US 20190025310A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2019 /0025310 A1 DUVAL et al. (43 ) Pub . Date : Jan . 24 , 2019 (54 ) METHODS FOR PREDICTING THE Publication Classification SURVIVAL TIME OF PATIENTS SUFFERING (51 ) Int. CI. FROM A MICROSATELLITE UNSTABLE GOIN 33 /574 (2006 .01 ) CANCER (52 ) U .S . CI. ( 71 ) Applicant: INSERM ( INSTITUT NATIONAL CPC . .. GOIN 33 /57419 ( 2013 .01 ) ; GOIN 2800 / 56 DE LA SANTE ET DE LA (2013 . 01 ) ; GOIN 2800 /52 ( 2013 .01 ) ; GOIN RECHERCHE MEDICALE ) , Paris 2333/ 90241 (2013 .01 ) (FR ) (72 ) Inventors : Alex DUVAL , Paris ( FR ) ; Thierry ( 57) ABSTRACT ANDRE , Paris ( FR ) ; Magali SVRCEK , Paris ( FR ) ; Aurelien DE The present invention relates to methods for predicting the REYNIES , Paris (FR ) ; Laetitia survival time of patients suffering from a micro satellite MARISA , Paris (FR ) unstable cancer . In particular, the present invention relates to a method for predicting the survival time of a patient (21 ) Appl. No. : 16 / 066, 949 suffering from a micro satellite unstable cancer comprising i ) determining the expression level of at least one gene (22 ) PCT Filed : Dec . 28 , 2016 encoding for an immune checkpoint protein in a tumor tissue sample obtained from the patient, ii ) comparing the expres ( 86 ) PCT No. : PCT/ EP2016 /082745 sion level determined at step i ) with a predetermined refer ence value and iii ) concluding that the patient will have a $ 371 ( c) ( 1 ), long survival time when the level determined at step i ) is ( 2 ) Date : Jun . 28 , 2018 lower than the predetermined reference value or concluding ( 30 ) Foreign Application Priority Data that the patient will have a short survival time when the level determined at step i ) is higher than the predetermined Dec . 29, 2015 ( EP ) .. .. .. 15307157 . 6 reference value . CIT + TCGA series . - - - - - - - - : OLO : - - - - - - - . - 1 . B - - - - - - - - - . - - - - - - - - - OverallSurvival - - - - . - - cms 1 :- - - . - - - . cms2 msi cms3 p = 0 .032 1 mss p = 0 .031 7 cms4 34 4 5 Time from diagnostic (years ) Time from diagnostic (years ) Patent Application Publication Jan . 24 , 2019 Sheet 1 of 8 US 2019 / 0025310 A1 . - - - - - - - - - - - - - - - - - - - 5 cms1: cms2 cms3 cms4 4 - - - - - - - - . - - - - - - - - . - - - . 3 Timefromdiagnostic(years) 2 031.0=pp=0.051 0 CIT+TCGAseries - - - - - - - - - - - - - - - - - - - - - - - , 5 4 msi[ Imss Timefromdiagnostic(years) 3 2 032p=0.0320=p 1 0 Survival Overall Figure 1A Patent Application Publication Jan . 24 , 2019 Sheet 2 of 8 US 2019 / 0025310 A1 MSI CIT + TCGA series variable p -value HR 95 % CI. ICK 0 . 0068 3 .5 ( 1 . 4 - 8 . 5 ) TH1 0 .013 2 . 2 ( 1 . 2 - 4 . 1 ) Metagenes CTL 0 .052 1 . 7 ( 1 - 3 ) CYTOX 0 .038 1 . 6 ( 1 . 0 - 2 . 5 ) PDCD1 0 .059 2 . 8 ( 1 . 0 - 8 . 0 ) TNERSF18 0 .025 2 . 6 ( 1 . 1 - 5 . 8 ) HAVCR2 0 .016 2 . 3 ( 1 . 2 - 4 . 7 ) CD40 0 . 028 2 . 3 ( 1 . 1 - 4 . 7 ) CD274 0 .0050 2 . 2 ( 1. 3 - 3 . 9 ) LAG3 0 .017 2 . 2 ( 1. 2 - 4 . 2 ) VTCN1 0 .067 2 . 1 ( 1 . 0 - 4 . 7 ) TNFRSFS 0 . 057 2 . 0 ( 1 . 0 - 4 . 2 .) ImmuneCheckpoints+Modulator IL2RB 0 .034 1 . 8 ( 1 . 1 - 3 . 1 ) ID01 0 .0090 1 . 4 ( 1 . 1 - 1 . 8 ) TNFRSF4 0 . 1 1 . 8 ( 1 . 0 - 3 . 8 ) CTLA4 0 . 27 1 .6 ( 0 . 7 - 3 . 4 ) PDCD1LG2 0 . 16 1 . 5 ( 0 . 9 - 2 . 8 ) ICOS 0 . 16 1 . 5 ( 0 . 9 - 2 . 6 ) CD276 0 . 93 1 . 1 ( 0 . 4 - 3 . 1 ). CD3G 0 .011 2 , 7 ( 1 . 3 - 5 . 6 ) CD3E 0 .054 2 . 0 ( 1 . 0 - 3 . 9 ) CD3D 0 .099 1 . 6 (0 . 9 - 2 . 8 ) CTL PTPRC 0 .07 1 . 4 ( 1 . 0 - 1 . 9 ) CDSA 0 . 12 1 . 4 (0 . 9 - 2 . 0 ) PRF1 0 .035 1 . 9 ( 1 . 0 - 3 . 3 ) GZMH 0 .0090 1 . 7 ( 1 . 1 - 2 . 5 ) GNLY 0 .039 1 . 5 ( 1 . 0 - 2 . 3 ) GZMB 0 .033 1 . 4 ( 1 . 0 - 2 .0 ) Cytotoxicity GZMK 0 .064 1 . 4 ( 1 . 0 - 2 . 0 ) GZMA 0 . 16 1. 3 (0 . 9 - 1 , 7 ) TBX21 0 . 022 2 .6 ( 1 . 2 - 6 . 1 ) Th1 JENG 0 ,02 1. 7 . ( 1 , 1 - 2 , 8 ) . LOOD Age ( > 60 yo ) 0 . 08 2 .7 ( 0 . 9 -8 . 2 ) Sex ( M ) 0 . 12 2 .0 ( 0 . 8 -4 . 7 ) BRAF ( m ) 0 . 75 1 . 2 ( 0 . 5 - 2 . 8 ) Clinical Loc (Right ) 0 . 87 1 . 1 (0 .4 - 2 . 7 ) KRAS ( m ) 0 . 93 1 . 0 ( 0 . 4 - 2 .5 ) Lynch S 0 .68 0 . 8 ( 0 . 4 - 2 ) 0 . 25 16 . Overall Survival Hazard Ratio Figure 1B Patent Application Publication Jan . 24 , 2019 Sheet 3 of 8 US 2019 / 0025310 A1 msiICK msiICK+ Imss 12345 Timefromdiagnostic(years) p=0.024 0 mssICK mssICK+ 12345Timefromdiagnostic(years) p=0.94 msiICK ICK+msi 12345Timefromdiagnostic(years) 0490.p= 0 Survival Overall Figure 10 Patent Application Publication Jan . 24 , 2019 Sheet 4 of 8 US 2019 / 0025310 A1 value- P y ou wake LS 1 < HR 1 > HR Wit CRC(n=202) See hr=1.4 hr-1.5 31.hr= hr=1.5 hr=1, WM pv=0.33 pv=0.063 22.pv=0 hr-1.6033pv=0. pv=0.061 61.pv=0 IE S 51 46hr=0.051PV0.= WWWWW56.hr=0 ??????- py=0.021 hr=0.032.0 =pv hr=0.48 W SA CRC(n=355)100 37pv=0.024I pv=0.06611py hr-0.63=56OV=0.018Ip0181 . SHARE 92 hr=0.9 69.pv=0 br=0.86 vahr=0.9 53.pv=0 8.0=PV hr=0.73 i 1 CRC(n=29) hr=0.4 65.pv=0 hr=0.75 71.pv=0 hr=0.72 pv=0.61 hr=0.88 pv=0.91 hr=0.75 72.pv=0 46.hr=0 pv=0.32 . CIT+TCGAseries ERANT 21e-037 (n=791) hr=0.91 43.=0pv 890.hr= 19.pv=0SHONA hr=0.95 50.pv= hr=1 92.py=0 hr=0.91 33.pv=0 .82810: :6hr1 2hr-/ p=0.1 MSICRC(n=194) 0540.=py 042py0,= 015pv0.* hra17 pv=0.056 AllCRC hr=0.97 76.pv0= hr=0.94 4.pv=0 hr=0.9989 .pv=0 hr=1. pv=0.51 hr=0.95 55.pv=0 83hr0.=D=0.016 ICK CTL CYTOX IS-likev1CD3,CDBAPTPRC IS-likev2 CD8A,PTPRCGZMBMS4A1 Figure 1D Patent Application Publication Jan . 24 , 2019 Sheet 5 of 8 US 2019 / 0025310 A1 . 16 4 OSHazardRatio 0.25 Wald test 95%CIp-value (0.5-58)0.17 MSICITseries (1.5-290)0022 (0.1-5)0.17 (0.7-110)098 (0.3-19)0.53 (0.17-42)0.83 (2.-440)0.011 0.096(0.07-12) (2.-230)00082 (0.13-12)096 ICK21 CTL0.38 ICK8.7 CYTOX0.73 ICK5.3 TH10.84 ICK31 CK23 variableHR IS-Iv20.30 IS-Iv30.39 Cox 0.02 0.05 model p-value 0.042 0.012 0.010 ICK+IS-likev1 ICK+IS-likev2 Bivariate model ICK+CTL ICK+CYTOX ICK+TH1 Figure 1E Patent Application Publication Jan . 24 , 2019 Sheet 6 of 8 US 2019 / 0025310 A1 HR 95 % 0 p - value HAVORZ 3 . 3 ( 1 . 4 - 7. 9 ) 0 .007 LAG3 1 . 6 (0 . 89 - 2 . 7 ) 0 . 12 CD274 1 . 51092 5 ( 0 .92 - 2 .6A ) 0 . 1 PDCD1LG2 1. 2 ( 0 .69 - 2 .2 ) 0 . 48 PD1 0 .84 ( 0 . 47 - 1 . 5 ) 0 .56 CTLA4 0 . 79 (0 . 39 - 1. 6 ) 0 .51 ICOS 0 .68 ( 0 . 3 - 1 . 5 ) 0 .35 0 . 25 A 16 OS Hazard Ratio HR 95 % a pvalue HAVCR2 25 ( 1 . 1 -5 . 6 ) 0 . 031 CD274 18 ( 1 . 0 -0 1. 0037 LAG 15 (0 .9 - 2 .5 ) 0 . 12 PDCDUGZ 1. 5 ( 0 .74 - 32 ) 0 . 25 PDCD1 L1 ( 0 .63 - 18 ) 081 CTLA4 0 .95 ( 0 .48 - 2 } 0 . 95 ICOS 0 . 60 ( 0 . 26 - 13 ) 0 .21 0 . 25 4 16 SAR Hazad Ratio Figure 2A HR 95 % 0 p - value 23 ( 1. 10 - 4 . 90 ) 0 .023 CTL 13 ( 0 .65 - 2 .40 ) 0 . 5 CYTOX 14 (0 .78 - 2 .50 ) 0 . 27 TH1 14 ( 0 . 55 - 3 .80 ) 0 . 46 Me IS -like vl 13 (0 . 67 - 2 .6 ) 0 . 42 0 . 25 OS Hazard Ratio 16 HR 95 % a p -value ICK 2 . 2 ( 1 . 10 - 4 . 40 ) 0 . 024 CIL 1. 1 (0 .61 - 2. 20 ) 0 .67 CYTOX 1 . 4 (0 . 80 -230 ) 0 . 25 TH1 1. 7 ( 0 .68 - 4 .50 ) 0 . 25 Slike v1 1. 2 (0 .64 -23 ) 0 . 56 wowwwwwwwwww . core vwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww 0 . 25 SAR Hazard Ratio Figure 2B Patent Application Publication Jan . 24 , 2019 Sheet 7 of 8 US 2019 / 0025310 A1 p -value HR 95 % a p - value logrank ICK CTL ICK 3 . 9 (13 - 12 ) 0 .017 0 .035 CIL 0 . 55 ( 0 .21 - 1 . 4 0 .21 KCK + CYTOX ICK 5 ( 14 - 18 ) 0 .013 0 .024 CYTOX 0 .5 ( 0. 2 - 1 .3 ) 0 . 14 KCK + TH1 ICK 3 . 6 ( 12 - 11) 0 .022 0 .043 THI 0 . 49 ( 0 . 14 - 1 . 8 ) 0 .27 TI ICKHS I v1 ICK 3 . 7 ( 1- 2 - 12 ) 0 . 021 0 . 038 IS v10 . 57 ( 0 .22 - 1 . 5 ) 0 . 25 0 25 1 16 OS Hazard Ratio p - value HR 95 % CI p -value logrank ICK + CTL TCK 4 . 9 ( 1 . 6 - 15 ) 0 .0057 0 .015 CIL 0 .41 (0 . 16 - 1 ) 0 .058 ICK CYTOX ICK 3 . 8 ( 1 . 2 - 12 ) 0 .020 0 .034 CYTOX 0 .