Abstract A041: The immunotherapeutic targeting of glioblastoma at the minimal residual disease state

Abstract Introduction: Glioblastoma (GBM) is the most common and deadliest primary brain malignancy in adults, with a staggering 90-95% of patients succumbing to the disease within 5 years. Despite an aggressive standard of care (SoC) treatment involving maximal surgical resection followed by radiotherapy and chemotherapy, GBM invariably recurs after about 7 months, at which point no standardized treatment protocol exists. Although chimeric antigen receptor (CAR) T cell therapy has been revolutionary for liquid cancers, its efficacy remains underwhelming in GBM. Tumor infiltration and molecular heterogeneity present significant hurdles to its efficiency in recurrent disease. Minimal residual disease (MRD) in GBM presents a valuable yet underutilized opportunity for pre-emptive intervention that can bypass these hurdles. Methods: Mice were intracranially injected with primary GBM cells to generate patient-derived xenografts (PDXs). A subset of these PDXs were treated with a PDX-adapted SoC regimen to model GBM at its lowest disease burden post-treatment. This stage of cancer progression represents MRD in our models. GBM cells were extracted at MRD and analyzed. Results: Bulk transcriptomics revealed a cell-surface CAR T cell target that is highly expressed at MRD. Further in silico analysis of transcriptomic and proteomic data from online datasets and our patient-derived cell lines corroborated this finding and showed that this target is overexpressed in GBM compared to normal tissue. Functional assays of recurrent GBM demonstrated a role for our target in promoting a protumor phenotype. Conclusions: The prevalence of our target at MRD presents an opportunity for immunotherapeutic targeting in newly diagnosed GBM patients. As such, we will investigate the efficacy of CAR T treatment against our target post-SoC. Ongoing work is aimed at developing and validating these CAR T cells. Immunotherapeutic intervention at MRD may delay recurrence by targeting GBM at its most vulnerable state, thereby improving patient outcomes and quality of life. Citation Format: Mohamed Taleb, Maleeha Qazi, Shan Grewal, William Maich, Darel Martinez-Bedoya, Lucas Asselstine, Chitra Venugopal, Denis Migliorini, Sheila Singh. The immunotherapeutic targeting of glioblastoma at the minimal residual disease state [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A041.