Abstract 4827: Cell state targeting CAR T cell therapies for glioblastoma

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Abstract Despite decades of concerted research and clinical efforts, patient outcomes in glioblastoma (GBM) remain dismal. The emergence of chimeric antigen receptor (CAR) T cell therapies offer great promise as immunotherapies in this disease. To date, efforts to utilize CAR T cell therapies in GBM have resulted in isolated reports of impressive efficacy in individual patients, but these have yet to generalize to larger trial populations. It is thought that inter and intra patient tumor heterogeneity contributes to the variability of these responses. Single cell RNA sequencing has demonstrated that this heterogeneity can be organized along axes representing cellular states. The ability of existing CAR T cell therapies to target these cell states is unclear, and the dynamics of this heterogeneity under the selective pressure of therapy is uncertain. We present the development of a panel of tool CAR T cells targeting cell state associated surface markers with the objective of selective targeting of these cellular states in GBM. We show that these CAR T cells have target specific activity against GBM model systems representing these cellular states. Using single cell RNA sequencing, we model the dynamics of these treatment effects, with the aim of understanding the mechanisms of GBM dynamics in response to the selective pressure of CAR T cell therapies. We demonstrate global shifts in the transcriptional landscape at the single cell level and identify state dependent and state independent effects. We anticipate that these cell state targeted CAR T cells have great potential to elucidate mechanisms of GBM adaptation to the selective pressure of CAR T cell activity and will inform foundational biology necessary for rational design of multi target constructs for therapeutic application. Citation Format: Christopher Mount, Emily Boxer, Sophia Kovatsis, Demi Gerovasilis, Sydney Dumont, Jun Zhong, Jack Lu, Itay Tirosh, Mario Suva. Cell state targeting CAR T cell therapies for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4827.

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