CELL INTELLIGENCE · 肿瘤细胞治疗研究

Glioblastoma (GBM) is an aggressive primary brain tumor marked by a poor prognosis and limited effectiveness of current therapies, which are often accompanied by substantial recurrence rates. To address this challenge, we developed BM03, an engineered mesenchymal stem cell (MSC) line specifically designed for glioblastoma therapy. BM03 is structured to enhance migration to GBM sites and deliver targeted, multimodal gene-based therapies.

This cell line was developed by transducing bone marrow-derived MSCs with lentiviral vectors to enable (1) continuous growth through immortalization, (2) tumor-targeted migration via GBM-associated chemokine receptors CCR2 and CXCR4, and (3) direct tumoricidal effects through TRAIL and CD::UPRT gene expression for apoptosis and prodrug activation.

BM03 demonstrated strong chemotaxis toward GBM cells in both in vitro and in vivo models, facilitated by CCR2 and CXCR4 co-expression, which was maintained through tetracycline transactivator (tTA)-mediated transcriptional control. The combination of TRAIL and CD::UPRT showed significant cytotoxicity, effectively overcoming TRAIL resistance in GBM cells and exhibiting enhanced antitumor effects in a GBM mouse xenograft model. Moreover, repeated BM03 administration, particularly when combined with temozolomide (TMZ), resulted in sustained tumor regression and improved survival.

To enhance clinical relevance, we evaluated intraventricular administration, which effectively bypasses the blood-brain barrier and targets dispersed GBM lesions. This study establishes BM03 as a potent, safe, and multifunctional stem cell platform with potential to advance targeted GBM therapy through improved migration, multimodal cytotoxicity, and a strategic administration route for enhanced therapeutic efficacy.