Page 145 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

INTRODUCTION
DLBCL is an aggressive, potentially fatal, but curable form of lymphoma. It is the most common lymphoma subtype, representing 30% of all lymphoma. This malignancy develops from the B-cells in the lymphatic system and is characterized by expression of CD20, a transmembrane protein. The function of CD20 is still unknown, but as it is only expressed on B cells and not on other tissues, it is a usefull target for treatment. Rituximab, an anti-CD20 mAb, is currently incorporated in all first line and subsequent treatment regimens. The introduction of rituximab in first line treatment has improved the prognosis of a three-year event-free survival (EFS) from 59% to 79% for patients of 18 to 60 years old. However, patients with relapsed/refractory DLBCL have a three-year overall survival (OS) of only 49% (1). Early relapse (<12 months) and prior rituximab treatment are associated with a worse outcome, with a three-year EFS of 21% versus 47%, suggesting rituximab resistance. Although it is standard practice to include rituximab in second line treatment, it is unclear whether individual patients benefit from repeated rituximab treatment. To obtain clinical benefit from mAb treatment tumor targeting is required. It comprises target antigen expression, as well as a drug that reaches and binds to the target.
Target expression of CD20 is assessed by IHC on a single tumor biopsy as 7 part of the routine work up to confirm the diagnosis of DLBCL, or to confirm relapsed/refractory disease (2). [Fluorine-18]-2-fluoro-2-deoxy-D-glucose (18F-FDG)-PET is incorporated in staging and response evaluation of DLBCL (3),
but provides no information on expression of CD20.
Molecular imaging with 89Zirconium (89Zr)-labeled mAbs, also known as
immuno-PET, allows for visualization and quantification of tumor uptake and whole body biodistribution of 89Zr-mAbs. Since tumor uptake depends on target expression and accessibility, it is a potential imaging biomarker for tumor targeting.
Two clinical trials on immuno-PET with 89Zr-labeled mAbs have reported whether tumor uptake on immuno-PET and target expression in biopsies are correlated. These studies were on 89Zr-bevacizumab, an anti-endothelial growth factor (VEGF)-A mAb, in patients with breast cancer (5) and 89Zr-labeled anti- membrane-bound surface glycoprotein mesothelin (MSLN) mAb in patients with pancreatic and ovarian cancer (6). Correlations between a measure of tumor uptake and a measure of target status were reported, to provide evidence that immuno-PET may be used as an imaging biomarker to assess tumor targeting.
89Zr-rituximab-PET in lymphoma
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