Objective:Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor(CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells,especially the lower incidence rate of severe...Objective:Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor(CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells,especially the lower incidence rate of severe adverse events.However,the median progression-free survival(mPFS)of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta(2.9 months vs.5.9 months),suggesting that Kymriah was limited in the long-term efficacy.Thus,a safe and durable 4-1BB-based CD19 CAR-T needs to be developed.Methods:We designed a CD19-targeted CAR-T(named as IM19)which consisted of an FMC63 scFv,4-1BB and CD3ζintracellular domain and was manufactured into a memory T-enriched formulation.A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory(r/r)B cell non-Hodgkin lymphoma(B-NHL).Dose-escalation investigation(at a dose of 5×10^(5)/kg,1×10^(6)/kg and 3×106/kg)was performed in 22 r/r B-NHL patients.All patients received a single infusion of IM19 after 3-day conditional regimen.Results:At month 3,the overall response rate(ORR)was 59.1%,the complete response rate(CRR)was 50.0%.The mPFS was 6 months and the 1-year overall survival rate was 77.8%.Cytokine release syndrome(CRS)occurred in 13 patients(59.1%),with 54.5%of grade 1−2 CRS.Only one patient(4.5%)experienced grade 3 CRS and grade 3 neurotoxicity.Conclusions:These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T,IM19,which is promising for further development and clinical investigation.展开更多
Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow...Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow for quick transport of nutrients and signals.Moreover,ASTs interact with OLGs through connexin(Cx)-mediated networks to modulate various physiological processes in the brain.In this article,following a brief description of the infrastructural basis of the glial networks and exocrine factors by which ASTs and OLGs may crosstalk,we focus on recapitulating how the interactions between these two types of glial cells modulate myelination,and how the AST-OLG interactions are involved in protecting the integrity of the blood-brain barrier(BBB)and regulating synaptogenesis and neural activity.Recent studies further suggest that AST-OLG interactions are associated with myelin-related diseases,such as multiple sclerosis.A better understanding of the regulatory mechanisms underlying AST-OLG interactions may inspire the development of novel therapeutic strategies for related brain diseases.展开更多
CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4+CD25+...CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4+CD25+ Tregs can regulate recipient mouse macrophages is unknown. The effect of allogeneic donor CD4+CD25+ Tregs on recipient mouse resident F4/80+macrophages was investigated using a mouse model in which allogeneic donor CD4+CD25+ Tregs were adoptively transferred into the peritoneal cavity of host NOD-scid mice. The phenotype and function of the recipient macrophages were then assayed. The peritoneal F4/80+ macrophages in the recipient mice that received the allogeneic CD4+CD25+ Tregs expressed significantly higher levels of CD23 and programmed cell death-ligand I(PD-L1) and lower levels of CD80, CD86, CD40 and MHC II molecules compared to the mice that received either allogeneic CD4+CD25- T cells (Teffs) or no cells. The resident F4/80+ macrophages of the recipient mice injected with the allogeneic donor CD4+CD25+ Tregs displayed significantly increased phagocytosis of chicken red blood cells (cRBCs) and arginase activity together with increased IL-IO production, whereas these macrophages also showed decreased immunogenicity and nitric oxide (NO) production. Blocking arginase partially but significantly reversed the effects of CD4+CD25+ Tregs with regard to the induction of the M2 macrophages in vivo. Therefore, the allogeneic donor CD4+CD25+ Tregs can induce the M2 macrophages in recipient mice at least in part via an arginase pathway. We have provided in vivo evidence to support the unknown pathways by which allogeneic donor CD4+CD25+ Tregs regulate innate immunity in recipient mice by promoting the differentiation of M2 macrophages.展开更多
基金supported by the Beijing Natural Science Foundation (No. 7202026)Capital’s Funds for Health Improvement and Research (No. 2020-2Z-2157)
文摘Objective:Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor(CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells,especially the lower incidence rate of severe adverse events.However,the median progression-free survival(mPFS)of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta(2.9 months vs.5.9 months),suggesting that Kymriah was limited in the long-term efficacy.Thus,a safe and durable 4-1BB-based CD19 CAR-T needs to be developed.Methods:We designed a CD19-targeted CAR-T(named as IM19)which consisted of an FMC63 scFv,4-1BB and CD3ζintracellular domain and was manufactured into a memory T-enriched formulation.A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory(r/r)B cell non-Hodgkin lymphoma(B-NHL).Dose-escalation investigation(at a dose of 5×10^(5)/kg,1×10^(6)/kg and 3×106/kg)was performed in 22 r/r B-NHL patients.All patients received a single infusion of IM19 after 3-day conditional regimen.Results:At month 3,the overall response rate(ORR)was 59.1%,the complete response rate(CRR)was 50.0%.The mPFS was 6 months and the 1-year overall survival rate was 77.8%.Cytokine release syndrome(CRS)occurred in 13 patients(59.1%),with 54.5%of grade 1−2 CRS.Only one patient(4.5%)experienced grade 3 CRS and grade 3 neurotoxicity.Conclusions:These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T,IM19,which is promising for further development and clinical investigation.
基金supported by the Ministry of Science and Technology of China(2021ZD0201700)the National Natural Science Foundation of China(31921003).
文摘Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow for quick transport of nutrients and signals.Moreover,ASTs interact with OLGs through connexin(Cx)-mediated networks to modulate various physiological processes in the brain.In this article,following a brief description of the infrastructural basis of the glial networks and exocrine factors by which ASTs and OLGs may crosstalk,we focus on recapitulating how the interactions between these two types of glial cells modulate myelination,and how the AST-OLG interactions are involved in protecting the integrity of the blood-brain barrier(BBB)and regulating synaptogenesis and neural activity.Recent studies further suggest that AST-OLG interactions are associated with myelin-related diseases,such as multiple sclerosis.A better understanding of the regulatory mechanisms underlying AST-OLG interactions may inspire the development of novel therapeutic strategies for related brain diseases.
基金The authors wish to thank Drs Shuping Zhou and Zeqing Niu for their kind review of the manuscript, Ms ling Wang, Mr Yabing Liu and Ms Xiaoqiu Liu for their expert technical assistance, Ms Qinghuan Li and ]ianxia Peng for their excellent laboratory management and Mr Baisheng Ren for his outstanding animal husbandry. This work was supported by grants from the National Natural Science Foundation (C81072396, U0832003, YZ C31171407 and 81273201, GL), the Ministry of Science and Technology of China (2010CB945301, YZ) and the Chinese Academy of Sciences for Distinguished Young Scientists (KSCX2-EW-Q-7, GL).
文摘CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4+CD25+ Tregs can regulate recipient mouse macrophages is unknown. The effect of allogeneic donor CD4+CD25+ Tregs on recipient mouse resident F4/80+macrophages was investigated using a mouse model in which allogeneic donor CD4+CD25+ Tregs were adoptively transferred into the peritoneal cavity of host NOD-scid mice. The phenotype and function of the recipient macrophages were then assayed. The peritoneal F4/80+ macrophages in the recipient mice that received the allogeneic CD4+CD25+ Tregs expressed significantly higher levels of CD23 and programmed cell death-ligand I(PD-L1) and lower levels of CD80, CD86, CD40 and MHC II molecules compared to the mice that received either allogeneic CD4+CD25- T cells (Teffs) or no cells. The resident F4/80+ macrophages of the recipient mice injected with the allogeneic donor CD4+CD25+ Tregs displayed significantly increased phagocytosis of chicken red blood cells (cRBCs) and arginase activity together with increased IL-IO production, whereas these macrophages also showed decreased immunogenicity and nitric oxide (NO) production. Blocking arginase partially but significantly reversed the effects of CD4+CD25+ Tregs with regard to the induction of the M2 macrophages in vivo. Therefore, the allogeneic donor CD4+CD25+ Tregs can induce the M2 macrophages in recipient mice at least in part via an arginase pathway. We have provided in vivo evidence to support the unknown pathways by which allogeneic donor CD4+CD25+ Tregs regulate innate immunity in recipient mice by promoting the differentiation of M2 macrophages.