Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesothelioma

Our plain-English summary of Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesothelioma, by J. Kurai, H. Chikumi, K. Hashimoto, et al (International Journal of Oncology, 2012).

The study

• Authors: J. Kurai, H. Chikumi, K. Hashimoto, M. Takata, T. Sako, K. Yamaguchi, N. Kinoshita, M. Watanabe, H. Touge, H. Makino, T. Igishi, H. Hamada, S. Yano, E. Shimizu
• Journal: International Journal of Oncology
• Published: 2012;41(5):1610-8
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Epidermal growth factor receptor (EGFR) is commonly overexpressed in malignant pleural mesothelioma (MPM). Cetuximab is a chimeric mouse-human antibody targeted against EGFR and induces potent antibody-dependent cellular cytotoxicity (ADCC). The action of cetuximab against MPM cells has not been well studied. Therefore, in this study, we investigated the antitumor activity of cetuximab against MPM cell lines, particularly with respect to ADCC activity in vitro and in vivo. EGFR expression of MPM cells was measured by a quantitative flow cytometric analysis and immunohistochemistry. The effect of cetuximab on growth inhibition was assessed using a modified MTT assay. The ADCC activity was measured by a 4-h 51Cr release assay using fresh or IL-2-activated peripheral blood mononuclear cells. In vivo antitumor activity of cetuximab was evaluated using an orthotopic implantation mouse model. Cetuximab-mediated ADCC activity against MPM cells was observed at low concentration (0.25 mg/ml) and was enhanced by IL-2, whereas no direct effect on growth inhibition was detected. A logarithmic correlation was observed between the number of EGFRs on MPM cells and ADCC activity. Low EGFR expression on the MPM cells, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity. In the mouse model, cetuximab treatment with or without IL-2 significantly inhibited intrathoracic tumor growth and prolonged their survival. Our study shows that cetuximab has potent anti-MPM activity both in vitro and in vivo, mainly through the immunologic mechanism of ADCC. Cetuximab has the potential to be used as a novel therapy for MPM patients.

In plain English

This laboratory and animal study, from Tottori University in Japan, tested cetuximab, an antibody drug that targets a protein called EGFR, against malignant pleural mesothelioma. It did not study asbestos exposure. The authors used five mesothelioma cell lines, immune cells from the blood of healthy volunteers, and mice with human mesothelioma cells injected into the chest. On its own, cetuximab did not slow the cancer cells' growth: all five cell lines were completely resistant. It did help immune cells kill the cancer cells, a process called antibody-dependent cellular cytotoxicity. This happened even in cell lines with low EGFR levels, and the immune-boosting substance IL-2 increased the killing. In the mice (5 per group), cetuximab given into the chest reduced tumor area and lengthened survival compared with the control group. Adding IL-2 further reduced tumor area; survival tended to be longer than with cetuximab alone, but not significantly. The authors said five mice per group may have been too few to detect a difference. The authors concluded that cetuximab could possibly be used in combination therapies for mesothelioma patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (cell line) experiments and an animal experiment in mice
• Who was studied: Five malignant pleural mesothelioma cell lines (EHMES-1, MSTO-211H, H2052, EHMES-10, H28) and one epidermoid carcinoma cell line (A431) used as a comparison; blood immune cells (PBMCs) from healthy individuals; male C.B-17 SCID mice (5 weeks old, 5 per group) given MSTO-211H cells in the chest; Tottori University, Japan
• Exposure: No asbestos exposure was studied. The treatment studied was the anti-EGFR antibody cetuximab, alone or with IL-2. In mice it was given into the chest cavity at 0.05 mg per mouse, with or without IL-2 at 30 IU/ml, on day 7.
• Main results:
  • In all mesothelioma cell lines, cetuximab had no direct effect on cell growth, whatever their EGFR level.
  • Two cell lines (EHMES-1 and MSTO-211H) had low EGFR numbers and scored 1+ on staining. The other three had moderate EGFR numbers and scored 2+.
  • In the MSTO-211H cell line, cetuximab-driven immune killing (ADCC) reached its maximum at a cetuximab concentration of 0.25 mg/ml, as the article's text states.
  • Across the mesothelioma cell lines, immune killing rose with the logarithm of the number of EGFR molecules on the cells. Near-maximum killing was already seen in MSTO-211H cells, which have few EGFRs.
  • Treating the blood immune cells with low-dose IL-2 increased cetuximab-driven killing in all cell lines.
  • In mice (5 per group), tumor area on day 21 was lower with cetuximab and with cetuximab plus IL-2 than in the control group (P less than 0.001 for each). Cetuximab plus IL-2 also gave lower tumor area than cetuximab alone (P less than 0.01).
  • Cetuximab given into the chest significantly lengthened survival of the mice compared with the control group (P less than 0.01).
  • Adding IL-2 to cetuximab tended to improve mouse survival, but the difference from cetuximab alone was not statistically significant (P=0.28).
  • In a preliminary experiment, cetuximab doses of 0.5, 0.05 and 0.005 mg per mouse gave no statistically significant difference in survival time.
• The authors' conclusion: The authors concluded that their observations suggest cetuximab could possibly be used as a therapeutic agent, in combination therapies, for patients with malignant pleural mesothelioma.
• Limitations the authors state:
  • Five mice per group may not have been enough to detect a survival difference between cetuximab with IL-2 and cetuximab alone.
  • Effects on tumor growth might not translate into survival, because of distant metastasis or IL-2 side effects such as cardiac failure. The cause of death in the mice was not determined.
  • Mouse immune cells may produce only part of the immune-killing effect of a human antibody.
  • The authors stated that local treatment may not be expected to cure patients.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cetuximab (Erbitux), Pleural Mesothelioma, EGFR, Immunohistochemistry, Intrathoracic.

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