Page 17 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

0 Can 89Zr-immuno-PET be used to assess tumor targeting 1 and is uptake correlated to target expression in biopsies?
0 Can 89Zr-immuno-PET be used to assess target-mediated specific uptake in normal tissues (defined as dose- dependent uptake)?
0 Can 89Zr-immuno-PET be used to assess non-specific uptake in normal tissues (defined as reversible, (e.g. blood volume) or irreversible (due to 89Zr-residualization after mAb degradation)?
Outline of this thesis
The aim of this thesis was to develop 89Zr-immuno-PET as a clinical tool to guide antibody-based treatment in cancer. This thesis consists of two parts.
Part I describes the feasibility of the first clinical 89Zr-immuno-PET study ever. The step from preclinical research to clinical translation of 89Zr-immuno- PET was performed by the first-in-human study with 89Zr-labeled chimeric monoclonal antibody (cmAb) U36. Twenty patients with head and neck cancer, scheduled for surgery, received 89Zr-cmAb U36. Chapter 2 evaluates safety, biodistribution, dosimetry and PET quantification of immuno-PET with 89Zr- cmAb U36. Chapter 3 reports on the diagnostic imaging performance of 89Zr- immuno-PET for the detection of primary head and neck tumors and lymph node metastases for the same cohort of patients.
In Chapter 4, a review is provided of the first 15 clinical trials with 89Zr- immuno-PET in oncology. Lessons learned and technical aspects of study design are discussed.
Part II focuses on validation of 89Zr-immuno-PET. Chapter 5 describes the measurement of variability due to noise. In Chapter 6, interobserver reproducibility of tumor uptake measures of 89Zr-immuno-PET was investigated. Chapter 7, deals on the performance of 89Zr-rituximab-PET as an imaging biomarker to assess CD20 targeting in patients with relapsed/refractory diffuse large B cell lymphoma. Chapter 8 describes the use of immuno-PET in a phase I dose escalation study for detection of specific, target-mediated uptake in normal tissues, using the antiCD44 antibody RG7356 as an example. In Chapter 9, non-specific uptake in normal tissues for therapeutic mAbs (antiCD20, antiEGFR, antiPSMA and antiHER2) was determined as a critical step towards quantification of target engagement. In Chapter 10, the results presented in this thesis are summarized and future perspectives are discussed.
Introduction
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