PD-1 blockade modulates chimeric antigen receptor (CAR)–modified T cells refueling the CAR 2017 Elise A. Chong.pdf

该【PD-1 blockade modulates chimeric antigen receptor (CAR)–modified T cells refueling the CAR 2017 Elise A. Chong 】是由【赖大文档】上传分享，文档一共【10】页，该文档可以免费在线阅读，需要了解更多关于【PD-1 blockade modulates chimeric antigen receptor (CAR)–modified T cells refueling the CAR 2017 Elise A. Chong 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。FromestonJanuary1,,prepublishedonlineDecember28,2016;-2016-09-738245PD-1BlockadeModulatesChimericAntigenReceptor(CAR)ModifiedTCellsandInducesTumorRegression:,,,,VanessaGonzalez2,BruceLevine2,,,AbramsonCancerCenterUniversityofPennsylvaniaPhiladelphia,,PACorrespondence:,.,PerelmanCenterforAdvancedMedicine,3400enterBlvd.,Philadelphia,PA,19104;Stephen.******@:Antibodiesblockingtheprogrammeddeath1receptor(PD-1)onTcellsproducetumorregressioninmultiplecancersbydisruptingthePD-L1/PD--5Thisapproachtocancerimmunotherapywouldseemtobeanidealpartnerforchimericantigenreceptor(CAR)modifiedTcelltherapiesbutis,asyet,-1blockingantibodywasadministeredtoapatientwithrefractorydiffuselargeBcelllymphoma(DLBCL)andprogressivelymphomaaftertherapywithCARmodifiedTcellsdirectedagainstCD19(CART19).FollowingPD-1blockade,thepatienthadaclinicallysignificantantitumorresponse,anexpansionofCART19cells,anddecreasedco-expressionofPD----year-oldmanwithmultiplypretreated,refractoryDLBCLofprimarymediastinaloriginwithextranodalinvolvementofsmallintestineatdiagnosis,andmediastinum,lung,myocardium,andpericardiumatprogressionwastreatedonaclinicaltrialattheUniversityofPennsylvaniawithautologousCART19cellsexpressingmurineanti-CD1911Copyright?2016AmericanSocietyofHematologyFromestonJanuary1,-1BB-CD3ζcostimulatory-activationdomains(NCT02030834).,8Hereceivedlymphodepletingchemotherapywithhyperfractionatedcyclophosphamide(300mg/m2x6doses),followedbyautologousCART19cellinfusion(),-’sclinicalstatuswithrapidlyprogressivehypoxiaandrespiratorydistress,,,2mg/kg,-PD-1therapypotentlyenhancestheeradicationofestablishedtumorsbygene-modifiedTcells9andbecausethepatient’stumorcellsstronglyexpressedPD-L1(Figure1A).Otherthanfever,,significantclinicalimprovementwasnoted;chestCTatthattimeshowedintervalimprovementofmultiplepulmonarynodules,pleuraleffusion,mediastinallymphadenopathy,andpericardialnodularity(Figure1B).Thus,pseudoprogressionafterCART19wasconsideredunlikelysincetherewasreductioninthesizeoflesionsafteradministrationofpembrolizumab,,,2mg/kg,wascontinuedevery3weeks;PET/CTscansonday67andday186showedcontinuedanatomicimprovementinmediastinaladenopathywithresidualFDGuptake(partialmetabolicresponse);,(datanotshown),percentageCART19cellsbyflowcytometry,andchangesinserumcytokinesincludingIL-6(Figure2A,B).7CART19DNAcopynumberincreasedtoamaximumof2,350copiespermcgDNAfollowingCART19cellinfusionandincreasedagainfrom49722FromestonJanuary1,(beforepembrolizumab)to1,-expressingTcellsincreasedafterCART19infusionstabilizingarounddays10-14;however,for48hoursafterpembrolizumab,weobservedthehighestpercentagesCAR19+Tcells(Figure2A).ThisreflectsanincreaseinbothCAR19+CD8+andCD4+Tcellsafterpembrolizumab,particularlytheCAR19+CD8+cells(datanotshown).ThehighestserumIL-6levelswereobserveddays3-7followingCART19cellinfusionandduringthe24hoursafterpembrolizumab(Figure2B).Afterpembrolizumabinfusion,CART19cellsco-expressingPD1/Eomesdecreased,especiallyintheCD8+CAR19+cells(Figures2C,D,E,F);nochangeswereobservedincellsco-expressingPD-1andCTLA4,TIM3,orLAG3(datanotshown).GranzymeB+expressionincreasedafterpembrolizumabinbothCD4+andCD8+Tcellsubsets,particularlyinCAR19+CD8+cells(datanotshown).WeperformedTCRβdeepsequencingontheapheresisproduct,theCAR19transducedTcellproductandonperipheralbloodatday14(priortopembrolizumab),atday26(1hourafterpembrolizumab),andatday45(19daysafterpembrolizumab)(Figure2G).Afterpembrolizumab(day45),weobservedeightdominantclones(frequency≥1%,%-%).Twooftheseclones(clones1,2)initiallyexpandedafterCART19cellinfusion(day14)andcontinuedtofurtherexpandafterpembrolizumab(days26to45).FourcloneswerepresentatlowlevelsafterCART19cellinfusionandexpandedafterpembrolizumab(clones3,4,5,6).Twodominantcloneswereonlypresentafterpembrolizumab(clones7,8).Together,ourclinicalobservationandcorrelativelaboratoryfindingssuggestthatpembrolizumabmayenhancetheefficacyofCART19cells,-1/PD-,wearecurrentlyconductingaphaseI/IIclinicaltrialofpembrolizumabinpatientswithCD19+lymphomasfailingtorespondtoCART19therapy(NCT02650999).33FromestonJanuary1,:TheauthorsacknowledgephilanthropicsupportfromJamesandFrancesMaguire,MargaritaLouis-Dreyfus,:,interpretedthedata,,assistedwithdataanalysis,,providedclinicaldataandclinicalcareforthepatient,interpretedthedata,-of-interestdisclosure:.,,.,.,.,,HodiFS,BrahmerJR,,activity,andimmunecorrelatesofanti-PD-;366:2443-,TykodiSS,ChowLQM,-PD-;366:2455-,RobertC,DaudA,(anti-PD-1);369:134-,KlugerH,CallahanMK,;369:122-,SznolM,McDermottDF,,durabletumorremission,andlong-;32:1020-,SvobodaJ,NastaSD,(CTL019)inpatientswithrelapsedorrefractoryCD19+;126(23):183(abstract).,HwangWT,FreyNV,;7(303):,,FishJD,CarpenitoC,;17(8):1453-,DevaudC,DuongCP,-PD-1AntibodyTherapyPotentlyEnhancestheEradicationofEstablishedTumorsByGene-;19(20):5636-,:-L1immunhistochemistryandCTscansdemonstratingclinicalresponsetotherapy.(A)PD-L1(CD274)expressionbythepatient’sdiffuselargeB--PD-L1antibodyfromCellSignaling(cloneE1J2J,cat#15165BF).Themainimageisat40xmagnification,theupper-:LeicaDM2500,:Leica,:.(B)CTimagingondayofpembrolizumabinfusion(day26)and3weeksafterpembrolizumabinfusion(day45).66FromestonJanuary1,:.(A)PercentageofCART19+CD3++ofCD3+cellspriortoCART19infusion(pre),threedaysafterCART19infusion(Day3),7daysafterCART19(Day7),tendaysafterCART19(Day10),fourteendaysafterCART19(Day14),twenty-sixdaysafterCART19andonehourafterpembrolizumabinfusion(Day26),twenty-sevendaysafterCART19and1dayafterpembrolizumab(Day27),twenty-eightdaysafterCART19and2daysafterpembrolizumab(Day28),andforty-fivedaysafterCART19andfourteendaysafterpembrolizumab(Day45).(B)FoldchangefrombaselineinIL-6serumlevels.(C)PercentageofPD1+CD4+cellsandPD1+Eomes+CD4+cellsinperipheralblood.(D)PercentageofPD1+CD4+CART19+cellsandPD1+Eomes+CD4+CART19+cellsinperipheralblood.(E)PercentageofPD1+CD8+cellsandPD1+Eomes+C8+cellsinperipheralblood.(F)PercentageofPD1+CD8+CART19+cellsandPD1+Eomes+CD8+CART19+cellsinperipheralblood.(G)ChangesinTcellclonesasdeterminedbyTCRβdeepsequencing(Adaptivebiotechnologies,immunoSEQ).77FromestonJanuary1,,%%%%%%%%%%%%%%%%%%%%%%%%%%%Figure2FromestonJanuary1,,2016;doi:-2016-09-738245PD-1BlockadeModulatesChimericAntigenReceptor(CAR)ModifiedTCellsandInducesTumorRegression:,,,,VanessaGonzalez,BruceLevine,:e/misc/#repub_requestsInformationaboutorderingreprintsmaybefoundonlineat:e/misc/#reprintsInformationaboutsubscriptionsandASHmembershipmaybefoundonlineat:e/subscriptions/(edited,typesetversionsmaybepostedwhenavailablepriortofinalpublication).Advanceonlinearticlesarecitableandestablishpublicationpriority;(DOIs)(printISSN0006-4971,onlineISSN1528-0020),ispublishedweeklybytheAmericanSocietyofHematology,2021LSt,NW,Suite900,;allrightsreserved.