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Molecular imaging on the move – From feasibility to contribution in clinical questions (#619)
1 University Medical Center Groningen, Dpt. of Medical Oncology, Groningen, Netherlands
During early cancer drug development, detailed information on drug pharmacokinetics, including normal organ distribution, target expression at baseline and target kinetics over time are of great interest. This information increases insight in the mechanism of action, and potentially can optimize treatment schedule and patient selection. Furthermore, information on the immune system and its changes over time is of potential relevance for future immunotherapy related drug development and design of combination therapies. However, whole body information of normal organ drug distribution and target expression in humans is usually not available, as current pharmacokinetic and pharmacodynamic analyses are based on blood and/or tumor sampling. Assumptions about pharmacokinetics are mainly based on empirical models, which are simplified approximations of reality. Moreover, preclinical knowledge of whole body drug effects in animal models do not completely reflect the situation in men. Furthermore, pharmacodynamic analysis in humans can be hampered by the invasiveness of biopsy procedures or by the limited amount of available tumor material as lesions may not be accessible for a biopsy. Therefore, target expression, as well as potential heterogeneity within and between metastases, at baseline and over time are disregarded.
Molecular imaging with positron emission tomography (PET) is a non-invasive technique which can make use of monoclonal antibodies labeled with a radionuclide to assess their biodistribution and target expression at the whole body level. Performing serial PET scans before and during treatment allows investigation of target accessibility during treatment and may therefore be used to determine whether target saturation has been achieved. Multiple imaging trials in cancer patients have delivered detailed information on target distribution and dynamics, but data is not comparable due to different analysis approaches. With analysis of new targets and comparative analysis of already gathered data, PET could support understanding of working mechanisms, as well as development of future therapies, and improve patient selection.
The aim of the research described in my thesis was to investigate the role of molecular imaging with monoclonal antibodies to increase knowledge of whole body pharmacokinetics and pharmacodynamics, and to evaluate the contribution of molecular imaging to therapy decision making and to response prediction.
To that end, we developed three new monoclonal antibody-based PET tracers which target the anti-human epidermal growth factor receptor 3 (HER3; antibody lumretuzumab), the transforming growth factor beta (TGF-β; antibody fresolimumab) and the programmed death ligand 1 (PD-L1; antibody atezolizumab) and assessed their biodistribution in first-in human clinical trials. In these trials we also performed blood based pharmacokinetic analysis of the radionuclide Zirconium-89 (89Zr) and of the antibody or components of the signaling pathway. Fresh and/or archival tumor tissue was collected for target assessment by immunohistochemistry and/or RNA sequencing. Finally, autoradiography of fresh metastasis biopsies and in vitro internalization experiments with tumor cells and immune cells were conducted within the 89Zr-atezolizumab imaging trial.
Next, the additive value of the HER2-targeting tracer 89Zr-trastuzumab was evaluated in breast cancer patient presenting with a clinical dilemma. And finally, the first comparative biodistribution analysis of four 89Zr-labeled monoclonal antibodies was performed to create a basis for a prospectively growing imaging data warehouse of antibody-based tracers.
1. Bensch F, Lamberts LE, Smeenk MM, Jorritsma-Smit A, Lub-de Hooge MN, Terwisscha van Scheltinga AGT, de Jong JR, Gietema JA, Schröder CP, Thomas M, Jacob W, Abiraj K, Adessi C, Meneses-Lorente G, James I, Weisser M, Brouwers AH, de Vries EGE. 89Zr-lumretuzumab PET imaging before and during HER3 antibody lumretuzumab treatment in patients with solid tumors. Clin. Cancer Res. 2017;23:6128-37.
2. Den Hollander MW, Bensch F, Glaudemans AW, Oude Munnink TH, Enting RH, den Dunnen WF, Heesters MA, Kruyt FA, Lub-de Hooge MN, de Groot JC, Pearlberg J, Gietema JA, de Vries EG, Walenkamp AM. TGF-β antibody uptake in recurrent high grade glioma imaged with 89Zr-fresolimumab PET. J. Nucl. Med. 2015;56:1310-4.
3. Bensch F, Smeenk MM, van Es SC, de Jong JR, Schröder CP, Oosting SF, Lub-de Hooge MN, Menke-van der Houven van Oordt CW, Brouwers AH, Boellaard R, de Vries EGE. Comparative biodistribution analysis across four different 89Zr-monoclonal antibody tracers—The first step towards an imaging warehouse. Theranostics. 2018;8:4295-304.
4. Bensch F, van der Veen EL, Lub-de Hooge MN, Jorritsma-Smit A, Boellaard R, Kok IC, Oosting SF, Schröder CP, Hiltermann TJN, van der Wekken AJ, Groen HJM, Kwee TC, Elias SG, Gietema JA, Sanabria Bohorquez S, de Crespigny A, Williams SP, Mancao C, Brouwers AH, Fine BM, de Vries EGE. Clinical 89Zr-atezolizumab imaging as a potential PD-L1 biomarker in cancer patients. Nat. Med. 2018;24:1852-1858.
5. Bensch F, Brouwers AH, Lub-de Hooge MN, de Jong JR, van der Vegt B, Sleijfer S, de Vries EGE, Schröder CP. 89Zr-trastuzumab PET supports clinical decision making in breast cancer patients, when HER2 status cannot be determined by standard work up. Eur. J. Nucl. Med. Mol. Imaging. 2018;45:2300-2306.
Keywords: Molecular PET imaging, HER2, HER3, TGF-beta, PD-L1