Mesothelin as a target for cervical cancer therapy.

Abstract

The cell surface glycoprotein Mesothelin is overexpressed in several tumor entities and novel immune-based therapies are currently under the early clinical evaluation for the treatment of malignant pleura mesothelioma, ovarian cancer, and pancreatic cancer. Cervical cancer has not been recognized as a suitable target for Mesothelin-directed immune therapies so far. To exploit a possible role of Mesothelin in cervical cancer treatment, we analysed Mesothelin expression in 79 cervical carcinomas and aligned expressions patterns with tumor growth parameters. A novel anti-Mesothelin drug conjugate (Anetumab Ravtansine) was applied for dose-efficiency studies in a Mesothelin positive tumor model for cervical cancer in Scid mice. In more than three-quarters (77%) of cervical adenocarcinomas, Mesothelin was expressed to high levels. Among squamous cell carcinomas of the cervix uteri expression levels were lower and expression patterns were less intense, but still ranged between 50-60% (57%). A significant correlation between Mesothelin expression levels and tumor grade, metastatic behaviour, and lymph- or hemangiosis was not found. The novel anti-Mesothelin-drug conjugate (Anetumab Ravtansine) showed a substantial dose-dependent therapeutic efficiency in a xenotransplant model for cervical cancer in SCID mice (hela cell tumors). Applying the ADC at a dose of 10mg/kg twice weekly induced complete tumor regression in 88% of animals within 6weeks. Mesothelin should be taken into account as a target in cervical cancer therapy and histological determination of Mesothelin expression should be considered in routine diagnostics of cervical carcinomas.