A safety and efficacy study of local delivery of interleukin-12 transgene by PPC polymer in a model of experimental glioma

Adam M. Sonabend, Simona Velicu, Ilya V. Ulasov, Yu Han, Betty Tyler, Henry Brem, Majed M. Matar, Jason G. Fewell, Khursheed Anwer, MacIej S. Lesniak

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Abstract

Interleukin-12 (IL-12) triggers an antitumoral immune response and an antiangiogenic effect against cancer. In this study, we tested a novel polymeric vehicle for IL-12 gene therapy along with adjuvant local biodegradable carmustine (BCNU) chemotherapy for the treatment of malignant glioma. Highly concentrated DNA/PPC (polyethylenimine covalently modified with methoxypolyethyleneglycol and cholesterol) complexes were used to deliver a murine plasmid encoding IL-12 (pmIL-12). For toxicity assessment, mice received intracranial injections with different volumes of pmIL-12/PPC. For efficacy, mice with intracranial GL261 glioma were treated with local delivery of pmIL-12/PPC and/or BCNU-containing polymers. Intracranial injections of 5-10 μl of pmIL-12/PPC were well tolerated and led to IL-12 expression in the brains of treated animals. Treatment with pmIL-12/PPC led to a significant increase in survival compared with untreated mice (median survival 57 days; 25% long-term survival >95 vs. 45 days for control; P<0.05). Treatment with BCNU led to a significant increase in survival compared with untreated mice, with 75% of treated mice having a long-term survival >95 days, (P<0.05). Most importantly, the combination of BCNU and pmIL-12/PPC led to a survival of 100% of the mice for 95 days after treatment (P<0.0001). This novel strategy is safe and effective for the treatment of malignant glioma. The synergy resultant from the combination of locally administered pmIL-12/PPC and BCNU suggests a role for this approach in the treatment of malignant brain tumors.

Original languageEnglish (US)
Pages (from-to)133-142
Number of pages10
JournalAnti-cancer drugs
Volume19
Issue number2
DOIs
StatePublished - Feb 1 2008

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Keywords

  • Brain tumor
  • Gene therapy
  • Glioma
  • Immunotherapy
  • Interleukin-12
  • Polymer

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

Cite this

Sonabend, A. M., Velicu, S., Ulasov, I. V., Han, Y., Tyler, B., Brem, H., Matar, M. M., Fewell, J. G., Anwer, K., & Lesniak, M. S. (2008). A safety and efficacy study of local delivery of interleukin-12 transgene by PPC polymer in a model of experimental glioma. Anti-cancer drugs, 19(2), 133-142. https://doi.org/10.1097/CAD.0b013e3282f24017