Adenosine Signature Genes Associate with Tumor Regression in Renal Cell Carcinoma
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PRAME TNFSF18 CXCL1 CXCL6 BST1 CLEC5A PSMD7 DMBT1 40 CEACAM6 FOXJ1 CXCR1 CXCR2 ALCAM 20 ITCH Adenosine signature genes associate with tumor regression in renal cell carcinoma CXCL3 CXCL5 C2 CSF1 STAT2 0 MAP2K2 (RCC) patients treated with the adenosine A2A receptor (A2AR) antagonist, CPIADA -444. IRAK4 CT45A1 1 1 2 3 4 5 6 7 CCR6 7 8 9 Andrew Hotson, Stephen Willingham, −20 Lawrence Fong, John Powderly II, Jason Luke, Mario Sznol, Saby George, Toni K. Choueiri, C9 Marios Giannakis, Brian Rini, Shivaani Kummar, 10 1 1 1 1 1 1 LBP Erik Evensen, Ian McCaffery, Chunyan Gu, Long Kwei, Ginna Laport, Joe Buggy and Richard Miller TLR5 TNFSF14 CFD 1 −40 2 3 STAT3 4 5 Corvus Pharmaceuticals, Burlingame, CA; University of California, San Francisco, San Francisco, CA; Carolina BioOncology Institute, Huntersville, NC; BCL6 University of Chicago Medical Center, Chicago, IL, Yale 6 7 8 CXCR4 9 University School of Medicine, New Haven, CT; Roswell Park, Buffalo, NY; Dana-Farber Cancer Institute, Boston, MA; Cleveland Clinic, Cleveland, OH;CCL20 Stanford University School of Medicine, Stanford, CA; CEBPB 10 LIF Basis Bioscience, Foster City, CA−60 SAA1 C1R C1S PTGS2 PRAME C4BPA TNFSF18 Background CXCL1 CCL11 Adenosine Signature and Co-expressed Genes Identified in Patient Subset by Unsupervised ClusteringCXCL6 CXCL2 BST1 adeno_sig CLEC5A 40 A separate patient subset is low for adenosine signature and expresses alternate biological pathwaysTREM1 PSMD7 • DMBT1 Adenosine blocks T-cell activation and promotes myeloid SLC11A1 CEACAM6 TNFRSF11A FOXJ1 20 suppression BIRC5 CXCR1 • Gene expression was collected from pre-treatment biopsies CXCR2 CDK1 ALCAM CARD11 ITCH • 0 CPI-444 is an oral small molecule antagonist of the adenosine 2A • TTK CXCL3 Expression was correlated across patients and clustered CXCL5 IL8 C2 receptor (A2AR) that has shown efficacy in animal models and is • Biology self-organized to reveal modules of gene co-expressionPLAUR CSF1 −20 RIPK2 STAT2 a,b Spearman rho ModuleMAP2K2 scaled log2 expressionIndividual patients gene expressionAdeno_sig IFI16 associated with T cell activation. 1 ADA 1.2 High LY96 IRAK4CCL20 0.5 1.1−40 Low Spearman’sCD14 Scaled Log2 CT45A1SAA1 Gene by gene correlation CCR6 • Ongoing clinical trial of CPI-444 +/- anti-PD-L1 atezolizumab FCGR2A 0 CXCL3 1 Adenosine Response Growth Factor ExpressionC9 0.9 CorrelationCSF2RB −0.5 LBPCX3CL1 R demonstrates tumor responses to monotherapy and combination in LYN −1 TLR5GF 0.8−60 NR TNFSF14 Module High Module High CCL8 Module ReclusterCFD Module NA c,d PRAMEPRAME PRAME TNFSF4 TNFSF18TNFSF18 STAT3 CCL20 TNFSF18 multiple indications including renal cell carcinoma (RCC). CXCL1 CCL20 recluster_186 BOPCTCHG CXCL1 CXCL1 CXCL6 BCL6 MFGE8 CXCL6 Adenosine-response CXCL6 BST1 SAA1 BST1 SAA1 CXCR4recluster_163 50 BST1 CLEC5A THY1 CLEC5A CLEC5A PSMD7 CXCL3 PSMD7 CXCL3genes are highlightedCCL20recluster_438 PSMD7 • DMBT1 0 Future trials in RCC would benefit from a biomarker that predicts DMBT1 DMBT1 DOCK9 CEACAM6 CEBPB CEACAM6 CX3CL1 CEACAM6 FOXJ1 CX3CL1 NA FOXJ1 −50 FOXJ1 NOTCH1 CXCR1 LIF CXCR1 GF CXCR1 CXCR2 CXCR2 GF SAA1 CXCR2 CD36 ALCAM −100 patient response. ALCAM ALCAM ITCH ITCH C1R Recluster ITCH CXCL3 MCAM CXCL3Recluster BOR CXCL3 CXCL5 C1S CXCL5 CXCL5 C2 recluster_186 TRAF6 C2 recluster_186 PTGS2 C2 CSF1CSF1 PR CSF1 STAT2STAT2 C4BPA recluster_163 STAT2 CD34 MAP2K2 MAP2K2 recluster_163 SD MAP2K2 scaled log2 expression Adeno_sig ADA CCL11 ADA recluster_438 ADA 1.2 High ENG IRAK4IRAK4 recluster_438 IRAK4 CT45A1 CXCL2 PD 1.1 Low CT45A1 NA CT45A1 JAM3 CCR6CCR6 adeno_sig CCR6 1 C9 NA NE Response C9 Adenosine C9 LBP TREM1 LBP 0.9 NRP1 LBP LBP R TLR5TLR5 SLC11A1 TLR5 0.8 NR TNFSF14TNFSF14 DCR.6mo TNFSF14 ITGA1 CFD Module NA CFD TNFRSF11A CFD STAT3STAT3 Signature & >6mo STAT3 CCL20 BOPCTCHG CDH5 BCL6BCL6 BIRC5 BCL6 SAA1 CXCR4CXCR4 CXCR4 50 CCL20 CDK1 <6mo CXCL3 TAL1 CCL20 CCL20 0 CEBPB CEBPB CX3CL1 CEBPB CARD11 −50 LIF LIF FALSE LIF GF AKT3 SAA1 Associated SAA1 SAA1 TTK −100 C1RC1R C1R Recluster MAPK3 C1S C1S BOR C1S IL8 HClust_complete C1S recluster_186 PTGS2PTGS2 PTGS2 PR C4BPA PLAUR C4BPA recluster_163 ITGB3 C4BPA 1 C4BPA SD CCL11CCL11 GenesRIPK2 CCL11 recluster_438 CXCL2 CXCL2 PD MAPK8 CXCL2 CXCL2 NA adeno_sigAdeno Sig IFI16 2 adeno_sigAdeno Sig NE PRKCE TREM1TREM1 TREM1 SLC11A1SLC11A1 LY96 3 SLC11A1 DCR.6mo TNFRSF11ATNFRSF11A TNFRSF11A >6mo MAF BIRC5 CD14 BIRC5 BIRC5 4 <6mo CDK1CDK1 FCGR2A CDK1 VEGFA CARD11CARD11 CARD11 FALSE TTKTTK CSF2RB HClust_ward TTK IL8 IL8 IL8 HClust_complete CD164 LYN PLAUR PLAURPLAUR PLAUR 1 RIPK2 RIPK2RIPK2 Spearman rho Module CCL8 1 HMGB1 IFI16 IFI16 2 IFI16 1 LY96 CCL20 LY96 3 LY96 0.5 SAA1 TNFSF4 2 SMAD2 CD14CD14 CD14 0 CXCL3 4 FCGR2AFCGR2A MFGE8 FCGR2A −0.5 CX3CL1 3 CSF2RB TXNIP CSF2RBCSF2RB CSF2RB HClust_ward GF THY1 LYN LYNLYN −1 1 CCL8CCL8 Module Recluster 4 CCL8 TNFSF12 DOCK9 TNFSF4 TNFSF4TNFSF4 CCL20 recluster_186 2 MFGE8 MFGE8MFGE8 SAA1 recluster_163NOTCH1 3 BMI1 THY1THY1 RPMM THY1 CXCL3 recluster_438 DOCK9 4 DOCK9DOCK9 CD36 DOCK9 CX3CL1 NA NOTCH1 CREB1 NOTCH1NOTCH1 NOTCH1 GF MCAM CD36 RPMM CD36CD36 rRL CD36 MCAM MCAMMCAM Recluster MCAM rRL CYFIP2 TRAF6 TRAF6 TRAF6TRAF6 recluster_186 rRR TRAF6 rRR CD34 CD34CD34 recluster_163 CD34 ECSIT ENG rLL ENGENG recluster_438 rLL ENG JAM3 JAM3JAM3 NA rLR NRP1 CDH1 NRP1NRP1 JAM3 rLR ITGA1 KMeans_HW ITGA1ITGA1 CDH5 RORA CDH5CDH5 NRP1 1 TAL1 TAL1TAL1 KMeans_HW AKT3 2 AKT3AKT3 ITGA1 MIF MAPK3 3 MAPK3MAPK3 a) Willingham et al, Cancer Immunology Research, 2018 CDH5 ITGB3 ITGB3ITGB3 1 MAPK8 TLR3 MAPK8MAPK8 TAL1 PRKCE PRKCEPRKCE b) Leone et al, Cancer Immunology Immunotherapy, 2018 2 MAF CCL15 MAFMAF AKT3 VEGFA VEGFAVEGFA AdenosineMAPK3 3 CD164 CD164CD164 c) Hotson et al, SITC, 2017 (oral presentation by Luke, J) EPCAM HMGB1 HMGB1HMGB1 ITGB3 SMAD2 SMAD2SMAD2 DEFB1 TXNIP TXNIPTXNIP MAPK8 d) Fong et al, SITC, 2018 (oral presentation, Sat @ 4:40pm) TNFSF12 TNFSF12TNFSF12 BMI1 CREB5 BMI1BMI1 Signature Low:PRKCE CREB1 CREB1CREB1 MAF CYFIP2 ATG10 CYFIP2CYFIP2 ECSIT ECSITECSIT VEGFA CDH1 CDH1CDH1 CD24 RORA RORARORA CD164 CD26 and MIF MIFMIF CD46 TLR3 TLR3TLR3 HMGB1 CCL15 CCL15CCL15 SMAD2 EPCAM CXCL14 EPCAMEPCAM DEFB1 DEFB1DEFB1 Phase 1/1b Clinical Study with CPI-444 TXNIP CREB5 CREB5 Growth Factor CREB5 CX3CL1 ATG10 ATG10ATG10 TNFSF12 CD24 CD24CD24 IFIT1 BMI1 CD46 CD46 CD46 CXCL14 CXCL14 MAPK1 CXCL14 CREB1 CX3CL1 CX3CL1CX3CL1 Signaling IFIT1 IFIT1IFIT1 CYFIP2 SPA17 MAPK1 MAPK1MAPK1 ECSIT SPA17 Eligibility SPA17SPA17 APP APP APPAPP CDH1 CD59 CD59CD59 ITGA6 CD59 ITGA6ITGA6 RORA MAP2K4 CPI-444 Monotherapy MAP2K4MAP2K4 MIF IGF1R • Heavily pretreated ITGA6 IGF1RIGF1R STAT5B STAT5BSTAT5B TLR3 RORC RORCRORC TOLLIP 100 mg BID MAP2K4 TOLLIPTOLLIP CCL15 MASP1 MASP1MASP1 PPARG (median 3 prior therapies) IGF1R PPARGPPARG EPCAM BCL2 BCL2 BCL2BCL2 DEFB1 DPP4 STAT5B DPP4DPP4 CREB5 C2 C9 IL8 LIF MIF LYN TTK LBP C1S C1R APP ADA CFD MAF ENG LY96 TAL1 IFI16 ITCH BMI1 IFIT1 TLR5 TLR3 BST1 BCL6 AKT3 BCL2 JAM3 CSF1 CD14 CCL8 THY1 CD36 CD34 CD24 CD46 CD59 SAA1 DPP4 CDK1 NRP1 CCR6 CDH5 CDH1 RORA STAT2 STAT3 IRAK4 RIPK2 ITGA1 ITGB3 ITGA6 RORC BIRC5 TXNIP ECSIT RORC IGF1R SPA17 ATG10 FOXJ1 MCAM • CCL20 CCL11 CD164 CCL15 C4BPA TRAF6 CXCL1 CXCL6 CXCL3 CXCL5 CXCL2 DEFB1 PTGS2 PLAUR VEGFA CREB1 CREB5 1349 1297 1340 PPARG DMBT1 CXCR1 CXCR2 CXCR4 TREM1 CEBPB MAPK3 MAPK8 MAPK1 MASP1 Prior anti-PD-(L)1 allowed TOLLIP PSMD7 ALCAM MFGE8 DOCK9 PRKCE SMAD2 CYFIP2 STAT5B PRAME HMGB1 EPCAM ATG10 CT45A1 TNFSF4 CXCL14 CX3CL1 CLEC5A MAP2K2 CARD11 CSF2RB MAP2K4 FCGR2A NOTCH1 SLC11A1 Renal Cell TNFSF18 TNFSF14 TNFSF12 adeno_sig CEACAM6 300133 300111 100407 200432 200111 300135 100435 102231 100933 103035 300136 103210 100431 102417 102010 103101 200232 103231 103213 200231 102413 101001 102410 102512 103232 101111 102531 TNFRSF11A TOLLIP CD24 Cancer PRAME TNFSF18 CXCL1 CXCL6 BST1 CLEC5A PSMD7 DMBT1 CEACAM6 FOXJ1 CXCR1 CXCR2 ALCAM ITCH CXCL3 CXCL5 C2 CSF1 STAT2 MAP2K2 ADA IRAK4 CT45A1 CCR6 C9 LBP TLR5 TNFSF14 CFD STAT3 BCL6 CXCR4 CCL20 CEBPB LIF SAA1 C1R C1S PTGS2 C4BPA CCL11 CXCL2 Adeno Sig TREM1 SLC11A1 TNFRSF11A BIRC5 CDK1 CARD11 TTK IL8 PLAUR RIPK2 IFI16 LY96 CD14 FCGR2A CSF2RB LYN CCL8 TNFSF4 MFGE8 THY1 DOCK9 NOTCH1 CD36 MCAM TRAF6 CD34 ENG JAM3 NRP1 ITGA1 CDH5 TAL1 AKT3 MAPK3 ITGB3 MAPK8 PRKCE MAF VEGFA CD164 HMGB1 SMAD2 TXNIP TNFSF12 BMI1 CREB1 CYFIP2 ECSIT CDH1 RORA MIF TLR3 CCL15 EPCAM DEFB1 CREB5 ATG10 CD24 CD46 CXCL14 MASP1CX3CL1 IFIT1 MAPK1 SPA17 APP CD59 ITGA6 MAP2K4 IGF1R STAT5B RORC TOLLIP MASP1 PPARG BCL2 DPP4 CD46 Adeno_sig • Progressive disease on CXCL14 Response PPARG CX3CL1 BOPCTCHG BCL2 IFIT1 BOR prior therapy DCR.6mo CPI-444 100 mg BID + DPP4 MAPK1 SPA17 HClust_complete • No selection for PD-L1 APP HClust_ward C2 C9 atezolizumab 840 mg, Q2W IL8 LIF RPMM MIF LYN TTK LBP C1S CD59 C1R APP ADA CFD Adenosine Signature Biomarker and Outcome MAF ENG LY96 TAL1 IFI16 ITCH BMI1 IFIT1 TLR5 TLR3 BST1 BCL6 AKT3 BCL2 JAM3 CSF1 CD14 CCL8 THY1 CD36 CD34 CD24 CD46 CD59 SAA1 KMeans_HW DPP4 CDK1 NRP1 CD26 Negatively Correlates with Adenosine CCR6 CDH5 CDH1 RORA STAT2 STAT3 IRAK4 RIPK2 ITGA1 ITGB3 ITGA6 RORC BIRC5 TXNIP ECSIT IGF1R SPA17 ITGA6 ATG10 FOXJ1 MCAM CCL20 CCL11 CD164 CCL15 C4BPA TRAF6 CXCL1 CXCL6 CXCL3 CXCL5 CXCL2 DEFB1 PTGS2 PLAUR VEGFA CREB1 CREB5 PPARG DMBT1 CXCR1 CXCR2 CXCR4 TREM1 CEBPB MAPK3 MAPK8 MAPK1 MASP1 TOLLIP PSMD7 ALCAM MFGE8 DOCK9 PRKCE SMAD2 CYFIP2 STAT5B PRAME HMGB1 EPCAM CT45A1 TNFSF4 CXCL14 CX3CL1 CLEC5A expression MAP2K2 CARD11 CSF2RB MAP2K4 FCGR2A NOTCH1 MAP2K4 SLC11A1 TNFSF18 TNFSF14 TNFSF12 adeno_sig CEACAM6 IGF1R TNFRSF11A ADENOSINESTAT5B SIGNATURE LOW ADENOSINE SIGNATURE HIGH SignatureSheet 2 100 RORC 100 90 TOLLIP CPI-444