Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ...Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy,the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized,and clinical safety and efficacy also need to be proven.Therefore,we developed a novel formula to improve the expansion of peripheralγδT cells from healthy donors.Then,we used a humanized mouse model to validate the therapeutic efficacy of expandedγδT cells in vivo;furthermore,the expandedγδT cells were adoptively transferred into late-stage liver and lung cancer patients.We found that the expanded cells possessed significantly improved immune effector functions,including proliferation,differentiation,and cancer cell killing,both in vitro and in the humanized mouse model.Furthermore,a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells.Among these 132 patients,8 liver cancer patients and 10 lung cancer patients who received≥5 cell infusions showed greatly prolonged survival,which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy.Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy,which will inspire further clinical investigations and eventually benefit cancer patients.展开更多
Immunotherapy has limited efficacy against locally advanced pancreatic cancer(LAPC)due to the presence of an immunosuppressive microenvironment(ISM).Irreversible electroporation(IRE)can not only induce immunogenic cel...Immunotherapy has limited efficacy against locally advanced pancreatic cancer(LAPC)due to the presence of an immunosuppressive microenvironment(ISM).Irreversible electroporation(IRE)can not only induce immunogenic cell death,but also alleviate immunosuppression.This study aimed to investigate the antitumor efficacy of IRE plus allogeneicγδT cells in LAPC patients.A total of 62 patients who met the eligibility criteria were enrolled in this trial,then randomized into two groups(A:n=30 and B:n=32).All patients received IRE therapy and after receiving IRE,the group A patients received at least two cycles ofγδT-cell infusion as one course continuously.Group A patients had better survival than group B patients(median OS:14.5 months vs.11 months;median PFS:11 months vs.8.5 months).Moreover,the group A patients treated with multiple courses ofγδT-cell infusion had longer OS(17 months)than those who received a single course(13.5 months).IRE combined with allogeneicγδT-cell infusion is a promising strategy to enhance the antitumor efficacy in LAPC patients,yielding extended survival benefits.展开更多
基金This work was supported by the Key Program of the National Natural Science Foundation of China(31830021)Major International Joint Research Program of China(31420103901)+12 种基金“111 project”(B16021)Scientific and Technological Plan of Guangdong Province(201704KW010)(Z.Y.)Fundamental Research Funds for the Central Universities,Natural Science Foundation of Guangdong Province,China(2020A1515010132)(Y.W.)General Research Fund,Research Grants Council of Hong Kong(17122519,17121214,17115015,and 17126317)(W.T.)Hong Kong SAR,ChinaThis work was also partially supported by the National Natural Science Foundation of China(31570898)the Natural Science Foundation of Guangdong Province,China(2016A030313112)(Z.X.)grant Ka 502/19-1 from the German Research Council(Deutsche Forschungsgemeinschaft)the Cluster of Excellence ExC 306“Inflammation-at-Interfaces”(Deutsche Forschungsgemeinschaft)(D.K.)Y.H.was supported by the China Postdoctoral Science Foundation(2017M622898)Y.X.was supported by the Postdoctoral Fund of the First Affiliated Hospital of Jinan University(809008)L.K.was supported by a long-term fellowship from the German Academic Exchange Service(DAAD)C.P.is the recipient of a grant from the Erich und Gertrud Roggenbruck Foundation.
文摘Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy,the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized,and clinical safety and efficacy also need to be proven.Therefore,we developed a novel formula to improve the expansion of peripheralγδT cells from healthy donors.Then,we used a humanized mouse model to validate the therapeutic efficacy of expandedγδT cells in vivo;furthermore,the expandedγδT cells were adoptively transferred into late-stage liver and lung cancer patients.We found that the expanded cells possessed significantly improved immune effector functions,including proliferation,differentiation,and cancer cell killing,both in vitro and in the humanized mouse model.Furthermore,a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells.Among these 132 patients,8 liver cancer patients and 10 lung cancer patients who received≥5 cell infusions showed greatly prolonged survival,which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy.Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy,which will inspire further clinical investigations and eventually benefit cancer patients.
基金supported by grants from the National Natural Science Foundation of China(no.81971895)the NSFC-Guangdong Joint Foundation of China(no.U1601225)the Guangdong Provincial Key Laboratory Construction Project of China(no.2017B030314034).
文摘Immunotherapy has limited efficacy against locally advanced pancreatic cancer(LAPC)due to the presence of an immunosuppressive microenvironment(ISM).Irreversible electroporation(IRE)can not only induce immunogenic cell death,but also alleviate immunosuppression.This study aimed to investigate the antitumor efficacy of IRE plus allogeneicγδT cells in LAPC patients.A total of 62 patients who met the eligibility criteria were enrolled in this trial,then randomized into two groups(A:n=30 and B:n=32).All patients received IRE therapy and after receiving IRE,the group A patients received at least two cycles ofγδT-cell infusion as one course continuously.Group A patients had better survival than group B patients(median OS:14.5 months vs.11 months;median PFS:11 months vs.8.5 months).Moreover,the group A patients treated with multiple courses ofγδT-cell infusion had longer OS(17 months)than those who received a single course(13.5 months).IRE combined with allogeneicγδT-cell infusion is a promising strategy to enhance the antitumor efficacy in LAPC patients,yielding extended survival benefits.