CART.docx
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CART
1.NatRevClinOncol.2014Nov11.doi:
10.1038/nrclinonc.2014.190.[Epubaheadof
print]
Immunotherapy:
Treatmentofaggressivelymphomaswithanti-CD19CARTcells.
KlebanoffCA,YamamotoTN,RestifoNP.
Authorinformation:
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).
Authorinformation:
(1)CenterforCellEngineering,MemorialSloanKetteringCancerCenter,NewYork,NY
10065,USA.ThoracicService,DepartmentofSurgery,MemorialSloanKettering
CancerCenter,NewYork,NY10065,USA.adusumip@mskcc.orgsadelaim@mskcc.org.
(2)CenterforCellEngineering,MemorialSloanKetteringCancerCenter,NewYork,NY
10065,USA.ThoracicService,DepartmentofSurgery,MemorialSloanKettering
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.
PMID:
25378643[PubMed-inprocess]
3.CancerRes.2014Oct8.pii:
canres.0079.2014.[Epubaheadofprint]
EfficacyofCARTcelltherapyinlargetumorsreliesuponstromaltargetingby
IFNγ
TextorA
(1),ListopadJ
(2),WührmannLL(3),PerezC
(1),KruschinskiA
(1),
ChmielewskiM(4),AbkenH(5),BlankensteinT(3),CharoJ(6).
Authorinformation:
(1)MolecularImmunologyandGeneTherapy,MDC.
(2)Immunology,Max-Delbrück-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