Potential for HIV Cure by stem cell transplantation IciStem · Monique Nijhuis University Medical...
Transcript of 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
6 CCR5WT 2014 undetectable undetectable undetectable undetectable
17CCR5WT 2010 undetectable undetectable undetectable undetectable
27CCR5WT 2009 undetectable undetectable undetectable undetectable
28 CCR5WT 2013 undetectable undetectable undetectable undetectable
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
6 CCR5WT 2014 undetectable undetectable undetectable undetectable
17CCR5WT 2010 undetectable undetectable undetectable undetectable
27CCR5WT 2009 undetectable undetectable undetectable undetectable
28 CCR5WT 2013 undetectable undetectable undetectable undetectable
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
6 CCR5WT 2014 undetectable undetectable undetectable undetectable
17CCR5WT 2010 undetectable undetectable undetectable undetectable
27CCR5WT 2009 undetectable undetectable undetectable undetectable
28 CCR5WT 2013 undetectable undetectable undetectable undetectable
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
6 CCR5WT 2014 undetectable undetectable undetectable undetectable
17CCR5WT 2010 undetectable undetectable undetectable undetectable
27CCR5WT 2009 undetectable undetectable undetectable undetectable
28 CCR5WT 2013 undetectable undetectable undetectable undetectable
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
6 CCR5WT 2014 undetectable undetectable undetectable undetectable
17CCR5WT 2010 undetectable undetectable undetectable undetectable
27CCR5WT 2009 undetectable undetectable undetectable undetectable
28 CCR5WT 2013 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)
patients