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      Evaluation and reflection on claudin 18.2 targeting therapy in advanced gastric cancer

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          Abstract

          Claudin 18.2 (CLDN18.2) is a tight-junction protein. CLDN18.2-targeting strategy has cut a striking figure in CLDN18.2 positive patients with advanced gastric cancer. Zolbetuximab, the CLDN18.2 antibody, obtained a better clinical benefit in patients compared with the controlled. In phase II trials, combination treatment of epirubicin, oxaliplatin and capecitabine (EOX) + zolbetuximab achieved the optimal effects of overall survival which extended to 13.2 months with tolerable safety events, indicating its greater potential playing the second promising target in gastric cancer. This review will reveal the definitive clinical benefit CLDN18.2-targeting therapies have achieved and update the highlighting development (like chimeric antigen receptor T-cell immunotherapy) to CLDN18.2 positive patients. We then focus on 10 questions arisen from recent progress and anticipate to provide a future perspective for novel cancer treatment.

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          Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development.

          Dirk Usener, Gunda Brandenburg, Christoph Huber … (2008)
          Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer. We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage-specific cell surface molecules and to validate them as therapeutic antibody targets. We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP-responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells. Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors.
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            Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer

            Guoxiu Du, Hua Jiang, Zhimin Shi … (2018)
            Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in the treatment of this deadly disease.
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              A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study

              Ö Türeci, U Sahin, H Schulze-Bergkamen … (2019)
              Abstract Background Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells. Patients and methods Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile. Results From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent. Conclusions Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials. ClinicalTrials.gov number NCT01197885.
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                Author and article information

                Contributors
                Lin Shen
                Journal
                Journal ID (nlm-ta): Chin J Cancer Res
                Journal ID (iso-abbrev): Chin. J. Cancer Res
                Journal ID (publisher-id): CJCR
                Title: Chinese Journal of Cancer Research
                Publisher: AME Publishing Company
                ISSN (Print): 1000-9604
                ISSN (Electronic): 1993-0631
                Publication date (Print): April 2020
                Volume: 32
                Issue: 2
                Pages: 263-270
                Affiliations
                [1 ] Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
                [2 ] Health Science Center, Peking University, Beijing 100191, China
                Author notes
                Lin Shen, MD, PhD. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China. Email: linshenpku@ 123456163.com
                Article
                Publisher ID: cjcr-32-2-263
                DOI: 10.21147/j.issn.1000-9604.2020.02.13
                PMC ID: 7219097
                PubMed ID: 32410803
                SO-VID: bb2186a0-8efd-49c1-a593-604cb950fd12
                Copyright © Copyright © 2020 Chinese Journal of Cancer Research. All rights reserved.
                License:

                This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                Date received : 21 February 2020
                Date accepted : 13 April 2020
                Categories
                Subject: Review Article

                Keywords: claudin 18.2,gastric cancer,zolbetuximab,chimeric antigen receptor therapy
                Data availability:
                Keywords: claudin 18.2, gastric cancer, zolbetuximab, chimeric antigen receptor therapy

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