EXTH-81. Developing cell-state guided chimeric antigen receptor (CAR)-T cell therapies for IDH-mutant glioma

Abstract

Abstract Isocitrate dehydrogenase (IDH)-mutant glioma is the most common primary brain tumor diagnosed in patients younger than 50 years old. While IDH inhibitors have shown promise for patients with low-grade disease, patients with higher-grade tumors still have limited treatment options and face poor clinical outcomes. Chimeric antigen receptor (CAR)-T cell therapies have demonstrated potential in other molecularly-distinct gliomas, but directing this immunotherapeutic strategy towards IDH-mutant glioma remains largely unexplored. Our prior work using single-cell RNA sequencing (scRNAseq) has defined a hierarchical model of transcriptional states in IDH-mutant glioma, including a central ‘stem-like’ population that is enriched for cycling cells and drives overall disease progression. We hypothesize that targeting this stem-like population in IDH-mutant glioma using CAR-T cell therapy will enable effective control of these tumors. To design CAR constructs that target this population, we performed in silico screening of scRNAseq data from IDH-mutant glioma patient samples to identify highly expressed genes associated with the stem-like surfaceome. Candidate targets with publicly available single-chain variable fragments (scFvs) were engineered into tool 2nd generation CARs and screened for antitumor activity against patient-derived IDH-mutant glioma models. Coculture assays demonstrated in vitro cytokine production and antitumor cytotoxicity against these patient-derived models. Additionally, we demonstrate the ability of these CAR-T cells to clear an aggressive patient-derived orthotopic IDH-mutant glioma xenograft model and significantly extend survival. In summary, our findings validate the potential of a cell state-directed strategy to identify CAR-T cell targets in IDH-mutant gliomas that may inform future translational efforts.