Discovery of Mesothelin and Exploiting It as a Target for Immunotherapy
Open Access
- 29 May 2014
- journal article
- review article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 74 (11), 2907-2912
- https://doi.org/10.1158/0008-5472.can-14-0337
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. Cancer Res; 74(11); 2907–12. ©2014 AACR.Keywords
This publication has 47 references indexed in Scilit:
- Identification and elimination of an immunodominant T-cell epitope in recombinant immunotoxins based onPseudomonasexotoxin AProceedings of the National Academy of Sciences of the United States of America, 2012
- Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopesProceedings of the National Academy of Sciences of the United States of America, 2012
- A Live-Attenuated Listeria Vaccine (ANZ-100) and a Live-Attenuated Listeria Vaccine Expressing Mesothelin (CRS-207) for Advanced Cancers: Phase I Studies of Safety and Immune InductionClinical Cancer Research, 2012
- Cytotoxic Activity of Immunotoxin SS1P Is Modulated by TACE-Dependent Mesothelin SheddingCancer Research, 2011
- Pentostatin Plus Cyclophosphamide Safely and Effectively Prevents Immunotoxin Immunogenicity in Murine HostsClinical Cancer Research, 2011
- Structural Analysis of the Cancer-specific Promoter in Mesothelin and in Other Genes Overexpressed in CancersPublished by Elsevier BV ,2011
- Phase I Clinical Trial of the Chimeric Anti-Mesothelin Monoclonal Antibody MORAb-009 in Patients with Mesothelin-Expressing CancersClinical Cancer Research, 2010
- Inhibition of mesothelin–CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapyLung Cancer, 2010
- Phase I Trial of Continuous Infusion Anti-Mesothelin Recombinant Immunotoxin SS1PClinical Cancer Research, 2009
- Immunotoxin therapy of cancerNature Reviews Cancer, 2006