Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 46, Pages 20021-20026Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1008261107
Keywords
targeted glioma therapeutics; immunotoxins; adenoviral vectors; GBM12 tumors; TetON system
Categories
Funding
- National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) [1R21-NS054143, 1U01 NS052465, 1R01 NS057711, 1R01 NS 054193, R01 NS061107, 1F32 NS058156]
- The Bram and Elaine Goldsmith and the Medallions Group Endowed Chairs in Gene Therapeutics
- The Linda Tallen and David Paul Kane Foundation
- The Drown Foundation
- Board of Governors at Cedars-Sinai Medical Center
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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 (IL13R alpha 2) 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 IL13Ra2 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 IL13Ra2, 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 similar to 40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery ofmhIL-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 end-points 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.
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