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Tumor Necrosis Factor Sensitizes Low Epidermal Growth Factor Receptor (EGFR)-expressing Carcinomas for Anti-EGFR Therapy¹

Department of Otorhinolaryngology [M. H., M. R., J. K., R. K.], Department of Obstetrics and Gynecology [C. S., M. S.], Central Research Unit [A. S-K.], School of Medicine, J. W. Goethe University, 60590 Frankfurt, Germany, and Lukas Krankenhaus [H-G. S.], 41460 Neuss, Germany

Analysis of 1060 xenotransplants derived from cancer cell lines as well as spontaneously occurring tumors from the larynx, pharynx, mammary gland, uterine cervix, and vulva revealed that tumor regression induced by treatment with monoclonal antibodies (EMD 55900 and EMD 72000) against the epidermal growth factor receptor (EGFR) could be enhanced by tumor necrosis factor (TNF-) treatment in vivo. Moreover, tumors that primarily do not respond to antibody treatment can be made susceptible by additional TNF- treatment. To investigate the in vivo effects of monoclonal antibodies, we treated tumors derived from cell lines (A431 and Detroit 562) as well as spontaneously occurring squamous cell carcinomas and adenocarcinomas (transplanted on NMRI-nu/nu mice) generally with EMD 55900 (40 µg/g mouse) and its humanized version EMD 72000 (40 µg/g mouse). When treated with EMD 55900 and EMD 72000, carcinomas with an EGFR concentration of 70 fmol/mg protein showed significant reduction in tumor size compared with untreated controls. The degree of tumor regression correlated with the EGFR concentration of the tumor. In mice treated with TNF- (0.5 µg/g mouse) and EMD 55900/72000 simultaneously, we observed enhanced antitumor effects up to complete tumor eradication. Carcinomas with an EGFR concentration <70 fmol/mg protein could be made susceptible to treatment with EMD 55900 and EMD 72000 by simultaneous treatment with TNF-, resulting in a significant reduction in tumor size.

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