Radiolabeled anti-EGFR-antibody improves local tumor control after external beam radiotherapy and offers theragnostic potential.
OBJECTIVE
The effect of radioimmunotherapy (RIT) using the therapeutic radionuclide Y-90 bound to the anti-EGFR antibody cetuximab combined with external beam irradiation (EBRT) (EBRIT) on permanent local tumor control in vivo was examined.


METHODS
Growth delay was evaluated in three human squamous cell carcinoma models after RIT with [(90)Y]Y-(CHX-A''-DTPA)₄-cetuximab (Y-90-cetuximab). The EBRT dose required to cure 50% of the tumors (TCD₅₀) for EBRT alone or EBRIT was evaluated in one RIT-responder (FaDu) and one RIT-non-responder (UT-SCC-5). EGFR expression and microenvironmental parameters were evaluated in untreated tumors, bioavailability was visualized by PET using ([(86)Y]Y-(CHX-A''-DTPA)₄-cetuximab (Y-86-cetuximab) and biodistribution using Y-90-cetuximab.


RESULTS
In UT-SCC-8 and FaDu but not in UT-SCC-5 radiolabeled cetuximab led to significant tumor growth delay. TCD₅₀ after EBRT was significantly decreased by EGFR-targeted RIT in FaDu but not in UT-SCC-5. In contrast to EGFR expression, parameters of the tumor micromilieu and in particular the Y-90-cetuximab biodistribution or Y-86-cetuximab visualization in PET correlated with the responsiveness to RIT or EBRIT.


CONCLUSIONS
EGFR-targeted EBRIT can improve permanent local tumor control compared to EBRT alone. PET imaging of bioavailability of labeled cetuximab appears to be a suitable predictor for response to EBRIT. This theragnostic approach should be further explored for clinical translation.
Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany.
Lydia
L
Koi
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden - Rossendorf, Germany.
Ralf
R
Bergmann
Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden - Rossendorf, Germany.
Kerstin
K
Brüchner
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Chemistry and Food Chemistry, Technische Universität Dresden, Germany.
Jens
J
Pietzsch
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Chemistry and Food Chemistry, Technische Universität Dresden, Germany.
Hans-Jürgen
HJ
Pietzsch
Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden - Rossendorf, Germany; German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mechthild
M
Krause
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Chemistry and Food Chemistry, Technische Universität Dresden, Germany.
Jörg
J
Steinbach
Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, University Hospital, Eberhard Karls Universität Tübingen, Germany.
Daniel
D
Zips
Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden - Rossendorf, Germany; German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: michael.baumann@uniklinikum-dresden.de.
Michael
M
Baumann
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D017879:Isothiocyanates / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000276:immunology; D011897:Random Allocation; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
D061067:Antibodies, Monoclonal, Humanized; D000922:Immunotoxins; D017879:Isothiocyanates; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
Cetuximab; Combined treatment; Epidermal growth factor receptor (EGFR) inhibition; Radioimmunotherapy; Radiotherapy