OS09.6.A IMMUNOLOGICAL CHANGES AFTER IDH-INHIBITION IN LOW-GRADE GLIOMA PATIENTS

Abstract BACKGROUND IDH inhibition in patients with CNS WHO grade 2 low-grade glioma is associated with significantly improved progression-free survival and delayed time to next intervention. While the precise antitumor mechanisms of IDH inhibition-especially its effects on the immune system-remain unclear, it is known to markedly reduce intratumoral levels of the oncometabolite R-2-hydroxyglutarate (R-2-HG). Given that R-2-HG suppresses antitumor T cell immunity in low-grade glioma, we hypothesized that IDH inhibition would enhance antitumor T cell activation. MATERIAL AND METHODS Peripheral blood mononuclear cells (PBMCs) were collected from seven patients before and after 28 days of daily Vorasidenib (40 mg) treatment. Single-cell RNA sequencing of PBMCs was performed using a microfluidic platform. Cell populations were clustered, and differential gene expression was analyzed before and after treatment. 5′-libraries were generated for simultaneous assessment of gene expression and T cell receptor (TCR) repertoires. TCR data were used to evaluate clonal expansion within T cell subsets. RESULTS Gene expression data from 238,868 cells (median 31,787 genes per cell) revealed 16 distinct PBMC subpopulations, including myeloid and lymphoid lineages. In total, 148,210 T cells were analyzed for TCR clonality. IDH inhibition was associated with clonal expansion of CD8+ effector T cells in all seven patients. CONCLUSION To our knowledge, this is the first study to explore the immunomodulatory effects of IDH inhibition in low-grade glioma patients. Our data reveals systemic activation and clonal expansion of T cells following Vorasidenib treatment. Further analyses of the antitumor specificity of these proliferating T cell clones are ongoing.