PRAMETNFSF18CXCL1CXCL6BST1CLEC5APSMD7DMBT1CEACAM6FOXJ1CXCR1CXCR2ALCAMITCHCXCL3CXCL5C2CSF1STAT2MAP2K2ADAIRAK4CT45A1CCR6C9LBPTLR5TNFSF14CFDSTAT3BCL6CXCR4CCL20CEBPBLIFSAA1C1RC1SPTGS2C4BPACCL11CXCL2adeno_sigTREM1SLC11A1TNFRSF11ABIRC5CDK1CARD11TTKIL8PLAURRIPK2IFI16LY96CD14FCGR2ACSF2RBLYNCCL8TNFSF4MFGE8THY1DOCK9NOTCH1CD36MCAMTRAF6CD34ENGJAM3NRP1ITGA1CDH5TAL1AKT3MAPK3ITGB3MAPK8PRKCEMAFVEGFACD164HMGB1SMAD2TXNIPTNFSF12BMI1CREB1CYFIP2ECSITCDH1RORAMIFTLR3CCL15EPCAMDEFB1CREB5ATG10CD24CD46CXCL14CX3CL1IFIT1MAPK1SPA17APPCD59ITGA6MAP2K4IGF1RSTAT5BRORCTOLLIPMASP1PPARGBCL2DPP4
PRAM
ETN
FSF18
CXC
L1CXC
L6BS
T1CLEC5A
PSMD7
DMBT
1CEA
CAM
6FO
XJ1
CXC
R1
CXC
R2
ALCAM
ITCH
CXC
L3CXC
L5 C2
CSF
1STAT2
MAP
2K2
ADA
IRAK
4CT45A1
CCR6
C9
LBP
TLR5
TNFS
F14
CFD
STAT3
BCL6
CXC
R4
CCL20
CEB
PB LIF
SAA1
C1R C1S
PTGS2
C4BPA
CCL11
CXC
L2adeno_sig
TREM
1SLC11A1
TNFR
SF11A
BIRC5
CDK1
CAR
D11
TTK
IL8
PLAU
RRIPK2
IFI16
LY96
CD14
FCGR2A
CSF
2RB
LYN
CCL8
TNFS
F4MFG
E8TH
Y1DOCK9
NOTC
H1
CD36
MCAM
TRAF
6CD34
ENG
JAM3
NRP1
ITGA1
CDH5
TAL1
AKT3
MAP
K3ITGB3
MAP
K8PR
KCE
MAF
VEGFA
CD164
HMGB1
SMAD
2TX
NIP
TNFS
F12
BMI1
CREB
1CYF
IP2
ECSIT
CDH1
RORA
MIF
TLR3
CCL15
EPCAM
DEF
B1CREB
5ATG10
CD24
CD46
CXC
L14
CX3CL1
IFIT1
MAP
K1SPA17
APP
CD59
ITGA6
MAP
2K4
IGF1R
STAT5B
RORC
TOLLIP
MAS
P1PPAR
GBC
L2DPP
4
Spearman rho
−1−0.500.51
ModuleCCL20SAA1CXCL3CX3CL1GF
Reclusterrecluster_186recluster_163recluster_438NA
ModuleCCL20SAA1CXCL3CX3CL1GF
Reclusterrecluster_186recluster_163recluster_438NA
PRAMETNFSF18CXCL1CXCL6BST1CLEC5APSMD7DMBT1CEACAM6FOXJ1CXCR1CXCR2ALCAMITCHCXCL3CXCL5C2CSF1STAT2MAP2K2ADAIRAK4CT45A1CCR6C9LBPTLR5TNFSF14CFDSTAT3BCL6CXCR4CCL20CEBPBLIFSAA1C1RC1SPTGS2C4BPACCL11CXCL2Adeno
SigTREM1SLC11A1TNFRSF11ABIRC5CDK1CARD11TTKIL8PLAURRIPK2IFI16LY96CD14FCGR2ACSF2RBLYNCCL8TNFSF4MFGE8THY1DOCK9NOTCH1CD36MCAMTRAF6CD34ENGJAM3NRP1ITGA1CDH5TAL1AKT3MAPK3ITGB3MAPK8PRKCEMAFVEGFACD164HMGB1SMAD2TXNIPTNFSF12BMI1CREB1CYFIP2ECSITCDH1RORAMIFTLR3CCL15EPCAMDEFB1CREB5ATG10CD24CD46CXCL14CX3CL1IFIT1MAPK1SPA17APPCD59ITGA6MAP2K4IGF1RSTAT5BRORCTOLLIPMASP1PPARGBCL2DPP4
Adenosinesignaturegenesassociatewithtumorregressioninrenalcellcarcinoma(RCC)patientstreatedwiththeadenosineA2Areceptor(A2AR)antagonist,CPI-444.1AndrewHotson,1StephenWillingham,2LawrenceFong,3JohnPowderlyII,4JasonLuke,5MarioSznol,6SabyGeorge,7ToniK.Choueiri,7MariosGiannakis,8BrianRini,9ShivaaniKummar,10ErikEvensen,1IanMcCaffery,1ChunyanGu,1LongKwei,1GinnaLaport,1JoeBuggyand1RichardMiller1CorvusPharmaceuticals,Burlingame,CA;2UniversityofCalifornia,SanFrancisco,SanFrancisco,CA;3CarolinaBioOncology
Institute,Huntersville,NC;4UniversityofChicagoMedicalCenter,Chicago,IL,
5YaleUniversitySchoolofMedicine,NewHaven,CT;
6RoswellPark,Buffalo,NY;7Dana-FarberCancerInstitute,Boston,MA;8ClevelandClinic,Cleveland,OH;
9StanfordUniversitySchoolofMedicine,Stanford,CA;10BasisBioscience,FosterCity,CA
Background
Phase1/1bClinicalStudywithCPI-444
AdenosineSignature:InvitroDiscoveryandInvivoApplication
AdenosineSignatureandCo-expressedGenesIdentifiedinPatientSubsetbyUnsupervisedClusteringAseparatepatientsubsetislowforadenosinesignatureandexpressesalternatebiologicalpathways
Summary•
Adenosine-responsegenesdefineanAdenosineSignaturebiomarkerthatenrichesforpatientswithtumorsthatrespondtoA2ARantagonismbyCPI-444
• GeneclusteringanalysisidentifiedtwodistinctpopulationsofRCC1)
AdenosineSignaturehigh/growthfactorlow2)
AdenosineSignaturelowandhighforgrowthfactor
responsegenes&CD26•
EnablesfuturestudiestoemployAdenosineSignatureforidentificationofsub-groupsthatassociatewithtumorresponse
PBMCs
+TCRActivation
+Adenosineanalog(NECA)
48hr
AdenosineResponsiveGenes• Comprisedofmyeloidcell
recruitmentandactivation• InhibitionofTcellactivation
SignalIdentification
AppliedtoClinicalSamples
Tumors can generateadenosine in response to anti-PD-(L)1
(Beavis et al, Can Immunol Res 2015)
Adenosine
A2ARATP
AMP
CD73
Tumor
T Cell
CD39
T Cell
PD1PD-L1
Anti-PD-1Biopsyfrom
patientscreening
GeneExpression(Nanostring)
AdenosineSignatureHighEnrichedfortumorresponderstoCPI-444
AdenosineSignatureLowNotumorregression
• Geneexpressionwascollectedfrompre-treatmentbiopsies•
Expressionwascorrelatedacrosspatientsandclustered•
Biologyself-organizedtorevealmodulesofgeneco-expression
AdenosineSignature&AssociatedGenes
AdenosineSignatureLow:CD26andGrowthFactorSignaling
Spearman’sCorrelation
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400
1500 1600
Dpp4
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
AdenoSig
Sheet2
CD26(Dpp4)
Aden
osineSignature • CD26isabindingpartner
forsolubleadenosinedeaminase(ADA)
• ADAdecreaseslocaladenosineconcentration
Eligibility• Heavilypretreated
(median3priortherapies)• Prioranti-PD-(L)1allowed•
Progressivediseaseon
priortherapy• NoselectionforPD-L1
expression
p =0.003
CD26NegativelyCorrelateswithAdenosineSignature
•
AdenosineblocksT-cellactivationandpromotesmyeloidsuppression
•
CPI-444isanoralsmallmoleculeantagonistoftheadenosine2Areceptor(A2AR)thathasshownefficacyinanimalmodelsandisassociatedwithTcellactivation.a,b
• OngoingclinicaltrialofCPI-444+/-
anti-PD-L1atezolizumabdemonstratestumorresponsestomonotherapyandcombinationinmultipleindicationsincludingrenalcellcarcinoma(RCC).c,d
•
FuturetrialsinRCCwouldbenefitfromabiomarkerthatpredictspatientresponse.
a)Willinghametal,CancerImmunology Research,2018b)
Leoneetal,CancerImmunology Immunotherapy, 2018c)
Hotsonetal,SITC,2017(oralpresentationbyLuke,J)d)
Fongetal,SITC,2018(oralpresentation,Sat@4:40pm)
Renal Cell Cancer
CPI-444 Monotherapy100 mg BID
CPI-444 100 mg BID +atezolizumab 840 mg, Q2W
PRAMETNFSF18CXCL1CXCL6BST1CLEC5APSMD7DMBT1CEACAM6FOXJ1CXCR1CXCR2ALCAMITCHCXCL3CXCL5C2CSF1STAT2MAP2K2ADAIRAK4CT45A1CCR6C9LBPTLR5TNFSF14CFDSTAT3BCL6CXCR4CCL20CEBPBLIFSAA1C1RC1SPTGS2C4BPACCL11CXCL2adeno_sigTREM1SLC11A1TNFRSF11ABIRC5CDK1CARD11TTKIL8PLAURRIPK2IFI16LY96CD14FCGR2ACSF2RBLYNCCL8TNFSF4MFGE8THY1DOCK9NOTCH1CD36MCAMTRAF6CD34ENGJAM3NRP1ITGA1CDH5TAL1AKT3MAPK3ITGB3MAPK8PRKCEMAFVEGFACD164HMGB1SMAD2TXNIPTNFSF12BMI1CREB1CYFIP2ECSITCDH1RORAMIFTLR3CCL15EPCAMDEFB1CREB5ATG10CD24CD46CXCL14CX3CL1IFIT1MAPK1SPA17APPCD59ITGA6MAP2K4IGF1RSTAT5BRORCTOLLIPMASP1PPARGBCL2DPP4
300133
300111
100407
1349
200432
200111
1297
300135
100435
102231
100933
103035
300136
103210
100431
102417
102010
103101
1340
200232
103231
103213
200231
102413
101001
102410
102512
103232
101111
102531
−60
−40
−20
0
20
40
Adeno_sigResponseBOPCTCHGBORDCR.6moHClust_completeHClust_wardRPMMKMeans_HW
scaled log2 expression
0.80.911.11.2
ModuleCCL20SAA1CXCL3CX3CL1GF
Reclusterrecluster_186recluster_163recluster_438NA
Adeno_sigHighLow
ResponseRNRNA
BOPCTCHG
−100−50050
BORPRSDPDNE
DCR.6mo>6mo6mo
