Engineering5(2019)5–9Contents lists available at ScienceDirectEngineeringTopicInsights
CellTherapy:PharmacologicalInterventionEntersaThirdEra
WeiHe
Professor,MD,ChairmanoftheDepartmentofImmunology,InstituteofBasicMedicalSciences,ChineseAcademyofMedicalSciences&SchoolofBasicMedicine,PekingUnionMedicalCollege,China1.IntroductionOnAugust30,2017,theUSFoodandDrugAdministration(FDA)releasedanewsstatementonitswebsitetitled‘‘FDAapprovalbrings?rstgenetherapytotheUnitedStates”[1].ThearticledisclosedtheuseofFDA-approvedKymriah(tisagenle-cleucel),acell-basedgenetherapydevelopedbyNovartisPharma-ceuticalsCorporation,forcertainpediatricandyoungadultpatientswithrefractoryorrelapseacutelymphoblasticleukemia(ALL).ALLisacancerofthebonemarrowandblood,whichpro-gressesquicklyandisthemostcommonchildhoodcancerintheUnitedStates.Kymriah,whichisageneticallymodi?edautologousTcellimmunotherapy,isapprovedforuseinthoseupto25yearsofagewithBcellprecursorALL.Theindividualpatient’sownTcellsaregeneticallymodi?edwithanewgenethatcontainsaspeci?cprotein(chimericantigenreceptor,CAR)directingtheTcellstotargetandkillleukemiacellswithaspeci?cantigen(clus-terofdifferentiation19,i.e.CD19)onthesurface.Infact,Kymriahrepresentsakindofadoptivecellularimmunotherapyusinggene-engineeredTcells.‘‘We’reenteringanewfrontierinmedicalinno-vationwiththeabilitytoreprogramapatient’sowncellstoattackadeadlycancer,”saidFDACommissionerScottGottlieb,MD.Fromahistoricpointofview,celltherapy—or,moreaccurately,cell-basedgenetherapy—representsanimportantmarkerindicatingthatpharmacologicaldiseaseinterventionhasenteredanewera.The?rsteraofdiseaseinterventionbydrugswasbasedonchem-icalmedicine,andtheseconderawasbasedonbiologicaldrugs.Nowthethirderahasarrived:celltherapy.Thisarticleoutlinesthehistoricalprogressandcharacteristicsofthreeerasofpharma-cologicaldiseaseintervention,andanalyzestheprospectsforcelltherapy.2.ThethreeerasofpharmacologicaldiseaseinterventionDrugshavelongbeenusedasatechnicalmeansofinterveninginthecourseofadiseaseinordertoachieveacure.Writtenbetween221BCE–220CE,HuangdiNeijing(literallytheInnerCanonofHuangdi)holds13prescriptionsforthetreatmentofdiseases.Sincethen,traditionalChinesemedicinepractitionershaveaccu-mulatedrichexperienceinthetreatmentofhumandiseaseswithChinesemedicine.Humanuseofopiumanditsnaturalactiveingredient,morphine,alsohasa5000-yearhistory[2].Withdevel-opmentsinmodernscienceandtechnology,thematerialbasisoftheuseofthisancientempiricaldrughasbeenfullyestablished.Thispaperputsforwardtheconceptofthreeerasofpharmacolog-icaldiseaseinterventionwithafocusonthein?uenceofscienceandtechnologyonhistoricalprogressindruginterventioninhumandisease.Ourpurposeistoanalyzethefar-rangingeffectsofthekeytechnicalmilestonesineachera,andtoidentifythechangingregularityanddevelopmenttrends.Itisnotablethattherelationshipbetweenthethreeerasofpharmacologicaldiseaseinterventionisnotoneofsubstitution;rather,itinvolvessuperim-positionorevenmutualreinforcement.Oneofthemostimportanthistoricaladvancesinmedicineisthediagnosisofdisease,whichcontributestomedicalprogressthroughtwodisciplines:basicmedicineandclinicalmedicine.Accordingtothe10threvisionoftheWorldHealthOrganization’sInternationalClassi?cationofDiseases(ICD)(ICD-10),thereare2468majorcategoriesofhumandiseaseand19707subcategories.Anotherimportantadvanceinmedicineistheuseofdrugtreat-mentfordiseaseintervention.In1763,theBritishclericEdwardStoneextractedsalicinfromwillowbark.In1899,BayerAGinGermanyintroducedthe?rstsyntheticchemicaldrug,aspirin(developedfromsalicin),tothemarket,therebyinitiatingtheeraofchemicalmedicinetreatment—the?rsteraofpharmacologicaldiseaseintervention.2.1.The?rsteraofpharmacologicaldiseaseintervention:ChemicalmedicinetreatmentThemajorcharacteristicsoftheeraofchemicaldrugtherapyarediscussedbelowintermsofdemand,technology,andsociety.2.1.1.Demandfordiseasetreatment:ThedrivingforceforthedevelopmentandapplicationofchemicaldrugsThedemandfordiseasetreatmentdeterminesthetypesandvarietiesofchemicaldrugs,theconcentrationandallocationofresearchanddevelopment(R&D)resources,andthedirectionandfocusofapplication.Changesinthedemandfordiseasetreat-mentalsohaveanimpact.Sincethe19thcentury,andparticularlysinceWorldWarII,improvementsinlivingconditionshavegreatlyimprovedhumanhealthandextendedourlifeexpectancy.Healthcaredevelopments,theuseofvaccinesforlarge-scalepreventionofinfectiousdiseases,andimprovementsinlivingconditionshaverelievedthethreattohumanhealththathaslongbeenposedbyclassicdeadlyinfectious6W.He/Engineering5(2019)5–9diseasessuchassmallpoxandtheplague.However,infectiousdis-easessuchasin?uenza,tuberculosis,andacquiredimmunode?-ciencysyndrome(AIDS)stillthreatenthehealthofpeopleincertaincountriesandregions.Cross-speciestransmissionofmicroorganismsalsothreatensthehealthofpeopleincertainareasbyinfectingpeoplewithavianin?uenzavirusandEbolavirusintheformofemergingandreemerginginfectiousdiseases.Nevertheless,theextensionofhumanlifeexpectancyhascausedtheglobalpopulationtobecomeanagingone.Senescenceisamajorriskfactorindisease.Thus,chronicnon-communicablediseases,suchascancer,cardiovascularandcerebrovasculardis-eases,diabetes,Alzheimer’sdisease,osteoporosis,obesity,andpain,havegraduallybecomethemajorthreattohumanhealthworldwide.ThischangeinthediseasespectrumisaffectingthedirectionandemphasisoftheR&Dofchemicaldrugs.Morethan2600chemicalentitydrugswithdifferentchemicalstructuresarecurrentlyavailableintheworld.Whencombinationsofbasicmolecules,structuralmodi?cations,andsoforthareincluded,therearemorethan10000listeddrugs[2].Thesedrugscanbeusedtotreatmorethan1100majorcategoriesofhumandisease.Atpresent,thehottestareasofresearchandfundingincludecanceranddiabetes,amongothers[3].However,itisclearthattherehasbeeninsuf?cientinvestmentintheR&DofAlzheimer’sdisease,pain,schizophrenia,andmore,dueatleastinparttotheirunclearmechanismsandhighR&Dbusinessrisk.2.1.2.Technologicaldrugresearch:Shiftingfocusfromactivechemicalcomponentstomolecular-targetingreceptorsTheclassicdrugR&Dmodeisbasedonactivechemicalcompo-nents.First,atoxin,herb,orotherplantmaterialexhibitingaphar-macologicaleffectonlaboratoryanimalsisfound,anditsactivechemicalcomponent(orcomponents)isseparated.Next,itsmolecularstructureiscon?rmedandawaytosynthesizethemoleculeisidenti?ed.Finally,thebiologicalactivityofthecom-poundisidenti?ed.Afterthat,themoleculecanbemodi?edtooptimizeitsstructureinordertoreducethedosageandimprovethecurativeeffect.Mostofthefrequentlyused433molecularenti-tiesatpresentwerefoundusingtheclassicdrugR&Dmode.Thismode,whichwasusedinthedevelopmentofchemicaldrugsfromtheearly20thcenturytothemiddleofthe20thcentury,hastwomajordisadvantages:①Thetargetsofthedrugforthemoleculeorcellaremostlyunknown;and②theprocessiscostlyandtimeconsumingduetothestrictrequirementsforapotentialdrug,whichincludealargequantityofsyntheticcompoundsandagreatdealofanimalexperimentation.Infact,receptortheoryandquantitativepharmacologicalanal-ysismethodsofdrugresearchhavealwaysbeenassociatedwiththeclassicdrugR&Dmode,andgraduallybecamethemainstreamofdrugR&Dbythemiddleofthe20thcentury.Receptortheorywas?rstputforwardintheearly19thcenturybytheBritishphys-iologistJohnNewportLangleyandtheGermanimmunologistPaulEhrlich,andhadagreatandfar-reachingimpactondrugdevelop-ment.In1933,AlfredJosephClarkputforwardtheembryonicformof‘‘occupationtheory,”andin1956,RobertP.Stephensonintro-ducedtheconceptof‘‘ef?cacy”andperfectedthetheoryofrecep-toroccupation.In1966,RobertFurchgottproposedtheconceptof‘‘intrinsicef?cacy,”whichseparatedtheeffectivenessoftheorga-nizationalresponsefromtheef?cacyoftheagonistreceptorcom-plex;theconceptof‘‘relativeef?ciency”hassincebeenwidelyusedtodescribedifferentreceptorsystems.Thetwo-statetheory(1957)andratetheory(1961)furtherperfectedthereceptortheoryinregardstotheopeningandclosingoftheionchannelandthedifferenceintheantagonistandagonistrates,whilethestudyofGprotein-coupledreceptorsdevelopedthereceptortheoryintothemorecomplexandelaboratetripartitemultistatereceptorsystem.Inthepastfewdecades,amodelwithdrugmoleculartargetsatitscorehasgraduallyreplacedthetraditional‘‘blackbox”modelintheR&Dofchemicaldrugs.Theimportanceofreceptortheoryinthedevelopmentofchemicaldrugsisthatitcauseschemicaldrugstobemoretargeted;activeresearchinreceptortheory,alongwithincreasedoutput,istakingplaceindrugdevel-opmentforcancerandcardiovasculardiseases.About50kindsofantitumorsmall-molecule-targeteddrugshavebeendevelopedforthetreatmentofcancers;thesehavegoodtherapeuticeffectandfewersideeffectsthanconventionalchemotherapy.Althoughdoctorsandpatientsfavorthesetargeteddrugs,theircostsarehigh.Duetothedif?cultyin?ndingnewdrugtargets,targetingthesamemoleculeorreceptorforanoveldrugisauniversalchar-acteristicintheindustry.2.1.3.Stablegrowthofthepharmaceuticalindustry:Abalancebetweenstrictgovernmentalsupervisionandcontrolandnewhigh-techindustriesAllcountriesadoptstrictregulatorypoliciesandlawsfordrugR&D.Clinicaltrialsinvolvethekeyaspectofsupervision,alongwithafocusonsecurityandeffectiveness.Highriskisaprimaryfeatureofchemicaldrugdevelopment.Itisgenerallybelievedthattheprobabilityofproducingadesiredcompoundis1in5000com-pounds,whileonly10%oftestedcompoundsinclinicaltrialsareapproved[2].Asaresult,drugR&Dhasalongcycleandrequiresahighlevelofinvestment.Ittakes10–15yearstodevelopaninno-vativedrug.Atthebeginningofthe21stcentury,thetotalR&Dexpenditureofaninnovativedrugrequiredabout800millionUSD.Thatcostrosetoabout1billionby2013.TheR&Dofaninno-vativedrugre?ectsadependenceonhigh-techinnovationandtal-ents,theneedforpatent-centricintellectualpropertyrights,andhighlyspecializedpersonnelsupport.Therefore,theR&Dofaninnovativedrugisahighlysystematicwork,andaninsurmount-ableprobleminanylinkofthechainleadstoitsfailure.However,thedevelopmentofinnovativedrugsalsohasahighreturn:Afteranewdrugislisted,ahighincomeisobtained.Ingeneral,drugR&Disdividedbetweensmallcompaniesthatengageinpreclinicalresearchondrugswiththesupportofventurecapital,andbigpharmaceuticalcompaniesthatmergewiththeformerwhentheirclinicaltrialshavegoodprospects.Bayer’stran-sitionfromadyestuffchemicalcompanyintoachemicalpharma-ceuticalcompany120yearsagostartedthedevelopmentofthepharmaceuticalindustry.Theglobaldrugmarkethasexpandedrapidlyoverthepast50years,withitstotalmarketvaluedoublingonaverageeverysixyears[2].In2017,thetotalsalesoftheglobaldrugmarketwere1.128trillionUSDandtheannualgrowthratewas4.81%.Thedrugmarketthusaccountedfor1.5%oftheglobalGDP,withthetop15oftheworld’spharmaceuticalcompaniesaccountingforabout50%ofthemarket.Oftheglobaldrugmarket,40%islocatedinNorthAmerica,22%inEUcountries,20%inChina,8%inJapan,and10%inothercountries.2.2.Theseconderaofpharmacologicaldiseaseintervention:BiopharmaceuticalsIn1922,FrederickGrantBantingandCharlesHerbertBestattheUniversityofTorontodiscoveredinsulinandusedanimal-derivedinsulintotreatdiabeticpatients,therebyinitiatingtheeraofbio-logicaldrugs.In1982,EliLillyandCompanyintroducedrecombi-nanthumaninsulin,theworld’s?rstgeneticallyengineereddrug,intothemarket,thusbringingpharmacologicaldiseaseinterven-tionintothesecondera—thebiopharmaceuticalera,whichintro-ducedchangesintermsofdemand,technology,andsociety.2.2.1.Demand:AddressingmanyrefractorydiseasesThelarge-scaleapplicationoflow-cost,safe,andeffectiverecombinanthumaninsulinhasgreatlybene?tedthemajorityofW.He/Engineering5(2019)5–97diabeticpatients.Furthermore,erythropoietin(EPO)canbeusedforanemiainpatientswithchronicrenalfailure,tissueplasmino-genactivator(tPA)andurokinasecanbeusedtotreatmyocardialinfarction,andgrowthhormone(GH)canbeusedinthetreatmentofdwar?sm.Interferon-bisnowavailableforscleroderma,whichhashadnoeffectivedrugtreatmentforalongtime,andantitumornecrosisfactorantibodydrugscanrelieverefractoryrheumatoidarthritis(RA).AsofJune2016,theUSFDAhadapproved72tar-getedantitumordrugs,including24targetedantibodydrugs.Antibodydrugstargetingimmunecheckpoints—includingtheanti-cytotoxicT-lymphocyte-associatedprotein4(CTLA-4)anti-bodydrugipilimumabofBristol-MyersSquibb(BMS),theanti-programmedcelldeathprotein1(PD-1)antibodydrugspembrolizumabofMerckSharp&DohmeandnivolumabofBMS,andtheanti-programmeddeath-ligand1(PD-L1)antibodydrugatezolizumabofGenentech/Roche—havedemonstratedgoodresultsonsolidrefractorymalignanttumors.Thesebiopharmaceu-ticalsaregenerallysafeandhavebeenshowntohaveacurativeeffect,withmorethan30%ofpatientsresponding[3].2.2.2.Technology:AcleartargetBiopharmaceuticalshavecleartargetsandaclearmechanismofaction.Theirhighselectivityavoidsthesideeffectscausedby‘‘off-target”toxicity.Therefore,theyaresaferthansmall-moleculechemicaldrugs.Inparticular,antibodydrugsarehighlyfavoredbyresearchersduetotheirspeci?citytoantigens.2.2.3.Society:MonoclonalantibodiesasadrivingforceforthedevelopmentofbiologicaldrugsAntibodydrugsarehighlytargetedandhavelittleclinicalriskoffailure.Comparedwithsmall-moleculechemicaldrugs,thedevel-opmenttimeofanantibodydrugisshort,thecostislow,andthemarketisgrowingrapidly.Therefore,antibodydrugshavebeenthefocusofR&Dinlargepharmaceuticalcompaniesaswellasinsmallandmedium-sizeddrugR&Dcompanies,andtheirprospectsarepromising.2.3.Thethirderaofpharmacologicaldiseaseintervention:CelltherapyToday,pharmacologicaldiseaseinterventionhasenteredthethirderaofcelltherapy.First,letustakealookbackatthemajormilestonesofthisera.Whenbonemarrowtransplantationwascarriedoutinthe1980s,Tcellswereinadvertentlydiscoveredtohavetherapeuticuses.Tcellsinwhole-bonemarrowgraftsshowantitumoractivity.However,adoptiveTcelltransfer(ACT)notonlycausesagraftantitumorresponse,butalsoinducesgraft-versus-hostdisease(GVHD)[4].InviewofthesideeffectsofallogeneicTcells,researchershaveturnedtheirattentiontoautologousTcells.Inthisregard,StevenRosenbergattheUSNationalCancerInstitute(NCI)isapioneerinthetreatmentofcancerwithACT.In1986,Rosenberg’steam?rstconductedtheautotransfusionoflymphokine-activatingkiller(LAK)cellswithinterleukin-2(IL-2)inthetreatmentofmetastatictumorpatients[5].High-doseIL-2injectioncanresultincapillaryleaksyndromeinpatients,whichstoppedtheclinicaluseofLAKcellinfusion.During1987–1994,Rosenberg’steamconductedaseriesofstudiesontumor-in?ltrat-inglymphocytes(TIL)inthetreatmentofmetastaticmelanoma.Onestudywith88casesshowedaneffectiverateof34%[6].ThepreparationforTILiscomplex,andthepolyclonalcharacteristicsofTILmakeitdif?culttofullyre?ectitstumorspeci?city.In2006,Rosenberg’steamreportedforthe?rsttimethatTcellsmod-i?edbyaTcellreceptor(TCR)speci?ctothetumor-associatedmelanomaantigenrecognizedbyTcells1(MART-1)couldbeadoptedforthetreatmentofcancerpatients[7].Thistumor-speci-?cautologousTcellgene-engineeringtechniquecandevelopso-calledgeneticallyengineeredTCR-Tcells,inparallelwithCAR-Tcelltechnology.ThesetechnologiesrepresenttwodirectionsofTcellengineeringforcancertreatment.TCR-Tcelltechnologyiscur-rentlywidelystudiedinclinicaltrialsinthe?eldofsolidmalignan-cies.TargetingNY-ESO-1withTCR-Tcellshasattractedwidespreadattentionduetoitswideanti-tumorspectrumandfewtoxicsideeffects.Somescholarshopethatthistechniquecanbeaimedatthefrequentoccurrenceofmutatedantigensduringthedevelopmentofmalignanttumors,makingtheindividualizedtreatmentoftumorsmorespeci?c.In1989,Eshharetal.[8],agroupofIsraeliscientists,reportedforthe?rsttimeaCARwithantibodyspeci?city.In2011,Juneetal.[9]oftheUniversityofPennsylvaniareportedtheuseofCAR-Tcellsforchroniclymphocyticleukemia(CLL)inthetreat-mentofBcelllymphomasinthebloodsystemwithCD19target-ing.Multiplelaboratories,includingthoseofSadelainetal.[10]attheMemorialSloan-KetteringCancerCenterin2013,Gruppetal.[11]attheUniversityofPennsylvaniain2014,andTurtleetal.[12]attheFredHutchinsonCancerResearchCenterin2016,havereportedtheuseofCAR-TcellsforALL;thistreatmenthasyieldedahighrateofresponse(70%–90%)andhashadadur-ableeffect.InAugust2017,NovartislaunchedCAR-TcelltechnologyasaKymriahproduct;asthe?rstFDA-approvedCAR-Tcelltechnology,thisproductusheredinaneweraofcelltherapyapplication.InOctoberofthesameyear,theUSpharmaceuticalcompanyKitePharmatargetedCD19CAR-Tcelltherapy(Yescarta,axicabtageneciloleucel);theUSFDAapprovedthistherapyforsecond-linether-apyoradditionalroundsoftreatmentforadultswithrecurrentorrefractorylargeBcelllymphoma.DespitetheriskofserioussideeffectsintheuseofCAR-Tcelltherapy,theUSFDAhascarefullyandconditionallyapprovedthislandmarktechnology.Changeshavealsooccurredinthedemand-related,technologi-cal,andsocialcharacteristicsofpharmacologicaldiseaseinterven-tionintheeraofcelltherapy,asrepresentedbyCAR-Tcelltherapy.2.3.1.Demand:TacklingmorecomplexandrefractorydiseasesKymriahisadaptabletorefractoryorrecurrentALL,andthesameistrueofYescartatreatmentforlargeBcelllymphoma.Theindicationsofthesetreatmentsarebasicallyfailedcasestrea-tedbychemotherapy,targeteddrugs,andbonemarrowtransplan-tation;therefore,KymriahandYescartabelongtoasecond-lineorthird-linetherapyscheme.OngoingresearchprojectsarefocusingonrefractoryBurkitt-likeleukemia/lymphoma(BLL)andmultiplemyeloma.Ofcourse,thevalidityoftheapprovedCAR-Tcellther-apyislimitedtomalignantBcelllymphomasinthebloodsystem.Aneffectivetreatmentstrategyhasnotyetbeenfoundformostmalignanttumorsinvolvingnon-Bcelllymphomasinthebloodsystem,orforsolidtumors.2.3.2.Technology:Strategiesbasedoncellsascarriers,syntheticgene-expressedproteins,andotherkeytechnologiesTechnologicalstrategiesforpharmacologicaldiseaseinterven-tioninthethirderaaresupportedbytheuseofcellsasdrugdeliv-erycarriers,syntheticgene-expressedproteinsasactionmolecules,andkeytechnologiesfromcellengineering,antibodyengineering,geneticengineering,andsyntheticbiologytech-niques.CelltherapyusestheTcell,whichcanproliferateinvitroasaneffectorcell.Inthisway,itsolvestheproblemthatmostmaturenormalsomaticcellscannotbeampli?edinvitro,andhasthereforebecomeamodelforthesuccessfulapplicationofcellengineeringinhumans.Cellinfusionandcelltherapyef?cacyarebasedoncellengi-neering.Tcellsarechosenaseffectorcellsbecausetheycanproliferateinvitro.CAR-Tcelltherapyviaantibodyengineeringtechnologyusesmonoclonalantibodyfragmentsastargetedmole-culesfortreatment,thusgivingfullplaytotheadvantageofthe8W.He/Engineering5(2019)5–9highantigenspeci?cityofmonoclonalantibodies.InCAR-Tcelltechnology,aTcellsurfacereceptorgenehasbeensuccessfullysynthesizedbymeansofgeneticengineeringandsyntheticbiolog-icaltechniques;thegeneisthentransfectedintothepatient’sownTcellsbyaretrovirusorlentivirusvectorinvitro.Asaresult,theextracellularfragmentoftheCAR-Tcellisaspeci?cantibodythatcantargettheantigenonthetumorcells,whereastheintracellularfragmentofthecelliscomprisedofnormalmoleculesthatcanmediateTcellsignaltransductionandTcellactivation,thuskillingthetumorcell.ThissyntheticCARcanberegardedasaninnovativeapplicationofdrugreceptortheoryinthe21stcentury.Inthisway,celltherapybuildsonpracticalsupportfromgeneticengineeringandsyntheticbiologytechniques,andreceivestheoreticalsupportfromoncologyandtumorimmunology.2.3.3.Society:Governmentandsocietalresponsetothehigh-riskchallengesofnewCAR-TcelltherapytechnologiesCAR-Tcelltherapywas?nallylaunched,largelyduetoitsuseasaneffectivetreatmentforrefractorycancers.Aninitial,typicalcasebroughtthisnewtechnologyintoprominence.InApril2012,asix-year-oldgirlnamedEmilyWhitehead,whohadALL,wascontinu-ingtogetworseaftertworoundsofchemotherapy.SheacceptedCAR-TcelltherapyfromtheJune’steam.ThetreatmentproducedastrongsideeffectonEmily—somuchsothatshewasunconsciousatonetime.Later,however,sherevivedandrecovered.Subsequentbonemarrowexaminationrevealedthathertumorcellshadmiraculouslydisappeared.Researcherslaterdiscoveredthatthissideeffectismainlycausedbycytokinereleasesyndrome(CRS).In2014,NCIpediatriccliniciansintheUnitedStatesusedanti-IL-6antibodies—adrugforrheumatoidarthritis—totreatCRS,andachievedgoodresults[13].Inasense,withthepositivecoopera-tionofpatientsandtheirfamilies,doctorsandscientistshaveengagedinclinicaltrialsinordertocontinuetocarryoutinnova-tiveexplorationbasedonproblemsolving.Thishasbeenanimportantscienti?candtechnologicalfactorinthesuccessofCAR-Tcelltherapy,andhaslaidasolidfoundationforregulatoryscience.Nevertheless,innovationingovernmentregulationremainsakeyfactorinthesuccessofCAR-Tcelltherapy.CAR-TcelltherapytargetingtheCD19moleculehasbeenusedinthetreatmentofBcelltumors.Threepharmaceuticalcompa-niesledthiswork:abigpharmaceuticalcompany,Novartis,workingincooperationwithJune’steam;asmallcompany,KitePharma,workinginpartnershipwithRosenberg’steam;andanothersmallpharmaceuticalcompany,JunoTherapeutics,work-ingwithSadelain’steam.In2016,withintheJCAR015clinicaltrialoftheJunoTherapeuticsforALL,?vepatientsdiedofcere-braledema.InJulyofthesameyear,theprojectceasedcarryingoutclinicaltrials,andinMarch2017,JunoTherapeuticsannouncedtheterminationoftheJCAR015project.Althoughtheproductsoftheothertwocompanieswereeventuallylisted,theUSFDAtooktwoimportantmeasuressimultaneouslywhenKymriahwasapproved,asCAR-TcellscancausefatalCRSandcertainsideeffectsofnervoussystemtoxicity.First,thescopeofindicationsoftheanti-IL-6antibodydrugActemra(tocilizu-mab)wasexpandedinthetreatmentofCRSinducedbyCAR-Tcelltherapy.Second,ariskevaluationandmitigationstrategy(REMS)forKymriahproductswasestablishedthatisinitiatedasrequired,andincludeselementstoassuresafeuse(ETASU).Itsproceduresalsoincluderelevanttechnicalrequirementsforclinicalmedicalinstitutionsandpersonnelresearchers,inordertoensurethatthebene?tsoftheproductsaregreaterthantherisks.TheUSFDAgrantedKymriahthedesignationsPriorityReviewandBreakthroughTherapy,thusensuringthatitwillnotonlybelistedassoonaspossible,butwillalsoinvolveriskcontrol.3.Prospectsforcelltherapy3.1.GeneticengineeringimmunocytotherapydevelopmentGeneticengineeringimmunocytotherapywillbedevelopedincombinationwithothertherapiesinamulti-targetdirectionwithdynamictargeting,anexpandingscope,andfunctionoptimization.CelltherapyhasbeenderivedfromimmuneTcellsforcancerimmunotherapy.Intheforeseeablefuture,celltherapywillbefur-therdevelopedintheareaofimmunotherapyforcancers.Here,thefocuswillbeontargetingmalignantsolidtumors,inwhichtheselectionoftheappropriatetargetisakeyfactor.Thistherapeuticstrategymaybecombinedwithchemotherapyandtargetedther-apyinordertoattainbetterresults.Consideringthepolygeniccor-relationofcancers,multi-targetingmaybethedesignchoiceforthenextgenerationofgeneticallyengineeredimmuneeffectorcells.Duetotumorheterogeneityandmutation,dynamictargetingstrategiesmayberequiredindifferenttreatmentphases.Inaddi-tion,celltherapywillexpandinthetreatmentofdiseases.Autoim-munediseases,infections,in?ammation,degenerativediseases,and?brosismayallbecomenew?eldsforcelltherapy[14].Fur-thermore,thefunctionofgeneticallyengineeredimmunecellswillbeoptimized,forexamplebyreducingthereleaseofharmfulcytokinesandcausingcellstolivelongerinvivo.3.2.Activecelltherapydevelopmentinintelligence,automation,andfacilitationActivecelltherapyisanimportantstartingpointforthedevel-opmentofprecisionmedicine.Usingcellsascarriersresultsinacomprehensiveperformancethatismuchbetterthanthoseofsingle-chemicalandbiologicaldrugs.Cellscanachieveintelligentfunctions,suchasdirectionalmigrationandaggregation,orcelldeathafterthecompletionoftherole,thusdrivingacertainfunc-tionatagivenstage.Theautomationofcellproductioninvitroisalsoatrend.Arti?cialintelligenceandautomationcanbeusedtoachievethecollectionofcells,culture,infusion,andothercompo-nentsofautomation,thusreplacingmanuallabor.Celltherapyhasmadeindividualizedmedicinepossible,andhasbecomeanimportantstartingpointforthedevelopmentofprecisionmedicine.3.3.LivecelltherapychallengesthegovernmentregulatorysystemandbringsopportunitiesforreformanddevelopmentThequestionofwhethercelltherapyisatechnologyoradrughasalwaysbeenacontroversialone.Ifagovernmentregulatorysystemisdrug-based(asitisinmostcountries),thenhowcanamulti-targetcontinuallyadjustingtreatmentregimenbeapprovedandregulated?Perhapsaninnovativesupplysystemwillvigor-ouslypromotetherapiddevelopmentofcelltherapy,andtherebybene?tallofhumanity.References[1]FDAapprovalbrings?rstgenetherapytotheUnitedStates[Internet].SilverSpring:USFoodandDrugAdministration;2017Aug30[updated2018Mar26;cited2018Jul22].Availablefrom:https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm.[2]BartfaiT,LeesGV.Drugdiscovery:frombedsidetoWallStreet.Burlington:AcademicPress;2006.[3]BartfaiT,LeesGV.Thefutureofdrugdiscovery:whodecideswhichdiseasestotreat?Burlington:AcademicPress;2013.[4]FerraraJL,DeegHJ.Graft-versus-hostdisease.NEnglJMed1991;324(10):667–74.[5]RosenbergSA,SpiessP,LafreniereR.Anewapproachtotheadoptiveimmunotherapyofcancerwithtumor-in?ltratinglymphocytes.Science1986;233(4770):1318–21.W.He/Engineering5(2019)5–9[6]RosenbergSA,PackardBS,AebersoldPM,SolomonD,TopalianSL,ToyST,etal.Useoftumor-in?ltratinglymphocytesandinterleukin-2intheimmunotherapyofpatientswithmetastaticmelanoma.Apreliminaryreport.NEnglJMed1988;319(25):1676–80.[7]MorganRA,DudleyME,WunderlichJR,HughesMS,YangJC,SherryRM,etal.Cancerregressioninpatientsaftertransferofgeneticallyengineeredlymphocytes.Science2006;314(5796):126–9.[8]GrossG,WaksT,EshharZ.Expressionofimmunoglobulin-T-cellreceptorchimericmoleculesasfunctionalreceptorswithantibody-typespeci?city.ProcNatlAcadSciUSA1989;86(24):10024–8.[9]KalosM,LevineBL,PorterDL,KatzS,GruppSA,BaggA,etal.Tcellswithchimericantigenreceptorshavepotentantitumoreffectsandcanestablishmemoryinpatientswithadvancedleukemia.SciTranslMed2011;3(95):95ra73.9[10]BrentjensRJ,DavilaML,RiviereI,ParkJ,WangX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药物干预进入细胞疗法的第三纪元
