Despite the promise of immunotherapy such as the immune checkpoint inhibitors(ICIs)anti-PD-1 and anti-CTLA-4 for advanced melanoma,only 26%–52%of patients respond,and many experience grade III/IV immune-related adver...Despite the promise of immunotherapy such as the immune checkpoint inhibitors(ICIs)anti-PD-1 and anti-CTLA-4 for advanced melanoma,only 26%–52%of patients respond,and many experience grade III/IV immune-related adverse events.Motivated by the need for an effective therapy for patients non-responsive to clinically approved ICIs,we have developed a novel nanoimmunotherapy that combines locally administered Prussian blue nanoparticle-based photothermal therapy(PBNP-PTT)with systemically administered agonistic anti-CD137 monoclonal antibody therapy(aCD137).PBNP-PTT was administered at various thermal doses to melanoma cells in vitro,and was combined with aCD137 in vivo to test treatment effects on melanoma tumor progression,animal survival,immunological protection against tumor rechallenge,and hepatotoxicity.When administered at a melanoma-specific thermal dose,PBNP-PTT elicits immunogenic cell death(ICD)in melanoma cells and upregulates markers associated with antigen presentation and immune cell co-stimulation in vitro.Consequently,PBNP-PTT eliminates primary melanoma tumors in vivo,yielding long-term tumor-free survival.However,the antitumor immune effects generated by PBNP-PTT cannot eliminate secondary tumors,despite significantly slowing their growth.The addition of aCD137 enables significant abscopal efficacy and improvement of survival,functioning through activated dendritic cells and tumor-infiltrating CD8^(+)T cells,and generates CD4^(+)and CD8^(+)T cell memory that manifests in the rejection of tumor rechallenge,with no long-term hepatotoxicity.This study describes for the first time a novel and effective nanoimmunotherapy combination of PBNP-PTT with aCD137 mAb therapy for melanoma.展开更多
基金the George Washington University(GWU)Flow Cytometry Core Facility(Kimberlyn Acklin),the GWU Office of Animal Research(Bethany Rentz),and the GWU Research Pathology Core Lab,for supporting our studies.Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Nos.R41CA217294 and R37CA226171.
文摘Despite the promise of immunotherapy such as the immune checkpoint inhibitors(ICIs)anti-PD-1 and anti-CTLA-4 for advanced melanoma,only 26%–52%of patients respond,and many experience grade III/IV immune-related adverse events.Motivated by the need for an effective therapy for patients non-responsive to clinically approved ICIs,we have developed a novel nanoimmunotherapy that combines locally administered Prussian blue nanoparticle-based photothermal therapy(PBNP-PTT)with systemically administered agonistic anti-CD137 monoclonal antibody therapy(aCD137).PBNP-PTT was administered at various thermal doses to melanoma cells in vitro,and was combined with aCD137 in vivo to test treatment effects on melanoma tumor progression,animal survival,immunological protection against tumor rechallenge,and hepatotoxicity.When administered at a melanoma-specific thermal dose,PBNP-PTT elicits immunogenic cell death(ICD)in melanoma cells and upregulates markers associated with antigen presentation and immune cell co-stimulation in vitro.Consequently,PBNP-PTT eliminates primary melanoma tumors in vivo,yielding long-term tumor-free survival.However,the antitumor immune effects generated by PBNP-PTT cannot eliminate secondary tumors,despite significantly slowing their growth.The addition of aCD137 enables significant abscopal efficacy and improvement of survival,functioning through activated dendritic cells and tumor-infiltrating CD8^(+)T cells,and generates CD4^(+)and CD8^(+)T cell memory that manifests in the rejection of tumor rechallenge,with no long-term hepatotoxicity.This study describes for the first time a novel and effective nanoimmunotherapy combination of PBNP-PTT with aCD137 mAb therapy for melanoma.
