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Fifiiiffet Cell Numbers(1X106)

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Fifiiiffet Cell Numbers(1X106) US 20180353544A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0353544 A1 REZVANI et al. (43 ) Pub . Date : Dec . 13 , 2018 ( 54 ) METHODS OF TREATMENT WITH Publication Classification NATURAL KILLER CELLS MATCHED FOR (51 ) Int . Ci. KILLER IMMUNOGLOBULIN RECEPTOR A61K 35 / 17 (2006 . 01 ) TYPE A61P 35 / 02 ( 2006 .01 ) CO7K 14 / 725 ( 2006 . 01 ) (71 ) Applicant: Board of Regents , The University of COZK 14 / 47 ( 2006 . 01 ) Texas System , Austin , TX (US ) CO7K 14 / 705 (2006 .01 ) CO7K 16 / 28 (2006 .01 ) ( 72 ) Inventors: Katy REZVANI, Houston , TX (US ); A61P 37706 ( 2006 .01 ) Elizabeth SHPALL , Houston , TX (52 ) U . S . CI. ( US ) ; Enli LIU , Houston , TX (US ) CPC .. .. .. .. A61K 35 / 17 ( 2013 . 01 ) ; A61P 35 / 02 (2018 . 01 ) ; CO7K 14 / 7051 (2013 .01 ) ; CO7K ( 73 ) Assignee : Board of Regents , The University of 14 / 4748 ( 2013 .01 ) ; A61K 31 /4525 ( 2013 .01 ) ; Texas System , Austin , TX (US ) CO7K 16 / 28 ( 2013 .01 ) ; A61P 37 /06 ( 2018 . 01 ) ; A61K 2300 / 00 ( 2013 .01 ) ; C07K 14 /70521 (21 ) Appl. No. : 15 /579 ,330 (2013 . 01) Jun . 6 , 2016 ( 57 ) ABSTRACT ( 22 ) PCT Filed : The present invention concerns methods of treating a disease ( 86 ) PCT No. : PCT/ US16 / 36024 such as leukemia in a subject by administering natural killer (NK ) cells . In particular aspects , HLA -C1 - licensed $ 371 ( c ) ( 1 ) , KIR2DL2 / 3 and KIR2DS2 NK cells are administered to a ( 2 ) Date : Dec . 4 , 2017 subject with an HLA - C genotype either homozygous or heterozygous for the C1 allele, or HLA - C2 licensed cells are administered to a subjectwith an HLA - C genotype homozy Related U . S . Application Data gous for the C2 allele . In further aspects , the NK cells are (60 ) Provisional application No. 62/ 171, 520 , filed on Jun . genetically modified to express a chimeric antigen receptor 5 , 2015 . and interleukin 15 . NT- NK CELLNUMBERS(1X106) FIFIIIFFET * CAR -NK TI wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww 1 3 7 9 14 22 25 DAYS IN CULTURE Patent Application Publication Dec . 13 , 2018 Sheet 1 of 41 US 2018 /0353544 A1 DAY44+CAR CAR- 99.8%0238 0103104105 CAR-+ 11.8%882 0103104105 647-A:CAR 647-A:CAR COMP-ALEXAFLUOR GEREKESKKKK yor COMP-ALEXAFLUOR Ñ og aof CD56 :A - Cy7 - PE- COMP A- Cy7 - PE- COMP wy CAR+ 87.6% DAY30 CARECAR 98.9%106 Ronymouspepenegro 0103104105 1 0103104105 COMP-ALEXAFLUOR 647-A:CAR EXITETET 647-A:CAR CAR- 12.4% pornoa COMP-ALEXAFLUOR 3830 o CD56 :A - Cyr - PE - COMP A- Cy7 - PE - COMP CAR+ 0.426% CAR+ %80.5 DAY24 0103104105 647-A:CAR 0103104105 CAR- 99.6% 647-A:CAR COMP-ALEXAFLOUR CAR- 135%. COMP-ALEXAFLUOR wy ã ã cã ZA Ž og CAR FIG.1A CD56 :: A - Cy7 - PE- COMP A- Cy7 - PE- COMP ga CAR+ CAR+ 13.2%867 0103104105 DAY18 99.8%0147 wwWMWWWWW 0103104105 647-A:CAR w COMP-ALEXAFLUOR647-A:CAR porooropp COMP-ALEXAFLUOR TAI 105G 4105A -07 - PE - COMP CD :: A -CV7 9103- PE - COMP CAR-NKS+15.2%848 0103104105 DAY10 CAR-NKS+ 99.2%0832 0103104105 647-A:CAR foresega COMP-ALEXAFLUOR 647-A:CAR COMP-ALEXAFLUOR za a V CD56 : A- 20 _ 605 BV605- COMP CD5: : A- 20 _ 605 BV605- COMP CD56 NT-NK CAR-NK Patent Application Publication Dec . 13 , 2018 Sheet 2 of 41 US 2018 /0353544 A1 KIR2DL2/ DL3 KIR2DL1 NKG2A NKP30 NKP44 NKP46 EXPANDED who AINER EXPANDEDCB NK LAUKUengelsk EXPANDED matematicaTenim ? ?? . ?? ? ?? ?? nagrangengnum ?? FIG . 1B 8 - II - I - . IR - L ILIRIPAISII KARAREASAAREMAA tem . 8 . & IIII %OFMAX man,www. wwwwww 9 mbiwakiwthornkommitmentwmillionthantuntumaanluonastirumbautinnollisteniwathamining wachawinanong 828o WOWANIU It commamontandohommeSimone & wpCWM o Set XXXXXXX 0 102 103 104 105 0 102 103 104 105 <ALEXA FLUOR 647 - A > < ALEXA FLUOR 647- A > O SOTYPE CONTROL ISOTYPE CONTROL 13 BASELINE BASELINE D D14 EXPANSION Q D14 EXPANSION ARE WLL T -BET FIG . 10 w wwwwwwwwwwwwwwwwwwwww NT- NK CELLNUMBERS(1X106) * CAR -NK ALPALOPATINIUPA1I111. 22 WWWWA 17.222 WWW - - 1 dok 3 owdown7 wwwwwwwwww9 14 22 25 DAYS IN CULTURE FIG . 1D Patent Application Publication Dec . 13 , 2018 Sheet 3 of 41 US 2018 /0353544 A1 C BASELINE hog inimo ' WWE O 025 ,upongyoogops osobigassetoolguisto nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnn insiantis EXPANSION EOMES T -BET KLRG1 FIG . 1E NEG CONTROL K562 Raji LS2 CAR+ winnnnnnnnnnnnn 900 % -102 8. 6 % 12. 2 % CD56 RaRozga1020 103 104 105 1020 103 104 105 102 1 103 104 105 CAR www Entre -1022 5 .0 % -102 - 102 103 104 105 - 102 103 104 105 -102 103 104 105 IFN -2 FIG . 1F Patent Application Publication Dec . 13 , 2018 Sheet 4 of 41 US 2018 /0353544 A1 PERFORIN PHALLOIDIN CAR FIG . 1G NON - TRANSDUCED NK CAR - TRANSDUCED- 1212NK WORLIKE 1 MAR WAMAWAMAMAWAMAMAMAKKAAMMWMMWANAWAKAKAWAWALALALALALAMIKAMAMMWMMMM.MAU SISA7% NESSA porte SISA7% en comm WWWWWWWY wwwwwwwwwwwwwwwwwwwwwwwwwww e nt RATIO 20 : 1 RATIO 10 : 1 RATIO 5 : 1 RATIO 1 : 1WWWwwwwww FREAK RATIO 20: 1 RATIO 10: 1 RATIO 5: 1RATIO 1: 1 WWWWWWWWWWW EFFECTOR :TARGET RATIO EFFECTOR :TARGET RATIO K562 W WARTO RAJI + * F * CLL FIG . 1H1 WEB Patent Application Publication Dec . 13 , 2018 Sheet 5 of 41 US 2018 /0353544 A1 wwy - NO REVLIMID * nnnnnnnnnnnnnnnnnnn - - PLUS REVLIMD nnnnnnnnnnnnnnnnnnnnn P < 0 .001 AT 1 : 1 AND 10 : 1 PERCENTSPECIFICLYSIS oö83 ???????????????????? E :T RATIO nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn FIG . 11 Patent Application Publication Dec . 13 , 2018 Sheet 6 of 41 US 2018 /0353544 A1 U? Day 9 FIG2000 . 2A WWWWWWWWW HINA FIG . 2B Patent Application Publication Dec . 13 , 2018 Sheet 7 of 41 US 2018 /0353544 A1 CD16+ 92.2% CD16+pwr94.1% COMP-BV650660_20A:CD16 MMMMM Anwwwwwwwwwwwwww WWWWWWWWWW pornograpynagog 1051041030 via 103 COMP-AlexaFluor647A:CARBV650660_20CD16 A- Cy7 - PE- COMP 10510410301051041030 A- Cy7 - PE- COMP CAR+96.7% myCARto- COMP-AlexaFluor647A:CAR CAR torpoowwwporn 4.37%956 power20105 104103 0 Alexa-MP 1031 A- CY7- PE- COMP A- CY7 - PE -COMP * wwwwwwwwrope COMP-APCH7A:CD3 COMP-APCH7A:CD3 NK$ w 1051041030 *105104 1030 LAN111 WW FIG.2C 62.8% 86.5% * NKS+ * INKS ???? ????? ???????????? wwwwwwwwww wy Z 23 CD56 :A - Cy7- PE - COMP CD56 : A- Cy7 -PE - COMP wwwwwwwwwww CD19+ 0.045% CD19+0.029% 0103104105 103104105 CD19 COMP-PEA:CD19 COMP-PEA:CD19 mogymegenwowwwwwwwwwww 4 . 1 . 21 0 50K ok o 250K200K 150K$ 100K 250K A - SSC 1 MMALMX hCD45+ +hCD45 94.5% mon 98.5%MA .MALHULAAMK WWWWWW OlenkovouhudownicaSantos0103104105 COMP-PerCPeFluor710A:hCD45 0103104105 wwwwwwwwwwwwlhacinandodh COMP-PerCPeFluor710A:hCD45 ??og A- SSC A- SSC BLOOD Patent Application Publication Dec . 13 , 2018 Sheet 8 of 41 US 2018 /0353544 A1 CD16+1 CD16+ 89.2% 97.1% COMP-BV650660_20A:CD16 0103104105 COMP-BV65066020A:CD16 CD16 0103104105 AG?NUGERAGONÈSaGdawathuling P ago 2 % 3 A- Cy7- PE- COMP A- Cy7 - PE- COMP COMP-AlexaFLUOR647A:CAR 10.2%-898 0103104105 COMP-AlexaFLUOR647ACAR CAR-_CAR+ 0103104105 CAR-ht1051P ???????????? 8 $ 30 Ž à A- Cy7- PE - COMP A -C7 - PE- COMP SUV4444 ol NKS+ 83.7% NKS COMP-APCH7A:CD3 INKS COMP-APCH7A":CD3 agai105 1041030 0103104105 FIG.2CCont wingpoonop OUR 852 o CD56 :: A - CY7- PE - COMP CD56 : A- Cy7 - PE- COMP 1051041030 COMP-PEA:CD19 0103104105 COMP-PEA:CD19 CD19+ 0.025% +CD19250K onangpangunan 250K 50K 200K SSCA SSCA wawasanbCD45+1 82.6% 99.8% A . 1051041030 11 0103104105 hCD45 persvoor COMP-PerCPeFluor710A:hCD45 COMP-PerCPeFluor710A.HCD45 150K100K 50K 250K 50K A- SSC BONEMARROW N Patent Application Publication Dec . 13 , 2018 Sheet 9 of 41 US 2018 /0353544 A1 w CD16+96.4% COMP-BV650 36020-A:CD16 hCD16 2 & 3lakritsi A. Cy7- PE - COMP 923% COMP-ALEXA FLUOR647-A:CAR ]+CAR-LCAR CAR ISBL ???????????????????????????????? C77A- PE- COMP 87.2% COMP-APCH7A:CD3 NKS immbarenetahonetaneresuntdisheshorelowaniskaElbasaurshakurye hCD3 PXL12 . 119 Ž a FIG.2D CD56= A - Cy7 - PE - COMP CD19+0.080% COMP-PEA:CD19 32322 hCD19 LIISIUNI 250KT200K A- SSC hCD45+ COMP-PerCPeFLOUR710-A:hCD45 240% hCD45 tinkantistatiškistanbulrinktiniai 250K A- SSC Patent Application Publication Dec . 13, 2018 Sheet 10 of 41 US 2018 /0353544 A1 PRATHATHURTHITHERITA SR)/CM2SEC/(P RADIANCE MIN=4,00e5 MAX=7.00e6 0.6- |4.0100 -20 COLORSCALE DAWC Min ROLEROI23ROT3=47R014-2.901e605 CAR-NKS+RajiFFLUC 952RolROMROI15-2.RO 229922 99999999999pg999popoyoooops 02299 EL20141203164938A2. EL20141210100130A EL20141217102054A FIG.2E 2033.47RONROI o NT-NKS+RajiFFLUC ROI18IROI1718|RO1920-3085051IRO12TRO13TROI14TRO153.238e5FIRO2TROI=532739e45 0922 o 222227) ooooo ROJF2R012-RO13=R0148RO1519112H00ROTEROTRO141.707e+05 250 EL20141203170501A EL20141210102001A EL20141217103640Aooooooooooooooooooooooooo ROTTRO008-ROROOTROT1033.RO17ROTO Raji-FFLUCONLY ograd ooo EL20141203163752AOOOOooooooooo IEL20141210094507AWysyyyyyy999 EL20141217100737Ao DAYO DAY7 DAY14 Patent Application Publication Dec . 13, 2018 Sheet 11 of 41 US 2018 /0353544 A1 (PISEC/CM2ISR) RADIANCE COLORSCALE MIN=4.00e5 MAX=7.00e6 ||4.0x108 -20 wwwwww W 058102-.2=FLRO1ROL R015-ROI6=23,519e05 139e05ROI-2.ROLE CAR-NKs+RajiFFLUC IEL20141224100521A IEL20150107104806A* kwkwkwkwkwkwk FIG.2F NT-NKs+Raji ROI3-7.425€+05 FFLUC RO-89RON102832e175 you RO16=ROIZEROTERO9:ROI104232e107ERO12RO13R014R0151.0008-06 EL20141224005216A EL20141230103558A EL20150107103637A RAJ.-FFLUC ONLY EL20141224099954A ROI2=8.04ROISROT4834812+08 EL20141230101648A DAY21 DAY28 DAY35 Patent Application Publication Dec . 13, 2018 Sheet 12 of 41 US 2018 /0353544 A1 800? ? 6000 2000| - - - - - FIG* . 2G Percentsurvival - - - - - - - - - - ??? Days FIG . 2H Patent Application Publication Dec . 13, 2018 Sheet 13 of 41 US 2018 /0353544 A1 NT - NO AP1903 NT + AP1903 n 10. 8 % + 9 .5 % Ž Ž waliolewekiherkku Uuuuuuuuuuuuuuuuuuuuuuuu manbusbbwbannhanhnikenakannbundns3ssohnnkakshassland
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