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Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2010 Nov 16; Vol. 107 (46), pp. 20021-6. Date of Electronic Publication: 2010 Oct 28. - Publication Year :
- 2010
-
Abstract
- Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme (GBM). GBMs express an IL-13 receptor (IL13Rα2) that differs from the physiological IL4R/IL13R receptor. We developed a regulatable adenoviral vector (Ad.mhIL-4.TRE.mhIL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specifically binds to IL13Rα2 to provide sustained expression, effective anti-GBM cytotoxicity, and minimal neurotoxicity. The therapeutic Ad also encodes mutated human IL-4 that binds to the physiological IL4R/IL13R without interacting with IL13Rα2, thus inhibiting potential binding of mhIL-13-PE to normal brain cells. Using intracranial GBM xenografts and syngeneic mouse models, we tested the Ad.mhIL-4.TRE.mhIL-13-PE and two protein formulations, hIL-13-PE used in clinical trials (Cintredekin Besudotox) and a second-generation mhIL-13-PE. Cintredekin Besudotox doubled median survival without eliciting long-term survival and caused severe neurotoxicity; mhIL-13-PE led to ∼40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery of mhIL-13-PE led to tumor regression and long-term survival in over 70% of the animals, without causing apparent neurotoxicity. Although Cintredekin Besudotox was originally developed to target GBM, when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity. Limitations of Cintredekin Besudotox include its short half-life, which demanded frequent or continued administration, and binding to IL4R/IL13R, present in normal brain cells. These shortcomings were overcome by our therapeutic Ad, thus representing a significant advance in the development of targeted therapeutics for GBM.
- Subjects :
- Adenoviridae genetics
Animals
Brain Neoplasms pathology
Cell Line, Tumor
Exotoxins genetics
Exotoxins therapeutic use
Genetic Vectors genetics
Glioma pathology
Humans
Immunocompetence immunology
Interleukin-13 genetics
Interleukin-13 therapeutic use
Mice
Mice, Nude
Mutation genetics
Neurotoxins toxicity
Pseudomonas metabolism
Transgenes genetics
Treatment Outcome
Xenograft Model Antitumor Assays
Brain Neoplasms drug therapy
Cytotoxins genetics
Cytotoxins therapeutic use
Gene Transfer Techniques
Genetic Therapy
Glioma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 107
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 21030678
- Full Text :
- https://doi.org/10.1073/pnas.1008261107