title: Vascular Targeted Radioimmunotherapy for the Treatment of Glioblastoma.
abstract: 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-emitting225Ac. Pharmacokinetic studies investigated the tissue distribution and blood clearance of the225Ac-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 with225Ac-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York behlingk@mskcc.org m-mcdevitt@ski.mskcc.org.
authors.forename: Katja
authors.initials: K
authors.lastname: Behling
authors.affiliation: Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: William F
authors.initials: WF
authors.lastname: Maguire
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: López Puebla
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shanna R
authors.initials: SR
authors.lastname: Sprinkle
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ruggiero
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Donoghue
authors.affiliation: Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Gutin
authors.affiliation: Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York Department of Pharmacology, Weill Cornell Medical College, New York, New York; and.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York Department of Medicine, Weill Cornell Medical College, New York, New York behlingk@mskcc.org m-mcdevitt@ski.mskcc.org.
authors.forename: Michael R
authors.initials: MR
authors.lastname: McDevitt
mesh_terms: D000186:Actinium; D000512:Alpha Particles / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001808:Blood Vessels / Q000378:metabolism / Q000528:radiation effects*; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D060787:Neoplasm Grading; D011854:Radiochemistry; D016499:Radioimmunotherapy / Q000379:methods*; D011879:Radiotherapy Dosage
chemical_list: D000911:Antibodies, Monoclonal; D000186:Actinium
keywords: 225Ac; glioblastoma (GBM); radioimmunotherapy (RIT); vascular endothelium (VE)