Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-11, Vol.107 (46), p.20021-20026
• Main Authors: Candolfi, Marianela, Xiong, Weidong, Yagiz, Kader, Liu, Chunyan, Muhammad, A. K. M. G., Puntel, Mariana, Foulad, David, Zadmehr, Ali, Ahlzadeh, Gabrielle E., Kroeger, Kurt M., Tesarfreund, Matthew, Lee, Sharon, Debinski, Waldemar, Sareen, Dhruv, Svendsen, Clive N., Rodriguez, Ron, Lowenstein, Pedro R., Castro, Maria G., Cavenee, Webster K.
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animal models; Animals; Antitumor agents; Binding sites; Biological Sciences; Brain; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Brain tumors; Cell Line, Tumor; Clinical trials; Cytotoxicity; Cytotoxins; Cytotoxins - genetics; Cytotoxins - therapeutic use; Drug development; Exotoxins; Exotoxins - genetics; Exotoxins - therapeutic use; Expression vectors; Gene expression; Gene therapy; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors - genetics; glioblastoma multiforme; Glioma; Glioma - drug therapy; Glioma - pathology; Heterologous transplantation; Humans; Immunocompetence - immunology; Interleukin 1; Interleukin 13; Interleukin 13 receptors; Interleukin 4; Interleukin 4 receptors; Interleukin-13 - genetics; Interleukin-13 - therapeutic use; Medical treatment; Mice; Mice, Nude; Mutation - genetics; Neurons; Neurotoxicity; Neurotoxins - toxicity; Physiology; Pseudomonas; Pseudomonas - metabolism; Receptors; Rodents; Survival; Toxicity; Transgenes; Transgenes - genetics; Treatment Outcome; Tumor cells; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1008261107

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 ledto 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.