P06.06 Clever-1 blockade as a potential immunomodulatory treatment for brain tumors

Background Common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) is a scavenger receptor expressed primarily by lymphatic and sinusoidal endothelial cells and immunosuppressive macrophages. 1 Clever-1 expression is upregulated in several types of cancer and is associated with poor prognosis. Bexmarilimab, an inhibitory antibody targeting Clever-1, has demonstrated clinical benefit in subsets of patients with advanced solid malignancies by reprogramming immunosuppressive macrophages, enhancing their antigen presentation, and activating adaptive immunity.2 Initial survival analyses of patient-derived brain tumor tissues stained for Clever-1 expression revealed a strong correlation between higher Clever-1 expression and poor overall and progression-free survival. Based on these findings, our study investigates the potential of macrophage reprogramming with bexmarilimab as an immunomodulatory treatment for pediatric and adult brain tumors, that are characterized by a macrophage-rich tumor microenvironment (TME).Material and methods We used patient derived explant cultures (PDEC) derived from primary brain tumor tissues including glioblastoma (n=3), medulloblastoma (n=1), astrocytoma (n=7), oligodendroglioma (n=2), meningioma (n=2), atypical teratoid/rhabdoid tumor (n=1), and brain squamous cell carcinoma (n=1) and treated them with Bexmarilimab (50μg/mL) and its isotype control IgG4 (50μg/mL) for 16 hours. Following the treatment, we performed bulk RNA-sequencing, immunofluorescence staining and multiplex cytokine analyses with the PDECs to assess the impact of Clever-1 inhibition on the brain TME.Results Immunofluorescence staining of the PDECs showed that Clever-1 is predominantly expressed on the myeloid cell populations within the brain TME. Using a core response gene signature derived from clinical data of patients who responded favourably to Bexmarilimab treatment, 3 we distinctly identified potential responders and non-responders amongst the treated PDECs of brain tumors. Preliminary findings suggested transcriptomic and cytokine profile changes in response to Bexmarilimab treatment compared to the isotype control treatment, with key immune pathways activated in responsive samples. These responders exhibited low IFN signalling at baseline while Bexmarilimab induced pro-inflammatory immune responses implying enhanced antigen-presentation, upregulated IFN-γ, IFN-α and TNF-α signalling and downregulated M2 macrophage signature.Conclusion Our findings support Bexmarilimab as a promising treatment to induce antitumor responses by reprogramming immunosuppressive macrophages in pediatric and adult brain tumors and provide a means to predict the efficacy of Bexmarilimab using patient-derived tumor tissues.References Hollmén M, Figueiredo CR, Jalkanen S. New tools to prevent cancer growth and spread: a ‘clever’ approach. Br J Cancer. 2020;123:501–509.Rannikko JH, Verlingue L, de Miguel M, Pasanen A, Robbrecht D, Skytta T, et al. Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: the phase I/II first-in-human MATINS trial. Cell Rep Med. 2023;4:101307.Rannikko JH, Turpin R, Boström P, Virtakoivu R, Harth C, Takeda A, et al. Macrophage sensitivity to bexmarilimab-induced reprogramming is shaped by the tumor microenvironment. J Immunother Cancer 2025;13:e011292. M. Hollmén: Faron Pharmaceuticals Ltd, Turku, Finland: significant, R. Suresh: None, R. Turpin: None, K. Nordfors: None, M. Mieskolainen: None, I. Hermelo: None, J. Kolivuori: None, H. Haapasalo: None, J. Haapasalo: None