Wu Bill Xingjun, Kreatsoulas Daniel, Cam Hakan, Bolyard Chelsea, Chang Yuzhou, Mandula Jay, Welsh Parker W, Wang Ziyu, Li Anqi, Weltge Payton, Elder J Bradley, Giglio Pierre, Otero Jose J, Rajappa Prajwal, Gerald Damien, Chung Dongjun, Ma Qin, Velegraki Maria, Li I Zihai
Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA.
Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Neuro Oncol. 2025 Aug 27. doi: 10.1093/neuonc/noaf195.
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.
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.
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.
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).
糖蛋白A重复序列占主导的蛋白（GARP）是一种细胞表面非信号受体，用于对接和激活由调节性T细胞、血小板和肿瘤细胞表达的潜伏转化生长因子β（LTGFβ）。在肺癌和乳腺癌中，其表达与晚期和不良预后相关——这表明GARP可能成为一个治疗靶点。本研究通过在胶质母细胞瘤（GBM）小鼠模型中采用一种新型的表达抗GARP嵌合抗原受体的T细胞（CAR-T）方式，研究靶向GARP对GBM的治疗效果。
我们研究了多个人类胶质瘤数据库，以关联GARP的表达与临床结果。然后，我们对人类GBM样本进行多重成像，以了解GARP表达对肿瘤微环境（TME）的影响。重要的是，我们开发了一种新型的抗GARP CAR-T细胞策略来治疗GBM。我们研究这种疗法对免疫健全的同基因和免疫缺陷小鼠的GBM原位模型是否有效。
我们证明，人类GBM中GARP表达升高与总体生存率低、间充质亚型以及与TME中的血管生成和免疫排斥相关的基因特征有关。我们新型的抗GARP CAR-T在体外和体内对多种GBM临床前模型均有效，包括患者来源的异种移植（PDX）模型，且无明显毒性。
GARP-LTGFβ在GBM的发生发展和预后中起关键作用，靶向GARP的CAR-T疗法在小鼠GBM原位模型中显示出有前景的疗效和安全性。一项针对复发性GBM患者的首次人体I期临床试验于2025年5月开始招募患者（NCT06964737）。
