肿瘤细胞治疗研究
英文原题：Targeting TGFβ docking receptor glycoprotein A repetitions predominant (GARP) via novel chimeric antigen receptor (CAR)-T cell platform to treat glioblastoma.
GARP-LTGF 在 GBM 的发生和预后中发挥关键作用，靶向 GARP 的 CAR-T 治疗在小鼠原位 GBM 模型中显示出有前景的疗效和安全性。
背景：富含糖蛋白A重复序列的跨膜蛋白（GARP）是一种细胞表面非信号型受体，可结合并激活潜伏型转化生长因子β（LTGF-β），表达于调节性T细胞、血小板和肿瘤细胞。在肺癌和乳腺癌中，GARP表达与疾病分期较晚及预后较差相关，提示其可能是治疗靶点。本研究在GBM小鼠模型中，借助新型表达抗GARP嵌合抗原受体的T细胞（CAR-T）疗法，评估靶向GARP的治疗作用。 方法：我们分析了多个胶质瘤人群数据库，以评估GARP表达与临床结局的相关性；随后对人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，我们开发了新型抗GARP CAR-T策略治疗GBM，并在免疫健全的同基因小鼠及免疫缺陷小鼠的原位GBM模型中评估其疗效。 结果：在人GBM中，GARP高表达与总生存期较短、间充质亚型以及TME中血管生成和免疫排斥相关基因特征相关。新型抗GARP CAR-T在体外和体内均有疗效，可作用于多种GBM临床前模型，包括患者来源异种移植（PDX）模型，且未见显著毒性。 结论：GARP-LTGF通路在GBM的发生发展和预后中发挥重要作用；在小鼠原位GBM模型中，靶向GARP的CAR-T疗法显示出良好的疗效和安全性。首个人体I期复发性GBM临床试验已于2025年5月开始招募患者（NCT06964737）。
BACKGROUND: Glycoprotein A-repetitions predominant (GARP) is a cell surface non-signaling receptor for docking and activating latent transforming growth factor beta (LTGF ) 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-LTGF 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).
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