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Tumor necrosis factor alpha sensitizes low epidermal growth factor receptor (EGFR)-expressing carcinomas for
M Hambek1, C Solbach, H G Schnuerch
1Department of Otorhinolaryngology School of Medicine, J. W. Goethe University, Frankfurt, Germany.
Abstract:
Analysis of 1,060 xenotransplants derived from cancer cell lines as wel 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 alpha (TNF-alpha) treatment in vivo. Moreover, tumor that primarily do not respond to antibody treatment can be made suscep tible by additional TNF-alpha 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 carci nomas and adenocarcinomas (transplanted on NMRI-nu/nu mice) gener ally with EMD 55900 (40 microg/g mouse) and its humanized version EMD 72000 (40 microg/g mouse). When treated with EMD 55900 and EMD 72000 carcinomas with an EGFR concentration of > or = 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-alpha (0.5 microg/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-alpha, resulting in a significant reduction in tumor size.
Insights
Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) showed tumor regression. Combining EGFR antibodies with tumor necrosis factor alpha (TNF-alpha) enhanced antitumor effects and made resistant tumors susceptible.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Research
Background:
- Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) are used in cancer therapy.
- Tumor necrosis factor alpha (TNF-alpha) is a cytokine with potential antitumor activity.
- The combination of EGFR-targeted antibodies and TNF-alpha for enhanced cancer treatment requires further investigation.
Purpose of the Study:
- To investigate the in vivo effects of combining EGFR-targeted monoclonal antibodies (EMD 55900 and EMD 72000) with TNF-alpha treatment.
- To determine if this combination therapy can enhance tumor regression and overcome resistance to antibody treatment.
Main Methods:
- Analysis of 1,060 xenotransplants from cancer cell lines and spontaneous tumors.
- Treatment of tumors in NMRI-nu/nu mice with EMD 55900 and EMD 72000, alone and in combination with TNF-alpha.
- Correlation of tumor regression with epidermal growth factor receptor (EGFR) concentration.
Main Results:
- EGFR-targeted antibodies (EMD 55900, EMD 72000) significantly reduced tumor size in carcinomas with high EGFR concentration (> or = 70 fmol/mg protein).
- Simultaneous treatment with TNF-alpha and EGFR antibodies resulted in enhanced antitumor effects, including complete tumor eradication.
- Tumors with low EGFR concentration (<70 fmol/mg protein) became susceptible to antibody treatment when combined with TNF-alpha.
Conclusions:
- Combination therapy of EGFR-targeted monoclonal antibodies and TNF-alpha demonstrates enhanced antitumor efficacy in vivo.
- This combined approach can overcome resistance to EGFR-targeted antibody therapy.
- The findings suggest a potential therapeutic strategy for enhancing cancer treatment outcomes.