Vascular Targeted Radioimmunotherapy for the Treatment of Glioblastoma

Abstract

Rationale Glioblastoma is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 months 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 (VE) of glioblastoma with cytotoxic short-range, high-energy alpha particles would be an effective therapeutic approach. Methods E4G10, an antibody directed at an epitope of monomeric VE cadherin, is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow. E4G10 was labeled with alpha particle emitting 225Actinium (225Ac). Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac-E4G10 radioimmunoconstruct in a transgenic Ntva-mouse model of high-grade glioblastoma. Histological 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 alpha-particle therapy of glioblastoma in the transgenic Ntva-model resulted in significantly improved survival compared to controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 days (versus 9 days for vehicle treated animals). Histological analyses showed a remodeled glioblastoma vascular microenvironment. Conclusion Targeted alpha-particle anti-vascular 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.

Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles

“…The RCAS-vector carries the tumor-driver human Platelet-derived growth factor (PDGF) B. Tumor was induced by stereotactic intracranial surgery as previously described (13). …”

“…225 Ac-E4G10 as an alternative anti-vascular approach and our preclinical studies in transgenic glioblastoma mice showed therapeutic activity and increased survival significantly as monotherapy (13). We imaged the microenvironment architecture and function in remodeled tumor resulting from α-particle irradiation.…”

“…Potent efficacy of 225Ac-E4G10 has been reported against carcinomas (9,10) and glioblastoma (13). Glioblastomas are histologically distinct from lower-grade tumors (14).…”

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

“…2). Because of the particle range, this cross-fire effect is thought to be higher with b-emitters, but recent studies showing a-particles to have a significant therapeutic effect on large tumors question this concept (6)(7)(8). In addition to direct effects, indirect radiation effects have been observed.…”

Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with 211At-MX35-F(ab′)2: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival

“…Although studies of biologic effects from a-particles would gain from a dosimetry more detailed than mean absorbed dose to whole organs in most cases, we chose to evaluate the antitumor effects with respect to mean absorbed dose to whole tumor. Using targeted a-therapy on solid tumors, antitumor effects may arise not only from irradiation of tumor cells but also from other targets, such as intratumoral vasculature (25)(26)(27)39,40). High-resolution a-camera imaging of the same tumor model as used here (21) showed clearly heterogeneous intratumoral activity distributions of up to 7 h after injection.…”