Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to c...Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to combine in situ vaccination and gene-mediated anti-PD therapy,which was generated by unmethylated cytosine-phosphate-guanine(CpG) and pshPD-L1 gene co-delivery.PEI worked as the delivery carrier to co-deliver the CpG and pshPD-L1 genes,the formed PDC(PEI/DNA/CpG)nanoparticles were further shielded by aldehyde modified polyethylene glycol(OHC-PEG-CHO) via pH responsive Schiff base reaction for OHC-PEG-CHO-PEI/DNA/CpG nanoparticles(P(PDC) NPs) prepa ration.All steps could be finished within 30 min.Such simple nanoparticles achieved the synergistic antitumor efficacy in B16 F10 tumor-bearing mice,and the amplified T cell responses,together with enhanced NK cells infiltration were observed after the combined treatments.In addition,the pH responsive delivery system reduced the side effects triggered by anti-PD therapy.The facile and effective combination strategy we presented here might provide a novel treatment for tumor inhibition.展开更多
Second near-infrared(NIR-Ⅱ)light triggered in-situ tumor vaccination(ISTV)represents one of the most promising strategies in boosting the whole-body antitumor immunity.While most of previously developed nano-adjuvant...Second near-infrared(NIR-Ⅱ)light triggered in-situ tumor vaccination(ISTV)represents one of the most promising strategies in boosting the whole-body antitumor immunity.While most of previously developed nano-adjuvants for NIR-Ⅱ-triggered ISTV are“all-in-one”formulations,which may indiscriminately damage both the tumor cells and the immune cells,limiting the overall effect of immune response.To overcome this obstacle,we designed a“cocktail”nano-adjuvant by physically mixing hyaluronidases(HAase)-decorated gold nanostars(HA)for NIR-Ⅱlight triggered in situ production of tumor-associated antigens and CpG functionalized gold nanospheres(CA)for immune cells activation.Compared to“all-in-one”formulation,the“cocktail”nano-adjuvants displayed a significantly stronger immune response on NIR-Ⅱlight induced dendritic cells(DCs)mutation and T cells differentiation,greater effect on tumor-growth inhibition,and higher efficacy in inhibition of pulmonary metastases.What is more,increasing the molar ratio of HA to CA led to an enhanced anticancer immune responses.This study highlight the nano-adjuvant formulation effects on the treatment of tumors with multiple targets.展开更多
Oncolytic viruses(OVs)are at the forefront of biologicals for cancer treatment.They represent a diverse landscape of naturally occurring viral strains and genetically modified viruses that,either as single agents or a...Oncolytic viruses(OVs)are at the forefront of biologicals for cancer treatment.They represent a diverse landscape of naturally occurring viral strains and genetically modified viruses that,either as single agents or as part of combination therapies,are being evaluated in preclinical and clinical settings.As the field gains momentum,the research on OVs has been shifting efforts to expand our understanding of the complex interplay between the virus,the tumor and the immune system,with the aim of rationally designing more efficient therapeutic interventions.Nowadays,the potential of an OV platform is no longer defined exclusively by the targeted replication and cancer cell killing capacities of the virus,but by its contribution as an immunostimulator,triggering the transformation of the immunosuppressive tumor microenvironment(TME)into a place where innate and adaptive immunity players can efficiently engage and lead the development of tumor-specific long-term memory responses.Here we review the immune mechanisms and host responses induced by ssRNA(-)(negative-sense single-stranded RNA)viruses as OV platforms.We focus on two ssRNA(-)OV candidates:Newcastle disease virus(NDV),an avian paramyxovirus with one of the longest histories of utilization as an OV,and influenza A(IAV)virus,a well-characterized human pathogen with extraordinary immunostimulatory capacities that is steadily advancing as an OV candidate through the development of recombinant IAV attenuated platforms.展开更多
基金The authors are thankful to the National Natural Science Foundation of China(Nos.51925305,51803210,51520105004,51873208,51973217 and 51833010)Jilin province science and technology development program(Nos.20200201075JC,20180414027GH)National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2018ZX09711003-012).
文摘Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to combine in situ vaccination and gene-mediated anti-PD therapy,which was generated by unmethylated cytosine-phosphate-guanine(CpG) and pshPD-L1 gene co-delivery.PEI worked as the delivery carrier to co-deliver the CpG and pshPD-L1 genes,the formed PDC(PEI/DNA/CpG)nanoparticles were further shielded by aldehyde modified polyethylene glycol(OHC-PEG-CHO) via pH responsive Schiff base reaction for OHC-PEG-CHO-PEI/DNA/CpG nanoparticles(P(PDC) NPs) prepa ration.All steps could be finished within 30 min.Such simple nanoparticles achieved the synergistic antitumor efficacy in B16 F10 tumor-bearing mice,and the amplified T cell responses,together with enhanced NK cells infiltration were observed after the combined treatments.In addition,the pH responsive delivery system reduced the side effects triggered by anti-PD therapy.The facile and effective combination strategy we presented here might provide a novel treatment for tumor inhibition.
基金financially supported by the National Natural Science Foundation of China(No.52273163)the Science Technology and Innovation Commission of Shenzhen Municipality(No.JCYJ20190807163003704)Open Research Fund of Jiangsu Key Laboratory of Environmentally Friendly Polymeric Materials(No.PML2201)。
文摘Second near-infrared(NIR-Ⅱ)light triggered in-situ tumor vaccination(ISTV)represents one of the most promising strategies in boosting the whole-body antitumor immunity.While most of previously developed nano-adjuvants for NIR-Ⅱ-triggered ISTV are“all-in-one”formulations,which may indiscriminately damage both the tumor cells and the immune cells,limiting the overall effect of immune response.To overcome this obstacle,we designed a“cocktail”nano-adjuvant by physically mixing hyaluronidases(HAase)-decorated gold nanostars(HA)for NIR-Ⅱlight triggered in situ production of tumor-associated antigens and CpG functionalized gold nanospheres(CA)for immune cells activation.Compared to“all-in-one”formulation,the“cocktail”nano-adjuvants displayed a significantly stronger immune response on NIR-Ⅱlight induced dendritic cells(DCs)mutation and T cells differentiation,greater effect on tumor-growth inhibition,and higher efficacy in inhibition of pulmonary metastases.What is more,increasing the molar ratio of HA to CA led to an enhanced anticancer immune responses.This study highlight the nano-adjuvant formulation effects on the treatment of tumors with multiple targets.
基金This work was partly supported by NCI grant R01CA229818 to Garcia-Sastre A.
文摘Oncolytic viruses(OVs)are at the forefront of biologicals for cancer treatment.They represent a diverse landscape of naturally occurring viral strains and genetically modified viruses that,either as single agents or as part of combination therapies,are being evaluated in preclinical and clinical settings.As the field gains momentum,the research on OVs has been shifting efforts to expand our understanding of the complex interplay between the virus,the tumor and the immune system,with the aim of rationally designing more efficient therapeutic interventions.Nowadays,the potential of an OV platform is no longer defined exclusively by the targeted replication and cancer cell killing capacities of the virus,but by its contribution as an immunostimulator,triggering the transformation of the immunosuppressive tumor microenvironment(TME)into a place where innate and adaptive immunity players can efficiently engage and lead the development of tumor-specific long-term memory responses.Here we review the immune mechanisms and host responses induced by ssRNA(-)(negative-sense single-stranded RNA)viruses as OV platforms.We focus on two ssRNA(-)OV candidates:Newcastle disease virus(NDV),an avian paramyxovirus with one of the longest histories of utilization as an OV,and influenza A(IAV)virus,a well-characterized human pathogen with extraordinary immunostimulatory capacities that is steadily advancing as an OV candidate through the development of recombinant IAV attenuated platforms.
