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Targeted Dual-Modality Imaging in Renal Cell Carcinoma: an Ex Vivo Kidney Perfusion Study

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Targeted Dual-Modality Imaging in Renal Cell Carcinoma: an Ex Vivo Kidney Perfusion Study Author Manuscript Published OnlineFirst on April 21, 2016; DOI: 10.1158/1078-0432.CCR-15-2937 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Targeted dual-modality imaging in renal cell carcinoma: An ex vivo kidney perfusion study Authors: Marlène C.H. Hekman1,2, Otto C. Boerman1, Mirjam de Weijert2, Desirée L. Bos1, Egbert Oosterwijk2, Hans F. Langenhuijsen2, Peter F.A. Mulders2, Mark Rijpkema1. Affiliations: 1. Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands. 2. Department of Urology, Radboudumc, Nijmegen The Netherlands. Running title: Targeted dual-modality imaging in renal cell carcinoma Keywords. Renal cell carcinoma, molecular imaging, near-infrared fluorescence imaging, image-guided surgery, targeted imaging. Financial support: none. Corresponding author: Marlène C.H. Hekman, Dept. of Radiology & Nuclear Medicine, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, [email protected], Tel: 024-3614048, Fax: 024- 3618942. Conflicts of interest: None. Word count: 4290 Total number of figures and tables: 2 tables, 4 figures, 8 supplementary files. 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 21, 2016; DOI: 10.1158/1078-0432.CCR-15-2937 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of translational relevance: Intraoperative dual-modality imaging may provide the surgeon with valuable information about tumor localization and resection margins, and therefore may improve locoregional control and patient outcome. In the current study we bridge the gap between preclinical studies and the clinical application of intraoperative dual-modality imaging using radiolabeled and fluorescently labeled tumor-targeting antibodies. In an ex vivo perfusion study of human kidneys with renal cell carcinoma dual-modality imaging was tested in a translational setting. Real-time fluorescence images acquired with a clinical fluorescence camera system clearly visualized uptake in tumor tissue and tumor-to-normal tissue borders, as confirmed (immuno)histochemically and by gamma counting. These results demonstrate the clinical potential of dual-modality imaging and have lead to the initiation of the first targeted dual-modality image-guided surgery study in clear cell renal cell carcinoma patients (NCT02497599). Targeted dual-modality imaging has the potential to revolutionize oncologic surgery. 2 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 21, 2016; DOI: 10.1158/1078-0432.CCR-15-2937 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: Purpose: Antibodies labeled with both a near-infrared fluorescent dye and a radionuclide can be used for tumor-targeted intraoperative dual-modality imaging. Girentuximab is a chimeric monoclonal antibody against carbonic anhydrase IX (CAIX), an antigen expressed in 95% of clear cell renal cell carcinoma (ccRCC). This study aimed to assess the feasibility of targeted dual-modality imaging with 111In-girentuximab-IRDye800CW using ex vivo perfusion of human tumorous kidneys. Experimental design: Seven radical nephrectomy specimens of ccRCC patients were perfused during 11-15h with dual-labeled girentuximab and subsequently rinsed during 2.5–4h with Ringer’s Lactate solution. Then, dual-modality imaging was performed on a 5-10-mm thick lamella of the kidney. Fluorescence imaging was performed with a clinical fluorescence camera set-up as applied during image-guided surgery. The distribution of Indium-111 in the slice of tumor tissue was visualized by autoradiography. In two perfusions an additional dual-labeled control antibody was added to demonstrate specific accumulation of dual-labeled girentuximab in CAIX-expressing tumor tissue. Results Both radionuclide and fluorescence imaging clearly visualized uptake in tumor tissue and tumor- to-normal tissue borders, as confirmed (immuno)histochemically and by gamma counting. Maximum uptake of girentuximab in tumor tissue was 0.33 % of the injected dose per gram 3 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 21, 2016; DOI: 10.1158/1078-0432.CCR-15-2937 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. (mean 0.12 %ID/g, range 0.01 – 0.33 %ID/g), while maximum uptake in the normal kidney tissue was 0.04 %ID/g (mean 0.02 %ID/g, range 0.00 – 0.04 %ID/g). Conclusion: Dual-labeled girentuximab accumulated specifically in ccRCC tissue, indicating the feasibility of dual-modality imaging to detect ccRCC. A clinical study to evaluate intraoperative dual- modality imaging in ccRCC patients has been initiated. 4 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 21, 2016; DOI: 10.1158/1078-0432.CCR-15-2937 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction In oncological surgery, radical tumor resection is crucial for treatment outcome and patient survival (1-6). During surgery, differentiation of tumor tissue from non-tumorous tissue with the naked eye may be challenging. Intraoperative imaging techniques that can distinguish tumor from normal tissue will help the surgeon to achieve complete tumor resection. One of these techniques, radio-guided surgery, has already been implemented in clinical practice, for example to detect sentinel lymph nodes (7-9). The high tissue penetration depth of gamma radiation allows accurate localization of tumors, almost regardless of tissue depth. However, exact tumor delineation with a gamma probe is difficult and for precise real-time tumor delineation during surgery an optical signal may be more beneficial. For this purpose, a fluorescent probe can be used, but since the penetration depth of light in biological tissue is limited, fluorescence imaging is mainly useful for the detection of superficially located tumors (10, 11). Therefore, dual-modality image-guided surgery, combining the advantages of radioguided and fluorescence-guided surgery may be a synergistic combination (12-15). A dual- labeled tumor-targeting imaging probe could allow intraoperative tumor detection, tumor delineation, and assessment of resection margins and remnant disease. Results from preclinical studies are promising (16-19) and tumor-targeted dual-modality imaging is awaiting its first use in patients. Monoclonal antibodies against tumor-associated antigens tagged both with a radiolabel and a fluorophore may be used as probes during image-guided surgery (20). Girentuximab, a chimeric monoclonal IgG1 antibody, is an excellent vehicle to target clear cell renal cell carcinoma (ccRCC). It specifically recognizes carbonic anhydrase IX (CAIX), a cell surface antigen that is expressed abundantly in more than 95 percent of ccRCC and is absent in normal 5 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 21, 2016; DOI: 10.1158/1078-0432.CCR-15-2937 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. kidney tissue (21, 22). Previous research has shown that after administration of radiolabeled girentuximab both primary tumors and metastases can be detected by PET/CT or SPECT/CT in patients (23-25). Animal studies using 111In-girentuximab-IRDye800CW have illustrated the potential of dual-modality imaging (17, 18). Dual-labeled girentuximab accumulates highly and specifically in CAIX-expressing SK-RC-52 subcutaneous tumors (18). Next, a proof-of-principle study was performed to show the feasibility of image-guided surgery using an intraperitoneal tumor model (17). After administration of dual-labeled girentuximab submillimeter CAIX- expressing tumor nodules could be detected preoperatively with SPECT/CT. Subsequently, during surgery superficially located tumor nodules could be visualized and resected based on the fluorescent signal. However, animal studies only partly reflect the clinical situation. To test the translation of dual-modality imaging to the clinic, models using clinical imaging systems and intact tumors obtained from patients are required. In the present study, tumorous kidneys resected from ccRCC patients were connected ex vivo to a perfusion system via the renal artery as has been described previously (26). Subsequently, the tumorous kidneys were perfused with dual-labeled girentuximab and investigated using the clinical imaging system to be used during image-guided surgery. In preparation of the first targeted dual-modality image-guided surgery study in patients, this study aimed to show the feasibility of tumor-targeted dual-modality imaging in renal cell carcinoma using dual-labeled girentuximab in an ex vivo kidney perfusion model. 6 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 21, 2016; DOI: 10.1158/1078-0432.CCR-15-2937 Author manuscripts have been peer reviewed
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