Abstract P015: Targeting SPP1 to enhance CAR T cell therapy in glioblastoma: Implications for integrating radiation therapy in resistant solid tumors
Authors: Gholamin Sharareh , Natri Heini , Zhao Yuqi , Xu Shengchao , Aftabizadeh Maryam , CominAnduix Begonya , Saravanakumar Supraja , Masia Christian , Wong Robyn , Peter Lance , Chung Mei-i , Mee Evan D. , Aguilar Brenda , Torrejon Davis Y. , Kalbasi Anusha , Alizadeh Darya , Wu Xiwei , Ribas Antoni , Forman Stephen , Badie Behnam , Williams Terence M. , Banovich Nicholas E. , Brown Christine E. 
Published: January 2025

In the evolving landscape of glioblastoma (GBM) treatment, clinical trials exploring chimeric antigen receptor (CAR) T cell therapies have shown promise; however, their therapeutic efficacy remains constrained, particularly due to the immunosuppressive tumor microenvironment (TME). Emerging evidence highlights that the TME, especially myeloid-driven suppressive networks, plays a central role in resistance to CAR T cell therapy. Despite progress in elucidating these mechanisms, significant ambiguities endure, particularly regarding patient-specific TME heterogeneity and its impact on therapeutic outcomes. Radiation therapy remains a cornerstone in GBM management, known not only for its direct cytotoxic effects but also for its ability to modulate the TME and potentially enhance immune responses. However, the combination of radiation with CAR T cell therapy has not been fully explored, particularly in the context of targeting suppressive myeloid subsets. Recent studies suggest that radiation may induce immunogenic changes within the TME, potentially enhancing CAR T cell infiltration and activity. Our study seeks to investigate how targeting key suppressive mediators, such as SPP1-expressing macrophages, can reshape the TME, setting the stage for combinatorial approaches that leverage the immunomodulatory effects of radiation therapy In this study, we utilized single-cell RNA sequencing to analyze tumors from 41 glioma patients undergoing IL13Rα2-targeted CAR T cell therapy. Our findings revealed heightened suppressive extracellular matrix (ECM) remodeling and immunosuppressive signatures driven by SPP1-expressing myeloid cells, predominantly in non-responsive tumors. Elevated SPP1 expression and increased infiltration of SPP1+ myeloid cells were associated with poor clinical outcomes. Functional transcriptomic analyses demonstrated that SPP1-high macrophages exhibited reduced antigen presentation, impaired phagocytosis, and enhanced ECM biogenesis, coupled with elevated lipid metabolism and non-glycolytic ATP production. These metabolic adaptations were linked to a suppressive immunophenotype that hindered CAR T cell efficacy. To explore therapeutic strategies, we assessed the impact of SPP1 blockade in preclinical syngeneic glioma models. Pre-treatment with anti-SPP1 antibodies prior to CAR T cell infusion significantly reprogrammed the TME, enhancing CAR T cell efficacy and reversing resistance in previously non-responsive models. These results highlight the potential of targeting SPP1 to disrupt suppressive macrophage networks, thereby augmenting CAR T cell responses. Our findings underscore SPP1 as a promising target to overcome resistance in CAR T cell therapies for GBM. This study lays the groundwork for future integration of targeted therapies, such as SPP1 inhibition, with radiation therapy to potentially improve therapeutic outcomes in resistant gliomas, offering new avenues for combinatorial therapeutic innovation.

Citation Format: Sharareh Gholamin, Heini Natri, Yuqi Zhao, Shengchao Xu, Maryam Aftabizadeh, Begonya CominAnduix, Supraja Saravanakumar, Christian Masia, Robyn Wong, Lance Peter, Mei-i Chung, Evan D. Mee, Brenda Aguilar, Davis Y. Torrejon, Anusha Kalbasi, Darya Alizadeh, Xiwei Wu, Antoni Ribas, Stephen Forman, Behnam Badie, Terence M. Williams, Nicholas E. Banovich, Christine E. Brown.Targeting SPP1 to enhance CAR T cell therapy in glioblastoma: Implications for integrating radiation therapy in resistant solid tumors.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P015