EXTH-37. Evaluating cell state-targeting CAR-T cells in glioblastoma

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Abstract Despite decades of concerted research and clinical efforts, patient outcomes in glioblastoma (GBM) remain dismal. While chimeric antigen receptor (CAR)- T cell therapies in GBM have produced individual reports of efficacy, they have yet to meaningfully alter standard of care. Tumor heterogeneity, both inter- and intra-patient, likely contributes to these variable responses. Single-cell RNA sequencing (scRNA-seq) conducted in our lab has revealed that this transcriptional heterogeneity is organized along distinct cellular state axes. We sought to overcome this heterogeneity by designing CAR-T cells directed against these cellular states. We hypothesize that CAR-T cells targeting a defined GBM cell state will lead to a depletion of those populations. We report the development of a panel of cell state-targeting CAR-T cell candidates engineered for target-specific activity in vitro. To model the three-dimensional tumor environment, we developed patient-derived GBM organoids that recapitulate the cell state landscape seen in primary tumors. We treated GBM organoids with these cell state-targeting CAR-T cells and assessed cell states by scRNA seq. Unexpectedly, we observed convergent transcriptome shifts to a new cell state with overlapping features of mesenchymal (MES) and interferon-induced signatures. To target this dynamic, we designed a novel CAR-T cell directed against this population and observed feedforward target enrichment in response to therapy. We anticipate that our findings will inform rational design of translational CAR-T cell candidates for GBM patients.

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