Daniel W. Stuckey1,2,†, Shawn D. Hingtgen1,2,†, Nihal Karakas1,2, Benjamin E. Rich3 andKhalid Shah1,2,4,5,*
Pseudomonas exotoxin (PE) potently blocks protein synthesis by catalyzing the inactivation of elongation factor-2 (EF-2), and PE-cytotoxins have been used as anti-tumor agents. However, their effective clinical translation in solid tumors has been confounded by off-target delivery, systemic toxicity and short chemotherapeutic half-life. To overcome these limitations we have created toxin-resistant stem cells by modifying endogenous EF-2, and engineered them to secrete PE-cytotoxins targeting IL13R2 and EGFR expressed by many glioblastomas (GBM). Molecular analysis correlated efficacy of PE-targeted cytotoxins with levels of cognate receptor expression, and optical imaging was applied to simultaneously track the kinetics of protein synthesis inhibition and GBM cell viability in vivo. Stem cell-based delivery of IL13-PE in a clinically-relevant GBM resection model led to increased long-term survival of mice compared to IL13-PE protein infusion. Moreover, multiple patient-derived GBM lines responded to treatment, underscoring its clinical relevance. In sum, integrating stem cell-based engineering, multimodal imaging and delivery of PE-cytotoxins in a clinically-relevant GBM model represents a novel strategy and a potential advancement in GBM therapy.
From: Stem Cells