potential for hiv cure by stem cell transplantation icistem · monique nijhuis university medical...

PotentialforHIVCurebystemcelltransplantation

IciStem

MoniqueNijhuisUniversityMedicalCenterUtrecht

theNetherlands

StemcelltransplantationinHIVpatients

•  PeoplelivingwithHIVhaveahigherriskforhematologicalmalignancies,suchasacutemyeloidleukemia(AML),orlymphoma‘sandoftenrequireatransplantationwithdonorstemcells(allogeneicstemcelltransplantation,allo-SCT)

•  PeoplelivingwithHIVhaveanloweroverallsurvivalrateafterallo-SCTascomparedtoamatchedcontrolgroupofHIVnegativeindividuals

Suttonetal,BrJHematol2001;Hutteretal,aidsResTher2016;Kaneretal,Blood2016;Aboulafiaetal,AIDS2002;RyuInternMed2001

TimothyBrown,thesocalled“Berlinpatient”wascuredfrombothAMLandHIV-infectionafterallo-SCTwithCCR5Δ32donorcells(12yearsago)

Specialaboutthesecells?

CellentryinCCR5WTcells:

Dominantrouteofinfection

HIVcellentry:CCR5WTcells

CellentryinCCR5Δ32cells:

Dominantrouteofinfection

HIVcellentry:CCR5Δ32cells

X

AlternativerouteofentryX

•  “Berlinpatient”:diagnosedwithAMLandtransplantedtwicewithCCR5Δ32donorcells1

•  Transplantedin2007,receivedtotalbodyirradiationandseverechemotherapy

• StoppedcARTatthemomentofthefirstallo-SCTandnoviralreboundoccurred•  Priortoallo-SCTafewvirusvariantspredictedtousetheCXCR4coreceptor•  LaboratoryanalysesdemonstratedthatthesevariantsstilldependedonCCR5

forviralentryandcouldnotinfectthedonorcellsofthe“BerlinPatient2

1Hutteretal,NEJM,2008;2Symonsetal,CID,2014;3Kordelasetal,NEJM,2014

TreatmentinterruptioninHIVpatientstransplantedwithCCR5Δ32stemcells

Oneotherpatientdescribed,thesocalled“Essenpatient”whostoppedcARTduringallo-SCTusingCCR5Δ32donorcells3

•  “Essenpatient”:diagnosedwithanaplasticlarge-celllymphomaandtransplantedwithCCR5Δ32donorcells1

•  27yearoldHIV-1infectedpatienttransplantedin2012

•  Successfulengraftment

•  cARTinterruption7daysbeforetransplantation

•  Reboundofvirus3weeksaftertransplantation

•  Laboratoryanalysesrevealedthiswasrelatedtopre-existingCXCR4-tropic4

1Kordelasetal,NEJM,2014;4Verheijenetal,CID,2018

TreatmentinterruptioninHIVpatientstransplantedwithCCR5Δ32stemcells(peri-SCT)

•  BostonPatients:transplantedwithCCR5WTdonorcells1

-Afterallo-SCT:noHIVDNAandinfectiousvirusdetectedinbloodandrectaltissue-2.6-4.3years:ATIandviralreboundwasobservedafter12,32weeks- ReboundviruswasrelatedtoviralPBMCDNAsequencesobservedbeforeallo-SCT

•  MinnesotaCase:transplantedwithCCR5WTdonorcells2

- Afterallo-SCT:HIVDNA+/-detectableinPBMCs,noinfectiousvirusdetectedinblood- Insituhybridizationwasnegativeincolon- 2.1years:ATIandviralreboundwasobservedafter41weeks- ReboundvirusisphylogeneticdistinctfromcirculatingPBMCspriortoallo-SCT

1Henrichetal,Ann.Intern.Med.,2014;2Cumminsetal,PLoSMedicine,2017

TreatmentinterruptioninHIVpatientstransplantedwithCCR5WTstemcells(post-SCT)

• RaisingtheQuestion:Whatwerethedeterminantforcureinthe“BerlinPatient”?

-  “BerlinPatient”hadinheritedalreadyoneCCR5Δ32genedefectfromoneofhisparents

-CCR5Δ32donorcells-  Receivedtwotransplants

-  Totalbodyirradiation

-  Conditioningregime,severechemotherapy

-  MildGraftversusHostDisease

Whatwerethedeterminantsforcureinthe“BerlinPatient”

IciStemConsortium

InternationalcollaborationtoguideandinvestigatethepotentialforHIVcureinHIV-

infectedpatientsrequiringallogeneicstemcelltransplantationforhematological

disorders

AIM1Toguideclinicians involved inallogeneicSCT procedures in HIV infectedindividuals

AIM2To better understand the underlyingbiological processes leading to viralreservoirreductionandpotentialcasesofHIV-1eradication/remission.

www.icistem.orgPrincipalInvestigators:JavierMartinezPicadoAnnemarieWensing

OverviewofCCR5Δ32donorsearch

•  45patientsregisteredfrom9differentcountries•  39patientshavebeentransplanted;26patientsarestillalive•  Medianfollow-up:1707days(>4.5years)

19patientsbeyond1thyearpost-SCT

Overviewofregistration

CCR5WTorheterozygous CCR5Δ32Adultdonor

UmbilicalCord29 7

1 2

36

330 9

alive 22 4

alive

251

IciStemConsortiumInternationalcollaborationtoguideandinvestigatethepotentialforHIVcureinHIV-

infectedpatientsrequiringallogeneicstemcelltransplantationforhematological

disorders

AIM1Toguideclinicians involved inallogeneicSCT procedures in HIV infectedindividuals

AIM2To better understand the underlyingbiological processes leading to viralreservoirreductionandpotentialcasesofHIV-1eradication/remission.

www.icistem.orgPrincipalInvestigators:JavierMartinezPicadoAnnemarieWensing

Developmentofultra-sensitivetechniques•  ManydifferentHIV-1variantscanbeobservedworldwideandhaveaslightlydifferentgenome;importantforallthegenomebaseddetectionmethods

•  SinglecopyofHIVRNAin10mLofplasmaorCSF1•  SinglecopyofHIVDNAinmillionsofcells2

•  Singleinfectiousvirusinmillionsofcells(PBMCorhumanizedmouseviraloutgrowthassay)3

1Duarteetal,LancetHIV,2015;2Bosmanetal,JIAS,2018;Metcalfetal,JID,2015

HIVReservoir

Blood

Leukapheresis

CSF

Lymphnode

Ileumbiopsy

BoneMarrow

Analysesofthedynamicsoftheviralreservoir

Analysesofthedynamicsoftheviralreservoir

•  Onlycurativeinterventioninwhichareductionoftheviralreservoirisobserved

•  Inthepresenceofantiretroviraltherapy

•  NodifferencebetweenpatientsreceivedCCR5WTcellsorCCR5Δ32donorcells

IciStemPatient HSCT Yearof

transplant

Singlecopyassay(HIV-RNAcp/ml)

TotalDNA(cp/106CD4)

qVOAinCD4(IUPM)

Ileum,CSF,LN,BM

1 CCR5WT 2012 5 25 0.034 -

3 CCR5WT 2013 undetectable undetectable undetectable undetectable


17CCR5WT 2010 undetectable undetectable undetectable undetectable

27CCR5WT 2009 undetectable undetectable undetectable undetectable


Summary

•  IciStemhasidentified>22.000CCR5Δ32donorsthatcanbeusedforallo-SCT

•  IciStemhascompiledthelargestregistryofallo-transplantsinpeoplelivingwithHIV•  Clinicalinformation•  Clinicalsamples

•  Developedanarrayofultra-sensitivetechniquestoanalysetheviralreservoir

•  Afterallo-SCT,asharpdeclineinHIVDNAintheblood,CSFandtissueisobservedtobelowthelevelofdetectioninmosttransplantedpatients

Directions:

• PatientstransplantedwithCCR5WTdonorcellsarecandidatesforATIwithcureintervention

•  Clinicallystable;>2yearsposttransplant;>1yearpostimmune-suppression•  Undetectableviralreservoirinblood,CSFandtissue•  2019:include5patientswhowillreceivebroadlyneutralizingantibodiesfor8months•  Additionalfollow-upof10months

• PatientstransplantedwithCCR5Δ32donorcells•  Fourpatientsarealive•  DataontwopatientsaregoingtobepresentedatCROIaslatebreakerabstracts

•  IciStempatient#36,oralpresentation5thMarch11.45hours,room6E•  IciStempatient#19,posterpresentation,6thMarch,14.30hours,4EF

Acknowledgement

Translational Virology, UMCU

IciStemresearchworkgroup:JuliàBlanco(Immunologist,AIDSResearchInstituteIrsiCaixa,Barcelona),JorgeCarrillo(Immunologist,AIDSResearchInstituteIrsiCaixa,Barcelona),JohannaEberhard(Immunologist,UniversityMedicalCenterHamburg-Eppendorf),MiKwon(Hematologist,HospitalGregorioMarañón),MaríaSalgado(Virologist,AIDSResearchInstituteIrsiCaixa,Barcelona)Managementteam:TinekeJohnstonandJosienStraver(Financialmanagement/projectassistanceUniversityMedicalCenterUtrecht),LauraHuyveneers(Medicalcoordination/IRBUniversityMedicalCenterUtrecht),PascualBalsalobre(GregorioMarañón,Madrid),JudithDalmau(AIDSResearchInstituteIrsiCaixa,Barcelona)ScientificAdvisors:KoenvanBesien(NewYork-Presbyterianhospital)IciStemparticipantsBelgium:LinosVandekerckhove,Marie-AngéliquedeScheerder,EvaSteel(UniversityofGhent)Canada:LisaBarrett,SharonOldford,JillMoore,ClarissaBrisseau(NSHA/DalhousieUniversity,Halifax)Germany:DieterHäussinger,GuidoKobbe,BjörnJensen(University

HospitalDüsseldorf),RolfKaiser,ElenaKnops(UniversityofCologne)MaximilianChristopeit(UniversityMedicalCenterHamburg-Eppendorf)Italy:AlessandraBandera,AntonioMuscatelloandAlessandroSoria(SanGerardoHospital,Monza,Italy),GabriellaScarlatti,SimonaPiemontese(IstitutoScientificoSanRaffaele)Netherlands:PaulineEllerbroek,LodewijkBrosens,AnkeBruns,ErikvanMaarseveen(UMCUtrecht)JanvanderMeer,SachaZeerleder(AMC),JaapJanBoelens(UniversityMedicalCenterUtrecht/MemorialSloanKetteringCancerCenter,NewYork)Spain:JonBadiola,ManuelJuradoChacón(ComplejoHospitalarioUniversitariodeGranada),RaquelSaldana(HospitalGeneraldeJerezdelaFrontera),LuzMartínCarbonero(LaPazHospital),IldefonsoEspigado(UniversityHospitalVirgendelRocío,Seville)SwedenPiotrNowak(KarolinskaInstitutet)SwitzerlandMitjaNabergoj,AlexandraCalmy(HôpitauxUniversitairesdeGenève)UnitedKingdom:KavitaRaj,FabioCruciani,VarunMehra,CarmelRice(KingsCollegeHospital,London)AngelaBailey(ImperialCollegeHealthcareNHSTrust,London),WaseemQasim(InstituteofChildHealth&GreatOrmondStreetHospital,London),RavindraGupta(UniversityCollegeLondonHospital)

Acknowledgements TheIciStemconsortium

JavierMartinez-Picado(Co-PI,Virologist,AIDSResearchInstituteIrsiCaixa,Barcelona)

AnnemarieWensing(Co-PI,ClinicalVirologist,UniversityMedicalCenterUtrecht)

JoseL.DíezMartin(Hematologist,HospitalGregorioMarañón,Madrid)

GeroHütter(Hematologist,Cellex

Dresden)JürgenKuball(Hematologist,UniversityMedicalCenterUtrecht)

MoniqueNijhuis(Virologist,UniversityMedicalCenterUtrecht)

VandersonRocha(HematologistCordBloodBankSpecialistOxfordUniversity)

AsierSáez-Cirión(Immunologist,PasteurInstitute,Paris)JulianSchulzezurWiesch(Infectiousdiseasespecialist,UMCHamburg-Eppendorf)

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