Discovery of mesothelin and exploiting it as a target for immunotherapy

Abstract

We have recently reported that an immunotoxin targeting mesothelin produced durable major tumor regressions in patients with extensive treatment-refractory mesothelioma. These unprecedented tumor responses have prompted us to review how mesothelin was discovered and the advances that led to these tumor responses. This review is not comprehensive but focuses on major developments over the past 20 years since mesothelin was first identified in our laboratory. Mesothelin is a cell-surface glycoprotein whose expression in normal human tissues is restricted to mesothelial cells. Because it is highly expressed by many solid tumors, it is an attractive immunotherapy target. Antibody-based therapies currently in clinical trials include an immunotoxin, a chimeric monoclonal antibody, and an antibody drug conjugate. In addition, a mesothelin tumor vaccine and a mesothelin- chimeric antigen receptor are being evaluated in the clinic. SS1P, an anti-mesothelin immunotoxin, was the first mesothelin-directed therapy to enter the clinic, and its use showed that mesothelin-targeted therapy was safe in patients. More importantly, our recent work has shown that SS1P in combination with pentostatin and cyclophosphamide can result in durable tumor regression in patients with advanced mesothelioma and opens up the possibility that such an approach can benefit patients with many common cancers.

Figure 1

Processing of the 71-kDa mesothelin precursor protein to MPF and membrane-bound mesothelin by the protease furin. Mesothelin is attached to the cell membrane by a GPI anchor (A). Mesothelin expression detected in different human tumors by immunohistochemistry using an anti-mesothelin antibody. Mesothelin positivity is shown by brown staining of the tumor cells (B). Schematic representation of the immunotoxin SS1P consisting of an anti-mesothelin Fv linked to the truncated Pseudomonas exotoxin, PE38 (C). Major tumor shrinkage in the neck and abdomen of a patient with metastatic peritoneal mesothelioma treated with SS1P in combination with pentostatin and cyclophosphamide (D). [A portion of this figure (B) was originally published in an article by Hassan and Ho in the Eur. J. Cancer 44:46–53, 2008, Elsevier publishers]