Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell–cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.

Anti-Claudin Treatments in Gastroesophageal Adenocarcinoma: Mainstream and Upcoming Strategies / G. Grizzi, K. Venetis, N. Denaro, M. Bonomi, A. Celotti, A. Pagkali, J. Claus Hahne, G. Tomasello, F. Petrelli, N. Fusco, M. Ghidini. - In: JOURNAL OF CLINICAL MEDICINE. - ISSN 2077-0383. - 12:8(2023), pp. 2973.1-2973.9. [10.3390/jcm12082973]

Anti-Claudin Treatments in Gastroesophageal Adenocarcinoma: Mainstream and Upcoming Strategies

K. Venetis;N. Fusco
Penultimo
;
2023

Abstract

Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell–cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.
gastric cancer; claudins; anti-claudin 18.2; esophageal cancer; zolbetuximab; car-T cells; chemotherapy
Settore MED/08 - Anatomia Patologica
Settore MED/06 - Oncologia Medica
2023
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1018838
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