RT Journal Article
SR Electronic
T1 Vascular Targeted Radioimmunotherapy for the Treatment of Glioblastoma
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1576
OP 1582
DO 10.2967/jnumed.115.171371
VO 57
IS 10
A1 Katja Behling
A1 William F. Maguire
A1 José Carlos López Puebla
A1 Shanna R. Sprinkle
A1 Alessandro Ruggiero
A1 Joseph O'Donoghue
A1 Philip H. Gutin
A1 David A. Scheinberg
A1 Michael R. McDevitt
YR 2016
UL http://jnm.snmjournals.org/content/57/10/1576.abstract
AB 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.