CellularTherapy:ProvidingNewHopeforCancerPatients

KathleenDorri-e,MDAssistantProfessor,DivisionofHematology-Oncology

October26,2018

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Objectives

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•  TodescribewhatCART-cellsareandhowtheywork

•  Todiscussuniquetoxici-esofCART-cells•  Toreviewmajorclinicaltrialresultsandwhat’snext

•  ToreviewwhatTILsareandhowtheyarebeingusedinsolidtumors

WhatareChimericAntigenReceptor(CAR)Tcells?

Tcellsgene-callyengineeredtoexpressanar-ficialTcellreceptorthroughwhichtheytargetspecificpopula-onsofcells

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CAR structure, according to signaling domains.

Shannon L. Maude et al. Blood 2015;125:4017-4023

©2015 by American Society of Hematology

CD19:ARationalTargetforTherapy

5

Adapted from Blanc V et al. Clin Cancer Res. 2011;17(20):6448-6458.

FL, follicular lymphoma; GC, germinal center; MCL, mantel cell lymphoma; MZL, marginal zone lymphoma; WM, Waldstrom’s macroglobulinemia.

•  CD19isexpressedonBcellsandB-cellprecursorsandisnotexpressedonbonemarrowstemcellsorother-ssues

CD19

ALL MCL

MZL

DLBCL

Stem cell

Pro-B cell

Pre-B cell

CLL FL

WM

Plasma cell

Late plasmablast

Native B cell

Activated B cell

Memory GC B cell

Bone marrow Periphery Bone marrow

FromBedsidetoBenchandBacktoBedside

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Priceman,SJ.CurrOpinOncol.2015

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CytokineReleaseSyndrome(CRS)

FeverHeadacheNauseaMyalgias

HypotensionTachycardiaHypoxia

OrganToxicity(renal/hepaBc)

Neurotoxicity

Somnolence(affecBngADLs)àobtundaBonConfusionàseveredisorientaBon/comaEncephalopathy(affecBngIADLs)àcoma

Dysphasia(wordfindingdifficulty)àcan’tread,write,orcommunicate

SeizureCerebralEdema

SpecialToxicityConsiderations

Toxicitymanagement•  Cytokinereleasesyndrome

–  Suppor-vecare:Abx,an--pyre-cs,fluid,pressors–  Tocilizumab(an--IL6Ab)– Moreseveretoxicity:Steroids

•  Neurotoxicity:–  Steroids+/-(Tocilizumab)–  Suppor-vecare:One-to-oneobserva-on,ICUmonitoringasneeded,NPOstatus,Telemetry/pulseox

OtherToxicities

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Cytopenias–canbeveryprolongedB-cellaplasia(infec-on)HypogammaglobulinemiaMacrophageAc-va-onSyndrome(MAS)/Hemophagocy-cLymphohis-ocytosis(HLH)ElectrolyteAbnormali-es(hyponatremia,hypokalemia)TumorlysisPotenBalToxiciBes:SecondarymalignancyReplica-on-competentretrovirusAutoimmunedisorders

B-CellAplasia

10

Maude,etal.NEJM,2018.

ClinicalTrialResults

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AcuteLymphoblasBcLeukemia(ALL)*DiffuseLargeBcellLymphoma(DLBCL)*ChronicLymphocyBcLeukemia(CLL)MulBpleMyeloma

*IndicatesFDAApproved*

•  Open-label,single-armmul-centerglobalstudy(Pivotalregistra-ontrial)

•  CTL019(Kymriah™,-sagenlecleucel)(4-1BB)•  Relapsed/RefractoryALLinpediatric/youngadultpopula-on

•  88pa-entsenrolled,68pa-entsinfused•  Medianfollow-upwas6.4months•  Medianage12

CAR-TcellsforALL:ELIANAtrial

Buechner,J.EHA,June24,2017,AbstractS476

CAR-TcellsforALL:ELIANAtrial

Completeresponse/Cri**allMRDnegaBveinmarrow

52(83%)

RFSprobabilityat6mo

75%(57%-87%)

OSprobabilityat6mo

89%(77%-94%)

OSprobabilityat12mo

79%(63%-89%)

N=63(allwithatleast3mofollow-up)

Buechner,J.EHA,June24,2017,AbstractS476

Survival

14Maude,SL.NEJM,2018.

DurationofRemission

15Maude,SL.NEJM,2018.

EffectofDiseaseBurdenonSurvival

16

ParkJ.NEJM,2018.

AdultALL,MSKseriesCR83%

ALLSummary•  Majorityofpediatricandadultpa-entswillachieveMRD-nega-veCR

•  Adultpa-entsseemtorelapsefaster•  Diseaseburdengoinginmaycorrelatewithoutcomeandtoxicity

•  Pediatric/youngadultpopula-onhasanFDAapprovedtherapy(Kymriah™)

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DLBCL–ZUMA-1(NIH/Kite)

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 377;26 nejm.org December 28, 2017 2531

The authors’ full names, academic de-grees, and affiliations are listed in the Ap-pendix. Address reprint requests to Dr. Neelapu at the University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at sneelapu@ mdanderson . org.

Drs. Neelapu and Locke contributed equal-ly to this article.

This article was published on December 10, 2017, at NEJM.org.

N Engl J Med 2017;377:2531-44.DOI: 10.1056/NEJMoa1707447Copyright © 2017 Massachusetts Medical Society.

BACKGROUNDIn a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chime-ric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.

METHODSIn this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lympho-ma who had refractory disease despite undergoing recommended prior therapy. Pa-tients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.

RESULTSAmong the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most com-mon adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.

CONCLUSIONSIn this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety pro-file that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216.)

A BS TR AC T

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma

S.S. Neelapu, F.L. Locke, N.L. Bartlett, L.J. Lekakis, D.B. Miklos, C.A. Jacobson, I. Braunschweig, O.O. Oluwole, T. Siddiqi, Y. Lin, J.M. Timmerman, P.J. Stiff, J.W. Friedberg, I.W. Flinn, A. Goy, B.T. Hill, M.R. Smith, A. Deol, U. Farooq,

P. McSweeney, J. Munoz, I. Avivi, J.E. Castro, J.R. Westin, J.C. Chavez, A. Ghobadi, K.V. Komanduri, R. Levy, E.D. Jacobsen, T.E. Witzig, P. Reagan, A. Bot, J. Rossi,

L. Navale, Y. Jiang, J. Aycock, M. Elias, D. Chang, J. Wiezorek, and W.Y. Go

Original Article

The New England Journal of Medicine Downloaded from nejm.org by WARREN SHLOMCHIK on January 16, 2018. For personal use only. No other uses without permission.

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

ZUMA-1•  Axicabtageneciloleucel:CD3ζandCD28intracellulardomains•  Phase2with22studycenters(21US)•  Allpa-entshad:

–  DiffuselargeB-celllymphoma(n=77)–  Transformedfollicularlymphomaorprimarymedias-nal(n=24)

•  Refractoryorrelapsewithin12monthsofautologoustransplant

Neelapu,S.S.etal,NEJM,377;26.

Results

•  Median-metoresponse:1mo(0.8-6.0mo)•  Responserateconsistentacrosskeycovariates

–  Includingexpression/intensityofCD19anduseoftocilizumabandsteroidsastreatmentofCRS

Atmin6mof/u

HistoricalcontrolORRtosalvage20%(P<0.001)

Neelapu,S.S.etal,NEJM,377;26.

DurationofResponse

Neelapu,S.S.etal,NEJM,377;26.

TakeAway:Responsesareholding!

•  JCAR017:CD19-directed4-1BBCARTcellproductinadefinedcomposi-onataprecisedoseofCD8andCD4CARTcells.

•  Inclusion:R/RDLBCL(includedtransformedfromFL),PMBCL,FLgrade3B,andMantlecelllymphoma

•  SecondaryCNSinvolvementandECOG2allowed

CARTcelltherapyforDLBCL:TRANSCEND

Abramson,JS.,ASH2017,ABSTRACT581

ResultsBest 3mo 6mo

ORR 75% 49% 40%

CR 56% 40% 37%

Abramson,JS.,ASH2017,ABSTRACT581

Results

PRCR

CR/PR

Abramson,JS.,ASH2017,ABSTRACT581

DLBCLSummary•  Excellentresultswithallproductsgiventhehighrisknatureofthestudysubjects

•  Consistentmanufacturing•  Somepa-entsdon’tgetcellsduetodiseaseprogression•  Differencesintoxicityprofiles

DLBCL–trialsstillongoingWhat’sthebest-mingofCART-celltherapy?

àShouldCARTbegivenearlier(beforeothersecondlinetreatments)?àIsCARTbeqerthanautologoustransplant?

ThesuccessinDLBCLhasledtotrialsinotherlymphomas:

MantlecellFollicular

MarginalZone

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CARTinCLLGill,S,etal.ASCO2017Abstract#7509

Ø  Pilotstudy10pa-entsnotinCRdespite>6monthsibru-nib(allhighrisk)Ø  At3months,8evaluableptsinMRD-negCR(89%)allinCRatlastf/uØ  4/6subjhadresolu-onofadenopathyØ  CRSin9/10pts(grade3orhigherin1)

27

JClinOncol35,2017(suppl;abstr7509)

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24ptswithmedianof5priortherapiesAllwithhigh-riskdiseaseAllhadreceivedibru-nib,19progressedonit

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1montha_erinfusionORR(CR+PR) 71%MarrowNega-ve 88%

TurtleC,JClinOncol,2017.

30 TurtleC,JClinOncol,2017.

SummaryofCARTforCLL

•  Earlyresultsareverypromising,eveninheavilypretreatedpa-ents

•  Pre-treatmentwithibru-nibmayenhanceCARTexpansionandresponse

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MyelomaCAR

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CD19notagoodtarget,notpresentonthebulkoftheMMcellsB-cellMatura-onAn-gen(BCMA)seemsmostpromisingsofar

àsomeBcellsànormalplasmacellsàMMcells**notexpressedonhematopoie-cstemcellsor nonhematologiccells

ASH2017Abstract#505

SafetyandEfficacyofB-cellMaturationAntigen(BCMA)-SpecificChimericAntigenReceptorTCells(CART-BCMA)withCyclophosphamideConditioningforRefractoryMultipleMyeloma

AdamCohen,etal.(UPenn/Novartis)

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Responses

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Efficacy(IMWG) TotalResponsesCohort1(n=9) 1sCR,2VGPR,1PR,2MR 6/9Cohort2(n=5) 1PR,1MR 2/5Cohort3(n=7) 1CR,3PR,1MR 5/6

CohenA,etal.ASH2017#505

Conclusion:CART-BCMAfollowingCylymphodepleBonisfeasibleandhasclinicalbenefitinhighly-refractorypaBents

withpoorriskdisease.Efficacylowerat10^7dose.

ASH2017Abstract#740

DurableClinicalResponsesinHeavilyPretreatedPa-entswithRelapsed/RefractoryMul-pleMyeloma:UpdatedResultsfromaMul-centerStudyofbb2121An--BcmaCARTCellTherapy

BerdegaJG,etal.(NCI/BluebirdBio)

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Multicenter,Phase1Dose-EscalationStudy

•  21pa-ents,median7linespriortherapy•  Allhadpriorauto

ORR94%,increasedto100%inpa-entswithhigherdoses

36

BerdejaJG,etal.ASH2017#740

SummaryofMyelomaStudies•  Studiesaresmall•  Mixedresultswithdifferenttrials•  Trialsunderway,alsolookingatdifferenttargetan-gen–  SLAMF7–  CD138–  CD38 –  Igκ lightchain

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BCMACARMyeloma

38Ali,Blood2016.

FutureofCART

ConBnuedModificaBonoftheCAR-addingcos-mulatorydomains-op-mizinghingeandtransmembranedomain-co-expressionofchemokinereceptortoimprovecelltrafficking-targe-ngtumor-specificAgderivedfromintracellularproteins

39

HowtoEnhancetheTherapeuticBenefit

–  Targetmul-plean-gensatone-me

– Movingtoearlierlineoftherapy–  Combinewithotherimmunetherapiessuchascheckpointblockade,smallmoleculeinhibitors

40

CLL-IbrutinibEnhancesEfficacy•  >5cyclesofibru-nibimprovedexpansionofCTL09•  AssociatedwithdecreasedexpressionofPD1

41 FraieqaJA,etal.Blood2016.

PD-1BlockadetoRestoreActivityofCART-Cells

•  CARTcellsexhibitupregula-onofPD-L1,CTLA-4,andLAG-3

•  CheckpointblockadecanrestoreCARTac-vity–  Hasbeendemonstratedinpreclinicalmodelsofsolidtumors–  Earlyclinicalresultsinhematologicmalignanciesarepromising

•  Combina-onvsbuilt-in42

“Built-In”Strategies:-engineerCARstosecretean--PD-1-knockdownorknockout-dominantnega-vereceptorstrategy

43

PD-1BlockadetoRestoreActivityofCART-Cells

44Maude,SL.NEJM,2018.

MitigatingToxicity

MitigatingToxicity-  Incorpora-onofsuicidegenes(eg.iCaspase9)ortaggingsurface

-  Iden-fyingpredic-vebiomarkersforneurotoxicityandCRS-  IL-1 -NO -Ang-2 -MIP-1β - IL-8 -IL-17A-  IL-15-VWF -MCP-1 -IL-10 -granzymeB

45

CARTherapyinSolidTumors

46

-  Difficulttofindanan-gen

-  Lookingatintracellular“neoan-gens”

-  SomeTcellreceptor

therapiesareHLA-restricted

WhatAboutTILs?•  Thepresenceoftumorinfiltra-nglymphocytes(TIL)inthe

tumormicroenvironmentcorrelateswithimprovedprognosis•  AutologousinfusionofTILcanresultindurableresponsesin

somesolidtumors,par-cularlymelanoma•  Cellsarecollected,expanded,andre-infused•  Alsorequirepre-condi-oning,similartoCART

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TILinMelanoma

48

3yearOS36%5yearOS29%InthosewithCR:3yearOS100%5yearOS93%

RosenbergSA,etal.ClinCancerRes,2011

HPV-TILinCervicalCarcinoma

49

StevanovicS,etal.JClinOncol,2015.

OtherThingstoConsider•  CARTtherapyisexpensive(hundredsofthousandsperinfusion),needtolookatthebigpicture–  Insurancecompaniesscramblingtofigureoutcoverage–  Medicareworkingtoincorporatecoverage–  Somecompanieshaveassistanceprograms–  Clinicaltrialsalsoprovideaccess–  Earlycost-effec-venessanalysissuggeststhebenefitmightbe

worththecost(QALY)

50

•  Onlyspecializedcenterscanadministeràlimitsaccess,butnecessaryforsafety

•  Requiresteamefforttoensuresafety àmusthavetrainednurses,variousphysiciansallworkingtogether

51

OtherThingstoConsider

CARTClinicalTrials

1.  R/RFollicular/MarginalZoneLymphoma2.  R/RDiffuseLargeB-cellLymphoma(DLBCL)3.  FirstRelapseDLBCLAutovs.CART4.  FirstRelapseDLBCLTransplantIneligible5.  R/RCLL6.  Myeloma

52

CommercialCART

Yescarta®(axicabtageneciloleucel)Kymriah™(-sagenlecleucel)JCAR–an-cipatedJanuary2019

53

CellularTherapyinSolidTumorsatUPMC

1.  Metasta-cMelanoma2.  UvealMelanoma3.  HeadandNeckCancer4.  CervicalCarcinoma5.  TCRforlungcancer

54

55

Thankyou!

Baseline 6monthsDay30

AbramsonJS,PalombaML,GordonLI,LunningMA,ArnasonJE,WangM,ForeroA,MaloneyDG,AlbertsonT,GarciaJ,LiD,XieB,andSiddiqiT.HighDurableCRRatesinRelapsed/Refractory(R/R)AggressiveB-NHLTreatedwiththeCD19-DirectedCARTCellProductJCAR017(TRANSCENDNHL001):DefinedComposi-onAllowsforDose-FindingandDefini-onofPivotalCohort.Abstract581.OralPresenta-onASH2017.AliSA,ShiV,MaricI,WangM,StroncekDF,RoseJJ,BrudnoJN,Stetler-StevensonM,FeldmanSA,HansenBG,FellowesVS,HakimFT,GressRE,KochendorferJN.TcellsexpressingananB-B-cellmaturaBonanBgenchimericanBgenreceptorcauseremissionsofmulBplemyeloma.Blood2016128:1688-1700;doi:hqps://doi.org/10.1182/blood-2016-04-711903BerdejaJG,LinY,RajeN,MunshiN,SiegelD,LiedtkeM,JagannathS,MausMV,TurkaA,LamLP,HegeK,MorganRA,PhD8,QuigleyMT,andKochenderferJN.DurableClinicalResponsesinHeavilyPretreatedPa-entswithRelapsed/RefractoryMul-pleMyeloma:UpdatedResultsfromaMul-centerStudyofbb2121An--BcmaCARTCellTherapy.Abstract740.OralPresenta-onASH2017.BuechnerJ,GruppSA,MaudeSL,BoyerM,BiqencourtH,LaetschTW,BaderP,VernerisMR,StefanskiH,MyersGD,QayedM,PulsipherMA,DeMoerlooseB,HiramatsuH,SchlisK,DavisK,Mar-nPL,NemecekE,PetersC,WoodP,TaranT,ThudiumMuellerK,ZhangY,RivesS.GlobalRegistra-onTrialofEfficacyandSafetyofCTL019InPediatricandYoungAdultPa-entswithRelapsed/Refractory(R/R)AcuteLymphoblas-cLeukemia(All):UpdatetoTheInterimAnalysis.Abstract:S476.OralPresenta-onEHA22.CohenAD,GarfallAL,StadtmauerEA,LaceySF,LancasterE,VoglDT,WeissBM,AmbroseDE,NelsonAM,ChenF,PlesaG,KulikovskayaI,GonzalezV,GuptaM,YoungRM,DengelK,O’keefeL,LeS,RichardsonC,IsaacsRE,MelenhorstJJ,LevineBL,JuneCH,andMiloneMC.SafetyandEfficacyofB-CellMatura-onAn-gen(BCMA)-SpecificChimericAn-genReceptorTCells(CART-BCMA)withCyclophosphamideCondi-oningforRefractoryMul-pleMyeloma(MM).Abstract505.OralPresenta-onASH2017FraieqaJA,BeckwithKA,PatelPR,RuellaM,ZhengZ,BarreqDM,LaceySF,MelenhorstJJ,McGe~ganSE,CookDR,ZhangC,XuJ,DoP,HuliqJ,KudchodkarSB,CogdillAP,GillS,PorterDL,WoyachJA,LongM,JohnsonAJ,MaddocksK,MuthusamyN,LevineBL,JuneCH,ByrdJC,MausMV.Ibru-nibenhanceschimerican-genreceptorT-cellengra�mentandefficacyinleukemia.Blood.2016Mar3;127(9):1117-27.doi:10.1182/blood-2015-11-679134.Epub2016Jan26.PubMedPMID:26813675;PubMedCentralPMCID:PMC4778162.GarfallAL,MausMV,HwangWT,LaceySF,MahnkeYD,MelenhorstJJ,ZhengZ,VoglDT,CohenAD,WeissBM,DengelK,KerrND,BaggA,LevineBL,JuneCH,StadtmauerEA.ChimericAn-genReceptorTCellsagainstCD19forMul-pleMyeloma.NEnglJMed.2015Sep10;373(11):1040-7.doi:10.1056/NEJMoa1504542.PubMedPMID:26352815;PubMedCentralPMCID:PMC4646711.

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