Engineered human adipose-derived stem cells delivering carboxylesterase and TRAIL for castration-resistant prostate...

Castration-resistant prostate cancer (CRPC) remains poorly controlled after sequential androgen receptor-targeted agents, taxanes, and radiopharmaceuticals. Tumor-tropic adipose-derived mesenchymal stem cells (ADSCs) offer a compelling platform for local delivery of gene-based therapeutics. This review synthesizes the mechanistic rationale, preclinical evidence, and translational strategy for hTERT-immortalized ADSCs engineered to express carboxylesterase (CE), secreted TRAIL (sTRAIL), or both, administered with irinotecan (CPT-11) in CRPC. We compared five studies from our group with independent work using mesenchymal stem cells, neural stem cells, and other carriers delivering CE- or TRAIL-based payloads, situating this platform within the broader field. Our studies used ubiquitin C promoter lentiviral vectors to express rabbit CE, rabbit CE2, human sTRAIL, or CE+sTRAIL. Efficacy was assessed mainly in subcutaneous PC3 xenografts and a PC3 tibial bone-metastasis model in male nude mice, using standardized migration, cytotoxicity, and apoptosis assays with in vivo tumor volume and osteolysis endpoints. Across all five studies, engineered ADSCs showed preferential tumor-tropic migration and localization after systemic delivery and consistently enhanced irinotecan efficacy at low prodrug doses, while becoming SN-38-sensitive themselves, providing built-in self-elimination. CE2, with superior CPT-11 hydrolytic efficiency over CE1, added anti-tumor potency and was active against bone-metastatic CRPC, including suppression of osteolysis. This program establishes a biologically coherent, iteratively refined platform for tumor-selective enzyme-prodrug activation and death receptor-mediated apoptosis in CRPC. Translation requires resolving integrating-vector and hTERT immortalization safety concerns, quantitative biodistribution and persistence characterization, pharmacogenomics-informed irinotecan dosing, and immunogenicity assessment of xenogeneic CE.