Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18....Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18.2 therapy. We conducted a retrospective analysis to explore the association of CLDN18.2 expression with clinicopathological characteristics and immunotherapeutic outcomes in GC.Methods: A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells(2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells(2+, 70%) were considered the two levels of positively expressed GC. The clinicopathological characteristics and immunotherapy outcomes of GC patients were analyzed according to CLDN18.2 expression status.Results: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of patients.Programmed death-ligand 1(PD-L1) and CLDN18.2 were co-expressed in 19.8% [combined positive score(CPS)≥1, CLDN18.2(cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2(cut-off: 2+, 70%)] of patients.CLDN18.2 expression positively correlated with younger age, female sex, non-gastroesophageal junction(nonGEJ), and diffuse phenotype(P<0.001). HER2 and PD-L1 expression were significantly lower in CLDN18.2-positive GC(both P<0.05). Uterine adnexa metastasis(P<0.001) was more frequent and liver metastasis(P<0.001)was less common in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival(ir PFS) were inferior in the CLDN18.2-positive group.Conclusions: CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.展开更多
BACKGROUND Claudin 18.2(CLDN18.2)is a cell surface protein expressed by gastric cancer cells.The monoclonal antibody zolbetuximab binds CLDN18.2-positive cancer cells and causes cancer cell death.A few studies researc...BACKGROUND Claudin 18.2(CLDN18.2)is a cell surface protein expressed by gastric cancer cells.The monoclonal antibody zolbetuximab binds CLDN18.2-positive cancer cells and causes cancer cell death.A few studies researched the prognostic effect of CLDN18.2 expression in metastatic gastric adenocarcinoma.AIM To identify the prognostic value of CLDN18.2 expression in patients with metastatic gastric adenocarcinoma.METHODS This study was conducted with 65 patients over the age of 18 who were diagnosed with metastatic gastric adenocarcinoma.We investigated the effect of CLDN18.2 expression on clinicopathological characteristics(age,sex,histological grade,Lauren classification,family history,metastatic site,HER2 expression)and prognosis for patients with metastatic gastric adenocarcinoma.RESULTS CLDN18.2 expression was positive in 73.8%(48)of the patients.During the median 17.7-mo follow-up period,89.2%(58)of the patients died.Median progression-free survival and overall survival(OS)were 6 mo(95%confidence interval:1.6-10.4)and 12 mo(95%confidence interval:7.5-16.5).There was no statistically significant correlation between CLDN18.2 expression and clinicopathological characteristics of the patients.In univariate and multivariate Cox regression analysis,there was no correlation between clinicopathological characteristics of patients and progression-free survival or OS.CONCLUSION CLDN18.2 expression was quite high in patients with gastric adenocarcinoma,identifying the proportion of the patients in whom zolbetuximab would be efficacious.There is no statistically significant correlation with clinicopathological characteristics and OS.CLDN18.2 is not a prognostic marker in patients with gastric adenocarcinoma,although it is predictive.展开更多
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 c...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.展开更多
BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is frequently diagnosed and treated in advanced tumor stages with poor prognosis.More effective screening programs and novel therapeutic means are urgently needed.Recen...BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is frequently diagnosed and treated in advanced tumor stages with poor prognosis.More effective screening programs and novel therapeutic means are urgently needed.Recent studies have regarded tight junction protein claudin 18.2(CLDN18.2)as a candidate target for cancer treatment,and zolbetuximab(formerly known as IMAB362)has been developed against CLDN18.2.However,there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AIM To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.METHODS The Cancer Genome Atlas,Genotype-Tissue Expression,Gene Expression Omnibus,and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue.Second,we analyzed the expression of CLDN18.2 in 93 primary PDACs,86 para-cancer tissues,and 13 normal pancreatic tissues by immunohistochemistry.Immunostained tissues were assessed applying the histoscore.subsequently,they fell into two groups according to the expression state of CLDN18.2.Furthermore,the correlations between CLDN18.2 expression and diverse clinicopathological characteristics,including survival,were investigated.RESULTS The gene expression of CLDN18 was statistically higher(P<0.01)in pancreatic tumors than in normal tissues.However,there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients.CLDN18.2 was expressed in 88(94.6%)of the reported PDACs.Among these tumors,50(56.8%)cases showed strong immunostaining.The para-cancer tissues were positive in 81(94.2%)cases,among which 32(39.5%)of cases were characterized for strong staining intensities.Normal pancreatic tissue was identified solely via weak immunostaining.Finally,CLDN18.2 expression significantly correlated with lymph node metastasis,distant metastasis,nerve invasion,stage,and survival of PDAC patients,while there was no correlation between CLDN18.2 expression and localization,tumor size,patient age and sex,nor any other clinicopathological characteristic.CONCLUSION CLDN18.2 expression is frequently increased in PDAC patients.Thus,it may act as a potential therapeutic target for zolbetuximab in PDAC.展开更多
The treatment of gastrointestinal cancer has always been a crucial research area,and targeted therapy has been receiving increasing attention.At present,the effect of targeted therapy is unsatisfactory for gastric can...The treatment of gastrointestinal cancer has always been a crucial research area,and targeted therapy has been receiving increasing attention.At present,the effect of targeted therapy is unsatisfactory for gastric cancer.Thus,the discovery of new targets is crucial.Claudin 18.2(CLDN18.2),a member of the claudin family,belongs to the tight junction protein family that controls the flow of molecules between cell layers.CLDN18.2 expression has been discussed in many studies.In recent years,there have been many studies on targeted therapy with CLDN18.2-ideal monoclonal antibody 362.Furthermore,CLDN18.2-specific chimeric antigen receptor T therapy has been used for CLDN18.2-positive tumors,such as gastric and pancreatic cancers.Considerable research has been focused on CLDN18.2.CLDN18.2,a newly discovered marker for precise targeted therapy of gastric cancer,could offer new hope for the treatment of gastric cancer.展开更多
基金supported by Beijing Natural Science Foundation (No. Z20J00105)the National Natural Science Foundation of China (No. 82272627)。
文摘Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18.2 therapy. We conducted a retrospective analysis to explore the association of CLDN18.2 expression with clinicopathological characteristics and immunotherapeutic outcomes in GC.Methods: A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells(2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells(2+, 70%) were considered the two levels of positively expressed GC. The clinicopathological characteristics and immunotherapy outcomes of GC patients were analyzed according to CLDN18.2 expression status.Results: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of patients.Programmed death-ligand 1(PD-L1) and CLDN18.2 were co-expressed in 19.8% [combined positive score(CPS)≥1, CLDN18.2(cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2(cut-off: 2+, 70%)] of patients.CLDN18.2 expression positively correlated with younger age, female sex, non-gastroesophageal junction(nonGEJ), and diffuse phenotype(P<0.001). HER2 and PD-L1 expression were significantly lower in CLDN18.2-positive GC(both P<0.05). Uterine adnexa metastasis(P<0.001) was more frequent and liver metastasis(P<0.001)was less common in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival(ir PFS) were inferior in the CLDN18.2-positive group.Conclusions: CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.
文摘BACKGROUND Claudin 18.2(CLDN18.2)is a cell surface protein expressed by gastric cancer cells.The monoclonal antibody zolbetuximab binds CLDN18.2-positive cancer cells and causes cancer cell death.A few studies researched the prognostic effect of CLDN18.2 expression in metastatic gastric adenocarcinoma.AIM To identify the prognostic value of CLDN18.2 expression in patients with metastatic gastric adenocarcinoma.METHODS This study was conducted with 65 patients over the age of 18 who were diagnosed with metastatic gastric adenocarcinoma.We investigated the effect of CLDN18.2 expression on clinicopathological characteristics(age,sex,histological grade,Lauren classification,family history,metastatic site,HER2 expression)and prognosis for patients with metastatic gastric adenocarcinoma.RESULTS CLDN18.2 expression was positive in 73.8%(48)of the patients.During the median 17.7-mo follow-up period,89.2%(58)of the patients died.Median progression-free survival and overall survival(OS)were 6 mo(95%confidence interval:1.6-10.4)and 12 mo(95%confidence interval:7.5-16.5).There was no statistically significant correlation between CLDN18.2 expression and clinicopathological characteristics of the patients.In univariate and multivariate Cox regression analysis,there was no correlation between clinicopathological characteristics of patients and progression-free survival or OS.CONCLUSION CLDN18.2 expression was quite high in patients with gastric adenocarcinoma,identifying the proportion of the patients in whom zolbetuximab would be efficacious.There is no statistically significant correlation with clinicopathological characteristics and OS.CLDN18.2 is not a prognostic marker in patients with gastric adenocarcinoma,although it is predictive.
基金supported by the National Key Research and Development Program of China(No.2017YFC1308900)。
文摘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.
基金Supported by the Basic Research Project of Natural Science of Shaanxi Province,No.2020JQ-943,2021JQ-916 and 2021JQ-914Research Project of Chinese Society of Clinical Oncology-Sai Sheng Fund,No.Y-2020Sciclone/qn-0181+2 种基金Science and Technology Support Program of Shaanxi Provincial People’s Hospital,No.2021JY-26,2021JY-38,2021JY-50 and 2021BJ-13Research Fund Project of Shaanxi Provincial People’s Hospital,No.2021YJY-18China Postdoctoral Science Foundation,No.2021M702607.
文摘BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is frequently diagnosed and treated in advanced tumor stages with poor prognosis.More effective screening programs and novel therapeutic means are urgently needed.Recent studies have regarded tight junction protein claudin 18.2(CLDN18.2)as a candidate target for cancer treatment,and zolbetuximab(formerly known as IMAB362)has been developed against CLDN18.2.However,there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AIM To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.METHODS The Cancer Genome Atlas,Genotype-Tissue Expression,Gene Expression Omnibus,and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue.Second,we analyzed the expression of CLDN18.2 in 93 primary PDACs,86 para-cancer tissues,and 13 normal pancreatic tissues by immunohistochemistry.Immunostained tissues were assessed applying the histoscore.subsequently,they fell into two groups according to the expression state of CLDN18.2.Furthermore,the correlations between CLDN18.2 expression and diverse clinicopathological characteristics,including survival,were investigated.RESULTS The gene expression of CLDN18 was statistically higher(P<0.01)in pancreatic tumors than in normal tissues.However,there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients.CLDN18.2 was expressed in 88(94.6%)of the reported PDACs.Among these tumors,50(56.8%)cases showed strong immunostaining.The para-cancer tissues were positive in 81(94.2%)cases,among which 32(39.5%)of cases were characterized for strong staining intensities.Normal pancreatic tissue was identified solely via weak immunostaining.Finally,CLDN18.2 expression significantly correlated with lymph node metastasis,distant metastasis,nerve invasion,stage,and survival of PDAC patients,while there was no correlation between CLDN18.2 expression and localization,tumor size,patient age and sex,nor any other clinicopathological characteristic.CONCLUSION CLDN18.2 expression is frequently increased in PDAC patients.Thus,it may act as a potential therapeutic target for zolbetuximab in PDAC.
文摘The treatment of gastrointestinal cancer has always been a crucial research area,and targeted therapy has been receiving increasing attention.At present,the effect of targeted therapy is unsatisfactory for gastric cancer.Thus,the discovery of new targets is crucial.Claudin 18.2(CLDN18.2),a member of the claudin family,belongs to the tight junction protein family that controls the flow of molecules between cell layers.CLDN18.2 expression has been discussed in many studies.In recent years,there have been many studies on targeted therapy with CLDN18.2-ideal monoclonal antibody 362.Furthermore,CLDN18.2-specific chimeric antigen receptor T therapy has been used for CLDN18.2-positive tumors,such as gastric and pancreatic cancers.Considerable research has been focused on CLDN18.2.CLDN18.2,a newly discovered marker for precise targeted therapy of gastric cancer,could offer new hope for the treatment of gastric cancer.
