Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive local...Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma(UC).The characteristic expression and scoring systems of HER2 are nonexistent in UC.We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC.Methods:A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2,respectively,from March 2009 to December 2018.The patients in cohort 2 were enrolled in a phase II study of RC48-ADC.UC samples were tested for HER2 status using immunohistochemistry(IHC)and/or fluorescence in situ hybridization(FISH).The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC.Results:The HER2-positive(IHC 2+or 3+)rate was 24.1%(33/137).In HER2 IHC 2+or 3+patients,the HER2 gene amplification rate was 31%(13/42).The objective response rates(ORRs)in RC48-ADC-treated patients with IHC 3+,IHC 2+and FISH+,IHC 2+and FISH-were 58.8%,66.7%and 40%,respectively.The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification(61.5%vs.44.8%,P=0.059).The heterogeneity of HER2 expression in the primary tumor was 55.5%(15/27),and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity.Conclusions:IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy.There was a trend toward a better benefit for patients with HER2 amplification,and tumor heterogeneity did not influence the drug efficacy.展开更多
JS001(toripalimab)is a humanized IgG monoclonal antibody which strongly inhibits programmed cell death protein 1(PD1).In this study,we used a different iodine isotype(nat/124/125I)to label JS001 probes to target the h...JS001(toripalimab)is a humanized IgG monoclonal antibody which strongly inhibits programmed cell death protein 1(PD1).In this study,we used a different iodine isotype(nat/124/125I)to label JS001 probes to target the human PD1(hPD1)antigen.In vitro,the half maximal effective concentration(EC50)value of natI-JS001 did not significantly differ from that of JS001.The uptake of 125I-JS001 by activated T cells was 5.63 times higher than that by nonactivated T cells after 2 h of incubation.The binding affinity of 125I-JS001 to T cells of different lineages after phytohemagglutinin(PHA)stimulation reached 4.26 nmol/L.Humanized PD1 C57 BL/6 mice bearing mouse sarcoma S180 cell tumors were validated for immuno-positron emission tomography(immuno-PET)imaging.Pathological staining was used to assess the expression of PD1 in tumor tissues.The homologous 124I-human IgG(124I-hIgG)group or blocking group was used as a control group.Immuno-PET imaging showed that the uptake in the tumor area of the 124I-JS001 group at different time points was significantly higher than that of the blocking group or the 124I-hIgG group in the humanized PD1 mouse model.Taken together,these results suggest that this radiotracer has potential for noninvasive monitoring and directing tumor-specific personalized immunotherapy in PD1-positive tumors.展开更多
基金supported by National Key Research and Development Plan(grant number:2022YFC2409902).
文摘Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma(UC).The characteristic expression and scoring systems of HER2 are nonexistent in UC.We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC.Methods:A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2,respectively,from March 2009 to December 2018.The patients in cohort 2 were enrolled in a phase II study of RC48-ADC.UC samples were tested for HER2 status using immunohistochemistry(IHC)and/or fluorescence in situ hybridization(FISH).The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC.Results:The HER2-positive(IHC 2+or 3+)rate was 24.1%(33/137).In HER2 IHC 2+or 3+patients,the HER2 gene amplification rate was 31%(13/42).The objective response rates(ORRs)in RC48-ADC-treated patients with IHC 3+,IHC 2+and FISH+,IHC 2+and FISH-were 58.8%,66.7%and 40%,respectively.The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification(61.5%vs.44.8%,P=0.059).The heterogeneity of HER2 expression in the primary tumor was 55.5%(15/27),and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity.Conclusions:IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy.There was a trend toward a better benefit for patients with HER2 amplification,and tumor heterogeneity did not influence the drug efficacy.
基金financially supported by the National Natural Science Foundation of China(81960538,81571705,81671733,81871386,81560356,61264004 and 81871387)the Beijing Nova Program(Z171100001117020,China)+4 种基金the Beijing Excellent Talents Funding(2017000021223ZK33,China)the Beijing Municipal Science&Technology Commission(Z161100000516062,China)Open Project funded by Key laboratory of Carcinogenesis and Translational Research,Ministry of Education/Beijing(2017 open project-1 and 2019 open project-06,China)High-level Creative Talent Training Program in Guizhou Province of China(Grant No.[2015]4015)the Science and Technology Foundation of Guizhou Province(No.gzwjkj2018-1-040 and no.[2019]1201,China)
文摘JS001(toripalimab)is a humanized IgG monoclonal antibody which strongly inhibits programmed cell death protein 1(PD1).In this study,we used a different iodine isotype(nat/124/125I)to label JS001 probes to target the human PD1(hPD1)antigen.In vitro,the half maximal effective concentration(EC50)value of natI-JS001 did not significantly differ from that of JS001.The uptake of 125I-JS001 by activated T cells was 5.63 times higher than that by nonactivated T cells after 2 h of incubation.The binding affinity of 125I-JS001 to T cells of different lineages after phytohemagglutinin(PHA)stimulation reached 4.26 nmol/L.Humanized PD1 C57 BL/6 mice bearing mouse sarcoma S180 cell tumors were validated for immuno-positron emission tomography(immuno-PET)imaging.Pathological staining was used to assess the expression of PD1 in tumor tissues.The homologous 124I-human IgG(124I-hIgG)group or blocking group was used as a control group.Immuno-PET imaging showed that the uptake in the tumor area of the 124I-JS001 group at different time points was significantly higher than that of the blocking group or the 124I-hIgG group in the humanized PD1 mouse model.Taken together,these results suggest that this radiotracer has potential for noninvasive monitoring and directing tumor-specific personalized immunotherapy in PD1-positive tumors.
