Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

CANDOLFI; XIONG; YAGIZ; LIU; MUHAMMAD; PUNTEL; FOULAD; ZADMER; ALZADEH; KROEGER; TESARFREUND; LEE; DEBINSKI; SAREEN; SVENDSEN; RODRIGUEZ; LOWENSTEIN; CASTRO

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Año: 2010 p. 20021 - 20026

0027-8424

Restricting the cytotoxicity of anticancer agents by targetingreceptors exclusively expressed on tumor cells is critical whentreating infiltrative brain tumors such as glioblastoma multiforme(GBM). GBMs express an IL-13 receptor (IL13Rα2) that differs fromthe physiological IL4R/IL13R receptor. We developed a regulatableadenoviral vector (Ad.mhIL-4.TRE.mhIL-13-PE) encoding a mutatedhuman IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specificallybinds to IL13Rα2 to provide sustained expression, effectiveanti-GBM cytotoxicity, and minimal neurotoxicity. The therapeuticAd also encodes mutated human IL-4 that binds to the physiologicalIL4R/IL13R without interacting with IL13Rα2, thus inhibiting potentialbinding of mhIL-13-PE to normal brain cells. Using intracranialGBM xenografts and syngeneic mouse models, we tested the Ad.mhIL-4.TRE.mhIL-13-PE andtwo protein formulations, hIL-13-PE usedin clinical trials (Cintredekin Besudotox) and a second-generationmhIL-13-PE. Cintredekin Besudotox doubled median survival withouteliciting long-term survival and caused severe neurotoxicity;mhIL-13-PE led to ∼40% long-term survival, eliciting severe neurologicaltoxicity at the high dose tested. In contrast, Ad-mediated deliveryofmhIL-13-PE led to tumor regressionandlong-termsurvival inover 70% of the animals, without causing apparent neurotoxicity.Although Cintredekin Besudotox was originally developed to targetGBM, when tested in a phase III trial it failed to achieve clinical endpointsand revealed neurotoxicity. Limitations of Cintredekin Besudotoxinclude its short half-life, which demanded frequent or continuedadministration, and binding to IL4R/IL13R, present in normalbrain cells. These shortcomings were overcome by our therapeuticAd, thus representing a significant advance in the development oftargeted therapeutics for GBM.