P08.01.A CELL STATE TARGETING CAR T CELL THERAPIES FOR IDH MUTANT GLIOMAS

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Abstract BACKGROUND Although targeted therapies have significantly altered the treatment landscape for patients with low grade IDH mutant gliomas, patients with high grade disease still face limited treatment options. Chimeric antigen receptor (CAR) T cell therapies may offer a new therapeutic strategy for these patients. Emerging translational evidence in other high grade gliomas suggests these therapies have promising potential for these patients, although heterogeneous responses in trial cohorts emphasize the need for individualized design of these therapies according to the biology of the targeted disease. Our laboratories have used single cell RNA sequencing (scRNAseq) to define cell states in IDH mutant gliomas, and have identified a stem-like cell population that may drive disease progression in these patients. We hypothesize that cell surface antigens associated with the stemlike cell state represent actionable targets for CAR T cell therapies in IDH-mutant gliomas. MATERIALS AND METHODS We report screening of a panel of CAR T cells designed against these targets. CAR T cell constructs were generated using scFv candidate sequences from established monoclonal antibodies. Targets were selected by review of scRNAseq datasets from our laboratories. In vitro models consist of patient derived gliomasphere cultures, as well as patient derived tumor organoids. CAR T cell activity was evaluated in these systems by cytokine generation and cytotoxic potential. In vivo studies were conducted using patient derived xenografts. CAR T cells were administered by systemic injection and tumors were monitored by in vivo bioluminescence imaging. In these systems, we report the use of scRNAseq to monitor stemlike state targeting with these CAR T cells. RESULTS We identify several candidates with activity against IDH mutant glioma models both in vitro and in vivo, including the ability to clear aggressive models of IDH mutant gliomas from in vivo xenografts. Using scRNAseq, we report the dynamics of transcriptional response of IDH mutant glioma models under the selective pressure of therapy to evaluate the effectiveness of stemlike state targeting. Treated models examined by scRNAseq show depletion of cells with stemlike state scores, potentially due to tumor plasticity. CONCLUSION Taken together, our findings support the use of scRNAseq to design targeting strategies for CAR T cell therapies in IDH mutant gliomas.

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