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Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma

Cancer Gene Therapy volume 22, pages 1–8 (2015)Cite this article

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Abstract

The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood–brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood–brain barrier through local, persistent delivery of an anti-angiogenesis monoclonal antibody.

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Acknowledgements

We thank Stephanie Phillips for help with these studies; N Mohamed and DN McCarthy for help with the manuscript; and Carolyn Wiener for her continued support. These studies were supported, in part, by the Starr Cancer Consortium and the National Foundation for Cancer Research. MJH was supported, in part, by NIH T32HL094284.

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Author notes

  1. M J Hicks and K Funato: These authors contributed equally to this work.

  2. V Tabar and R G Crystal: Co-senior authors.

Authors and Affiliations

  1. Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA

    M J Hicks, L Wang, D F Havlicek, E Z Frenk, B P De, M J Chiuchiolo, D Sondhi, N R Hackett, S M Kaminsky & R G Crystal

  2. Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,

    K Funato & V Tabar

  3. Department of Radiology, Weill Cornell Medical College, New York, NY, USA

    E Aronowitz, J P Dyke & D J Ballon

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Correspondence to R G Crystal.

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Hicks, M., Funato, K., Wang, L. et al. Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma. Cancer Gene Ther 22, 1–8 (2015). https://doi.org/10.1038/cgt.2014.58

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