Targeting TGFβ docking receptor Glycoprotein A Repetitions Predominant (GARP) via novel chimeric antigen receptor (CAR)-T cell platform to treat glioblastoma.

BACKGROUND

Glycoprotein A-repetitions predominant (GARP) is a cell surface non-signaling receptor for docking and activating latent transforming growth factor beta (LTGFβ) expressed by regulatory T cells, platelets and tumor cells. In lung and breast cancers, its expression correlates with advanced stage and poor prognosis - suggesting that GARP could act as a therapeutic target. This study examines the therapeutic impact of targeting GARP in glioblastoma (GBM) via a novel anti-GARP chimeric antigen receptor-expressing T cell (CAR-T) modality in murine models of GBM.

METHODS

We examined multiple human glioma databases to correlate the expression of GARP with clinical outcomes. We then performed multi-plex imaging of human GBM samples to understand the impact of GARP expression on the tumor microenvironment (TME). Importantly, we developed a novel anti-GARP CAR-T cell strategy to treat GBM. We examine if this therapy is efficacious against orthotopic models of GBM, in both immunocompetent syngeneic and immunodeficient mice.

RESULTS

We demonstrate that elevated GARP expression in human GBM correlates with poor overall survival, mesenchymal subtype, and gene signatures associated with angiogenesis and immune exclusion in the TME. Our novel anti-GARP CAR-T is efficacious in vitro and in vivo, against multiple preclinical models of GBM including patient-derived xenograft (PDX) models without significant toxicity.

CONCLUSIONS

GARP-LTGFβ plays a key role in the development and prognostics of GBM and GARP-targeted CAR-T therapy shows promising efficacy and safety in murine orthotopic GBM models. A first-in-human phase I clinical trial for patients with recurrent GBM began to enroll patients in May 2025 (NCT06964737).