cours du groupe d’oncologie de la société de...
Post on 12-Sep-2018
213 Views
Preview:
TRANSCRIPT
-----------------------
ImmunothérapieenCancérologie:checkpointsimmunologiquesetvoiesderecherche
---------------
ChristopheCAUX
CancerResearchCentreofLyonINSERMU1052,CentreLéonBérard
Director A. Puisieux
TeamN°11«TherapeuNctargeNngoftumorcellsandtheirimmuneenvironment»
Christophe Caux DR Inserm
CoursduGrouped’OncologiedelaSociétédePneumologiedeLangueFrancaise
(GOLF)20Septembre2016
#$$%&'"6%+8/.22,&1/!,&9!/61,-/!$/1),&.6$6!
!•! C8.9/&1/6!'>!(%$'+!.$$%&'"6%+8/.22,&1/!
•! "#$!%&&'($!)*)+$&!,)!,!-,..%$.!+/!+'&/.!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!0/.&,1/(!,(2!3./4.$))%/(!
•! 5,(6$.!6$77)8!9/:!+#$*!,;/%2!%&&'($!)'.;$%77,(6$!,(2!2$)+.'61/(!
•! <&&'($!5#$6=3/%(+)!
K%$'+!
K!1/226!
EvidencesofTumorImmuno-SurveillanceinImmunocompetentMice:ExampleofIFNg1
Wildtype129/SvIFN-gR-/-
Methylcholanthrene
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
Days
Tumorvolum
e ~20%
CarcinogeneLowdose
a-CD4,a-CD8a-IFN-g
EvidencesofTumorImmuno-SurveillanceinHuman:IncreasedCancerIncidenceinImmuno-DepressedTransplantedPaNents1
1.Birkeland,IntJCancer199530:183-9.
TumorSite RaNo
Skin(non-melanoma) 24.7
Thyroid 14.3
Endocrinesystem 13.8
ORL 10.8
Vulva,vagina 10.3
Non-HodgkinLymphoma
9.1
Kidney 5.5
Colorectal 3.6
Lung 2.4
Brain 2.4
Prostate 2.1
Melanoma 1.7
EffectorMemoryTCellsInfiltraNonPredictSurvivalinColorectalCancer1
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.
#$$%&'"6%+8/.22,&1/!,&9!/61,-/!$/1),&.6$6!
!•! X;%2$(6$)!/0!+'&/.!%&&'(/H)'.;$%77,(6$!
•! K)/!.$$%&/!6@6(/$!,6!,!W,++./+!('!(%$'+!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!>'+$,N'&!,&9!-+'3+/66.'&!
•! 5,(6$.!6$77)8!9/:!+#$*!,;/%2!%&&'($!)'.;$%77,(6$!,(2!2$)+.'61/(!
•! <&&'($!5#$6=3/%(+)!
K%$'+!
K!1/226!
e/$,('-'./N1!B(/$!1/22!
A]!1/226!
D,1+'-),3/6!
_/&9+.N1!1/226!
J!1/226!
K!1/226!
Z@!`!(,+'.,7!=%77$.?!>?!Z/.;$77!a?!<(8![.$(2$.4,)+!^5!$+!,7?!/'-0+*&,::)-;(<+*'=>?!R(2!$2?!X7)$;%$.D!RI>V8>>]RS?!
#&&,(/!#$$%&.(@!
5,(!.$6/4(%b$!(,1;$!)+.'6+'.$)!+#./'4#!)/&,16!$(6/2$2!.$6$3+/.)!0./&!
3,+#/4$()!,(2!(,)6$(+!+'&/.!6$77)!,(2!2$)+./*!
+#$&! D,1+'-),3/6!
J'()!#&&,(/!,&9!:9,-N8/!:+$6!'>!K)/!#$$%&/!B@6(/$!0,&!T.3)(!K%$'+6!
Q$6/4(%b$!,(2!$.,2%6,+$!3,+#/4$()!,(2!(,)6$(+!+'&/.!6$77)!+#./'4#!+#$%.!,(14$(!.$6$3+/.!"5Q!P!W5Q!T#%4#!2%;$.)%+*!2'$!
+/!4$($16!.$6/&-%(,1/(U!
:9,-N8/!#$$%&.(@!
TheInnateImmuneSystemFightTumorsViaaVarietyofFuncNonallySpecializedCells1
NK=naturalkiller.1.NorvellA.In:PrendergastGCetal.CancerImmunotherapy.2nded.Elsevier;2013:11–24.
Destruc1onofInfectedcellsbyCytotoxicity,PhagocytosisorAn1bodyDependentCellCytotoxicity
B'$/!K%$'+!0/226!CY-+/66!D%2N-2/!:&N3/&6!K),(!:+/!A'(!CY-+/66/9!W@!A'+$,2!0/226E!
>?!\%((!NM?!"&1-23&.&4+5?!RIICDVEC8RFIS]RF>E?!
K%$'+!1/226!/Y-+/66\+/2/,6/!,W&'+$,2!6/2>!,&N3/&6!(),(!1,%6/!()/$!('!W/!+/1'3&.i/9!,6!
>'+/.3&!/&NN/6!,&9!()/+/>'+/!/2.1.(!,&!.$$%&/!+/6-'&6/^!
A'+$,2!1/226!/Y-+/66\+/2/,6/!$'2/1%2/6!(),(!9'&Q(!/2.1.(!,&!.$$%&/!+/6-'&6/!U('2/+,&1/!('!
&'+$,2!6/2>V^!
AR=D:?!0C??! K;DR=!0C??!
MutaNonalHeterogeneityinCancerCreatesTherapeuNcChallengesandOpportuniNes
AlteredproteinscontainnewepitopesforimmunerecogniNon,providingacommondenominaNonforimmunotherapy
TUMOR
>?!J,*!@\!M.!$+!,7?!<(8![.$(2$.4,)+!^5!$+!,7?!/'-0+*&,::)-;(<+*'=>?!R(2!$2?!X7)$;%$.D!RI>V8>I>]>>V?!
1. Antigens are released by tumor cells and captured by dendritic cells.
Dendritic cell
K!1/226!:+/!#$-'+(,&(!.&!()/!:W.2.(@!'>!()/!#$$%&/!B@6(/$!('!_/(/1(!,&9!_/6(+'@!K%$'+!0/226E!
_0!&/(b'+5!.&!65.&!
TUMOR 2. Dendritic cells activate naive T cells in lymph
nodes.
1. Antigens are released by tumor cells and captured by dendritic cells.
Dendritic cell
LYMPH NODE
Naive T cell
LYMPH
>?!J,*!@\!M.!$+!,7?!<(8![.$(2$.4,)+!^5!$+!,7?!/'-0+*&,::)-;(<+*'=>?!R(2!$2?!X7)$;%$.D!RI>V8>I>]>>V?!
K!1/226!:+/!#$-'+(,&(!.&!()/!:W.2.(@!'>!()/!#$$%&/!B@6(/$!('!_/(/1(!,&9!_/6(+'@!K%$'+!0/226E!
TUMOR
3. Activated T cells migrate back to the tumor.
2. Dendritic cells activate naive T cells in lymph
nodes.
1. Antigens are released by tumor cells and captured by dendritic cells.
Activated T cell
Dendritic cell
LYMPH NODE
Naive T cell
LYMPH
>?!J,*!@\!M.!$+!,7?!<(8![.$(2$.4,)+!^5!$+!,7?!/'-0+*&,::)-;(<+*'=>?!R(2!$2?!X7)$;%$.D!RI>V8>I>]>>V?!
K!1/226!:+/!#$-'+(,&(!.&!()/!:W.2.(@!'>!()/!#$$%&/!B@6(/$!('!_/(/1(!,&9!_/6(+'@!K%$'+!0/226E!
TUMOR
4. T cells kill tumor cells through the release of lytic enzymes or
induction of apoptosis.
3. Activated T cells migrate back to the tumor.
2. Dendritic cells activate naive T cells in lymph
nodes.
1. Antigens are released by tumor cells and captured by dendritic cells.
Activated T cell
Dendritic cell
LYMPH NODE
Naive T cell
LYMPH
1. Antigens are released by tumor cells and
K%$'+!
K!1/226!
>?!J,*!@\!M.!$+!,7?!<(8![.$(2$.4,)+!^5!$+!,7?!/'-0+*&,::)-;(<+*'=>?!R(2!$2?!X7)$;%$.D!RI>V8>I>]>>V?!
K!1/226!:+/!#$-'+(,&(!.&!()/!:W.2.(@!'>!()/!#$$%&/!B@6(/$!('!_/(/1(!,&9!_/6(+'@!K%$'+!0/226E!
K"0/22!:1N8.(@!#6!=/3%2,(/9!J@!#$$%&/!0)/15-'.&(6!('!?.$.(!:%('.$$%&.(@E!!
TUMOR
5"LaHS!`!6*+/+/c%6!"H7*&3#/6*+$!,(14$(!SD![AH>!`!3./4.,&&$2!6$77!2$,+#!3./+$%(!>D!La^HV!`!7*&3#/6*+$!,61;,1/(!4$($!VD!"<JHV!`!"H6$77!%&&'(/47/-'7%(!,(2!&'6%(!3./+$%(!V?!>?![,.2/77!AJ?!"'(&8+9&/'-0+*?!RI>RD>R8RERHRGS?!!!
Activated T cell
Immune checkpoints, such as CTLA-4, PD-1, LAG-3, and TIM-3 function at
different phases in the immune response to regulate the duration and level of the T-
cell response.
Checkpoints
TUMORCheckpoints H H
Inactivated T cell
Inactivated T cell
LYMPH NODE
Dendritic cell
HH
#$$%&'"6%+8/.22,&1/!,&9!/61,-/!$/1),&.6$6!
!•! X;%2$(6$)!/0!+'&/.!%&&'(/H)'.;$%77,(6$!
•! "#$!%&&'($!)*)+$&!,)!,!-,..%$.!+/!+'&/.!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!0/.&,1/(!,(2!3./4.$))%/(!
•! 0,&1/+!1/2264!e'b!()/@!,8'.9!.$$%&/!6%+8/.22,&1/!,&9!9/6(+%1N'&!
•! <&&'($!5#$6=3/%(+)!
K%$'+!
K!1/226!
K%$'+!/61,-/!$/1),&.6$6!
>?!A.,=$!5^K!$+!,7?!#59!,::)-;3?!RIIGDBI8E>]C>D!R?!Y$)$7*!JAK!$+!,7?!#--)&8+9&,::)-;3?!RI>>DRB8RVE]RF>?!!!
U/3I!K+/36V!
U/3I!KPT"JV!
U/3I!9'b&!+/3%2,N'&!'>!De0!#V!
U/3I!9.6+%-N'&!'>!K"1/22!1)/15-'.&(!-,()b,@6V!
#&).W.N'&!'>!(%$'+!,&N3/&!-+/6/&(,N'&!
E
B/1+/N'&!'>!.$$%&'6%--+/66.8/!>,1('+6!
H
#&).W.N'&!'>!,j,15!W@!.$$%&/!1/226!
c
=/1+%.($/&(!'>!.$$%&'6%--+/66.8/!1/22!
(@-/6!
k
:S0!K%$'+!0/22!
K"+/3!:1N8,(/9!K"
1/22!
>B!
K%$'+!/61,-/!$/1),&.6$6!
>?!A.,=$!5^K!$+!,7?!#59!,::)-;3?!RIIGDBI8E>]C>D!R?!Y$)$7*!JAK!$+!,7?!#--)&8+9&,::)-;3?!RI>>DRB8RVE]RF>?!!!
U/3I!K+/36V!
U/3I!KPT"JV!
U/3I!9'b&!+/3%2,N'&!'>!De0!#V!
U/3I!9.6+%-N'&!'>!K"1/22!1)/15-'.&(!-,()b,@6V!
#&).W.N'&!'>!(%$'+!,&N3/&!-+/6/&(,N'&!
E
B/1+/N'&!'>!.$$%&'6%--+/66.8/!>,1('+6!
H
#&).W.N'&!'>!,j,15!W@!.$$%&/!1/226!
c
=/1+%.($/&(!'>!.$$%&'6%--+/66.8/!1/22!
(@-/6!
k
:S0!K%$'+!0/22!
K+/3!:1N8,(/9!K"
1/22!
RI!
MHC II
TCR
Adapté de : Wood, K.J. and Sakaguchi, S. (2003) Nat Rev Immunol 3, 199-210
conventional T cell
=/3%2,('+@!K!2@$-)'1@(/6!UK+/3V!.&).W.(!1'&8/&N'&,2!K!1/22!,1N8,N'&!
!! Involved in auto-immunity
!! Contributing to tumor development
-! Increase Treg frequency in blood of patients suffering from different cancer types (Udaya 2002, Wolf 2003)
- Negative Impact on patients survival in
ovarian cancer (Curiel 2004)
k^!=/1+%.N&3!#$$%&'6%--+/66.8/!0/226!4!./!K+/3!CY-2'.N&3!#$$%&/!K'2/+,&1/!S,()b,@6!
RegulatoryTcell(Treg)InfiltraNonIsaBadPrognosisFactorinOvarianTumor
Curiel.NatMed.2004;10:942.
Allstages
StagesIII StagesIV
S2,6$,1@('.9!_/&9+.N1!0/226!U-_0V!,&9!K+/3!,(!()/!0/&(/+!!
'>!#$$%&'6%--+/66.8/!A/(b'+56!.&!J+/,6(!K%$'+6!!
E?!^/-$.+!JK!/'-0+*&8+?@&RIIBD!H?!Jd(d+.%$.H5,'c!5K!/'-0+*&8+?@&RIIBD!k?!\,4$+!MK!Jd(d+.%$.H5,'c!5@&/'-0+*&8+?@&RI>>D!c?!L,-%2%H^,7*!W$(2.%))HY$.&,.$!Z@&/'-0+*&8+?&RI>>D!G?!\,4$+!MK!Jd(d+.%$.H5,'cK!/'-0+*&8+?@&RI>RD!X?!O%)%.,=!YK!W$(2.%))HY$.&,.$!Z@&/'-0+*&8+?&RI>RD!l?!O%)%.,=!YK!W$(2.%))HY$.&,.$!ZK!,-(&.&/'-0+*&RI>VD!d?!L$!J$.6%$.!<K!['%)%$'c!<K!^/'+,4(*!Z@&/'-0+*&8+?&RI>V!
e!,7%;$!3,
1$(+)!
I!
IKR!
IKS!
IKG!
IKC!
>KI!
K+/3).3)!
K+/3?'b!
I! RI! SI! GI! CI! >II!
R8/+,22!B%+8.8,2!
D'&()6!>+'$!9.,3&'6.6!
HFY!cFY!
-_0\K+/3!
R8/+,22!B%+8.8,2!e!,7%;$!3,
1$(+)!
PDC -
PDC +
D'&()6!>+'$!9.,3&'6.6!80 60 40 20 0
1,0 ,9 ,8 ,7 ,6 ,5 ,4 ,3 ,2 ,1
0,0 -!m!F^FFFE! U&mHGFV!
>?!^/-$.+!JK!/'-0+*&8+?@&RIIBD!R?!Jd(d+.%$.H5,'c!5K!/'-0+*&8+?@&RIIBD!V?!\,4$+!MK!Jd(d+.%$.H5,'c!5@&/'-0+*&8+?@&RI>>D!S?!L,-%2%H^,7*!W$(2.%))HY$.&,.$!Z@&/'-0+*&8+?&RI>>D!E?!\,4$+!MK!Jd(d+.%$.H5,'cK!/'-0+*&8+?@&RI>RD!G?!O%)%.,=!YK!W$(2.%))HY$.&,.$!Z@&/'-0+*&8+?&RI>RD!F?!O%)%.,=!YK!W$(2.%))HY$.&,.$!ZK!,-(&.&/'-0+*&RI>VD!C?!L$!J$.6%$.!<K!['%)%$'c!<K!^/'+,4(*!Z@&/'-0+*&8+?&RI>V!
X3%+#$7%,7!"'&/.!
KPT!
pDC
"!5$77!Xf$6+/.)!
+
X3%+#$7%,7pDC : plasmacytoïd DC
+ CD8
CD4
Treg
Treg
Treg
Treg
#TA"
#?"EF+ ICOS
S2,6$,1@('.9!_/&9+.N1!0/226!U-_0V!,&9!K+/3!,(!()/!0/&(/+!!
'>!#$$%&'6%--+/66.8/!A/(b'+56!.&!J+/,6(!K%$'+6!!
K%$'+!/61,-/!$/1),&.6$6!
>?!A.,=$!5^K!$+!,7?!#59!,::)-;3?!RIIGDBI8E>]C>D!R?!Y$)$7*!JAK!$+!,7?!#--)&8+9&,::)-;3?!RI>>DRB8RVE]RF>?!!!
U/3I!K+/36V!
U/3I!KPT"JV!
U/3I!9'b&!+/3%2,N'&!'>!De0!#V!
U/3I!9.6+%-N'&!'>!K"1/22!1)/15-'.&(!-,()b,@6V!
#&).W.N'&!'>!(%$'+!,&N3/&!-+/6/&(,N'&!
E
B/1+/N'&!'>!.$$%&'6%--+/66.8/!>,1('+6!
H
#&).W.N'&!'>!,j,15!W@!.$$%&/!1/226!
c
=/1+%.($/&(!'>!.$$%&'6%--+/66.8/!1/22!
(@-/6!
k
:S0!K%$'+!0/22!
K"+/3!:1N8,(/9!K"
1/22!
RE!
S_"E\S_"?E!
#$$%&'"6%+8/.22,&1/!,&9!/61,-/!$/1),&.6$6!
!•! X;%2$(6$)!/0!+'&/.!%&&'(/H)'.;$%77,(6$!
•! "#$!%&&'($!)*)+$&!,)!,!-,..%$.!+/!+'&/.!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!0/.&,1/(!,(2!3./4.$))%/(!
•! 5,(6$.!6$77)8!9/:!+#$*!,;/%2!%&&'($!)'.;$%77,(6$!,(2!2$)+.'61/(!
•! #$$%&/!0)/15-'.&(6!
K%$'+!
K!1/226!
ImmuneCheckpoints• Checkpointpathways
– CTLA-4andPD-1• OtherCheckpoints:B7familyandothers• BeyondCheckpoints:Cos1mulators• BeyondTcells:NK,DC,Macrophage• Markersforcheckpointpathwayinhibi1on
<&&'($!5#$6=3/%(+)!
[,.2/77?!"'(&8+9&/'-0+*%&AI>R?!
\,&%77$!WF!
\,&%77$!"Z\!
GJFreeman&AHSharpe.NatImmunol.2012.
TumorInfiltraNngLymphocytesExpressMulNpleImmunoinhibitoryReceptors
Thesearedruggabletargetsfortumorimmunotherapy
Signal1
Signal2
CTLA-4andPD-1PathwayInhibitsTCellResponses
GFreeman2008;PNAS105:10275
#-.2.$%$,W!U:&N"!0K?:cV!#$-+'8/!?'&3!K/+$!B%+8.8,2!.&!D/(,6(,N1!D/2,&'$,!
<3%7%&'&,-!37')!2,6,.-,b%($!0/.!3.$;%/')7*!'(+.$,+$2!&$+,)+,16!&$7,(/&,?>!!
<&3./;$2!)'.;%;,7!:%+#!%3%7%&'&,-!%(!3,1$(+)!:%+#!&$+,)+,16!&$7,(/&,?!R!
>?!Q/-$.+!5K!"#/&,)!LK!$+!,7?!"&1-23&.&4+5?!RI>>D!VGS8RE>FHRG?!R?!9/2%!\OK!NgA,*!OMK!$+!,7?!"&1-23&.&4+5%&RI>ID!VGV8F>>HRV!
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
AnN-PD-1andAnN-PD-L1mAbsBlockDisNnctInteracNons
ImmuneCheckpoints• Checkpointpathways
– CTLA-4andPD-1• OtherCheckpoints:B7familyandothers• BeyondCheckpoints:Cos1mulators• BeyondTcells:NK,DC,Macrophage• Markersforcheckpointpathwayinhibi1on
R()/+!#$$%&/!0)/15-'.&(6!
[,.2/77?!"'(&8+9&/'-0+*%!RI>R?!
Jl!>,$.22@!
?:PkI!K#DkI!p!
• Igsuperfamilymember• BindsMHCclassII(likeCD4)• ExpressedbyacNvatedTcells• LAG-3ligaNoninhibitsTCRsignaling• AlsoexpressedbyTregs.BlockingofLAG-3resultsininhibiNonofsuppressivecapacity
• AcNvaNonofCD8+TcellsleadstoLAG-3upregulaNon• LAG-3mayrenderCD8+Tcellsinatolerogenicstate• CombinedanN-PD1andanN-LAG-3mayhavebejeranN-tumoreffects
LAG-3(lymphocyteacNvaNongene-3)
TIM-3(Tcellimmunoglobulin-3)• IgsuperfamilymemberconsistsofanN-terminalIgV
domainandamucindomain• Tim-3ligand:S-typelecNngalecNn-9(Gal-9),soluble
moleculewidelyexpressed,upregulatedbyIFN-γ• Tim-3asanegaNveregulatorymolecule:negaNve
regulatorofIFN-g-secreNngCD4+Thelper1andCD8+Tcytotoxic1cells
• PromotedevelopmentofCD8+TcellexhausNon• Invivoblockaderesultsinexacerbatedautoimmunityand
abrogaNonoftoleranceinexperimentalmodels,• Induceexpansionofmyeloid-derivedsuppressorcells
(MDSC),expressinghighlevelsofGla-9• TumorinfiltraNnglymphocytesco-expressedPD-1and
TIM-3
SakuishiK,TrendsImmunol.2011;32:345-9AndersonAC.CurrOpinImmunol.2012;24:213-6
NewCombina1onImmunotherapies:
• An1-PD1/PDL1+an1-LAG3• An1-PD1/PDL1+an1-TIM-3• An1-PD1+agonis1can1-GITR• An1-PD1+otheragonis1can1bodies• Triplecombina1ons?(an1-CTLA4+an1-PD1+3rdnewdrug)
WooSetal.CancerRes.2012;72:917-927.
AnN-LAG-3+AnN-PD-1
CombinatorialanN–LAG-3/anN–PD-1TreatmentInhibitsTumorGrowth
EffectofTargeNngtheTim-3andPD-1SignalingPathwaysonTumorGrowth.
Sakuishi K et al. J Exp Med 2010;207:2187-2194
CT26 tumor cells implanted into wild-type BALB/c mice.
W7,(=!5pK!/)**+-(&E=&E-0;3%&AFGH%!
#$$%&/!0)/15-'.&(!S,()b,@6!.&!12.&.1,2!(+.,26!
ImmuneCheckpoints• Checkpointpathways
– CTLA-4andPD-1• OtherCheckpoints:B7familyandothers• BeyondCheckpoints:CosNmulators• BeyondTcells:NK,DC,Macrophage• Markersforcheckpointpathwayinhibi1on
W7,(=!5p?!/)**+-(&E=&E-0;3%!RI>S?!
#$$%&/!0'6N$%2,N'&!S,()b,@6!.&!02.&.1,2!K+.,26!
S'6.N8/!0'6N$%2,N'&!S,()b,@6!!
\,&%77$!"Z\!
TcellTargetsforImmunoregulatoryAnNbodyTherapy
Mellmanetal.Nature.2011;480,480-489.
BMS-663513
• BMS-936558• CT011• MK-3475SCH900475
AnNPDL-1BMS-936559
TRX518
AgonistanN-OX40
ICOS ICOS
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.
ImmuneCheckpoints• Checkpointpathways
– CTLA-4andPD-1• OtherCheckpoints:B7familyandothers• BeyondCheckpoints:Cos1mulators• BeyondTcells:NK,DC,Macrophage• Markersforcheckpointpathwayinhibi1on
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.
ImmuneCheckpoints• Checkpointpathways
– CTLA-4andPD-1• OtherCheckpoints:B7familyandothers• BeyondCheckpoints:Cos1mulators• BeyondTcells:NK,DC,Macrophage• MarkersforcheckpointpathwayinhibiNon
MarkersforCheckpointPathwayInhibiNon
• Issuesinclinicaltrials– PredictthepaNentsthatwillbenefitfromthetreatment(tolimitunbeneficialtox)
– DefinealternaNvetherapeuNcapproachesfornon-respondingpaNents
– DeterminebestpotenNalassociaNonwithtumortargetedtherapies
– Definebiomarkerforimmunotherapytreatmentsuspension
S_"?E!CY-+/66.'&!.&!A'&oB$,22"0/22!?%&3!0,&1/+6^!
!"#$%&'(&)*&"+,&-&'%.+&/&0)1&2345&
S/$W+'2.i%$,W!>'+!()/!K+/,($/&(!'>!A'&oB$,22"0/22!?%&3!0,&1/+!
a&/(4!,77!+#$!3,1$(+)K!N-j$61;$!Q$)3/()$8!!>B?Se!&$2%,(!2'.,1/(!/0!.$)3/()$8!>R?E!&/(+#)?!
[O8!3./3/.1/(!)6/.$!`!!e!/0![AHL>!$c3.$))%(4!!+'&/.!6$77)!
!"#$%&'(&)*&"+,&-&'%.+&/&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
R&1'3/&/!8/+6%6!K!1/22o_+.8/&!S_"?E!CY-+/66.'&!;-"=/3%2,N'&!
Ob(/7!J!$+!,7?!aO5N!RI>V?!a-)+.,6+!5QaBIIG?!
De0!De0!
S_"?E!S_"?E!S_"?E!S_"?E!
S_"E!S_"E!
S_"E!
S_"?E!S_"?E!
K"1/22!+/1/-('+!
S_"?H!
K!1/22!
ATvJ!R()/+!
S#k]!
K%$'%+!1/22!
#TAr!
#TAr=!
B)-"H!
R&1'3/&.1!-,()b,@!E!
H!
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.
J,.,-$77$!aK!5,'c!5?!C3;;5?!RI>RD!>RI8SSESHE?!
0'$W.&/9!K,+3/(/9!,&9!#$$%&'()/+,-@4!K)/!T%(%+/!'>!S/+6'&,2.i/9!D/9.1.&/!
top related