Page 81 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Initial clinical trials with 89Zr-immuno-PET in oncology
patients showed progressive disease on fresolimumab treatment, therefore no correlation between tumor uptake of 89Zr-fresolimumab and clinical response was observed. Because of absence of clinical benefit the study was closed after the first 12 patients.
In conclusion, this study showed that 89Zr-fresolimumab reaches brain
tumor lesions. mAb treatment with TGF-β targeting drugs remains an interesting
approach for treatment of high-grade glioma, especially since targeting of brain
tumor lesions has been observed by 89Zr-fresolimumab-PET. It remains unclear to
which extent antibody leakage due to disruption of the blood-brain barrier may
have caused non-specific uptake of 89Zr-fresolimumab. 4
89Zr-labeled cetuximab in colorectal carcinoma
Another target antigen of interest is EGFR, which can be targeted with cetuximab. Binding of cetuximab to EGFR prevents growth factor binding to the receptor, induces receptor internalization, and causes inhibition of the receptor tyrosine kinase activity. In this way cetuximab interferes with cell growth, differentiation and proliferation, apoptosis and cellular invasiveness. Colorectal cancer with RAS wild type can be effectively treated with cetuximab, while it is known that patients with a K-RAS or N-RAS mutation do not respond to anti-EGFR treatment (33). Only patients with RAS wild type colorectal cancer are eligible for anti-EGFR treatment. However, even in this selected patient group efficacy of single agent cetuximab remains limited, as clinical benefit is observed in only half of the patients (34). Additional growth activating mutations or insufficient tumor targeting may affect clinical efficacy. As EGFR is highly expressed on hepatocytes in normal liver tissue, this might lead to sequestration of anti-EGFR-mAbs shortly after administration and interfere with effective tumor targeting.
Assuming that response to treatment is dependent on uptake of cetuximab in tumor lesions, only patients in whom tumor targeting can be confirmed will be susceptible to treatment. Menke-van der Houwen van Oordt et al. performed a feasibility study in 10 patients with advanced colorectal cancer to investigate biodistribution and tumor uptake of 89Zr-cetuximab and evaluated 89Zr-cetuximab as a predictive imaging biomarker (35). While blood pool, spleen, kidney and lung activity decreased, uptake in the liver increased during the first 2 days, after which a plateau was reached. Total radioactivity derived from the whole body PET images decreased due to gastro-intestinal excretion, while no excretion via the bladder was observed.
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