Natural killer cell therapy in children with relap

NaturalKillerCellTherapyinChildrenwithRelapsedLeukemiaJeffreyE.Rubnitz,MD,PhD,HirotoInaba,MD,PhD,GuolianKang,MS,KwanGan,RN,ChristineHartford,MD,BrandonM.Triplett,MD,MariDallas,MD,DavidShook,MD,TanjaGruber,MD,PhD,Ching-HonPui,MD,andWingLeung,MD,PhDDepartmentsofOncology,BoneMarrowTransplantationandCellularTherapy,Biostatistics,andPathology,St.JudeChildren’sResearchHospital;andDepartmentofPediatrics,UniversityofTennesseeHealthScienceCenter,CollegeofMedicine,Memphis,TennesseeAbstractBackground—Noveltherapiesareneededforchildrenwithrelapsedorrefractoryleukemia.Wethereforetestedthesafetyandfeasibilityofhaploidenticalnaturalkillercelltherapyinthispatientpopulation.Procedure—Twenty-ninechildrenwhohadrelapsedorrefractoryleukemiaweretreatedwithchemotherapyfollowedbytheinfusionofhaploidenticalNKcells.Cohort1included14childrenwhohadnotundergonepriorallogeneichematopoieticcelltransplantation(HCT),whereasCohort2included15childrenwithleukemiathathadrelapsedafterHCT.Results—Twenty-six(90%)NKdonorswereKIRmismatched(14withoneKIRand12with2KIRs).ThepeakNKchimerismlevelswere10%donorin87%oftheevaluablerecipients.InCohort1,10hadresponsivediseaseand12proceededtoHCTthereafter.Currently,5(36%)arealivewithoutleukemia.InCohort2,10hadresponsivediseaseafterNKtherapyandsuccessfullyproceededtosecondHCT.Atpresent,4(27%)arealiveandleukemia-free.TheNKcellinfusionsandtheIL-2injectionswerewell-tolerated.Conclusions—NKcelltherapyissafe,feasible,andshouldbefurtherinvestigatedinpatientswithchemotherapy-resistantleukemia.KeywordsNKcell;childhoodleukemia;relapse;celltherapyCorrespondingAuthor:JeffreyE.Rubnitz,MD,PhD;St.JudeChildren’sResearchHospital,262DannyThomasPlace,Memphis,TN38105-2794([e-mail]).Phone:[phone],FAX:[phone].DisclosureofConflictofInterest:Theauthorsdeclarenoconflictsofinterest.AUTHORSHIPCONTRIBUTIONSW.L.,H.I.,andJ.R.designedthestudy,analyzedandinterpreteddata,andwrotethepaper.G.L.performedstatisticalanalyses.W.L.,H.I.,K.G.,C.H.,B.M.T.,M.D.,D.S.,T.G.,andC-H.Pprovidedstudymaterialandpatientinformation,andcontributedtotheinterpretationofdata.W.L.,H.I.,andJ.Rdraftedthepaper.Allauthorscontributedtotherevisionsofthedraftandapprovalofthefinalmanuscript.Theauthorsdeclarenoconflictsofinterest.HHSPublicAccessAuthormanuscriptPediatrBloodCancer.Authormanuscript;availableinPMC2015November05.Publishedinfinaleditedformas:PediatrBloodCancer.2015August;62(8):1468–1472.doi:10.1002/pbc.25555.AuthorManuscriptAuthorManuscriptAuthorManuscriptAuthorManuscriptINTRODUCTIONChildrenwithnewlydiagnosedacutelymphoblasticleukemia(ALL)oracutemyeloidleukemia(AML)experiencelong-termdiseasefreesurvivalratesgreaterthan80%and60%,respectively,whentreatedoncontemporaryclinicaltrials.[1–9]However,theoutcomeofpatientswithrefractoryorrelapseddiseaseremainspoor,withsurvivalratesoflessthan40%.[10–14]ExceptforthesmallgroupofpatientswithlaterecurrencesofB-lineageALL,childrenwithrelapsedALLorAMLareunlikelytobecuredwithchemotherapyalone,andhematopoieticcelltransplantation(HCT)isthetreatmentofchoice.[15,16]ThedevelopmentofnovelmethodsofgraftpreparationhasledtohighsuccessratesofHCTinchildrenregardlessofmatcheddonoravailability.[17–19]Inaddition,modernsupportivecaremeasureshavereducedtheriskofdeathrelatedtoregimentoxicity,infection,andgraft-versus-hostdisease(GVHD)tolessthan15%.Nevertheless,HCTisnotalwayssuccessful,asleukemiarelapseremainscommon.Inthisregard,themostpowerfulpredictorofrelapseafterHCTisthelevelofminimalresidualdisease(MRD)atthetimeoftransplantation.[20–22]Inthishighrisk,oftenheavilypretreatedpediatriconcologypopulation,additionalattemptsatMRDreductionwithchemotherapycombinationspriortoHCTordoseescalationofconditioningchemotherapyduringHCTareunlikelytoimproveoutcomeandmaycontributetooverallmorbidityandmortality.Therefore,newtherapeuticstrategiesthathavenon-crossresistantmechanismsofactionandnooverlappingtoxicitiesaredesirable.[23]Onesuchapproachisimmunotherapywiththeuseofallogeneicnaturalkiller(NK)cells.NKcellscantargetandkillleukemiacellswithoutpriorexposuretothosecells.[24]InthesettingofallogeneicHCT,severalstudieshavedemonstratedthepowerfuleffectofNKcellsagainstleukemia.[25–30]Recently,wedemonstratedthatinfusionsofhaploidenticalNKcellsinpatientswithAMLwerewelltoleratedandvoidofGVHD.[31]Inthepresentstudy,weinfusedhaploidenticalNKcellsfromparentaldonorsto29patientswithrelapsedorrefractorychildhoodleukemia.Thesafety,feasibilityandoutcomestronglysupportfurtherinvestigationsintotheuseofNKcellsinfrontlineleukemiatreatments.METHODSPatientsTwocohortsofpatientsweretreatedwithhaploidenticalNKcells.ThefirstcohortincludedpatientswhohadrefractoryleukemiaandhadnotreceivedpriorHCT.ThesecondcohorthadleukemiathathadrelapsedafterpriorallogeneicHCT.Availabilityofmatcheddonorswasnotanexclusioncriterion;thesepatientswereeligibletoproceedtoHCTwithamatcheddonoriftheyhadstableorresponsivediseaseafterthehaploidenticalNKcelltherapy.ConditioningandNKcellpurificationPatientswereenrolledontheSt.JudeNKAMLorNKHEMprotocols(ClinicalTrials.govNCT00697671andNCT00187096)a