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CenterforCancerResearch,SurgeryBranch,ImmunotherapySection,10Center

Drive,Building10/CRC,Room3West-5816,Bethesda,MA20892,USA.

PMID:

25384948[PubMed-assuppliedbypublisher]

2.SciTranslMed.2014Nov5;

6（261）:

261ra151.doi:

10.1126/scitranslmed.3010162.

Regionaldeliveryofmesothelin-targetedCARTcelltherapygeneratespotentand

long-lastingCD4-dependenttumorimmunity.

AdusumilliPS

（1）,CherkasskyL

（2）,Villena-VargasJ

（2）,ColovosC

（2）,Servais

E

（2）,PlotkinJ（3）,JonesDR（4）,SadelainM（5）.

（1）CenterforCellEngineering,MemorialSloanKetteringCancerCenter,NewYork,NY

10065,USA.ThoracicService,DepartmentofSurgery,MemorialSloanKettering

CancerCenter,NewYork,NY10065,USA.adusumip@mskcc.orgsadelaim@mskcc.org.

（2）CenterforCellEngineering,MemorialSloanKetteringCancerCenter,NewYork,NY

CancerCenter,NewYork,NY10065,USA.

（3）CenterforCellEngineering,MemorialSloanKetteringCancerCenter,NewYork,NY

10065,USA.

（4）ThoracicService,DepartmentofSurgery,MemorialSloanKetteringCancerCenter,

NewYork,NY10065,USA.

（5）CenterforCellEngineering,MemorialSloanKetteringCancerCenter,NewYork,NY

10065,USA.ImmunologyProgram,SloanKetteringInstitute,NewYork,NY10065,

USA.adusumip@mskcc.orgsadelaim@mskcc.org.

Translatingtherecentsuccessofchimericantigenreceptor（CAR）Tcelltherapy

forhematologicalmalignanciestosolidtumorswillnecessitateovercoming

severalobstacles,includinginefficientTcelltumorinfiltrationand

insufficientfunctionalpersistence.Takingadvantageofanorthotopicmodelthat

faithfullymimicshumanpleuralmalignancy,weevaluatedtworoutesof

administrationofmesothelin-targetedTcellsusingtheM28zCAR.Wefoundthat

intrapleurallyadministeredCARTcellsvastlyoutperformedsystemicallyinfused

Tcells,requiring30-foldfewerM28zTcellstoinducelong-termcomplete

remissions.AfterintrapleuralTcelladministration,promptinvivo

antigen-inducedTcellactivationallowedrobustCARTcellexpansionand

effectordifferentiation,resultinginenhancedantitumorefficacyandfunctional

Tcellpersistencefor200days.RegionalTcelladministrationalsopromoted

efficienteliminationofextrathoracictumorsites.Thistherapeuticefficacywas

dependentonearlyCD4（+）Tcellactivationassociatedwithahigherintratumoral

CD4/CD8cellratiosandCD28-dependentCD4（+）Tcell-mediatedcytotoxicity.In

contrast,intravenouslydeliveredCARTcells,evenwhenaccumulatedat

equivalentnumbersinthepleuraltumor,didnotachievecomparableactivation,

tumoreradication,orpersistence.TheabilityofintrapleurallyadministeredT

cellstocirculateandpersistsupportstheconceptofdeliveringoptimalCART

celltherapythrough"

regionaldistributioncenters."

Onthebasisofthese

results,weareopeningaphase1clinicaltrialtoevaluatethesafetyof

intrapleuraladministrationofmesothelin-targetedCARTcellsinpatientswith

primaryorsecondarypleuralmalignancies.

Copyright©

2014,AmericanAssociationfortheAdvancementofScience.

25378643[PubMed-inprocess]

3.CancerRes.2014Oct8.pii:

canres.0079.2014.[Epubaheadofprint]

EfficacyofCARTcelltherapyinlargetumorsreliesuponstromaltargetingby

IFNγ

TextorA

（1）,ListopadJ

（2）,Wü

hrmannLL（3）,PerezC

（1）,KruschinskiA

（1）,

ChmielewskiM（4）,AbkenH（5）,BlankensteinT（3）,CharoJ（6）.

（1）MolecularImmunologyandGeneTherapy,MDC.

（2）Immunology,Max-Delbrü

ck-CenterforMolecularMedicineandInstitutefor

Immunology,Charite.

（3）Robert-Roessle-Str10,Max-Delbrueck-Centrum.

（4）CenterforMolecularMedicineCologne,UniversityofCologne.

（5）Tumorgenetics,ClinicIforInternalMedicineandCentreforMolecularMedicine

Cologne（CMMC）,UniversityofCologne.

（6）OncologyInstitute,LoyolaUniversityChicagojehcha@.

AdoptiveTcelltherapyusingchimericantigenreceptor-modifiedTcells（CAR-T

therapy）hasshowndramaticefficacyinpatientswithcirculatinglymphoma.

However,eradicationofsolidtumorswithCAR-Ttherapyhasnotbeenreportedyet

tobeefficacious.Insolidtumors,stromadestruction,duetoMHC-restricted

cross-presentationoftumorantigenstoTcells,maybeessential.However,

CAR-TsrecognizeantigensinanMHC-independentmanneroncancercellsbutnot

stromacells.Inthisreport,weshowhowCAR-Tscanbeengineeredtoeradicate

largeestablishedtumorswithprovisionofasuitableCD28costimulatorysignal.

InaHER-2-dependenttumormode