Grizzi Giulia, Venetis Kostantinos, Denaro Nerina, Bonomi Maria, Celotti Andrea, Pagkali Antonia, Hahne Jens Claus, Tomasello Gianluca, Petrelli Fausto, Fusco Nicola, Ghidini Michele
Operative Unit of Oncology, ASST of Cremona, 26100 Cremona, Italy.
Division of Pathology, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy.
J Clin Med. 2023 Apr 19;12(8):2973. doi: 10.3390/jcm12082973.
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.
紧密连接蛋白（CLDNs）是一个蛋白质多基因家族，也是紧密连接（TJs）的主要成分，紧密连接通常介导细胞间粘附，并选择性地允许离子和小分子在细胞间进行旁细胞通量。紧密连接蛋白的下调会增加营养物质和生长刺激物对恶性细胞的旁细胞通透性，这有助于上皮细胞转化。紧密连接蛋白18.2（CLDN18.2）被确定为晚期胃食管腺癌（GEAC）治疗的一个有前景的靶点，在近30%的转移病例中发现其水平较高。CLDN18.2畸变在基因组稳定的GEAC亚组和弥漫性组织学亚型中富集，是单克隆抗体和嵌合抗原受体T细胞（CAR-T细胞）的理想候选靶点。zolbetuximab是一种高度特异性的抗CLDN18.2单克隆抗体，在II期研究中显示出疗效，最近在III期SPOTLIGHT试验中也有疗效，与标准化疗相比，无进展生存期（PFS）和总生存期（OS）均有所改善。抗CLDN18.2嵌合抗原受体（CAR）-T细胞在早期临床试验中显示出具有血液学毒性发生率的安全性。本综述的目的是介绍CLDN18.2阳性GEAC治疗的新发现，特别关注单克隆抗体zolbetuximab以及工程化抗CLDN18.2 CAR-T细胞的应用。
