Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

Abstract

Predictive tools for guiding therapy in children with brain tumors are urgently needed. In this first molecular drug imaging study in children, we investigated whether bevacizumab can reach tumors in children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of 89 Zr-labeled bevacizumab by PET. In addition, we evaluated the safety of the procedure in children and determined the optimal time for imaging. Methods: Patients received 89 Zr-bevacizumab (0.1 mg/kg; 0.9 MBq/kg) at least 2 wk after completing radiotherapy. Whole-body PET/CT scans were obtained 1, 72, and 144 h after injection. All patients underwent contrast (gadolinium)-enhanced MRI. The biodistribution of 89 Zr-bevacizumab was quantified as SUVs. Results: Seven DIPG patients (4 boys; 6-17 y old) were scanned without anesthesia. No adverse events occurred. Five of 7 primary tumors showed focal 89 Zr-bevacizumab uptake (SUVs at 144 h after injection were 1.0-6.7), whereas no significant uptake was seen in the healthy brain. In 1 patient, multiple metastases all showed positive PET results. We observed inter-and intratumoral heterogeneity of uptake, and 89 Zr-bevacizumab uptake was present predominantly (in 4/5 patients) within MRI contrast-enhanced areas, although 89 Zr-bevacizumab uptake in these areas was variable. Tumor targeting results were quantitatively similar at 72 and 144 h after injection, but tumor-to-blood-pool SUV ratios increased with time after injection (P 5 0.045). The mean effective dose per patient was 0.9 mSv/MBq (SD, 0.3 mSv/MBq). Conclusion: 89 Zr-bevacizumab PET studies are feasible in children with DIPG. The data suggest considerable heterogeneity in drug delivery among patients and within DIPG tumors and a positive, but not 1:1, correlation between MRI contrast enhancement and 89 Zr-bevacizumab uptake. The optimal time for scanning is 144 h after injection. Tumor 89 Zr-bevacizumab accumulation assessed by PET scanning may help in the selection of patients with the greatest chance of benefit from bevacizumab treatment.

Molecular Imaging in Cancer Drug Development

“…A point of discussion is whether mAbs reach brain metastases to the same extent as they reach extracranial metastases, since mAbs, being of heavy weight, cannot pass the blood-brain barrier. A study with 89 Zr-bevacizumab and gadolinium-enhanced MRI in 7 children with radiated diffuse intrinsic pontine glioma found heterogeneity in tumor tracer uptake (41). Two tumors showed no tracer uptake.…”

Advances in Molecular Imaging of Locally Delivered Targeted Therapeutics for Central Nervous System Tumors

“…Bevacizumab is a common anti-VEGF (vascular endothelial growth factor) antibody used in numerous cancers to contrast tumor angiogenesis, including glioblastoma multiforme (GBM) as a single agent [92]. The agent has been successfully coupled with 89 Zr, a PET-imageable atom, thus allowing clinicians to observe tumor uptake following delivery [93]. Our laboratory has experience with the synthesis of antibodies against the cancer-specific antigen B7-H3 and their coupling with 124 I—in this setup, the imaging agent (the radioactive iodide, detected with PET) is also the therapeutic one, with isotope decay being the main method of injury to cancer cells [83].…”

Theranostics Using Antibodies and Antibody-Related Therapeutics

“…A 89 Zr-bevacizumab study of advanced non-small cell lung cancer (NSCLC) demonstrated 4-fold-higher tracer uptake in tumor tissue than in nontumor tissue (22). In children with diffuse intrinsic pontine gliomas treated with radiotherapy, heterogeneity of tumor uptake of 89 Zr-bevacizumab was shown (23). 89 Zr-bevacizumab tracer uptake is not limited to malignant disease.…”