Work

606 Transport vehicle-enabled TREM2 agonist therapy potentiates anti-tumor immunity in preclinical mouse models of GBM

Year: 2026

Type: conference-abstract

Abstract: Background While immunotherapy such as immune checkpoint blockade (ICB) has proven successful in treating peripheral cancers, it has shown limited efficacy in glioblastoma (GBM). Here, we tested a TREM2 agonist antibody that was engineered to cross the blood-brain barrier by binding transferrin receptor (TfR), termed antibody transport vehicle (ATV), as an approach to activate myeloid cells in the GBM tumor microenvironment (TME) to support T cell function and bolster the ICB response.Methods Human TfR knock-in mice were implanted with orthotopic CT2A-ZsGreen-Luc glioma before administration of ATV:TREM2 (ATV:4D9) or isotype (ATV:ISO) antibody, alone or with anti-PD-1. Flow cytometry and EdU uptake experiments were used to profile functional and phenotypic changes in the TME, and cerebrospinal fluid (CSF) was assayed for soluble TREM2 (sTREM2). MALDI and LC-MS assessed the lipid composition of human and murine GBM for identification of potential TREM2 binding partners, and Trem2-mKate2 mice were used to probe TREM2 expression within the TME.Results TREM2 + cells were enriched in the tumor core compared with adjacent parenchyma (p = 0.0167). While ATV:4D9 treatment alone prolonged median overall survival (p = 0.0314) and decreased tumor burden (p = 0.04) relative to ATV:ISO, combination therapy with PD-1 blockade significantly improved these metrics (p = 0.0005 and p = 0.0008), with 7 of 9 mice completely rejecting their tumors. Protection from rechallenge was demonstrated with re-implanted tumors failing to grow in cured mice, suggesting the formation of immunologic memory. Within the TME, ATV:4D9 induced phagocytosis of tumor by myeloid cells (p = 0.0231), as well as polarizing microglia, but not other myeloid populations, toward a pro-inflammatory and antigen-presenting phenotype. Further, acute ATV:4D9 treatment induced proliferation of myeloid populations measured by EdU uptake in IBA1+ cells (p < 0.05), which was orthogonally confirmed by flow cytometry showing increased Ki-67+ microglia (p = 0.0002) but not other myeloid cells after treatment. CSF profiling showed decreased sTREM2 after treatment (p = 0.0226), indicating that this could serve as a biomarker for treatment efficacy. Lipidomic studies identified enrichment of candidate TREM2-binding lipids in human and murine mesenchymal subtype GBM, suggesting that the TREM2-dependent immune response to GBM may be modulated by the genotype and metabolic properties of these tumors.Conclusions Synergy of TREM2 agonism with ICB suggests its utility as a method for boosting immunotherapy responsiveness in GBM. The identification of potential TREM2-binding lipids enriched in mesenchymal tumors implies that TREM2 agonism may fill a clinical niche for treating aggressive disease subtypes, with CSF sTREM2 serving as a biomarker to enable translation of these data to the clinic.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0606