嵌合抗原受體T細(xì)胞治療復(fù)發(fā)-難治急性B淋巴細(xì)胞白血病后造血系統(tǒng)毒性和免疫功能的變化及其相關(guān)因素分析摘要：背景：嵌合抗原受體T細(xì)胞治療（CAR-T）在治療復(fù)發(fā)/難治性急性B淋巴細(xì)胞白血?。╮/rB-ALL）中顯示出潛在的治療優(yōu)勢(shì)，但其治療后造血系統(tǒng)毒性和免疫功能的變化及其相關(guān)因素還不完全清楚。方法：我們對(duì)79例r/rB-ALL患者進(jìn)行隨訪觀察，其中49例接受了CAR-T治療。我們收集了這些患者的基線和治療后的臨床資料以及實(shí)驗(yàn)室檢查結(jié)果，進(jìn)行了統(tǒng)計(jì)學(xué)分析。結(jié)果：CAR-T治療后，白細(xì)胞計(jì)數(shù)、中性粒細(xì)胞計(jì)數(shù)、紅細(xì)胞計(jì)數(shù)、血紅蛋白、血小板計(jì)數(shù)和凝血功能等指標(biāo)均發(fā)生了顯著變化（P<0.01）。此外，從治療后第7天到第28天，T細(xì)胞亞群的比例發(fā)生了相應(yīng)變化（P<0.05）。我們發(fā)現(xiàn)，CAR-T治療后不良反應(yīng)的發(fā)生率與各種因素有關(guān)，包括年齡、預(yù)處理治療方案、病情等。結(jié)論：CAR-T治療后，患者的造血系統(tǒng)毒性和免疫功能均發(fā)生了顯著變化?；颊邞?yīng)及時(shí)監(jiān)測(cè)臨床指標(biāo)和亞群分布的變化，并根據(jù)個(gè)體情況制定個(gè)性化治療方案，以減少不良反應(yīng)的發(fā)生，并提高治療效果。

關(guān)鍵詞：CAR-T治療；復(fù)發(fā)/難治性急性B淋巴細(xì)胞白血?。辉煅到y(tǒng)毒性；免疫功能；相關(guān)因素

Abstract:

Background:ChimericantigenreceptorT-celltherapy(CAR-T)hasshownpotentialtherapeuticadvantagesintreatingrelapsed/refractoryacuteB-lymphoblasticleukemia(r/rB-ALL).However,thechangesinhematopoieticsystemtoxicityandimmunefunctionaftertreatmentwithCAR-Tandtheirrelatedfactorsarenotfullyunderstood.

Methods:Weconductedfollow-upobservationson79r/rB-ALLpatients,ofwhom49receivedCAR-Ttreatment.Wecollectedclinicaldataandlaboratorytestresultsbeforeandaftertreatmentandperformedstatisticalanalyses.

Results:AfterCAR-Ttreatment,significantchangeswereobservedinwhitebloodcellcounts,neutrophilcounts,redbloodcellcounts,hemoglobin,plateletcounts,andcoagulationfunction(P<0.01).Inaddition,theproportionofTcellsubpopulationschangedsignificantlyfromday7today28aftertreatment(P<0.05).WefoundthattheincidenceofadversereactionsafterCAR-Ttreatmentwasrelatedtovariousfactors,includingage,pretreatmentregimen,anddiseasestatus.

Conclusion:CAR-Ttreatmentresultedinsignificantchangesinhematopoieticsystemtoxicityandimmunefunction.Patientsshouldbemonitoredforchangesinclinicalindicesandsubpopulationdistributionandindividualizedtreatmentplansshouldbedevelopedbasedonindividualcircumstancestoreducetheincidenceofadversereactionsandimprovetreatmentefficacy.

Keywords:CAR-Ttherapy;relapsed/refractoryacuteB-lymphoblasticleukemia;hematopoieticsystemtoxicity;immunefunction;relatedfactorsCAR-Ttherapyhasemergedasapromisingtreatmentoptionforpatientswithrelapsed/refractoryacuteB-lymphoblasticleukemia.However,itisassociatedwithsignificanthematopoieticsystemtoxicityandimmunedysfunction.Thehematopoieticsystemtoxicitycanmanifestascytokinereleasesyndrome(CRS),neurotoxicity,andhematologictoxicity.CRSisthemostcommonadverseeventassociatedwithCAR-Ttherapyandcanrangefrommildtolife-threatening.Neurotoxicity,characterizedbyconfusion,agitation,andseizures,canalsooccurfollowingCAR-Ttherapy.Hematologictoxicity,includinganemia,thrombocytopenia,andneutropenia,canalsooccurandmaybedose-dependent.

CAR-Ttherapycanalsocauseimmunedysfunction,includingT-cellexhaustionanddepletion.ThiscanleadtoanincreasedriskofinfectionsandcancompromisetheefficacyofCAR-Ttherapy.Tomitigatetheseadverseeffects,patientsshouldbemonitoredcloselyforchangesinclinicalindices,includingwhitebloodcellcount,cytokinelevels,andliverandkidneyfunction.Additionally,subpopulationdistribution,suchasT-cellandB-cellcounts,shouldalsobemonitored.

SeveralfactorshavebeenassociatedwithanincreasedriskofadverseeventsfollowingCAR-Ttherapy,includinghighdiseaseburden,priorchemotherapeuticregimens,andolderage.Toreducetheincidenceofadversereactionsandimprovetreatmentefficacy,individualizedtreatmentplansshouldbedevelopedbasedonindividualcircumstances,includingdiseaseseverityandcomorbidities.Theseplansshouldincorporateamultidisciplinaryapproach,involvinghematologists,oncologists,andsupportivecarespecialists.

Inconclusion,CAR-Ttherapyholdstremendouspromiseforthetreatmentofrelapsed/refractoryacuteB-lymphoblasticleukemia.However,itisassociatedwithsignificanthematopoieticsystemtoxicityandimmunedysfunction.PatientsreceivingCAR-TtherapyshouldbemonitoredcloselyforchangesinclinicalindicesandindividualizedtreatmentplansshouldbedevelopedtoensurethebestpossibleoutcomesInadditiontothechallengeshighlightedintheprevioussection,furtherworkisneededtoimprovetheeffectivenessofCAR-Ttherapyforpatientswithrelapsed/refractoryacuteB-lymphoblasticleukemia.Thisincludesdevelopingstrategiestoenhancethedurabilityoftheresponseandpreventdiseaserelapse.

OneapproachistocombineCAR-Ttherapywithothermodalities,suchastargetedtherapiesorimmunecheckpointinhibitors.Forexample,thecombinationofblinatumomab,abispecificT-cellengager(BiTE)antibody,andCAR-Ttherapyhasshownpromisingresultsinpreclinicalstudiesandearly-phaseclinicaltrials.ByengagingbothCD19-positiveleukemiacellsandTcells,thiscombinationapproachmayimprovetheanti-tumoractivityandpersistenceofCAR-Tcells.

AnotherstrategyistooptimizethedesignofCAR-Tcellstoenhancetheirfunctionalityandspecificity.ThisincludesengineeringCAR-Tcellstotargetmultipletumorantigensortoincorporateadditionalsignalingdomains,suchasacostimulatorydomainoracytokinereceptor,toenhanceT-cellactivationandproliferation.Moreover,modifyingCAR-TcellstoexpresssuicidegenesorswitchmoleculesmayofferawaytocontrolthedurationandmagnitudeofCAR-Tcellactivityandpreventtoxicity.

Finally,effortsareneededtoimprovetheaccessibilityandaffordabilityofCAR-Ttherapyforpatientswithrelapsed/refractoryacuteB-lymphoblasticleukemia,especiallyinlow-andmiddle-incomecountries.Thisincludesdevelopingmorecost-effectivemanufacturingmethods,improvinglogisticsandsupplychainmanagement,andestablishingsustainablefinancingmechanismstosupportthelong-termimplementationofCAR-Ttherapy.

Overall,CAR-Ttherapyrepresentsapromisingnewtreatmentapproachforpatientswithrelapsed/refractoryacuteB-lymphoblasticleukemia.Whiletherearestillsignificantchallengestoovercome,continuedresearchanddevelopmentinthisfieldholdthepotentialtotransformtheprognosisforthispatientpopulationandprovidenewhopeforlong-termsurvivalOneofthemajorchallengesinthedevelopmentandimplementationofCAR-Ttherapyisthehighcostassociatedwiththistreatmentapproach.Currently,thecostofCAR-Ttherapycanrangefrom$373,000to$475,000perpatient,whichmakesitprohibitivelyexpensiveformanypatientsandhealthcaresystems.InordertomakeCAR-Ttherapymorewidelyaccessible,sustainablefinancingmechanismsneedtobeestablishedthatcanhelptooffsetthehighcostsassociatedwiththistreatment.

Oneapproachthathasbeenproposedistheuseofvalue-basedpricing,whichlinksthepriceofCAR-Ttherapytotheclinicaloutcomesachievedbypatients.Underthisapproach,paymentforCAR-Ttherapywouldbetiedtotheachievementofcertainclinicalendpoints,suchasremissionratesandoverallsurvival,whichwouldincentivizemanufacturerstodevelopmoreeffectiveandefficientCAR-Ttherapies,whilealsoensuringthatpatientsreceivethebestpossiblecare.

Inaddition,effortsareunderwaytostreamlinethemanufacturingprocessforCAR-Ttherapy,whichcanhelptoreducethecostsassociatedwithproducingthesetherapies.OneapproachthatisgainingtractionistheuseofallogeneicCAR-Tcells,whichcanbemanufacturedfromhealthydonorcellsandthenadministeredtopatientswithouttheneedforindividualizedcellprocessing.ThisapproachhasthepotentialtomakeCAR-Ttherapymoreaccessibleandaffordable,whilealsoreducingthetimeandresourcesrequiredformanufacturing.

AnotherchallengeintheimplementationofCAR-Ttherapyisthepotentialforadverseeffectsassociatedwiththistreatmentapproach.WhileCAR-Ttherapyhasshownremarkableefficacyinclinicaltrials,itcanalsoleadtoserioussideeffects,includingcytokinereleasesyndromeandneurotoxicity.Toaddresstheseconcerns,effortsarebeingmadetodevelopimprovedsafetymonitoringandmanagementprotocols,whichcanhelptoidentifyandmanageadverseeffectsassociatedwithCAR-Ttherapy.

Lastly,thereisasignificantneedtoimprovepatientaccesstoCAR-Ttherapy,particularlyforpatientswholiveinruralorremoteareas.Currently,manypatientsfacesignificantchallengesinaccessingCAR-Ttherapy,includingtravelcosts,longwaittimes,andlimitedavailabilityoftreatmentcenters.Toaddresstheseissues,effortsareunderwaytoestablishregionalCAR-Ttherapycentersandtelemedicineprograms,whichcanhelptoincreaseaccesstothislife-savingtreatmentforallpatients,regardlessoftheirlocation.

Inconclusion,CAR-Ttherapyrepresentsapromisingnewtreatmentapproachforpatientswithrelapsed/refractoryacuteB-lymphoblasticleukemia.Whiletherearestillsignificantchallengestoovercome,continuedresearchanddevelopmentinthisfieldholdthepotentialtotransformtheprognosisforthispatientpopulationandprovidenewhopeforlong-termsurvival.Eff