancer patients. We have now validated CAR-T cell manufacturing using blood derived from GBM and DMG patients, and shown that these cells can effectively kill early-passage patient-derived Glioma Neural Stem cells (GNS). Furthermore we have performed extensive profiling of fresh and fixed GBM and DMG tissues using immunohistochemistry, flow cytometry and single cell RNAseq to show expression of our antigen of interest (GD2) but also to investigate the immune contexture of these tumours, something which is still not fully characterised. Finally, we have also identified a unique homing molecule expression profile for our CAR-T cells that we believe will promote their trafficking to the brain, and we have begun preclinical testing these in a orthotopic xenograft model of GBM in mice. Together these data provide the rational for two new phase I CAR-T cell trials: in adult glioblastoma patients at the Royal Adelaide Hospital and pediatric diffuse midline glioma patients at the Sydney Children's Hospital.