Page 90 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 4
treatment (therapeutic dose). An important pitfall to eliminate is a “false negative” 89Zr-immuno-PET due to absence of tumor uptake of the imaging dose, while there is tumor targeting of the therapeutic dose of unlabeled mAb. This situation may occur in case of expression of target antigen on normal tissue, or in case of a large tumor load with antigen expression. This causes an “antigen sink” that absorbs the tracer dose, leaving insufficient 89Zr-mAb to target all tumor lesions. Therefore, for each mAb, information should be obtained to assess whether a dose-dependent correlation between imaging dose and tumor uptake exists. Preferably a pilot study with different dose levels, within the same patient, is used to define the optimal 89Zr-mAb dose for imaging, i.e. the dose that reflects the therapeutic dose best. With respect to this, in case of co-administration of 89Zr- labeled and cold mAb, it should also be confirmed whether simultaneous administration is needed, or whether sequential administration immediate after each other is allowed.
Another requirement is that tumor uptake of the 89Zr-mAb reflects specific, antigen-mediated, tumor targeting. Next to specific uptake, also non-antigen mediated tumor uptake can occur, possibly caused by enhanced permeability and retention in tumor tissue. Even when tracer uptake is visualized in the tumor, no biological effect can be expected if tumor uptake is not primarily antigen-mediated (a “false positive” 89Zr-immuno-PET). Although no definitive proof has been reported that 89Zr-immuno-PET reflects specific, antigen-mediated binding, two clinical studies have reported a correlation between tumor uptake on PET and target expression in biopsies (26, 42). These results support the assumption that tumor uptake on 89Zr-immuno-PET is primarily driven by antigen-mediated targeting. This would allow the use of 89Zr-immuno-PET as an imaging biomarker to assess target expression, as well as tumor targeting. However, for every mAb- antigen combination this has to be confirmed. In order to evaluate to which extent tumor uptake is driven by nonspecific and/or specific binding, studies correlating tumor uptake to target expression in biopsies, as well as exploration of kinetic modelling, may provide further insight.
Assuming these two crucial requirements are met, 89Zr-immuno-PET can be expected to predict toxicity and response to treatment.
For RIT, it was shown that biodistribution of 89Zr-rituximab can be used to predict biodistribution and the dose-limiting organ for subsequent treatment with 90Y-ibritumomab tiuxetan (44). This allows for future application of 89Zr-immuno- PET for individualized doze optimization of RIT with the aim to reduce the risk
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