Somatic activating mutations in the epidermal growth factor receptor(EGFR)are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer(NSCLC),metastatic colorectal cancer,glioblastoma,hea...Somatic activating mutations in the epidermal growth factor receptor(EGFR)are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer(NSCLC),metastatic colorectal cancer,glioblastoma,head and neck cancer,pancreatic cancer,and breast cancer.Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy,but patients inevitably experience acquired resistance.Although immune checkpoint inhibitors(ICIs)targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types,their efficacy is limited in cancers harboring activating gene alterations of EGFR.Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3,B7x and HHLA2,is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment(TME).In this review,we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways.Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies.We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers,as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.展开更多
Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments,but its clinical implementation has been restricted by the low host antitumor response rate.Recently,chemotherapy is well rec...Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments,but its clinical implementation has been restricted by the low host antitumor response rate.Recently,chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication.The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism.Herein,a synergistic antitumor platform(designated as BMS/RA@CC-Liposome)was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug(RA-V)and PD-1/PD-L1 blockade inhibitor(BMS-202)to remarkably enhance antitumor immunity.In this study,the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem.To achieve the cell-specific targeting drug delivery,the combination therapy nanosystem was functionalized with cancer cell membrane camouflage.The biomimetic drug delivery system perfectly disguised as endogenous substances,and realized elongated blood circulation due to anti-phagocytosis capability.Moreover,the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells.The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response,RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells.Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically,demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.展开更多
基金supported by NIH R01CA175495 and R01DK100525,Department of Defense BC190403,Irma T.Hirschl/Monique Weill-Caulier Trust,and Cancer Research Institute.
文摘Somatic activating mutations in the epidermal growth factor receptor(EGFR)are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer(NSCLC),metastatic colorectal cancer,glioblastoma,head and neck cancer,pancreatic cancer,and breast cancer.Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy,but patients inevitably experience acquired resistance.Although immune checkpoint inhibitors(ICIs)targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types,their efficacy is limited in cancers harboring activating gene alterations of EGFR.Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3,B7x and HHLA2,is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment(TME).In this review,we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways.Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies.We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers,as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.
基金The authors wish to express sincere gratitude to National Natural Science Foundation of China(No.32070356)the National New Drug Innovation Major Project of Ministry of Science and Technology of China(No.2017ZX09309027)+1 种基金the Program of Innovative Research Team of Jiangsu Province,“Double First-Class”University Project of China Pharmaceutical University(No.CPU2018GF05,China)the Fundamental Research Funds for the Central Universities(No.2632018ZD08,China).
文摘Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments,but its clinical implementation has been restricted by the low host antitumor response rate.Recently,chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication.The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism.Herein,a synergistic antitumor platform(designated as BMS/RA@CC-Liposome)was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug(RA-V)and PD-1/PD-L1 blockade inhibitor(BMS-202)to remarkably enhance antitumor immunity.In this study,the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem.To achieve the cell-specific targeting drug delivery,the combination therapy nanosystem was functionalized with cancer cell membrane camouflage.The biomimetic drug delivery system perfectly disguised as endogenous substances,and realized elongated blood circulation due to anti-phagocytosis capability.Moreover,the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells.The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response,RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells.Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically,demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.
