Vascular targeted radioimmunotherapy for the treatment of glioblastoma Academic Article uri icon

Overview

MeSH Major

  • Blood Vessels
  • Brain Neoplasms
  • Glioblastoma
  • Radioimmunotherapy

abstract

  • Copyright © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.Glioblastoma is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 mo despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium of glioblastoma with cytotoxic short-range, high-energy α-particles would be an effective therapeutic approach. Methods: E4G10, an antibody directed at an epitope of monomeric vascular endothelium cadherin that is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow, was labeled with α-particle-emitting 225Ac. Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac-E4G10 radioimmunoconstruct in a transgenic Nestin-tumor virus A (Ntva) mouse model of high-grade glioblastoma. Histologic analysis was used to demonstrate local therapeutic effects in treated brain tumor sections. Radioimmunotherapy with 225Ac-E4G10 was performed in Ntva mice to assess overall survival alone and in combination with temozolomide, the standard-of-care chemotherapeutic agent. Results: 225Ac-E4G10 was found to accumulate in tissues expressing the target antigen. Antivascular α-particle therapy of glioblastoma in the transgenic Ntva model resulted in significantly improved survival compared with controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 d (vs. 9 d for vehicle-treated animals). Histologic analyses showed a remodeled glioblastoma vascular microenvironment. Conclusion: Targeted α-particle antivascular therapy is shown for the first time to be effective in increasing overall survival in a solid tumor in a clinically relevant transgenic glioblastoma mouse model.

publication date

  • October 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5050148

Digital Object Identifier (DOI)

  • 10.2967/jnumed.115.171371

PubMed ID

  • 27127217

Additional Document Info

start page

  • 1576

end page

  • 1582

volume

  • 57

number

  • 10