CAR-T肿瘤免疫治疗课件

Chimericantigenreceptor(CAR)T-cellImmunotherapy嵌合抗原受体T细胞免疫疗法Presenter：xxxDate：1.IntroductionofCAR-Ttherapy2.ClinicalapplicationsofCAR-Ttherapy3.ResistancetoCAR-Ttherapy4.ToxicitiesofCAR-Ttherapy目录Part1.IntroductionHallmarksofCancerCAR-TtherapyHanahanD,etal.Cell2011,144(5):646-674.PavlovaNN,etal.CellMetab2016,23(1):27-47.HallmarksofCancerSixacquiredbiologicalcapabilitiesduringthedevelopmentofhumantumorsEmerginghallmarks(e.g.metabolismhallmark)ImmunologicaltolerancetocancerFeinsS,etal.AmJHematol2019,94(S1):S3-s9.Breakingtoleranceto“self”antigensApproachestocircumventtoleranceInfusionofallogeneicTcells

AdoptivetransferofexpandedTILs Immunecheckpointsblockades(e.g.CTLA-4,PD-1inhibitors)VariousmAbs

BispecificT-cellenhancingantibodiesCAR-T More…ICBwithmAbsinhematologicmalignanciesFeinsS,etal.AmJHematol2019,94(S1):S3-s9.AbriefintroductiontoCAR-T/p/146532630Anectodomain

composedofasignalpeptide,antigenrecognitionregion, andspacerAtransmembranedomainAnendodomain

containsimmunoreceptortyrosine-basedactivationmotifs toactivateTcellsThebasicstructureofCARHolsteinSA,etal.ClinPharmacolTher2020,107(1):112-122.Anantigen-recognizingreceptor+signalingmoleculesFourgenerationsofCART-cellsHolsteinSA,etal.ClinPharmacolTher2020,107(1):112-122.includedaCD3ζorFcRγsignalingdomainadditionalsignalingdomains(CD28or4-1BB)Combinedmultiplesignalingdomains(e.g.CD3ζ-CD28-41BB)IncorporatedIL-12tothebaseofthe2ndconstructs.CART-cellmanufacturingprocessFeinsS,etal.AmJHematol2019,94(S1):S3-s9.HolsteinSA,etal.ClinPharmacolTher2020,107(1):112-122.Stepsinadministration

ofCART-cellsLeukopheresistocollecttheautologousT-cellsUndergoengineeringandexpansion+BridgingtherapyInfusionoftheCART-cellsManufacturingtechniquesmatter!ContaminationinhibitorycelltypesinenrichedTlymphocytesHamperefficientCARTcellexpansionincultureandsubsequently,invivoRarecaseasingleleukemiacellwasinadvertentlytransducedwiththeCARtransgeneduringT-cellmanufacturingProgressinmanufacturing:improvethesafetyandpotencyofcellularproductsFeinsS,etal.AmJHematol2019,94(S1):S3-s9.Part2.ClinicalApplicationAcutelymphoblasticleukemia(ALL)Relapsed/refractorydiffuselargeB-celllymphoma(DLBCL)Clinicaltrialsonmultiplemyeloma,solidtumor,etc.CD19expressionontheB-cellandthelackofexpressiononotherimportanttissuesKymriah(tisagenlecleucel)achievedFDAapproveinyear2017：61(81%)of75paediatricandyoungadultpatientswithrelapsedorrefractoryB-cellacutelymphoblasticleukaemiaachievedoverallremissionCD19-targetedCART-celltherapyforALLYescarta(axi-cel)：ZUMA-1trialCD19-targetedCART-celltherapyforDLBCLKymriah(tisagenlecleucel):JULIETtrialHolsteinSA,etal.ClinPharmacolTher2020,107(1):112-122.SchusterSJ,etal.NEnglJMed2019,380(1):45-56.BMCAisuniversallydetectedonpatient-derivedmyelomacellsSeveralBCMACARTproductsareunderevaluationinphaseIIorphaseIIItrials：mostofthemenrolledrel/refpatientsKarMMa-3study(NCT03651128)LCAR-B38M(NCT03758417)EVOLVEstudy(NCT03430011)More…bb2121BMCACART-cellformultiplemyelomaPart3.ResistancetoCAR-TAmechanismofCART-cellfailureinpediatricALL:LossoftheCD19antigenorepitope(alternativesplicing,homozygousorbiallelicframeshiftmutations,etc.)Failureofengraftmentand/orexpansionandpersistenceofengineeredTcellsTcellswithanearlymemoryphenotypemayhavesuperiorexpansionpotentialStrategiesutilizingdualormultitargetedapproachesmanipulatingthephenotypeoftheengineeredcellstopromotegreaterefficacyutilizationofadjunctivetherapies(e.g.checkpointinhibitors)ManypatientsultimatelyrelapseafterCART-celltherapyFeinsS,etal.AmJHematol2019,94(S1):S3-s9.CARTcellsdonotexpandordurablypersistinsomepatients,whileinothersrobustproliferationandclonaloutgrowthoftransferredTlymphocytesoccur.Predictiveindicatorsandmechanism(s)associatedwithremarkableproliferation,persistenceandfavorableclinicalresponsesarelargelyunknown.PredictivebiomarkerscanbeutilizedbyphysicianstoprescribeCART-celltherapyonlytotherespondingpatientpopulation,thuseliminatingtheunnecessaryexpenseandriskofimmune-relatedadverseeventsfornonresponders.PredictingresponsetoCART-celltherapyFeinsS,etal.AmJHematol2019,94(S1):S3-s9.Part4.ToxicitiesofCAR-TtherapyBrudnoJN,etal.Blood2016,127(26):3321-3330.DetaileddescriptionoftoxicitiesBrudnoJN,etal.Blood2016,127(26):3321-3330.HolsteinSA,etal.ClinPharmacolTher2020,107(1):112-122.TwokeytoxicitiesCytokine-releasesyndrome(CRS)triggeredbytheactivationoftheT-cells,leadingtoreleaseofmultiplecytokines,includingIL-2,IFNγ,IL-6variedclinicalmanifestations:fevers,hypotension,hypoxemia,etc.TypicallyoccurswithinthefirstweekafterCAR-TtherapyManagementdependsontheseverityNeurotoxicity:CART-cell-relatedencephalopathysyndrome(CRES)themechanismsremainincompletelyunderstoodmanifestasimpairedhandwriting,orlanguagedisturbance,etc.ThemanagementisbasedonthetoxicitygradeBrudnoJN,etal.Blood2016,127(26):3321-3330.HolsteinSA,etal.ClinPharmacolTher2020,107(1):112-122.SchusterSJ,etal.BloodAdv2020,4(7):1432-1439.TheCRSincidenceinclinicaltrialsInZUMA-1study93%ofpatientshadCRS(13%grade3orhigher)IntheJULIETtrial:58%ofpatientshadCRS(22%grade3orhigher)InthephaseIstudyofbb2121BCMACARTtherapy76%ofpatientswerereportedtohaveCRS(2weregrade3)Todate,therewasnoconsensusregardingthegradingandreportingofeitherCRSorCRESinCART-cellstudiesSimonettaI,etal.