title: Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer.
abstract: Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized (131)I-labeled anti-carcinoembryonic antigen antibody ((131)I-huA5B7), with cetuximab in colorectal cancer (CRC).
  
  
  METHODS
  Three human CRC cell lines--SW1222, LoVo, and LS174T--were used to generate subcutaneous xenografts, and stably luciferase-transfected SW1222 cells were used to establish a model of hepatic metastases in immunocompromised mice. Imaging and biodistribution studies were conducted to confirm the selective tumor localization of (131)I-huA5B7. Efficacy was evaluated on the basis of tumor growth delay and survival, along with markers of DNA damage response, cell cycle, proliferation, and apoptosis.
  
  
  RESULTS
  Selective tumor targeting was achieved with (131)I-huA5B7 alone or in combination with cetuximab without observable toxicity. Compared with monotherapy, combining cetuximab with radioimmunotherapy significantly and synergistically reduced tumor growth and prolonged survival of mice in 2 of the subcutaneous and in the metastatic tumor model. Evidence of DNA damage, G2/M arrest, significantly decreased proliferation, and increased apoptosis were observed with radioimmunotherapy and the combination therapy. However, a significant decrease in DNA-protein kinase expression with the combination regimen suggests that the addition of cetuximab suppressed DNA repair.
  
  
  CONCLUSIONS
  Our results demonstrate enhanced therapeutic efficacy with the combination of cetuximab and radioimmunotherapy in CRC, which could potentially translate into successful clinical outcomes. This strategy could improve the treatment of residual disease postoperatively and ultimately prevent or delay recurrence. Furthermore, other carcinoembryonic antigen-expressing malignancies could also benefit from this approach.
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London, United vessie_vassileva@hotmail.com.
authors.forename: Vessela
authors.initials: V
authors.lastname: Vassileva
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London, United.
authors.forename: Vineeth
authors.initials: V
authors.lastname: Rajkumar
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London, United.
authors.forename: Mario
authors.initials: M
authors.lastname: Mazzantini
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London, United.
authors.forename: Mathew
authors.initials: M
authors.lastname: Robson
authors.affiliation: Centre for Advanced Biomedical Imaging (CABI), Division of Medicine, University College London, London, United Kingdom; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Badar
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London, United.
authors.forename: Surinder
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Chemistry and Institute of Nuclear Medicine, University College London, London, United Kingdom.
authors.forename: Erik
authors.initials: E
authors.lastname: Årstad
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London, United.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hochhauser
authors.affiliation: Centre for Advanced Biomedical Imaging (CABI), Division of Medicine, University College London, London, United Kingdom; and.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: Translational Research Office, University College London.
authors.forename: Jane
authors.initials: J
authors.lastname: Kinghorn
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London, United.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Boxer
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London, United.
authors.forename: Rosmund Barbara
authors.initials: RB
authors.lastname: Pedley
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D017209:Apoptosis; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy*; D004249:DNA Damage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D016499:Radioimmunotherapy / Q000379:methods*; D011877:Radionuclide Imaging; D023041:Xenograft Model Antitumor Assays
chemical_list: C518613:A5B7 monoclonal antibody; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002272:Carcinoembryonic Antigen; D000068818:Cetuximab
keywords: anti-EGFR therapy; colorectal cancer; combination therapy; radioimmunotherapy; radiosensitization