Abstract A002: CCR5 inhibition with the human monoclonal antibody leronlimab enhances temozolomide- and radiation-induced killing of glioblastoma multiforme cells

Abstract Introduction. Glioblastoma multiforme (GBM) is associated with short survival and resistance to DNA-damaging agents (radiation (RT), temozolomide (TMZ)) and immune checkpoint inhibitors (ICI). Spatially resolved GBM sequencing identified microenvironment-driven gene expression programs in the tumor core vs invasive edges. The core often exhibits a mesenchymal-like (MES) gene signature, which is associated with increased tumor growth, immunosuppression, and heterotypic signals that augment cell activity at the tumor margin. Some glioma stem cells (GSCs) in the core are more resistant to chemotherapy and radiation. The hypoxic nature of the core draws a heavy infiltration of immune-suppressive cells. Methods. The current studies were conducted to determine the potential role of CCR5 in GBM therapeutic responses. Analysis of patient GBM gene expression and analysis of GBM cell lines were conducted to define the potential role of CCR5 inactivation as a therapeutic adjunct to current treatments. Results. We found in GBM (Primary tumor, N=154), CCR5 expression was significantly higher in GBM than in normal brain tissue, correlating with poor prognosis. CCR5 expression correlated with the “core” and not the “leading edge” GBM signature; and correlated with hallmarks of glycolysis, hypoxia, and inflammatory response. CCR5 was enriched the MES GBM subtype, associated with T cell exhaustion markers (PD-1, PD-L1, TIM3, PTX3), immune suppressive S100A4. Single-cell sequencing evidenced expression of CCR5 and its ligand CCL5 in the GBM tumor microenvironment (TME) and tumor glial cells (glycolytic/plurimetabolic (GPM) and mitochondrial (MTC) metabolic subtypes). CCR5 abundance on human GBM cell lines, of MTC expression type, increased upon neurosphere formation. CCR5 inhibition with leronlimab (humanized monoclonal antibody) or maraviroc (small molecule inhibitor) conveyed functional synergy in GBM cell killing by TMZ. Pretreatment with leronlimab enhanced GBM cell killing by RT. As glycolysis promotes recruitment of immunosuppressive cells into the TME, we assessed the impact of CCR5 inhibition on GBM oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) by Seahorse analysis. CCR5 inhibition reduced GBM OCR in a dose-dependent manner. Conclusions. CCR5 is overexpressed in GBM subtypes, correlating with a core, glycolytic, and immunosuppressive TME signature. CCR5 inhibitors synergize with TMZ and RT to kill GBM cells, reduce the production of acidic metabolites from cultured GBM cells, which are known to promote an immune suppressive TME. Leronlimab has been shown to be well-tolerated, crosses the blood-brain barrier in rhesus monkeys, and shows encouraging long-term survival in breast cancer with ICIs. As these findings suggest further exploration of leronlimab in GBM is warranted, a pilot study in second-line therapy is being planned, combining leronlimab with an ICI. Citation Format: Danni Li, Ritika Harish, Zhiping Li, Xuanmao Jiao, Neil E. Buss, Luciano Garofano, Jinan Behnan, Jacob P. Lalezari, Richard G. Pestell. CCR5 inhibition with the human monoclonal antibody leronlimab enhances temozolomide- and radiation-induced killing of glioblastoma multiforme cells [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 A002.