Background:Immune checkpoint inhibitors(ICIs)are effective in a subset of patients with metastatic solid tumors.However,the patients who would benefit most from ICIs in biliary tract cancer(BTC)are still controversial...Background:Immune checkpoint inhibitors(ICIs)are effective in a subset of patients with metastatic solid tumors.However,the patients who would benefit most from ICIs in biliary tract cancer(BTC)are still controversial.Materials and methods:We molecularly characterized tissues and blood from 32 patients with metastatic BTC treated with the ICI pembrolizumab as second-line therapy.Results:All patients had microsatellite stable(MSS)type tumors.Three of the 32 patients achieved partial response(PR),with an objective response rate(ORR)of 9.4%(95%confidence interval[CI],2.0–25.2)and nine showed stable disease(SD),exhibiting a disease control rate(DCR)of 37.5%(95%CI,21.1–56.3).For the 31 patients who had access to PD-1 ligand 1(PD-L1)combined positive score(CPS)testing(cut-off value≥1%),the ORR was not different between those who had PD-L1-positive(PD-L1+;1/11,9.1%)and PDL1-(2/20,10.0%)tumors(p=1.000).The tumor mutational burden(TMB)of PD-L1+BTC was comparable to that of PD-L1-BTC(p=0.630).TMB and any exonic somatic mutations were also not predictive of pembrolizumab response.Molecular analysis of blood and tumor samples demonstrated a relatively high natural killer(NK)cell proportion in the peripheral blood before pembrolizumab treatment in patients who achieved tumor response.Moreover,the tumors of these patients presented high enrichment scores for NK cells,antitumor cytokines,and Th1 signatures,and a low enrichment score for cancer-associated fibroblasts.Conclusions:This study shows the molecular characteristics associated with the efficacy of pembrolizumab in BTC of the MSS type.展开更多
The use of natural killer(NK)cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy.However,combination treatments are required to enhance the effector functions and therapeutic ...The use of natural killer(NK)cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy.However,combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells.In this study,we investigated the potential of daratumumab(Dara),bortezomib,and dexamethasone(Dvd)to augment the antitumor effects of NK cells in a multiple myeloma(MM)xenograft mouse model.NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients.A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull(NSG)mice.Tumor-bearing mice were divided into six treatment groups:no treatment,expanded NK cells(eNKs),Dara,Dara+eNKs,Dvd,and Dvd+eNKs.Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands,downregulating expression of NK cell inhibitory ligands,and promoting antibody-dependent cellular cytotoxicity.The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level.Furthermore,Dvd pretreatment significantly increased eNK persistence and homing to MM sites.Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.展开更多
基金supported by the MISP program at Merck Sharp&Dohme Corp.,USAa grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(Grant Number:HR20C0025).
文摘Background:Immune checkpoint inhibitors(ICIs)are effective in a subset of patients with metastatic solid tumors.However,the patients who would benefit most from ICIs in biliary tract cancer(BTC)are still controversial.Materials and methods:We molecularly characterized tissues and blood from 32 patients with metastatic BTC treated with the ICI pembrolizumab as second-line therapy.Results:All patients had microsatellite stable(MSS)type tumors.Three of the 32 patients achieved partial response(PR),with an objective response rate(ORR)of 9.4%(95%confidence interval[CI],2.0–25.2)and nine showed stable disease(SD),exhibiting a disease control rate(DCR)of 37.5%(95%CI,21.1–56.3).For the 31 patients who had access to PD-1 ligand 1(PD-L1)combined positive score(CPS)testing(cut-off value≥1%),the ORR was not different between those who had PD-L1-positive(PD-L1+;1/11,9.1%)and PDL1-(2/20,10.0%)tumors(p=1.000).The tumor mutational burden(TMB)of PD-L1+BTC was comparable to that of PD-L1-BTC(p=0.630).TMB and any exonic somatic mutations were also not predictive of pembrolizumab response.Molecular analysis of blood and tumor samples demonstrated a relatively high natural killer(NK)cell proportion in the peripheral blood before pembrolizumab treatment in patients who achieved tumor response.Moreover,the tumors of these patients presented high enrichment scores for NK cells,antitumor cytokines,and Th1 signatures,and a low enrichment score for cancer-associated fibroblasts.Conclusions:This study shows the molecular characteristics associated with the efficacy of pembrolizumab in BTC of the MSS type.
基金supported by grants from the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education,Science and Technology(2018R1A2B6006200,2018R1A5A2024181,and 2020R1A2C2010098).
文摘The use of natural killer(NK)cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy.However,combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells.In this study,we investigated the potential of daratumumab(Dara),bortezomib,and dexamethasone(Dvd)to augment the antitumor effects of NK cells in a multiple myeloma(MM)xenograft mouse model.NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients.A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull(NSG)mice.Tumor-bearing mice were divided into six treatment groups:no treatment,expanded NK cells(eNKs),Dara,Dara+eNKs,Dvd,and Dvd+eNKs.Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands,downregulating expression of NK cell inhibitory ligands,and promoting antibody-dependent cellular cytotoxicity.The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level.Furthermore,Dvd pretreatment significantly increased eNK persistence and homing to MM sites.Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.
