T-VEC的相关研究

ORIGINALARTICLE–MELANOMASPatternsofClinicalResponsewithTalimogeneLaherparepvec(T-VEC)inPatientswithMelanomaTreatedintheOPTiMPhaseIIIClinicalTrialRobertH.I.Andtbacka,MD,CM,FACSFRCSC1,MerrickRoss,MD2,IgorPuzanov,MD,MSI,FACP3,MohammedMilhem,MD4,FrancesCollichio,MD5,KeithA.Delman,MD,FACS6,ThomasAmatruda,MD7,JonathanS.Zager,MD,FACS8,LeeCranmer,MD,PhD9,EddyHsueh,MD10,LisaChen,PhD11,MarkShilkrut,MD,PhD11,andHowardL.Kaufman,MD,FACS121HuntsmanCancerInstitute,UniversityofUtah,SaltLakeCity,UT;2UniversityofTexasMDAndersonCancerCenter,Houston,TX;3VanderbiltUniversityMedicalCenter,Nashville,TN;4UniversityofIowaHospitalsandClinics,IowaCity,IA;5UniversityofNorthCarolina,ChapelHill,NC;6EmoryUniversity,Atlanta,GA;7MinnesotaOncology,Fridley,MN;8MoffittCancerCenter,Tampa,FL;9UniversityofWashingtonSchoolofMedicine,Seattle,WA;10SaintLouisUniversityCancerCenter,StLouis,MO;11AmgenInc.,ThousandOaks,CA;12RutgersCancerInstituteofNewJersey,Rutgers,NJABSTRACTPurpose.Talimogenelaherparepvec(T-VEC)isanonco-lyticimmunotherapydesignedtoinducetumorregressionofinjectedlesionsthroughdirectlyticeffects,andofuninjectedlesionsthroughinductionofsystemicantitumorimmunity.Inthisstudy,wedescribethepatternsandtimecourseofresponsetoT-VECfromthephaseIIIOPTiMtrialof436patientswithunresectedstagesIIIB–IVmelanoma.Methods.Lesion-levelresponseanalyseswereperformedbasedonthetypeoflesion(injectedoruninjectedcuta-neous,subcutaneous,ornodallesions;orviscerallesions[uninjected]),andthebestpercentagechangefrombaselineofthesumofproductsofthelongestdiameterswascal-culated.PatientsrandomizedtoT-VEC(n=295)whoexperiencedadurableresponse(continuouspartialorcompleteresponseforC6months)wereevaluatedforprogressionpriortoresponse(PPR),definedastheappearanceofanewlesionor[25%increaseintotalbaselinetumorarea.Results.T-VECresultedinadecreaseinsizebyC50%in64%ofinjectedlesions(N=2116),34%ofuninjectednon-viscerallesions(N=981),and15%ofviscerallesions(N=177).Completeresolutionoflesionsoccurredin47%ofinjectedlesions,22%ofuninjectednon-vis-cerallesions,and9%ofviscerallesions.Of48patientswithdurableresponses,23(48%)experiencedPPR,including14whodevelopednewlesionsonly.Nodiffer-enceinoverallsurvivalwasobserved,andmediandurationofresponsewasnotreachedinpatientswithPPRversusthosewithoutPPR.Conclusions.ResponsesinuninjectedlesionsprovidevalidationofT-VEC-inducedsystemicimmunotherapeuticeffectsagainstmelanoma.PPRdidnotnegativelyimpacttheclinicaleffectivenessofT-VEC.Immunotherapieshaveproventobepowerfulandeffectivetreatmentsforpatientswithadvancedmelanoma.Talimogenelaherparepvec(T-VEC)isaherpessimplexvirus(HSV)type1-basedoncolyticimmunotherapydesignedtoreplicateselectivelyintumorsandproducehumangranulocyte–macrophagecolony-stimulatingfactor(GM-CSF).1,2IntherandomizedphaseIIIOPTiMtrialofpatientswithunresectablestageIIIB–IVmelanoma,intralesionalT-VECadministrationyieldedanimprove-mentintheprimaryendpointofdurableresponserate(DRR;definedasaresponsebeginninginthefirst12monthsoftreatmentandlastingatleast6monthscon-tinuously)versussubcutaneousadministrationofGM-CSFElectronicsupplementarymaterialTheonlineversionofthisarticle(doi:10.1245/s10434-016-5286-0)containssupplementarymaterial,whichisavailabletoauthorizedusers.TheAuthor(s)2016.ThisarticleispublishedwithopenaccessatSpringerlink.comFirstReceived:6July2015;PublishedOnline:24June2016R.H.I.Andtbacka,MD,CM,FACSFRCSCe-mail:[e-mail](2016)23:4169–4177DOI10.1245/s10434-016-5286-0(16vs.2%;oddsratio8.9;p\0.0001).3Overallresponserate(ORR)was26%[11%completeresponse(CR)]inpatientstreatedwithT-VEC,and6%(1%CR)inpatientstreatedwithGM-CSF.Medianoverallsurvival(OS;asecondaryendpoint)intheT-VECarmwas23.3versus18.9monthsintheGM-CSFarm(hazardratio[HR]0.79,95%confidenceinterval[CI]0.62–1.00;p=0.051).3T-VECmayinducetumorregressionboththroughdirectlyticeffectsfollowingintratumoralinjectionintotumorsandthroughsecondaryinductionofsystemicantitumoralimmunityinthecontextofvirallymediatedGM-CSFproduction.1,4Thedirectlyticeffectsareexpectedtomediaterapidtumorresponsesininjectedlesions.Induc-tionofsystemicimmunitymayrequiremoretimetoprimeantigen-specificTcellresponses,butcouldleadtoregressionofuninjectedtumorsharboringsharedtumor-derivedantigenswithinjectedlesions.Similardynamicsofantitumorresponsehavebeenproposedforotherimmunotherapeuticagents,suchaswithPD-1pathwayinhibitors5–7andanti-CTLA-4inhibitors,6,7withsomepatientsexperiencingtumorprogressionpriortoeventualregression.Thus,theonsetofimmune-mediatedtumorresponsesmaybedelayedcomparedwiththeimmediateeffectsofcytotoxicagentsandtyrosinekinaseinhibitors.SinceresponsestoT-VECinuninjectedsitesweredocumentedinsomepatientswithmelanomainphaseIandIIstudies,2,4wesoughttovalidate,quantify,andcharac-terizethesystemiceffectsofT-VECinpatientsinOPTiM.WecomparedresponsepatternsofinjectedanduninjectedtumorsinT-VEC-treatedpatientsandconductedananal-ysisofoverallresponsestoassesswhetherT-VEC,aswithotherimmunotherapies,inducesdelayedantitumorresponses.MATERIALSANDMETHODSOPTiMTrialDesignandTreatmentInthisopen-la