Cours du Groupe d’Oncologie de la Société de...

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ImmunothérapieenCancérologie:checkpointsimmunologiquesetvoiesderecherche

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ChristopheCAUX

CancerResearchCentreofLyonINSERMU1052,CentreLéonBérard

Director A. Puisieux

TeamN°11«TherapeuNctargeNngoftumorcellsandtheirimmuneenvironment»

Christophe Caux DR Inserm

CoursduGrouped’OncologiedelaSociétédePneumologiedeLangueFrancaise

(GOLF)20Septembre2016

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Methylcholanthrene-inducedtumorsinIFN-g

RK.O.mice.1

1.KaplanDHetal.PNAS.1998;95:7556-7560

EvidencesofTumorImmuno-SurveillanceinImmunocompetentMice:RoleofTcells1

1.KoebelCM,LJOld,MSmyth&SchreiberRD,Nature2007,450(7171):903-7.

0 10 20 30 100 200 300 400 500 600 700

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EvidencesofTumorImmuno-SurveillanceinHuman:IncreasedCancerIncidenceinImmuno-DepressedTransplantedPaNents1

1.Birkeland,IntJCancer199530:183-9.

TumorSite RaNo

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1.PagesFetal.NEnglJMed.2005;353:2654–2666.2.GalonJetal.Science2006;313:1960–64.

ImmunogenicCellDeathinCancerTherapy

MichaudM,KroemerG.Science.2011;334:1573-7.KroemerG,ZitvogelL.AnnuRevImmunol.2013;31:51-72.

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different phases in the immune response to regulate the duration and level of the T-

cell response.

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ImmuneCheckpoints•  Checkpointpathways

–  CTLA-4andPD-1•  OtherCheckpoints:B7familyandothers•  BeyondCheckpoints:Cos1mulators•  BeyondTcells:NK,DC,Macrophage•  Markersforcheckpointpathwayinhibi1on

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GJFreeman&AHSharpe.NatImmunol.2012.

TumorInfiltraNngLymphocytesExpressMulNpleImmunoinhibitoryReceptors

Thesearedruggabletargetsfortumorimmunotherapy

Signal1

Signal2

CTLA-4andPD-1PathwayInhibitsTCellResponses

GFreeman2008;PNAS105:10275

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AnN-CTLA4ofIgG2aisotypeEnhanceAnNtumorAcNvityThroughDepleNonofIntratumoralTregs

SelbyMJ&KormanAJ.CancerImmunolRes.2013;1:32-42.

Fc-DependentDepleNonofTumorInfiltraNngTregco-DefinestheEfficacyofanN-CTLA4Therapy

SimpsonTR&QuezadaA.JExpMed.2013;210:1695-710.

GJFreeman&AHSharpe.NatImmunol.2012.

TumorInfiltraNngLymphocytesExpressMulNpleImmunoinhibitoryReceptors

Thesearedruggabletargetsfortumorimmunotherapy

PotentTherapeuNcEfficacyofPembrolizumab(anN-PD1MSD)inMelanoma

HamidO.NEJM.2013.

N=135,13%grade3/4toxicity

53%objec1veResponses

RibasA.NEnglJMed.2012;366:2517-2519.

DifferencesBetweenBlockingCTLA4/B7andBlockingPD-1/PD-L1

TumorAnNgen–SpecificCD8TcellsInfiltraNngtheTumorExpressHighLevelsofPD-1andAreFuncNonallyImpaired

TumorinfiltraNngTcellsupregulatePD1 PD1expressingTcellsaredysfuncNonal

AhmadzadehM&RosenbergSA.Blood.2009;114:1537-44

PD-L1:B7-1PathwayAlsoInhibitsTCellResponses

•  B7-1interactsmorestronglywithPD-L1(1.7μM)thanwithCD28(4μM)butlessstronglythanwithCTLA-4(0.2μM)

•  Alltherapeu1cPD-L1Absaredualblockers•  B7-1:PD-L1interac1oninhibitsTcellresponsespredominantroleincontrollingeffectorTcellresponses

Bule,etal.Immunity.2007.Paterson,etal.JI.2011.

AnN-PD-1andAnN-PD-L1mAbsBlockDisNnctInteracNons

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•  Igsuperfamilymember•  BindsMHCclassII(likeCD4)•  ExpressedbyacNvatedTcells•  LAG-3ligaNoninhibitsTCRsignaling•  AlsoexpressedbyTregs.BlockingofLAG-3resultsininhibiNonofsuppressivecapacity

•  AcNvaNonofCD8+TcellsleadstoLAG-3upregulaNon•  LAG-3mayrenderCD8+Tcellsinatolerogenicstate•  CombinedanN-PD1andanN-LAG-3mayhavebejeranN-tumoreffects

LAG-3(lymphocyteacNvaNongene-3)

TIM-3(Tcellimmunoglobulin-3)•  IgsuperfamilymemberconsistsofanN-terminalIgV

domainandamucindomain•  Tim-3ligand:S-typelecNngalecNn-9(Gal-9),soluble

moleculewidelyexpressed,upregulatedbyIFN-γ•  Tim-3asanegaNveregulatorymolecule:negaNve

regulatorofIFN-g-secreNngCD4+Thelper1andCD8+Tcytotoxic1cells

•  PromotedevelopmentofCD8+TcellexhausNon•  Invivoblockaderesultsinexacerbatedautoimmunityand

abrogaNonoftoleranceinexperimentalmodels,•  Induceexpansionofmyeloid-derivedsuppressorcells

(MDSC),expressinghighlevelsofGla-9•  TumorinfiltraNnglymphocytesco-expressedPD-1and

TIM-3

SakuishiK,TrendsImmunol.2011;32:345-9AndersonAC.CurrOpinImmunol.2012;24:213-6

NewCombina1onImmunotherapies:

•  An1-PD1/PDL1+an1-LAG3•  An1-PD1/PDL1+an1-TIM-3•  An1-PD1+agonis1can1-GITR•  An1-PD1+otheragonis1can1bodies•  Triplecombina1ons?(an1-CTLA4+an1-PD1+3rdnewdrug)

WooSetal.CancerRes.2012;72:917-927.

AnN-LAG-3+AnN-PD-1

CombinatorialanN–LAG-3/anN–PD-1TreatmentInhibitsTumorGrowth

EffectofTargeNngtheTim-3andPD-1SignalingPathwaysonTumorGrowth.

Sakuishi K et al. J Exp Med 2010;207:2187-2194

CT26 tumor cells implanted into wild-type BALB/c mice.

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TcellTargetsforImmunoregulatoryAnNbodyTherapy

Mellmanetal.Nature.2011;480,480-489.

BMS-663513

• BMS-936558• CT011• MK-3475SCH900475

AnNPDL-1BMS-936559

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Ipilimumab

BeyondCheckpoints:GITRCo-sNmulaNon

•  GITR(Glucocor1coid-InducedTumornecrosisfactor-relatedReceptor)iscons1tu1velyexpressedathighlevelsonTregsandatlowonres1ngCD4+andCD8+Tcells,andNKcellss1,2

•  GITRexpressionishighlyupregulatedonac1vatedCD4+andCD8+TcellsandNKcells,includingtumorinfiltra1nglymphocytes

•  GITRmodula1onhasbeenindicatedasoneofthetop25mostpromisingresearchareasbytheAmericanNa1onalCancerIns1tute,andclinicaltrialsstarted2

•  GITRliga1onbyGITRL(oran1-GITRagonistan1bodies)providesacos1mulatorysignalthatenhancesbothCD4+andCD8+Tcellprolifera1onandeffectorfunc1onsleadingtoenhancedcellularandhumoralimmunity

•  Inaddi1on,cos1mula1onthroughGITRhasbeenshowntorendernaiveoreffectorTcells(Teffs)resistanttothesuppressiveeffectsofTregs

•  Incontrast,blockingGITR-GITRLsignalingwithantagonistan1-GITRLan1bodiesinhibitsTlymphocyteac1va1on

1.  Mouseglucocor1coid-inducedtumornecrosisfactorreceptorligandiscos1mulatoryforTcells.Tone,M.,Tone,Y.,Adams,E.,Yates,S.F.,Frewin,M.R.,Cobbold,S.P.&Waldmann,H.(2003)Proc.Natl.Acad.Sci.USA100,15059–15064

2.  Pharmacologicalmodula1onofGITRL/GITRsystem:therapeu1cperspec1ves.GiuseppeNocen1ni,SimonaRonches,MariaGraziaPetrilloandCarloRiccardiBri1shJournalofPharmacology(2012)1652089–20992089

BeyondCheckpoints:CD137/4-1BBCo-sNmulaNon

•  CD137/4-1BB,memberoftheTNFreceptorsuperfamilyTcellcos1mulatoryreceptor,isinduced,whenTcellsreceivean1gen-specificsignals

•  SignalsviaCD137/4-1BBarecos1mulatoryinnature•  CD137/4-1BBsignalingbyan1-4-1BBac1vatesvariousimmunecompetentcells,

includingTandNKcells,andAPCs,leadingtoac1va1on,cytokineinduc1on,upregula1onofCTLac1vity,andincreasedsurvival

•  Signalsthrough4-1BBaremorebiasedtowardCD8+TcellsandNKcells,bothinvitro,andinvivo

•  Invivoadministra1onofagonis1can1-CD137/4-1BBintomicepromoteCD8+Tcellexpansion,andprotectagainstseveralpathologicalcondi1ons,includingautoimmunity,cancer,andtransplanta1on.Thereasonsunderlyingtheinvitrovs.invivofunc1onsofan1-4-1BBarecurrentlyunclear.

•  Targe1ngCD137/4-1BBeitherbyan1-4-1BBalone,orincombina1onwithotheragents,haspowerfulan1cancerproper1es.

•  AfullyhumanIgG4an1-CD137an1bodyisunderdevelopmentwithsignsofclinicalac1vityanddose-dependenteffects.

VinayDS,KwonBS.4-1BB(CD137),aninduciblecos1mulatoryreceptor,asaspecifictargetforcancertherapy.BMBRep.2014Mar;47(3):122-9.AsciertoPA,SimeoneE,SznolM,FuYX,MeleroI.Clinicalexperienceswithan1-CD137andan1-PD1therapeu1can1bodies.SeminOncol.2010Oct;37(5):508-16.

J/@'&9!K!0/2264!A]I!_0I!D,1+'-),3/!

Z@!5$77!A5iJ#!5ASF!5ASF!5ASF!5ASF!5ASF! A5iJ

Immuno-modulation des lymphocytes NK

Innate-pharma.com 57

Kandalau.JClinOncol.2011.

AnN-CD40toSNmulateDCandInducedAnN-TumorImmunity

AnN-CD40mAbinduceobjecNveresponses(20%)inpancreaNcandovariancancers

BealyGL,Science2011

PancreaNccancer

VonderheideRH,Oncoimmunology2013

PR,N=6(20%)1Ovariancancer

PR,N=5(20%)

Ovariancancers

Blockthe“Don’tEatMe”Signal

HouotR,KohrtHE,MarabelleA,LevyR.Targe1ngimmuneeffectorcellstopromotean1body-inducedcytotoxicityincancerimmunotherapy.TrendsImmunol.2011;32:510-6.

AnN-tumormAb+anN-CD47:BoostMacrophagesAnNbodyDependentCellPhagocytosis(ADCP)

AnN-CD47mAbSynergizeswithRituximabtoPromotePhagocytosisandEradicateNon-HodgkinLymphoma.

ChaoMP,&,LevyR,WeissmanIL,Maje1R.An1-CD47an1bodysynergizeswithrituximabtopromotephagocytosisanderadicatenon-Hodgkinlymphoma.Cell.2010Sep3;142(5):699-713.


–  CTLA-4andPD-1•  OtherCheckpoints:B7familyandothers•  BeyondCheckpoints:Cos1mulators•  BeyondTcells:NK,DC,Macrophage•  MarkersforcheckpointpathwayinhibiNon

MarkersforCheckpointPathwayInhibiNon

•  Issuesinclinicaltrials–  PredictthepaNentsthatwillbenefitfromthetreatment(tolimitunbeneficialtox)

–  DefinealternaNvetherapeuNcapproachesfornon-respondingpaNents

–  DeterminebestpotenNalassociaNonwithtumortargetedtherapies

–  Definebiomarkerforimmunotherapytreatmentsuspension

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a&/(4!,77!+#$!3,1$(+)K!N-j$61;$!Q$)3/()$8!!>B?Se!&$2%,(!2'.,1/(!/0!.$)3/()$8!>R?E!&/(+#)?!

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!"#$%&'(&)*&"+,&-&'%.+&/&0)1&2345&

ORRaccordingtoPD-L1ExpressioninPaNentswithSolidTumors

RxAnNbody TesNngMethod N PD-L1+RR PD-L1-RRNivolumab1 Manualstaining–5H1

5%cutoffTumorstaining

49 13/3142%

0/180%

Nivolumab2 Dakoautomated5%cutoffTumorstaining

38 7/1741%

3/2114%

MPDL3280A3 AutomatedRocheDxIHC1%cutoffTumorimmunecellstaining

103 13/3636%

9/6713%

Ipi/Nivo4 Dakoautomated5%cutoffTumorstaining

56 8/1457%

17/4240%

MPDL3280A(an1-PD-L1)5

130 26/6043%

8/7011%

From:ImmuntherapyinCancer:FromPrinciplestoPrac1ce1.TopalianSL,etal.NEnglJMed.2012;366:2443-54.2.GrossoJ,etal.ASCO2013.Abstract3016.3.HerbstRS,etal.ASCO2013.Abstract3000.4.SznolM,etal.ASCO2014.LBA9003.5.PowlesT,Nature2014;515:558-562

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53pa1entsincluded,40%objec1veclinicalresponses,65%witheitherimmuneorclinicalresponseAtthehighestdose,53%clinicalresponsewith80%tumorregression

Nivolumab(AnN-PD1)+Ipilimumab(anN-CTLA4)inadvancedmelanoma

Nivolumab + Ipilimumab in advanced melanoma. Wolchok SL, et al., N Engl J Med. 2013

Progression-free Survival.

Larkin J et al. N Engl J Med 2015;373:23-34

BaselineDensity,LocaNonandProximityofCD8+,PD-1+,PD-L1+andT-cellRepertoirePredictAnN-PD1TreatmentOutcome.

PC Tumeh et al. Nature 515, 568-571 (2014)

Response Progression

Tumor

Invasive margin

PC Tumeh et al. Nature 515, 568-571 (2014)

CD8TCellInfiltraNonIncreasesFollowingAnN-PD1Treatment

CD8TcellsproliferatefollowinganN-PD1treatment

MutaNonalLandscapeofTumorsAccordingtoClinicalBenefitfromIpilimumabTreatment(melanoma).

SnyderAetal.NEnglJMed2014.

MutaNonallandscapedeterminessensiNvitytoPD-1blockadeinnon–smallcelllungcancer

RizviNAetal.Science2015

74

Combinaisons thérapeutiques

Approches explorées1-4

75

Chimiothérapie +

+ Immunothérapie

Radiothérapie +

+ Thérapie ciblée

Immunothérapie active

•  Rationnel, stratégie, séquence ?

1. Drake CG. Ann Oncol 2012;23(suppl 8):viii41-viii46. 2. Hannani D, et al. Cancer J 2011;17:351-8. 3. Ménard C, et al. Cancer Immunol Immunother 2008;57:1579-87. 4. Ribas A, et al. Curr Opin Immunol 2013:25:291-6.

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