靶向PSMA的嵌合抗原受体修饰的NK细胞对去势抵抗性前列腺癌的免疫治疗研究

靶向PSMA的嵌合抗原受体修饰的NK细胞对去势抵抗性前列腺癌的免疫治疗研究靶向PSMA的嵌合抗原受体修饰的NK细胞对去势抵抗性前列腺癌的免疫治疗研究

摘要：前列腺癌是男性最常见的恶性肿瘤之一，去势抵抗性前列腺癌（CRPC）是其最致命的亚型。目前，化疗、激素治疗和靶向治疗等治疗手段已被广泛应用，但治疗效果有限。因此，寻找更有效的治疗手段是非常必要的。针对前列腺特异性膜抗原（PSMA）的带有嵌合抗原受体（CAR）的NK细胞治疗，是一种新兴治疗手段。PSMA是一种限于前列腺细胞中的糖蛋白，它在前列腺癌细胞中的表达量较高。基于CAR的抗体识别机制，嵌合抗原受体修饰的NK细胞能够选择性地靶向前列腺癌细胞并杀死其。本文主要着重于介绍靶向PSMA的嵌合抗原受体修饰的NK细胞对CRPC的免疫治疗研究，包括构建CAR的方法、CAR-T细胞的制备、CAR-NK细胞的制备、临床研究进展等方面的内容。

关键词：前列腺癌、去势抵抗性前列腺癌、PSMA、CAR、NK细胞、免疫治疗。

Abstract:Prostatecancerisoneofthemostcommonmalignanttumorsinmen,andcastration-resistantprostatecancer(CRPC)isitsmostdeadlysubtype.Currently,chemotherapy,hormonetherapy,andtargetedtherapyhavebeenwidelyused,butthetreatmenteffectislimited.Therefore,itisverynecessarytofindmoreeffectivetreatments.Targetingtheprostate-specificmembraneantigen(PSMA)withchimericantigenreceptor(CAR)-modifiedNKcellsisanemergingtreatment.PSMAisaglycoproteinrestrictedtoprostatecells,anditsexpressionlevelishighinprostatecancercells.BasedontheCARantibodyrecognitionmechanism,CAR-modifiedNKcellscanselectivelytargetandkillprostatecancercells.ThisarticlemainlyfocusesontheimmunotherapyresearchofCRPCusingPSMA-targetedCAR-modifiedNKcells,includingtheconstructionofCAR,thepreparationofCAR-Tcells,thepreparationofCAR-NKcells,clinicalresearchprogress,etc.

Keywords:Prostatecancer;Castration-resistantprostatecancer;PSMA;CAR;NKcell;ImmunotherapyProstatecancerisoneofthemostcommoncancersinmen,withcastration-resistantprostatecancer(CRPC)beingtheadvancedstagethatisdifficulttotreat.ImmunotherapyhasbecomeapromisingapproachforthetreatmentofCRPC,withchimericantigenreceptor(CAR)-modifiednaturalkiller(NK)cellsbeingapotentialstrategy.

CARsarefusionreceptorsthatcontainanextracellularantigenrecognitiondomainandanintracellularsignalingdomain.ThePSMAantigenisoverexpressedonprostatecancercells,makingitasuitabletargetforCAR-modifiedimmunecells.PSMA-targetedCAR-NKcellshavetheadvantageoflowertoxicity,lessriskofcytokinereleasesyndrome,andpossiblepersistenceinthecirculation.

ThepreparationofCAR-NKcellsinvolvesthetransductionofNKcellswithaPSMA-specificCARlentiviralvector.TheCAR-NKcellscanthenrecognizeandkillPSMA-expressingcancercells,leadingtotumorcelldeath.PreclinicalstudieshaveshownthatPSMA-targetedCAR-NKcellscanefficientlyeliminateprostatecancercellsandinhibittumorgrowthinmousemodels.

Currently,clinicaltrialsareunderwaytoevaluatethesafetyandefficacyofPSMA-targetedCAR-NKcellsinpatientswithadvancedprostatecancer.InaphaseItrial,PSMA-targetedCAR-NKcellswerewelltoleratedandshowedantitumoractivityinpatientswithmetastaticCRPC.TheresultsofongoingtrialswillprovidevaluableinsightsintotheclinicalefficacyofCAR-NKcellsforthetreatmentofCRPC.

Insummary,PSMA-targetedCAR-NKcellshavegreatpotentialforthetreatmentofCRPC.FurtherresearchandclinicaltrialsareneededtooptimizeCAR-NKcelltherapyandimprovepatientoutcomesTherearestillseveralchallengesthatneedtobeaddressedinthedevelopmentandclinicalapplicationofCAR-NKtherapyforCRPC.OnechallengeisthelimitedavailabilityofCAR-NKcells,whichcanbeovercomebyoptimizingthemanufacturingprocessandexploringnewsourcesofNKcells.Anotherchallengeisthepotentialforoff-targeteffectsandtoxicity,whichcanbeminimizedbymodifyingCAR-NKcellstoenhancetheirspecificityandsafetyprofile.

Inaddition,theoptimaltimingandcombinationofCAR-NKtherapywithothertreatments,suchaschemotherapy,radiationtherapy,andimmunecheckpointinhibitors,needtobedeterminedthroughpreclinicalandclinicalstudies.Moreover,themechanismsofresistancetoCAR-NKtherapyandstrategiestoovercomeresistancerequirefurtherinvestigation.

Overall,PSMA-targetedCAR-NKcellsareapromisingimmunotherapeuticapproachforCRPCthatholdsgreatpotentialforimprovingpatientoutcomes.Withcontinuedresearchandclinicaltrials,CAR-NKtherapymaybecomeakeycomponentinthemanagementofadvancedprostatecancerPossiblecontinuation:

InadditiontoPSMA-targetedCAR-NKcells,otherimmunotherapeuticstrategiesarealsobeingexploredforCRPC.Forexample,checkpointinhibitorssuchaspembrolizumabandipilimumabhaveshownsomeactivityinasubsetofCRPCpatientswithmismatchrepairdeficiencyorhightumormutationburden.However,theirefficacyasmonotherapyislimited,andtheircombinationwithothertreatmentsmayincreasetoxicityandcost.Furthermore,someCRPCsubtypes,suchasneuroendocrineorsmallcellprostatecancer,maynotrespondwelltocheckpointinhibitorsduetotheirdistinctmolecularfeatures.

AnotherimmunotherapeuticapproachthathasshownpromiseinpreclinicalstudiesisbispecificTcellengagers(BiTEs)thatcanbindtobothprostatecancercellsandTcells,therebyactivatingTcell-mediatedcytotoxicityagainstcancercells.Forexample,aBiTEtargetingPSMAandCD3hasbeenshowntoinducepotentantitumorresponsesinvitroandinvivousingTcellsfromhealthydonorsorprostatecancerpatients.However,clinicaltrialsofBiTEsarestillongoing,andtheirpotentialtoxicitiesandresistancemechanismsneedtobefurtherinvestigated.

Overall,immunotherapyhasemergedasapromisingtreatmentoptionforCRPC,especiallyforpatientswhohaveexhaustedconventionaltherapiesorarenoteligibleforthemduetocomorbiditiesorintolerances.ThedevelopmentofPSMA-targetedCAR-NKcellsandotherimmunotherapeuticagentsshouldbeguidedbyrigorousscientificevidenceandclinicaltrials,andtheirintegrationintomultimodaltreatmentregimensshouldbetailoredtothespecificneedsandpreferencesofpatients.Inaddition,moreeffortsareneededtoidentifybiomarkersthatcanpredicttreatmentresponse,monitordiseaseprogression,