Abstract 6434: Senolytics decrease senescent microglia, remodel the vasculature, and improve survival in older adults with glioblastoma during co-treatment with immunotherapy

Abstract Background: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median overall survival (OS) of 15-18 months. The median age of a GBM diagnosis is 68-70 years old, and, increased subject age at the time of diagnosis is inversely associated with GBM patient OS such that older adults have significantly worse survival outcomes compared to similarly treated younger counterparts. Senescent cells accumulate in the body during progressive aging and contribute to worse outcomes in older adult mice with GBM. Senolytics are pharmacological compounds that cause senescent cells to undergo cell death. Objective: To comprehensively profile the treatment effect of senolytics combined with or without radio-immuno-therapy in mice with GBM across the lifespan. Methods: Young 7-9- and older adult 97-104-week-old wild-type (WT; C57BL/6) and 110-130-week-old INK-ATTAC (C57BL/6) mice with or without intracranial SB28 cells were treated with or without brain radiotherapy, PD-1 mAb, and an IDO enzyme inhibitor with the senolytics, dasatinib + quercetin, or the AP compound that induces p16INK4A+ senescent cell death in INK-ATTAC mice. Flow cytometric quantification of cells that are positive for beta-galactosidase, a marker for senescent cells, by flow cytometry was performed on brain-resident neurons, astrocytes, oligodendrocytes, as well as microglia in the tumor and non-bulk tumor mass brain parenchyma and correlated with overall survival. Immunofluorescence analysis of CD8+/granzyme A+ lymphocytes, CD68+/CD206+ macrophages, as well as endomucin+ endothelial cells was conducted across treatments and age groups. Results: The treatment with senolytics or AP compound decreases beta-galactosidase+ microglia in the older adult brain with GBM (p<0.05). Older adult mice with a brain tumor show a significant decrease of endomucin staining as compared to younger counterparts (p<0.05). Strikingly, treatment with senolytics reversed this effect in older adults. Combining radio-immuno-therapy with senolytics improved overall survival of older adult mice with intracranial GBM (p<0.05). Conclusions: Our ongoing work aims to understand how senescent microglia affect neuronal health and function in older adults with GBM, as well as how senolytic treatment-induced vascular remodeling is associated with enhanced immunotherapeutic efficacy. Citation Format: Manon Penco-Campillo, Lijie Zhai, Prashant Bommi, Patience Oluwatomilayo Odum, Kristen L. Lauing, Robert Ladd, Olaya de Dios, Irene Gómez-Soria, M Angeles Ramírez-González, Douglas E. Anderson, Anand V. Anand Germanwala, Vikram C. Prabhu, Jigisha P. Thakkar, Pilar Sanchez-Gomez, Derek A. Wainwright. Senolytics decrease senescent microglia, remodel the vasculature, and improve survival in older adults with glioblastoma during co-treatment with immunotherapy [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 6434.