EXTH-40. DIPGS SUPPRESS THE EFFICACY OF T CELL THERAPIES THROUGH DYSFUNCTIONAL IMMUNE SYNAPSE FORMATION

Abstract Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal pediatric brain tumors. Thus, there is an urgent need for novel therapeutics. While chimeric antigen receptor (CAR) T-cell therapy has the potential to meet this and early phase clinical studies with CAR T cells have shown safety some efficacy, additional needed understand lack of efficacy against DIPGs. The goal study was identify cell limiting factors in DIPG setting. To that, we focused on targeting GRP78, endoplasmic reticulum chaperone protein that broadly expressed surface We generated GRP78-specific compared their effector function U87 glioma patient-derived DIPG007 line. Despite GRP78-CAR recognize kill tumor vitro, they were only effective vivo. In addition, vitro cytokine production proliferation heavily diminished DIPG007, U87. For full activation, require a cell-to-cell interaction formation organized structure called immune synapse (IS). Experiments using confocal microscopy showed IS quality, measured as lytic granule accumulation cytoskeleton organization at IS, impaired when This dysfunctional correlated poor activation (calcium flux) determined by live imaging. observed same regardless specificity targeted expression level, indicating suppressive effect mediated. summary, demonstrate DIPGs suppress through formation. now testing genetic engineering approaches directed improving overcome effects