Clément Bailly

CR Divgi

CW Menke-van der Houven van Oordt

DP Tabassum

EC Dijkers

F Kraeber-Bodéré

Françoise Kraeber-Bodere

G Gebhart

H Sun

I Bahce

Jean-François Chatal

K Muylle

K Tamura

LE Lamberts

Michel Chérel

MW Hollander den

OC Boerman

RP Baum

SJ Asselt van

YW Jauw

Crossref

EDITORIAL COMMENTARYImmunoPET to help stratify patients for targeted therapiesand to improve drug developmentFrançoise Kraeber-Bodere1 & Clément Bailly1 & Michel Chérel1,2 &Jean-François Chatal2Received: 1 June 2016 /Accepted: 4 July 2016 /Published online: 18 August 2016# The Author(s) 2016. This article is published with open access at Springerlink.comMalignant tumours usually display intratumoral heterogeneityas well as phenotypic and genotypic heterogeneity amongpatients. Consequently, there is the need to develop treatmentsappropriate to each patient [1]. Screening of tumour pheno-types requires biopsy, a procedure that is invasive and limitedto accessible tumour sites. Moreover, it is difficult to obtainrepeated biopsies from the same lesions to explore changes inproperties and heterogeneity during therapy. There is thereforethe need for new noninvasive diagnostic technologies such asmolecular imaging to assess whole-body tumour phenotypesto allow more specific therapeutic strategies to be developed.There has been a considerable increase in the use oftargeted therapies, including monoclonal antibodies (mAbs),in cancer management. A recent review found that there aremore than 50 mAbs in advanced clinical development in on-cology, including several antibody–drug conjugates andradiolabelled mAbs for radioimmunotherapy (RIT) [2]. Untilnow, only immunohistochemistry (IHC) analysis and quanti-tative polymerase chain reaction analysis of tumour biopsieshave been able to identify patients with the highest chance ofresponse to antibody-based therapy. However, these ap-proaches do not allow whole-body mapping of tumour cell bio-marker expression and do not assess biomarker accessibility.mAbs can be labelled with radionuclides and are promisingprobes for theranostic approaches, offering a noninvasive so-lution to quantitatively assess in vivo target expression, toselect patients for expensive and potentially toxic therapiesand to monitor responses [3]. mAbs were initially labelledwith single-photon emitters, such as 131I or 111In, and weresubsequently used in planar imaging or SPECT imaging pro-cedures to improve RIT using dosimetry procedures. Accuratequantitative information can be obtained more readily usingPET. The good spatial resolution of PET allows better delin-eation of tumours and organs than with SPECT. Additionally,key factors for the superiority of PET over SPECT and planarimaging include exact attenuation correction, precise scattercorrection and high sensitivity, combined with the possibilityof performing true whole-body imaging in a reasonable time.Marrying mAbs and PET emitters requires an appropriatematch between the biological half-life of the protein and thephysical half-life of the isotope [4]. The use of 18F or 68Gawith a short half-life is limited to small molecules such asantibody fragments that distribute rapidly in the body, whereas89Zr and 124I are well suited to the labelling of larger mole-cules such as intact immunoglobulins. 64Cu with an interme-diate half-life of 12.7 h can be used for labelling a large num-ber of molecules of different sizes.In the present issue of EJNMMI, Sun et al. report the use ofan anti-CD146 mAb labelled with 64Cu for quantitativeimmunoPET imaging of CD146 antigen expression in lungcancer models [5]. This antigen induces epithelial-to-mesenchymal transition, has a favourable receptor density ex-pression (125,000 receptors per cell) and may be associatedwith the metastatic potential of cells and their resistance toapoptosis. Moreover, it has low expression levels in normaltissues. Therefore, a mAb specific for this antigen (YY146)has good potential for therapeutic application. In a preclinicalstudy the authors assessed six human lung cancer cell linesThis Editorial Commentary refers to the article http://dx.doi.org/10.1007/s00259-016-3442-1* Jean-François Chatalchatal@arronax-nantes.fr1 InsermU892, CNRSUMR 6299, University Hospital-ICO-CRCNA,Nantes-Saint-Herblain, France2 Groupement d’Intérêt Public Arronax, University of Nantes,Nantes, FranceEur J Nucl Med Mol Imaging (2016) 43:2166–2168DOI 10.1007/s00259-016-3458-6with different expression levels of CD146 and showed astrong correlation between tumour uptake of 64Cu-NOTA-YY146 and relative expression of CD146 in the tumour celllines. This radioimmunoconjugate is consequently appropri-ate for immunoPET for quantitative evaluation of CD146 ex-pression in lung cancers before therapy using coupled oruncoupled YY146 antibody.The first clinical proof that immunoPET is a powerful mo-lecular diagnostic tool was reported by Divgi et al. The mAbgirentuximab binds carbonic anhydrase IX, a cell-surface an-tigen highly and homogeneously expressed in more than 95%of clear-cell renal cell carcinomas (ccRCC). In 26 presurgicalpatients with renal masses, immunoPET using 124I-girentuximab demonstrated a sensitivity of 94 % and a spec-ificity of 100 %, with a negative predictive value of 90 % anda positive predictive value of 100 % [6]. These impressiveresults were corroborated in a phase III study, showing that124I-girentuximab immunoPET discriminates the presence orabsence of ccRCCwith an accuracy at least comparable to thatof biopsy analysis, suggesting that this invasive procedurewith its inherent risks could be avoided [7].Treatment strategies for individual patients could be tai-lored by using immunoPET. For example, anti-HER2 thera-peutic agents are only effective in patients who have HER2-positive breast cancer as determined by IHC. It has been prov-en that mAbs labelled with 68Ga, 64Cu or 89Zr can noninva-sively identify HER2-positive lesions and a few clinical stud-ies have shown that immunoPET with 89Zr-mAbs is able topredict 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+ orFISH ≥2.2 HER2-positive metastatic breast cancer scheduledfor treatment with trastuzumab emtansine (T-DM1) [12]. 18F-FDG PETwas performed at baseline and before cycle 2 of T-DM1. The study showed 29 % negative HER2 PET/CT.Based onRECIST1.1. criteria, immunoPETshowed a positivepredictive value of 72 % and a negative predictive value of88 %, and FDG PETa positive predictive value of 96 % and anegative predictive value of 83 %. The two imaging tech-niques combined gave a predictive value of 100 % and en-abled patients with time to treatment failure of 2.8 months tobe discriminated from those with time to treatment failure of15 months.In another study, the use of 89Zr-bevacizumab PET imagingfor predicting response to combination therapy withcarboplatin, paclitaxel and bevacizumab was assessed in sev-en patients with non-small-cell lung cancer. A positive butnonsignificant trend for a correlation between tumour uptakeand progression-free and overall survival after treatment wasfound [13]. The same encouraging trend was found in tenpatients with K-RAS advanced colorectal cancer who re-ceived 89Zr-cetuximab followed by treatment with cetuximab[14]. In other clinical applications such as 89Zr-bevacizumabfollowed by everolimus therapy in patients with neuroendo-crine tumours [15], and 89Zr-fresolimumab followed byfresolimumab therapy in patients with high-grade glioma[16], no correlation was found between tumour uptake andclinical response. Based on these promising preliminary clin-ical results, it appears that immunoPET has a realistic potentialfor predicting responses to antibody-based therapy assumingthat the biodistribution of the radioimmunoconjugate inimmunoPET is the same as the biodistribution of the mAbsused for therapy. One serious drawback would be a negativeimmunoPET result predicting nonresponse to subsequent ther-apy in a patient who could have responded to the therapy, ashas been shown in a few patients [14]. Randomizedmulticentre studies in stratified patients with different relevantindications are needed to demonstrate that immunoPETcan beconsidered a true diagnostic companion.Moreover, molecular in vivo imaging plays an in-creasing role in the development of new drugs by phar-maceutical companies. In vivo imaging is an effectivesolution for the rapid assessment of drug candidates,which may be radiolabelled to monitor their pharmaco-kinetics and biodistribution during preclinical and earlyclinical phases. Indeed, immunoPET is a powerful inno-vation to improve knowledge about the in vivo behav-iour of mAbs, and provides information regarding thequantitative variation in molecular targets during treat-ments. ImmunoPETcould provide information about tumourtargeting, pharmacokinetics and accumulation in critical nor-mal organs to determine optimal dosing and the impact ofpreloading with unlabelled antibody for RIT [17].Consideration of the cost and safety of immunoPET is alsoimportant. A cost approaching several thousand euros per pa-tient would be acceptable if the benefit in patient selection forexpensive therapies and in drug development could be con-firmed. Regarding dosimetry, the internal radiation doses es-timated for immunoPET are comparable to those from con-ventional imaging and are acceptable. Due to a shorter phys-ical half-life, the dose delivered with 64Cu is lower than thatwith 89Zr. Indeed, the internal radiation dose from 64Cu-trastuzumab absorbed by the patient has been estimated tobe 4.5 mSv, compared with 18 mSv from 89Zr-trastuzumab[10]. Using activities ranging from 370 to 740 MBq, the radi-ation dose absorbed from 18F-FDG PET has been estimated tobe 7 to 14 mSv.In conclusion, we consider that immunoPET is apromising tool for personalized medicine, allowing bet-ter patient selection for antibody-based therapies andaccelerating and improving drug development. Whilstthis innovative technology is currently associated witha significant cost, this cost could become acceptable ifthe benefit in stratifying patients before expensivetargeted therapies can be clearly demonstrated in largemulticentre randomized clinical trials.Eur J Nucl Med Mol Imaging (2016) 43:2166–2168 2167Acknowledgments This work was supported in part by grants from theFrench National Agency for Research called BInvestissements d’Avenir^Labex IRON no. ANR-11-LABX-0018-01 and Equipex ArronaxPlus no.ANR-11-EQPX-0004.Open Access This article is distributed under the terms of the CreativeCommons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /creativecommons.org/licenses/by/4.0/), which permits unrestricted use,distribution, and reproduction in any medium, provided you give appro-priate credit to the original author(s) and the source, provide a link to theCreative Commons license, and indicate if changes were made.References1. Tabassum DP, Polyak K. Tumorigenesis: it takes a village. Nat RevCancer. 2015;15:473–83.2. Lamberts LE, Williams SP, Terwisscha van Scheltinga AGT, Lub-de Hooge MN, Schröder CP, Gietema JA, et al. Antibody positronemission tomography imaging in anticancer drug development. JClin Oncol. 2015;33:1491–504.3. Boerman OC, Oyen WJ. Immuno-PET of cancer: a revival of anti-body imaging. J Nucl Med. 2011;52:1171–2.4. Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, Mathieu C,Guérard F, Frampas E, et al. Tumor immunotargeting using inno-vative radionuclides. Int J Mol Sci. 2015;16:3932–54.5. Sun H, England CG, Hernandez R, Graves SA, Majewski RL,Kamkaew A, et al. ImmunoPET for assessing the differential up-take of a CD146-specific monoclonal antibody in lung cancer. Eur JNucl Med Mol Imaging. 2016. doi:10.1007/s00259-016-3442-16. Divgi CR, Pandit-Taskar N, Jungbluth AA, Reuter VE, Gönen M,Ruan S, et al. Preoperative characterisation of clear-cell renal car-cinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial.Lancet Oncol. 2007;8:304–10.7. Divgi CR, Uzzo RG, Gatsonis C, Bartz R, Treutner S, Yu JQ, et al.Positron emission tomography/computed tomography identifica-tion of clear cell renal cell carcinoma: results from the REDECTtrial. J Clin Oncol. 2013;31:187–94.8. Dijkers EC, Kosterink JG, Rademaker AP, Perk LR, van DongenGA, Bart J, et al. Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. JNucl Med. 2009;50:974–81.9. Baum RP, Prasad V, Müller D, Schuchardt C, Orlova A, WennborgA, et al. Molecular imaging of HER2-expressing malignant tumorsin breast cancer patients using synthetic 111In- or 68Ga-labeledaffibody molecules. J Nucl Med. 2010;51:892–7.10. Tamura K, Kurihara H, Yonemori K, Tsuda H, Suzuki J, Kono Y,et al. 64Cu-DOTA-trastuzumab PET imaging in patients withHER2-positive breast cancer. J Nucl Med. 2013;54:1869–75.11. Jauw YW, Menke-van der Houven van Oordt CW, Hoekstra OS,Hendrikse NH, Vugts DJ, Zijlstra JM, et al. Immuno-positron emis-sion tomography with zirconium-89-labeled monoclonal antibodiesin oncology: what Can We learn from initial clinical trials? FrontPharmacol. 2016;7:131.12. Gebhart G, Lamberts LE, Wimana Z, Garcia C, Emonts P, AmeyeL, et al. Molecular imaging as a tool to investigate heterogeneity ofadvanced HER2-positive breast cancer and to predict patient out-come under trastuzumab emtansine (T-DM1): the ZEPHIR trial.Ann Oncol. 2016;27:619–24.13. Bahce I, Huisman MC, Verwer EE, Ooijevaar R, Boutkourt F,Vugts DJ, et al. Pilot study of (89)Zr-bevacizumab positron emis-sion tomography in patients with advanced non-small cell lungcancer. EJNMMI Res. 2014;4:35.14. Menke-van der Houven van Oordt CW, Gootjes EC, HuismanMC,Vugts DJ, Roth C, Luik AM, et al. 89Zr-cetuximab PET imaging inpatients with advanced colorectal cancer. Oncotarget. 2015;6:30384–93.15. van Asselt SJ, Oosting SF, Brouwers AH, Bongaerts AHH, de JongJR, Lub-de Hooge MN, et al. Everolimus reduces (89)Zr-bevacizumab tumor uptake in patients with neuroendocrine tumors.J Nucl Med. 2014;55:1087–92.16. den Hollander MW, Bensch F, Glaudemans AW, Oude MunninkTH, Enting RH, den Dunnen WF, et al. TGF-β antibody uptake inrecurrent high-grade glioma imaged with 89Zr-fresolimumab PET.J Nucl Med. 2015;56:1310–4.17. Muylle K, Flamen P, Vugts DJ, Guiot T, Ghanem G, Meuleman N,et al. Tumour targeting and radiation dose of radioimmunotherapywith (90)Y-rituximab in CD20+ B-cell lymphoma as predicted by(89)Zr-rituximab immuno-PET: impact of preloading withunlabelled rituximab. Eur J Nucl Med Mol Imaging. 2015;42:1304–14.2168 Eur J Nucl Med Mol Imaging (2016) 43:2166–2168

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

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

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