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      ImmunoPET to help stratify patients for targeted therapies and to improve drug development

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          Abstract

          Malignant tumours usually display intratumoral heterogeneity as well as phenotypic and genotypic heterogeneity among patients. Consequently, there is the need to develop treatments appropriate to each patient [1]. Screening of tumour phenotypes requires biopsy, a procedure that is invasive and limited to accessible tumour sites. Moreover, it is difficult to obtain repeated biopsies from the same lesions to explore changes in properties and heterogeneity during therapy. There is therefore the need for new noninvasive diagnostic technologies such as molecular imaging to assess whole-body tumour phenotypes to allow more specific therapeutic strategies to be developed. There has been a considerable increase in the use of targeted therapies, including monoclonal antibodies (mAbs), in cancer management. A recent review found that there are more than 50 mAbs in advanced clinical development in oncology, including several antibody–drug conjugates and radiolabelled mAbs for radioimmunotherapy (RIT) [2]. Until now, only immunohistochemistry (IHC) analysis and quantitative polymerase chain reaction analysis of tumour biopsies have been able to identify patients with the highest chance of response to antibody-based therapy. However, these approaches do not allow whole-body mapping of tumour cell biomarker expression and do not assess biomarker accessibility. mAbs can be labelled with radionuclides and are promising probes for theranostic approaches, offering a noninvasive solution to quantitatively assess in vivo target expression, to select patients for expensive and potentially toxic therapies and to monitor responses [3]. mAbs were initially labelled with single-photon emitters, such as 131I or 111In, and were subsequently used in planar imaging or SPECT imaging procedures to improve RIT using dosimetry procedures. Accurate quantitative information can be obtained more readily using PET. The good spatial resolution of PET allows better delineation of tumours and organs than with SPECT. Additionally, key factors for the superiority of PET over SPECT and planar imaging include exact attenuation correction, precise scatter correction and high sensitivity, combined with the possibility of performing true whole-body imaging in a reasonable time. Marrying mAbs and PET emitters requires an appropriate match between the biological half-life of the protein and the physical half-life of the isotope [4]. The use of 18F or 68Ga with a short half-life is limited to small molecules such as antibody fragments that distribute rapidly in the body, whereas 89Zr and 124I are well suited to the labelling of larger molecules such as intact immunoglobulins. 64Cu with an intermediate half-life of 12.7 h can be used for labelling a large number of molecules of different sizes. In the present issue of EJNMMI, Sun et al. report the use of an anti-CD146 mAb labelled with 64Cu for quantitative immunoPET imaging of CD146 antigen expression in lung cancer models [5]. This antigen induces epithelial-to-mesenchymal transition, has a favourable receptor density expression (125,000 receptors per cell) and may be associated with the metastatic potential of cells and their resistance to apoptosis. Moreover, it has low expression levels in normal tissues. Therefore, a mAb specific for this antigen (YY146) has good potential for therapeutic application. In a preclinical study the authors assessed six human lung cancer cell lines with different expression levels of CD146 and showed a strong correlation between tumour uptake of 64Cu-NOTA-YY146 and relative expression of CD146 in the tumour cell lines. This radioimmunoconjugate is consequently appropriate for immunoPET for quantitative evaluation of CD146 expression in lung cancers before therapy using coupled or uncoupled YY146 antibody. The first clinical proof that immunoPET is a powerful molecular diagnostic tool was reported by Divgi et al. The mAb girentuximab binds carbonic anhydrase IX, a cell-surface antigen highly and homogeneously expressed in more than 95 % of clear-cell renal cell carcinomas (ccRCC). In 26 presurgical patients with renal masses, immunoPET using 124I-girentuximab demonstrated a sensitivity of 94 % and a specificity of 100 %, with a negative predictive value of 90 % and a positive predictive value of 100 % [6]. These impressive results were corroborated in a phase III study, showing that 124I-girentuximab immunoPET discriminates the presence or absence of ccRCC with an accuracy at least comparable to that of biopsy analysis, suggesting that this invasive procedure with its inherent risks could be avoided [7]. Treatment strategies for individual patients could be tailored by using immunoPET. For example, anti-HER2 therapeutic agents are only effective in patients who have HER2-positive breast cancer as determined by IHC. It has been proven that mAbs labelled with 68Ga, 64Cu or 89Zr can noninvasively identify HER2-positive lesions and a few clinical studies have shown that immunoPET with 89Zr-mAbs is able to predict response to anti-HER2 antibody-based therapy [8–11]. In the ZEPHIR study, pretreatment PET using 89Zr-trastuzumab was assessed in 56 patients with IHC 3+ or FISH ≥2.2 HER2-positive metastatic breast cancer scheduled for treatment with trastuzumab emtansine (T-DM1) [12]. 18F-FDG PET was performed at baseline and before cycle 2 of T-DM1. The study showed 29 % negative HER2 PET/CT. Based on RECIST1.1. criteria, immunoPET showed a positive predictive value of 72 % and a negative predictive value of 88 %, and FDG PET a positive predictive value of 96 % and a negative predictive value of 83 %. The two imaging techniques combined gave a predictive value of 100 % and enabled patients with time to treatment failure of 2.8 months to be discriminated from those with time to treatment failure of 15 months. In another study, the use of 89Zr-bevacizumab PET imaging for predicting response to combination therapy with carboplatin, paclitaxel and bevacizumab was assessed in seven patients with non-small-cell lung cancer. A positive but nonsignificant trend for a correlation between tumour uptake and progression-free and overall survival after treatment was found [13]. The same encouraging trend was found in ten patients with K-RAS advanced colorectal cancer who received 89Zr-cetuximab followed by treatment with cetuximab [14]. In other clinical applications such as 89Zr-bevacizumab followed by everolimus therapy in patients with neuroendocrine tumours [15], and 89Zr-fresolimumab followed by fresolimumab therapy in patients with high-grade glioma [16], no correlation was found between tumour uptake and clinical response. Based on these promising preliminary clinical results, it appears that immunoPET has a realistic potential for predicting responses to antibody-based therapy assuming that the biodistribution of the radioimmunoconjugate in immunoPET is the same as the biodistribution of the mAbs used for therapy. One serious drawback would be a negative immunoPET result predicting nonresponse to subsequent therapy in a patient who could have responded to the therapy, as has been shown in a few patients [14]. Randomized multicentre studies in stratified patients with different relevant indications are needed to demonstrate that immunoPET can be considered a true diagnostic companion. Moreover, molecular in vivo imaging plays an increasing role in the development of new drugs by pharmaceutical companies. In vivo imaging is an effective solution for the rapid assessment of drug candidates, which may be radiolabelled to monitor their pharmacokinetics and biodistribution during preclinical and early clinical phases. Indeed, immunoPET is a powerful innovation to improve knowledge about the in vivo behaviour of mAbs, and provides information regarding the quantitative variation in molecular targets during treatments. ImmunoPET could provide information about tumour targeting, pharmacokinetics and accumulation in critical normal organs to determine optimal dosing and the impact of preloading with unlabelled antibody for RIT [17]. Consideration of the cost and safety of immunoPET is also important. A cost approaching several thousand euros per patient would be acceptable if the benefit in patient selection for expensive therapies and in drug development could be confirmed. Regarding dosimetry, the internal radiation doses estimated for immunoPET are comparable to those from conventional imaging and are acceptable. Due to a shorter physical half-life, the dose delivered with 64Cu is lower than that with 89Zr. Indeed, the internal radiation dose from 64Cu-trastuzumab absorbed by the patient has been estimated to be 4.5 mSv, compared with 18 mSv from 89Zr-trastuzumab [10]. Using activities ranging from 370 to 740 MBq, the radiation dose absorbed from 18F-FDG PET has been estimated to be 7 to 14 mSv. In conclusion, we consider that immunoPET is a promising tool for personalized medicine, allowing better patient selection for antibody-based therapies and accelerating and improving drug development. Whilst this innovative technology is currently associated with a significant cost, this cost could become acceptable if the benefit in stratifying patients before expensive targeted therapies can be clearly demonstrated in large multicentre randomized clinical trials.

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          Most cited references15

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          Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.

          Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1.
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            Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging.

            The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibody-based therapy, and to support early antibody development. The PET radiopharmaceutical (89)Zr-trastuzumab was compared with the SPECT tracer (111)In-trastuzumab, which we have tested in the clinic already. Trastuzumab was labeled with (89)Zr and (for comparison) with (111)In. The minimal dose of trastuzumab required for optimal small-animal PET imaging and biodistribution was determined with human HER2/neu-positive or -negative tumor xenograft-bearing mice. Trastuzumab was efficiently radiolabeled with (89)Zr at a high radiochemical purity and specific activity. The antigen-binding capacity was preserved, and the radiopharmaceutical proved to be stable for up to 7 d in solvent and human serum. Of the tested protein doses, the minimal dose of trastuzumab (100 microg) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of (89)Zr-trastuzumab in HER2/neu-positive tumors than in HER2/neu-negative tumors, especially at day 6 (33.4 +/- 7.6 [mean +/- SEM] vs. 7.1 +/- 0.7 percentage injected dose per gram of tissue). There were good correlations between the small-animal PET images and the biodistribution data and between (89)Zr-trastuzumab and (111)In-trastuzumab uptake in tumors (R(2) = 0.972). Clinical-grade (89)Zr-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution.
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              64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer.

              The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.
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                Author and article information

                Contributors
                chatal@arronax-nantes.fr
                Journal
                Eur J Nucl Med Mol Imaging
                Eur. J. Nucl. Med. Mol. Imaging
                European Journal of Nuclear Medicine and Molecular Imaging
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1619-7070
                1619-7089
                18 August 2016
                18 August 2016
                2016
                : 43
                : 12
                : 2166-2168
                Affiliations
                [1 ]Inserm U892, CNRS UMR 6299, University Hospital-ICO-CRCNA, Nantes-Saint-Herblain, France
                [2 ]Groupement d’Intérêt Public Arronax, University of Nantes, Nantes, France
                Article
                3458
                10.1007/s00259-016-3458-6
                5047921
                27539021
                6df7d7de-41e6-4d88-900c-b0d87d2c4473
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 1 June 2016
                : 4 July 2016
                Funding
                Funded by: French National Agency for Research called “Investissements d’Avenir” Labex IRON n°ANR-11-LABX-0018-01 and Equipex ArronaxPlus n°ANR-11-EQPX-0004.
                Categories
                Editorial Commentary
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2016

                Radiology & Imaging
                Radiology & Imaging

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