推动CAR T细胞向前发展

DrivingCART‑cellsforward推动CART细胞向前发展2016-11-241.TheCancer-ImmunityCycleTheCancer-ImmunityCycle.ChenDS,etal.Immunity.2013Jul25;39(1):1-10.ChenDS,etal.Immunity.2013Jul25;39(1):1-10.StimulatoryandInhibitoryFactorsintheCancer-ImmunityCycle.ChenDS,etal.Immunity.2013Jul25;39(1):1-10.KhalilDN,etal.NatRevClinOncol.2016May;13(5):273-90.TherapiesthatMightAffecttheCancer-ImmunityCycleChenDS,etal.Immunity.2013Jul25;39(1):1-10.Adoptivecelltransfer(ACT)1.TIL:Tumor-infiltratinglymphocyte2.CAR:Chimericantigenreceptor3.TCR:Tcellreceptor4.CytotoxicTlymphocyteRosenberg,S.

A.NatRevClinOncol.2011:8,577–585.2.TIL:Tumor-infiltratinglymphocyteZhangL,etal.NEnglJMed.2003Jan16;348(3):203-13.GalonJ,etal.Science.2006Sep29;313(5795):1960-4.SurvivalAnalysesofPatientswithOvarianCarcinoma,AccordingtothePresenceorAbsenceofTILs.TILtherapy.TranKQ,etal.JImmunother.2008Oct;31(8):742-51.RosenbergSA,etal.ClinCancerRes.2011Jul1;17(13):4550-7.

CombinationofRadiotherapyandImmunotherapy:ChangingtheGame.3.CAR:ChimericantigenreceptorThreesignalsarerequiredforantigen-specificTcellactivation.GutcherI,etal.JClinInvest.2007May;117(5):1119-27.CAR-T-celldesign.JacksonHJ,etal.NatRevClinOncol.2016Jun;13(6):370-83.CAR-T-celldesign.CD19CAR-TCellTherapy.ASH2015NEJM2013Apr18;368(16):1509-18.EmmainApril2012CD19CAR-TCellTherapy:ALongWayToGo.EmmatodayResponseRate:93%Relapse:1YearSurvival:79%1YearCR:55%SideEffect:CytokineStormBCellDepletionChenDS,etal.Immunity.2013Jul25;39(1):1-10.多抗原负载促成熟皮下注射采集DC前体未成熟DCDC+淋巴细胞共培养静脉回输CTL诱导成熟DCCTL激活Flowchartofmultipleantigenstimulatingcellulartherapy(MASCT)CherkasskyL,etal,JClinInvest.2016Aug1;126(8):3130-44.CotransductionofaPD-1DNRrescuesM28zCARTcells.RT:radiotherapyTC:tumorcellTV:tumorvolumSTM:sensitanttumormodelRTM:resistanttumormodelInvivoRT(5*2Gy)↑TC表达PD-L1RT(5*2Gy)+anti-PD-1/anti-PD-L1↑OS,↓TV上述联合方式：同步>续贯InvitroRT不能使TC表达PD-L1增加RT+CD8+Tcell↑↑↑TC表达PD-L1RT+CD4+Tcell↓TC表达PD-L1RT+IFNγ↑TC表达PD-L1RT+IFN

不能使TC表达PD-L1增加RT+IFN

+IFNγ↑↑↑TC表达PD-L1RT↑TC表达PD-L1依赖IFNγDovediSJ,etal.CancerRes.2014Oct1;74(19):5458-68.WangX,etal.CancerRes.2016Nov7.筛选出对anti-PD-1敏感（STM）和抵抗（RTM）的动物模型STM和RTM表达PD-L1无区别RTM表达MHCI,II下降RT(3*12Gy)↓RTM-TVanti-PD-1不能↓RTM-TVRT(3*12Gy)+anti-PD-1↓↓↓RTM-TVRT↑IFNβ表达RT激活IFNβ/IFNAR-MHCclassIpathwayRT(3*12Gy)↑MHCI表达CombinationofRadiotherapyandImmunotherapy:ChangingtheGame.4.TCR:TcellreceptorJacksonHJ,etal.NatRevClinOncol.2016Jun;13(6):370-83.ApproachestoimproveCAR-T-celltherapy.KhalilDN,etal.NatRevClinOncol.2016May;13(5):273-90.Antibodiesan