Cetuximab-based immunotherapy and radioimmunotherapy of head and neck squamous cell carcinoma.
OBJECTIVE
To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.


METHODS
EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using (64)Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with (90)Y-DOTA-cetuximab.


RESULTS
EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher (64)Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to (90)Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody.


CONCLUSIONS
Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.
Niu
Gang
G
Imaging Sciences Training Program, Radiology and Imaging Sciences, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD20892, USA.
Sun
Xilin
X
Cao
Qizhen
Q
Courter
Donald
D
Koong
Albert
A
Le
Quynh-Thu
QT
Gambhir
Sanjiv Sam
SS
Chen
Xiaoyuan
X
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003301:Copper Radioisotopes / Q000627:therapeutic use; D005260:Female; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy / Q000628:therapy*; D006571:Heterocyclic Compounds / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D016499:Radioimmunotherapy; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C113625:yttrium(III)-1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; D000068818:Cetuximab