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LETTEROPEN
IMMUNOTHERAPY
ChimericantigenreceptorTcellsforgamma–deltaTcell
malignancies
✉
,,,
©TheAuthor(s)2021
Leukemia;/s41375-021-01385-0
TOTHEEDITOR:transductionwithanti-CD19CAR,asmallproportionofγδTcells
Cancersderivedfromthemalignanttransformationofgamma–deltapersistedintheculture,includingsomewhichexpressedanti-
(γδ),foranti-γδTCRCAR,noγδTcellswere
recognisedareγδTacutelymphoblasticleukaemia(γδT-ALL),anddetectedintheculture,suggesting‘purging’ofthesecellsbythe
twolymphomasubtypes:hepatosplenicTcelllymphoma(HSTL)andtransducedpopulation().CAR-Tcellswerethenco-cultured
primarycutaneousγδTcelllymphoma(PCγδ-TCL)[1].γδT-ALLwithTcelllineswhichnativelyexpress(Loucy–Vγ9Vδ2,BE13–
representsapproximately10%ofcasesofT-ALLandisassociatedVγ8Vδ1,MOLT13–Vγ3Vδ1[8])orarenegativeforsurfaceγδTCR
withhighratesofinductionfailure,relapseandexcessmortality[2].(SupT1-CD19).Whilecontrolanti-CD19CARlysedonlySupT1-
HSTLisarare(approximately3%ofcasesofTcelllymphoma[1])butCD19cells,anti-γδTCRCAR-TlysedonlyγδTCR-positivecelllines
highlyaggressivedisorder,whichtypicallypresentsinmalesinthe().Inaddition,anti-γδTCRCAR-Tcellsdemonstratedspecific
2ndor3rddecadeoflife,ofteninassociationwithimmunosuppres-secretionofcytokinesincludinginterferon-γ,IL-2,IL-13andTNF-α
sivetherapy[3].Itcarriestheworstprognosisofalllymphoma().Next,weco-culturedanti-CD19oranti-γδCAR-Tcells
subtypes,withamediansurvivalofonly6–8months[4]:Tratio(1:1),target
isolatedcasesoflong-termsurvival[5].PCγδ-TCLisalsorarenormalγδTcellswerepartiallylysed(),withconcomitant
(approximately1%ofskinlymphomas[1])andpresentswithexpansionofanti-γδCAR-Tcells().Amarkeddown-
cutaneousinvolvement,typicallyassociatedwithvisceraland/orregulationofγδTCRexpressionwasnotedonsurvivingγδTcells
,outcomesarepoor,with75%1-year().Interestingly,bycontrast,atlowerE:Tratios(1:2and1:4),
mortalityinthelargestpublishedcaseseries[6].paradoxicalγδTcellexpansionwasinsteadobserved(),
Treatmentforγδmalignanciesiswithcytotoxicchemotherapy,associatedwithreductioninnumbersofanti-γδCAR-Tcells
withnotumour-,().Thissuggestslysisofanti-γδCAR-Tbytargetnormalγδ
inanalogousB-cellmalignancies,highlyeffectiveimmunothera-Tcells.
pies,includingmonoclonalantibodies,bispecificTcellengagersToassaytheinvivopotencyofanti-γδTCRCAR-Tcells,weutilised
andchimericantigenreceptor(CAR)-Tcells[7]-positiveleukaemia
Thesetherapieshaverevolutionisedthetreatmentandoutcome(,d).NSGmicewereintravenouslyinjectedonCARD-12with
ofadvancedB--TcellsagainstCD194×106Loucycells,engineeredtostablyexpressFireflyluciferase.
inparticularhavedemonstratedthepotentialtoinducelong-Tumourengraftmentwasconfirmedbybioluminescenceimaging
lastingcompleteremissionseveninpatientswithadvancedand(BLI)atD-1(datanotshown),thenmiceweretreatedonD0with8×
refractorycancers[7].105anti-γδTCRorcontrolanti-CD19CAR--
Forγδmalignancies,thedefiningimmunophenotypiccharac-γδTCRCARdemonstratedreductionoftumourburden,asassessed
teristicisexpressionoftheγδTcellreceptor(TCR),presentinbyflowcytometryofbonemarrowandspleenatnecropsyonD14
>95%ofcasesofHSTLandinallPCγδ-TCLandγδT-ALL[3].(,c,),BLI(,f)andbleedatD30
Importantly,innormaltissuesexpressionislimitedtoγδTcells,().Prolongedsurvival()wasseeninanti-γδTCRCAR
,werecipientscomparedtoCD19CAR-treatedanimals,althoughall
developedCAR-TcellstargetingtheγδTCRanddemonstrateanimalseventuallydiedofprogressiveγδTCR-positivedisease,with
dataoffersproof-of-conceptforγδTCR-targetingwithCAR-Tcellsmodels,CAR-Tcellpersistencewaslimited,withnodetectablecellsin
asapotentialapproachtobringhighlypotentimmunotherapytotheperipheralbloodatD30(datanotshown).
-cellmalignancies,alackofacceptable
PrimaryαβTcellswereretrovirallytransducedtoexpresstargetsmeanstargetedimmunotherapyisrarelyappliedto
anti-γδTCRCARorcontrolanti-CD19CAR().-CD30antibody-drugconjugate
1DepartmentofHaematology,CancerInstitute,UniversityCollegeLondon,London,,AziendaSocioSanitarioTerritorialePapaGiovanniXXIII
✉
Hospital,Bergamo,:p.******@
Received:7April2021Revised:6July2021Accepted:4August2021
.
2
γδγδflγδ
1234567890();,:--TCRCAR,-TCR
stainingonanti-CD19oranti-γδTCRCAR-Tcellsfollowingtransductioncco-culturesofanti-γδTCRorcontrolanti-CD19CAR-Tcellswith
CD19+(SupT1-CD19)orγδTCR+celllines(Loucy,MOLT13,BE13)(c)cytotoxicityat72h,asmeasuredbybioluminescence-basedassay(d)cytokine
–g120-hco-cultureofcontroloranti-γδTCRCAR-TcellswithautologousnormalγδTcells,n=
proportionofstartingcellsfExampleγδTCRstainingonnormalγδTcellsafterco-culturewithanti-γδTCRCAR-Toranti-CD19CAR-Tcellsgresidual
anti-γδTCRCAR-Toranti-CD19CAR-Tfollowingco-culture,asproportionofstartingcells.**p<,***p<.
-(n=6/group)bQuantificationoftumourin(b)marrow
and(c)spleenatD14followingCAR-(n=9/group)ebioluminescence(BLI)imagingatD21
followingCAR-
(mediansurvivalCAR1950daysvCARγδ69days,,p=,comparisonbylog-rankmethod).Allothercomparisonsby
Mann–WhitneyUtest.
Leukemia
.
3
,LaetschTW,BuechnerJ,BittencourtH,VernerisMR,BoyerMW,etal.
[9],however,CD30isnottypicallyexpressedinγδcancers[2].AnalysisofaglobalregistrationtrialoftheefficacyandsafetyofCTL019in
SuggestedapproachestotargetingTcellmalignanciesincludepediatricandyoungadultswithrelapsed/refractoryacutelymphoblasticleukemia
targetingpan-TcellantigenssuchasCD5[10]orCD7[11].(ALL).;128:221.
,VerhaafB,vanGastel-MolEJ,Wolvers-TetteroILM,deVosJ,MacLeod
However,suchstrategiesdepletetheentirenormalTcellfi
-denedTcellreceptorgenerearrange-
mentsascontrolsfortheBIOMED-2multiplexpolymerasechainreactiontubes.
[11],;21:230–7.
,O’ConnorOA,ProB,IllidgeT,FanaleM,AdvaniR,
MorerefinedapproachesthattargetclonalelementsoftheTCR,vedotinwithchemotherapyforCD30-positiveperipheralTcelllymphoma(ECHELON-
suchasselectivetargetingofTRBC1andTRBC2inαβTcell2):aglobal,double-blind,randomised,;393:229–40.
malignancies,,RouceRH,TashiroH,-directedchimericantigen
compartment[12].;126:983–92.
possibleinγδTCRmalignancies,-SilvaD,SrinivasanM,SharmaS,LeeCM,WagnerDL,DavisTH,etal.
CD7-editedTcellsexpressingaCD7-specificCARforthetherapyofTcell
–
<5%ofperipheralbloodTcells,;130:28596.
,WawrzynieckaPA,PhilipB,OnuohaSC,LegutM,SewellAK,etal.
aremoreabundantintissuesandhavearangeofproposedTargetingtheTcellreceptorβ-chainconstantregionforimmunotherapyofTcell
ancillaryimmunologicalfunctions[13].Importantly,;89:3909–12.
γδ-deficientmicedisplayaverymildphenotype[14],,-of-the-best:uniquecontributionsofγδTcellsto
;13:88–100.
-deficientmicehaveimpairedmucosal
beclinicallytolerable,;183:1929–35.
anti-γδTCRCAR-Tshouldproceedcautiously:,KokalakiE,MekkaouiL,ThomasS,StraathofK,FlutterB,
compactepitope-basedmarker/suicidegeneforeasierandsaferTcelltherapy.
co-expressionofasuicidegene[15],availabilityofback-up–
cryopreservedperipheralbloodmononuclearcells,;124:127787.
monitoringfordevelopmentofatypicalinfections.
Indeed,itisunclearifanti-γδCAR-Ttreatmentwouldleadtoγδ
ACKNOWLEDGEMENTS
,while
TheauthorswouldliketothankmembersofthePulelaboratoryforhelpandadvice.
anti-γδCAR-TexpandedwhenculturedwithnormalγδTcellsathigh
E:Tratio,thereversewasobservedwhennormalγδTwasinexcess.
Thus,anti-γδCAR-Twerethemselvesdepletedfromtheculture,with
γδAUTHORCONTRIBUTIONS
,performedandanalysedtheexperimentsandwrotethemanuscript.
bindingtotheTCRofγδTcellsinducedCARsignalling,
signallingviatheTCRoftheγδTcell,leadingtoa2-,designed,
.
outnumberedanti-γδCAR-T,thebalanceofcytotoxicityresultedin
anti-γδCAR-
potentialclinicalconsequencesforanti-γδTCRCARtherapyareCOMPETINGINTERESTS
unclearandwouldbedifficulttoascertainpre-clinicallyduetoalackPAW,
,inpatientsreceivingofficer,andholdsstocks/.
anti-γδCAR-T,itislikelythattheCAR-T:normalγδTcellratioatthe
tumoursitewouldbehighinthecriticalinitialCAR-Texpansion
phase,
Here,wehavedemonstratedthefeasibilityofengineeringSupplementaryinformationTheonlineversioncontainssupplementarymaterial
normalαβTcellstoexpressanti-γδTCRCARandhaveshownthatavailableat/s41375-021-01385-0.
anti-γδTCRCAR-Tcellscanspecificallykillmalignantγδcellsboth
.
strategytobringhighlypotentCAR-TcellstothetreatmentofReprintsandpermissioninformationisavailableat/
γδTcellmalignancies,wherethereisamajorunmetneedreprints
’snoteSpringerNatureremainsneutralwithregardtojurisdictionalclaims
inpublishedmapsandinstitutionalaffiliations.
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