Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Marianela Candolfi, Weidong Xiong, Kader Yagiz, Chunyan Liu, A. K.M.G. Muhammad, Mariana Puntel, David Foulad, Ali Zadmehr, Gabrielle E. Ahlzadeh, Kurt M. Kroeger, Matthew Tesarfreund, Sharon Lee, Waldemar Debinski, Dhruv Sareen, Clive N. Svendsen, Ron Rodriguez, Pedro R. Lowenstein, Maria G. Castro

Research output: Contribution to journalArticle

64 Scopus citations

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 end- points and revealed neurotoxicity. Limitations of Cintredekin Besu- dotox 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.

Original languageEnglish (US)
Pages (from-to)20021-20026
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number46
DOIs
StatePublished - Nov 16 2010
Externally publishedYes

Keywords

  • Adenoviral vectors
  • GBM12 tumors
  • Immunotoxins
  • Targeted glioma therapeutics
  • TetON system

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics'. Together they form a unique fingerprint.

  • Cite this

    Candolfi, M., Xiong, W., Yagiz, K., Liu, C., Muhammad, A. K. M. G., Puntel, M., Foulad, D., Zadmehr, A., Ahlzadeh, G. E., Kroeger, K. M., Tesarfreund, M., Lee, S., Debinski, W., Sareen, D., Svendsen, C. N., Rodriguez, R., Lowenstein, P. R., & Castro, M. G. (2010). Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics. Proceedings of the National Academy of Sciences of the United States of America, 107(46), 20021-20026. https://doi.org/10.1073/pnas.1008261107