Page 80 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 4
years received 0.9 MBq/kg (range 18-37 MBq) 89Zr–bevacizumab (0.1 mg/kg). Whole body PET scans were obtained at 1, 72 and 144 hours p.i.. Tumor uptake of 89Zr-bevacizumab was observed in 2 of 3 patients, limited to the T1-MRI contrast- enhanced part of the tumor. These findings suggest that disruption of the blood- brain barrier, as indicated by MRI contrast, is necessary for effective tumor targeting by 89Zr-bevacizumab. Uptake in normal organs was highest in the liver, followed by the kidneys, lungs and bone marrow. This study illustrates that also in children 89Zr-immuno-PET is a feasible procedure, and has potential as a response and toxicity predictor for treatment with bevacizumab and other targeted drugs.
89Zr-labeled fresolimumab in high-grade glioma
As indicated before, mAbs might be prevented from reaching tumor lesions in the brain by impermeability of the blood-brain barrier, while tumor targeting is a prerequisite for effective treatment. An appealing target molecule for treatment of high-grade glioma is transforming growth factor β (TGF-β), which functions as a tumor promotor and induces proliferation and metastasis, while suppressing the immune response. TGF-β and its receptors are overexpressed in high-grade glioma and can be targeted with several types of TGF-β inhibitors. Fresolimumab is a mAb capable of neutralizing all mammalian isoforms of TGF-β (i.e. 1, 2 and 3) and has been investigated in phase I trials with patients with melanoma, renal cell carcinoma and in a phase II trial in patients with mesothelioma.
Den Hollander et al. investigated uptake of 89Zr-fresolimumab in 12 patients with recurrent high-grade glioma and assessed clinical outcome after fresolimumab treatment (32). In this study an imaging dose of 37 MBq 89Zr-fresolimumab (5 mg) was used before start of treatment (5 mg/kg i.v. every 3 weeks) and PET scans were obtained for all patients on day 4 p.i., while 4 patients also received a scan at day 2 p.i..
In all patients uptake of 89Zr-fresolimumab was observed in brain tumor lesions (n=16), while in 8 patients not all known brain tumor lesions were visualized with 89Zr-fresolimumab-PET (mostly small lesions, <10 mm on MRI). The three lesions larger than 10 mm that were missed by 89Zr-fresolimumab-PET were suspected to represent radionecrosis instead of viable tumor tissue (therefore probably lacking TGF-β expression), based on previous irradiation or disappearance on follow-up MRI. Tumor-to-blood ratios increased from day 2 to 4 p.i. in patients who underwent whole body PET scans (n=4), which was considered to be suggestive for tumor-specific TGF-β-driven mAb uptake. All
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