JP2021501578A - 改変されたナチュラルキラー細胞を生成する方法および使用方法 - Google Patents
改変されたナチュラルキラー細胞を生成する方法および使用方法 Download PDFInfo
- Publication number
- JP2021501578A JP2021501578A JP2020524196A JP2020524196A JP2021501578A JP 2021501578 A JP2021501578 A JP 2021501578A JP 2020524196 A JP2020524196 A JP 2020524196A JP 2020524196 A JP2020524196 A JP 2020524196A JP 2021501578 A JP2021501578 A JP 2021501578A
- Authority
- JP
- Japan
- Prior art keywords
- cells
- population
- days
- cell
- activated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 210000000822 natural killer cell Anatomy 0.000 title claims abstract description 547
- 210000004027 cell Anatomy 0.000 claims abstract description 354
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 154
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 145
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 145
- 238000000034 method Methods 0.000 claims abstract description 138
- 102000004127 Cytokines Human genes 0.000 claims abstract description 49
- 108090000695 Cytokines Proteins 0.000 claims abstract description 49
- 239000013603 viral vector Substances 0.000 claims abstract description 41
- 238000012258 culturing Methods 0.000 claims abstract description 29
- 108010002350 Interleukin-2 Proteins 0.000 claims description 179
- 102000000588 Interleukin-2 Human genes 0.000 claims description 179
- 238000010361 transduction Methods 0.000 claims description 173
- 230000026683 transduction Effects 0.000 claims description 173
- 239000013598 vector Substances 0.000 claims description 107
- 241000700605 Viruses Species 0.000 claims description 55
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 claims description 49
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 claims description 49
- 206010028980 Neoplasm Diseases 0.000 claims description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 44
- 239000003112 inhibitor Substances 0.000 claims description 44
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 30
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 30
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 30
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 28
- VAVXGGRQQJZYBL-UHFFFAOYSA-N N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide Chemical compound N1=C(NCCCNC(=O)C=2SC=CC=2)C(I)=CN=C1NC(C=1)=CC=CC=1NC(=O)N1CCCC1 VAVXGGRQQJZYBL-UHFFFAOYSA-N 0.000 claims description 26
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 claims description 25
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- -1 Cerastrol Chemical compound 0.000 claims description 23
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 21
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 claims description 20
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 claims description 20
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 claims description 20
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims description 19
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- 108020004459 Small interfering RNA Proteins 0.000 claims description 15
- 230000003463 hyperproliferative effect Effects 0.000 claims description 15
- 108091005685 RIG-I-like receptors Proteins 0.000 claims description 14
- 108091027967 Small hairpin RNA Proteins 0.000 claims description 14
- 102000002689 Toll-like receptor Human genes 0.000 claims description 14
- 108020000411 Toll-like receptor Proteins 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 14
- 210000004881 tumor cell Anatomy 0.000 claims description 12
- 101000665442 Homo sapiens Serine/threonine-protein kinase TBK1 Proteins 0.000 claims description 10
- 102000001284 I-kappa-B kinase Human genes 0.000 claims description 10
- 108060006678 I-kappa-B kinase Proteins 0.000 claims description 10
- 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 claims description 10
- 230000002463 transducing effect Effects 0.000 claims description 10
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 9
- 238000004113 cell culture Methods 0.000 claims description 9
- 102100025390 Integrin beta-2 Human genes 0.000 claims description 8
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 claims description 8
- 208000036142 Viral infection Diseases 0.000 claims description 7
- 230000009385 viral infection Effects 0.000 claims description 7
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 claims description 6
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 claims description 6
- 102100040113 Tumor necrosis factor receptor superfamily member 10A Human genes 0.000 claims description 6
- 230000000692 anti-sense effect Effects 0.000 claims description 6
- 239000000427 antigen Substances 0.000 claims description 6
- 108091007433 antigens Proteins 0.000 claims description 6
- 102000036639 antigens Human genes 0.000 claims description 6
- 230000003834 intracellular effect Effects 0.000 claims description 6
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 5
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 5
- 101000610605 Homo sapiens Tumor necrosis factor receptor superfamily member 10A Proteins 0.000 claims description 5
- 108010008212 Integrin alpha4beta1 Proteins 0.000 claims description 5
- DOEWDSDBFRHVAP-KRXBUXKQSA-N (E)-3-tosylacrylonitrile Chemical compound CC1=CC=C(S(=O)(=O)\C=C\C#N)C=C1 DOEWDSDBFRHVAP-KRXBUXKQSA-N 0.000 claims description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 claims description 4
- DHPSFJYFPJRCTN-UHFFFAOYSA-N 5-[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]pyrimidin-4-yl]-2-pyrrolidin-1-ylbenzonitrile Chemical compound C=1C=C2NC(=O)CC2=CC=1NC(N=1)=NC=CC=1C(C=C1C#N)=CC=C1N1CCCC1 DHPSFJYFPJRCTN-UHFFFAOYSA-N 0.000 claims description 4
- 101000852483 Homo sapiens Interleukin-1 receptor-associated kinase 1 Proteins 0.000 claims description 4
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 4
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 4
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 claims description 4
- 102100036342 Interleukin-1 receptor-associated kinase 1 Human genes 0.000 claims description 4
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 4
- UKBGBACORPRCGG-UHFFFAOYSA-N N-[3-[[5-cyclopropyl-2-[3-(4-morpholinylmethyl)anilino]-4-pyrimidinyl]amino]propyl]cyclobutanecarboxamide Chemical compound C1CCC1C(=O)NCCCNC(C(=CN=1)C2CC2)=NC=1NC(C=1)=CC=CC=1CN1CCOCC1 UKBGBACORPRCGG-UHFFFAOYSA-N 0.000 claims description 4
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 4
- 102100035721 Syndecan-1 Human genes 0.000 claims description 4
- 102000004060 Transforming Growth Factor-beta Type II Receptor Human genes 0.000 claims description 4
- 108010082684 Transforming Growth Factor-beta Type II Receptor Proteins 0.000 claims description 4
- LEEIJTHMHDMWLJ-CQSZACIVSA-N ethyl (6r)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate Chemical compound CCOC(=O)C1=CCCC[C@H]1S(=O)(=O)NC1=CC=C(F)C=C1Cl LEEIJTHMHDMWLJ-CQSZACIVSA-N 0.000 claims description 4
- MQAQKNLCUSPSAF-UHFFFAOYSA-N n-[3-[[4-(3-cyano-4-pyrrolidin-1-ylphenyl)pyrimidin-2-yl]amino]phenyl]pyrrolidine-1-carboxamide Chemical compound C1CCCN1C(=O)NC(C=1)=CC=CC=1NC(N=1)=NC=CC=1C(C=C1C#N)=CC=C1N1CCCC1 MQAQKNLCUSPSAF-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- ZKZXNDJNWUTGDK-NSCUHMNNSA-N (E)-N-[2-(4-bromocinnamylamino)ethyl]isoquinoline-5-sulfonamide Chemical compound C1=CC(Br)=CC=C1\C=C\CNCCNS(=O)(=O)C1=CC=CC2=CN=CC=C12 ZKZXNDJNWUTGDK-NSCUHMNNSA-N 0.000 claims description 3
- 101001005269 Arabidopsis thaliana Ceramide synthase 1 LOH3 Proteins 0.000 claims description 3
- 101001005312 Arabidopsis thaliana Ceramide synthase LOH1 Proteins 0.000 claims description 3
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 claims description 3
- 102100028801 Calsyntenin-1 Human genes 0.000 claims description 3
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 claims description 3
- 241000701044 Human gammaherpesvirus 4 Species 0.000 claims description 3
- 101000668858 Spinacia oleracea 30S ribosomal protein S1, chloroplastic Proteins 0.000 claims description 3
- 101000898746 Streptomyces clavuligerus Clavaminate synthase 1 Proteins 0.000 claims description 3
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 claims 2
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 claims 2
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 claims 2
- 241000894007 species Species 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 58
- 230000003612 virological effect Effects 0.000 abstract description 13
- 230000014509 gene expression Effects 0.000 description 80
- 239000002609 medium Substances 0.000 description 56
- 108090000623 proteins and genes Proteins 0.000 description 52
- 108700019146 Transgenes Proteins 0.000 description 49
- 241000713666 Lentivirus Species 0.000 description 48
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 41
- 239000005090 green fluorescent protein Substances 0.000 description 38
- 238000001890 transfection Methods 0.000 description 35
- 102000003812 Interleukin-15 Human genes 0.000 description 34
- 108090000172 Interleukin-15 Proteins 0.000 description 34
- 102000004169 proteins and genes Human genes 0.000 description 34
- 230000000638 stimulation Effects 0.000 description 33
- 208000035475 disorder Diseases 0.000 description 27
- 230000000694 effects Effects 0.000 description 27
- 238000002474 experimental method Methods 0.000 description 27
- 230000000670 limiting effect Effects 0.000 description 26
- 239000001963 growth medium Substances 0.000 description 24
- 101710139464 Phosphoglycerate kinase 1 Proteins 0.000 description 23
- 102100028251 Phosphoglycerate kinase 1 Human genes 0.000 description 23
- 239000011324 bead Substances 0.000 description 23
- 238000000684 flow cytometry Methods 0.000 description 21
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 19
- 239000004055 small Interfering RNA Substances 0.000 description 19
- 239000013612 plasmid Substances 0.000 description 18
- 238000012546 transfer Methods 0.000 description 17
- 239000013604 expression vector Substances 0.000 description 16
- 230000035755 proliferation Effects 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 15
- 230000003833 cell viability Effects 0.000 description 13
- 241000701022 Cytomegalovirus Species 0.000 description 12
- 102100030704 Interleukin-21 Human genes 0.000 description 12
- 230000010261 cell growth Effects 0.000 description 12
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 12
- 108010074108 interleukin-21 Proteins 0.000 description 12
- 150000001413 amino acids Chemical group 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 206010039491 Sarcoma Diseases 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 230000035899 viability Effects 0.000 description 9
- 102000015696 Interleukins Human genes 0.000 description 8
- 108010063738 Interleukins Proteins 0.000 description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 108091005461 Nucleic proteins Proteins 0.000 description 7
- 239000011651 chromium Substances 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 210000005259 peripheral blood Anatomy 0.000 description 7
- 239000011886 peripheral blood Substances 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 208000034578 Multiple myelomas Diseases 0.000 description 6
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 description 6
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 6
- 239000006143 cell culture medium Substances 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 238000003501 co-culture Methods 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 108010056030 retronectin Proteins 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 5
- 101100369992 Homo sapiens TNFSF10 gene Proteins 0.000 description 5
- 108010074328 Interferon-gamma Proteins 0.000 description 5
- 102000007327 Protamines Human genes 0.000 description 5
- 108010007568 Protamines Proteins 0.000 description 5
- 102100035533 Stimulator of interferon genes protein Human genes 0.000 description 5
- 108700012411 TNFSF10 Proteins 0.000 description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 5
- 102100024598 Tumor necrosis factor ligand superfamily member 10 Human genes 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 210000005087 mononuclear cell Anatomy 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 5
- 229950008679 protamine sulfate Drugs 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000014616 translation Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 4
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 4
- 102100031256 Cyclic GMP-AMP synthase Human genes 0.000 description 4
- 101710118064 Cyclic GMP-AMP synthase Proteins 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 102000001398 Granzyme Human genes 0.000 description 4
- 108060005986 Granzyme Proteins 0.000 description 4
- 102100037850 Interferon gamma Human genes 0.000 description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 4
- 230000006051 NK cell activation Effects 0.000 description 4
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 4
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 230000003362 replicative effect Effects 0.000 description 4
- 102220003351 rs387906411 Human genes 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000013519 translation Methods 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 3
- 101000834253 Gallus gallus Actin, cytoplasmic 1 Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 3
- 101100332765 Homo sapiens EEF1A1 gene Proteins 0.000 description 3
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 102100021592 Interleukin-7 Human genes 0.000 description 3
- 108010002586 Interleukin-7 Proteins 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 102100037935 Polyubiquitin-C Human genes 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 108010056354 Ubiquitin C Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 229960000684 cytarabine Drugs 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000011194 good manufacturing practice Methods 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229940100994 interleukin-7 Drugs 0.000 description 3
- 230000004068 intracellular signaling Effects 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 230000001177 retroviral effect Effects 0.000 description 3
- 229960004641 rituximab Drugs 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 230000005909 tumor killing Effects 0.000 description 3
- HBLHLJXFIPCEMW-ZJSFPPFMSA-N (4r,7r,8ar)-1'-[2-[4-[[2-(2,4-dichlorophenoxy)acetyl]amino]phenyl]acetyl]-6-oxospiro[3,4,8,8a-tetrahydro-2h-pyrrolo[2,1-b][1,3]thiazine-7,2'-pyrrolidine]-4-carboxamide Chemical compound C([C@]12C[C@H]3SCC[C@@H](N3C2=O)C(=O)N)CCN1C(=O)CC(C=C1)=CC=C1NC(=O)COC1=CC=C(Cl)C=C1Cl HBLHLJXFIPCEMW-ZJSFPPFMSA-N 0.000 description 2
- KQJSQWZMSAGSHN-UHFFFAOYSA-N (9beta,13alpha,14beta,20alpha)-3-hydroxy-9,13-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic acid Natural products CC12CCC3(C)C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C2=CC=C2C1=CC(=O)C(O)=C2C KQJSQWZMSAGSHN-UHFFFAOYSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 102100038077 CD226 antigen Human genes 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- AQKDBFWJOPNOKZ-UHFFFAOYSA-N Celastrol Natural products CC12CCC3(C)C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C2=CC=C2C1=CC(=O)C(=O)C2C AQKDBFWJOPNOKZ-UHFFFAOYSA-N 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 101100118093 Drosophila melanogaster eEF1alpha2 gene Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010039471 Fas Ligand Protein Proteins 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 2
- 101000884298 Homo sapiens CD226 antigen Proteins 0.000 description 2
- 101100220044 Homo sapiens CD34 gene Proteins 0.000 description 2
- 101000589305 Homo sapiens Natural cytotoxicity triggering receptor 2 Proteins 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 102000043129 MHC class I family Human genes 0.000 description 2
- 108091054437 MHC class I family Proteins 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 102100032851 Natural cytotoxicity triggering receptor 2 Human genes 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 102000004503 Perforin Human genes 0.000 description 2
- 108010056995 Perforin Proteins 0.000 description 2
- KHGNFPUMBJSZSM-UHFFFAOYSA-N Perforine Natural products COC1=C2CCC(O)C(CCC(C)(C)O)(OC)C2=NC2=C1C=CO2 KHGNFPUMBJSZSM-UHFFFAOYSA-N 0.000 description 2
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 2
- 108010067390 Viral Proteins Proteins 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- 208000008383 Wilms tumor Diseases 0.000 description 2
- 241001492404 Woodchuck hepatitis virus Species 0.000 description 2
- MIFGOLAMNLSLGH-QOKNQOGYSA-N Z-Val-Ala-Asp(OMe)-CH2F Chemical compound COC(=O)C[C@@H](C(=O)CF)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)OCC1=CC=CC=C1 MIFGOLAMNLSLGH-QOKNQOGYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 238000002617 apheresis Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- HDRGJRSISASRAJ-WKPMUQCKSA-N bazlitoran Chemical compound CO[C@@H]1[C@H](O)[C@@H](COP(=O)(S)O[C@@H]2[C@@H](COP(=O)(S)O[C@H]3C[C@@H](O[C@@H]3COP(=O)(S)O[C@H]4C[C@@H](O[C@@H]4COP(=O)(S)O[C@H]5C[C@@H](O[C@@H]5COP(=O)(S)O[C@H]6C[C@@H](O[C@@H]6COP(=O)(S)O[C@H]7C[C@@H](O[C@@H]7COP(=O)(S)O[C@H]8C[C@@H](O[C@@H]8COP(=O)(S)O[C@H]9C[C@@H](O[C@@H]9COP(=O)(S)O[C@H]%10C[C@@H](O[C@@H]%10COP(=O)(S)O[C@@H]%11[C@@H](COP(=O)(S)O[C@@H]%12[C@@H](COP(=O)(S)O[C@H]%13C[C@@H](O[C@@H]%13COP(=O)(S)O[C@H]%14C[C@@H](O[C@@H]%14COP(=O)(S)O[C@H]%15C[C@@H](O[C@@H]%15COP(=O)(S)O[C@H]%16C[C@@H](O[C@@H]%16COP(=O)(S)O[C@H]%17C[C@@H](O[C@@H]%17COP(=O)(S)O[C@H]%18C[C@@H](O[C@@H]%18CO)N%19C=CC(=NC%19=O)N)N%20C=C(C)C(=O)NC%20=O)n%21cnc%22c(N)ncnc%21%22)N%23C=C(C)C(=O)NC%23=O)N%24C=CC(=NC%24=O)N)N%25C=C(C)C(=O)NC%25=O)O[C@H]([C@@H]%12OC)n%26cnc%27C(=O)NC(=Nc%26%27)N)O[C@H]([C@@H]%11OC)N%28C=CC(=O)NC%28=O)N%29C=C(C)C(=NC%29=O)N)n%30ccc%31C(=O)NC(=Nc%30%31)N)N%32C=C(C)C(=O)NC%32=O)N%33C=C(C)C(=O)NC%33=O)N%34C=CC(=NC%34=O)N)N%35C=C(C)C(=O)NC%35=O)N%36C=CC(=NC%36=O)N)N%37C=C(C)C(=O)NC%37=O)O[C@H]([C@@H]2OC)n%38cnc%39C(=O)NC(=Nc%38%39)N)O[C@H]1N%40C=CC(=O)NC%40=O HDRGJRSISASRAJ-WKPMUQCKSA-N 0.000 description 2
- RFCBNSCSPXMEBK-INFSMZHSSA-N c-GMP-AMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]3[C@@H](O)[C@H](N4C5=NC=NC(N)=C5N=C4)O[C@@H]3COP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 RFCBNSCSPXMEBK-INFSMZHSSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- KQJSQWZMSAGSHN-JJWQIEBTSA-N celastrol Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)[C@](C)(C(O)=O)CC[C@]1(C)CC[C@]2(C)C4=CC=C1C3=CC(=O)C(O)=C1C KQJSQWZMSAGSHN-JJWQIEBTSA-N 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 229960003677 chloroquine Drugs 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000011018 current good manufacturing practice Methods 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960002204 daratumumab Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 208000010932 epithelial neoplasm Diseases 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 201000003444 follicular lymphoma Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001476 gene delivery Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 102000053523 human CXCR4 Human genes 0.000 description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 2
- 229960004171 hydroxychloroquine Drugs 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 102000004114 interleukin 20 Human genes 0.000 description 2
- 108090000681 interleukin 20 Proteins 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- ZVHNDZWQTBEVRY-UHFFFAOYSA-N momelotinib Chemical compound C1=CC(C(NCC#N)=O)=CC=C1C1=CC=NC(NC=2C=CC(=CC=2)N2CCOCC2)=N1 ZVHNDZWQTBEVRY-UHFFFAOYSA-N 0.000 description 2
- 229950008814 momelotinib Drugs 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 201000008026 nephroblastoma Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229930192851 perforin Natural products 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 230000001124 posttranscriptional effect Effects 0.000 description 2
- 230000037452 priming Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 238000005199 ultracentrifugation Methods 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102000000412 Annexin Human genes 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000006274 Brain Stem Neoplasms Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 101710149858 C-C chemokine receptor type 7 Proteins 0.000 description 1
- 108010041397 CD4 Antigens Proteins 0.000 description 1
- 108091008928 CXC chemokine receptors Proteins 0.000 description 1
- 102000054900 CXCR Receptors Human genes 0.000 description 1
- 101150066398 CXCR4 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 102100024125 Embryonal Fyn-associated substrate Human genes 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 102100027286 Fanconi anemia group C protein Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 1
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 1
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 1
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101100383038 Homo sapiens CD19 gene Proteins 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101001053896 Homo sapiens Embryonal Fyn-associated substrate Proteins 0.000 description 1
- 101000914680 Homo sapiens Fanconi anemia group C protein Proteins 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101001023379 Homo sapiens Lysosome-associated membrane glycoprotein 1 Proteins 0.000 description 1
- 101001109503 Homo sapiens NKG2-C type II integral membrane protein Proteins 0.000 description 1
- 101000643024 Homo sapiens Stimulator of interferon genes protein Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 102000003810 Interleukin-18 Human genes 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 1
- 101150069255 KLRC1 gene Proteins 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 101710128836 Large T antigen Proteins 0.000 description 1
- 241000023320 Luma <angiosperm> Species 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 102100035133 Lysosome-associated membrane glycoprotein 1 Human genes 0.000 description 1
- 101100404845 Macaca mulatta NKG2A gene Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- SGDBTWWWUNNDEQ-UHFFFAOYSA-N Merphalan Chemical compound OC(=O)C(N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 101000579126 Mus musculus Phosphoglycerate kinase 1 Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 102000027581 NK cell receptors Human genes 0.000 description 1
- 108091008877 NK cell receptors Proteins 0.000 description 1
- 102100022682 NKG2-A/NKG2-B type II integral membrane protein Human genes 0.000 description 1
- 102100022683 NKG2-C type II integral membrane protein Human genes 0.000 description 1
- 229920002274 Nalgene Polymers 0.000 description 1
- 108010004217 Natural Cytotoxicity Triggering Receptor 1 Proteins 0.000 description 1
- 108010004222 Natural Cytotoxicity Triggering Receptor 3 Proteins 0.000 description 1
- 102100032870 Natural cytotoxicity triggering receptor 1 Human genes 0.000 description 1
- 102100032852 Natural cytotoxicity triggering receptor 3 Human genes 0.000 description 1
- 206010028811 Natural killer-cell leukaemia Diseases 0.000 description 1
- 108050003738 Neural cell adhesion molecule 1 Proteins 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 208000008601 Polycythemia Diseases 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 108010009736 Protein Hydrolysates Proteins 0.000 description 1
- 102000014450 RNA Polymerase III Human genes 0.000 description 1
- 108010078067 RNA Polymerase III Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 108700009124 Transcription Initiation Site Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 238000010162 Tukey test Methods 0.000 description 1
- 229940127174 UCHT1 Drugs 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241000711975 Vesicular stomatitis virus Species 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 108091093126 WHP Posttrascriptional Response Element Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 101150063416 add gene Proteins 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 208000015230 aggressive NK-cell leukemia Diseases 0.000 description 1
- 229940098174 alkeran Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 102000008373 cell-cell adhesion mediator activity proteins Human genes 0.000 description 1
- 108040002566 cell-cell adhesion mediator activity proteins Proteins 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000025997 central nervous system neoplasm Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 210000004252 chorionic villi Anatomy 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 208000016496 colorectal squamous cell carcinoma Diseases 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 208000016356 hereditary diffuse gastric adenocarcinoma Diseases 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 108091008042 inhibitory receptors Proteins 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 230000008611 intercellular interaction Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000003445 large cell neuroendocrine carcinoma Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000000207 lymphocyte subset Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 230000008481 normal tissue growth Effects 0.000 description 1
- 230000008689 nuclear function Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 108700004029 pol Genes Proteins 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 108700004030 rev Genes Proteins 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 230000002311 subsequent effect Effects 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 108700004027 tat Genes Proteins 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0646—Natural killers cells [NK], NKT cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4613—Natural-killer cells [NK or NK-T]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
- C12N15/867—Retroviral vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/0068—General culture methods using substrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/20—Cytokines; Chemokines
- C12N2501/23—Interleukins [IL]
- C12N2501/2302—Interleukin-2 (IL-2)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
- C12N2501/505—CD4; CD8
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
- C12N2501/515—CD3, T-cell receptor complex
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
- C12N2501/599—Cell markers; Cell surface determinants with CD designations not provided for elsewhere
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/65—MicroRNA
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2502/00—Coculture with; Conditioned medium produced by
- C12N2502/11—Coculture with; Conditioned medium produced by blood or immune system cells
- C12N2502/1135—Granulocytes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2502/00—Coculture with; Conditioned medium produced by
- C12N2502/30—Coculture with; Conditioned medium produced by tumour cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2502/00—Coculture with; Conditioned medium produced by
- C12N2502/99—Coculture with; Conditioned medium produced by genetically modified cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2510/00—Genetically modified cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2510/00—Genetically modified cells
- C12N2510/04—Immortalised cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
- C12N2740/15041—Use of virus, viral particle or viral elements as a vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
- C12N2740/15041—Use of virus, viral particle or viral elements as a vector
- C12N2740/15043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
- C12N2799/027—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a retrovirus
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Plant Pathology (AREA)
- Communicable Diseases (AREA)
- Mycology (AREA)
- Developmental Biology & Embryology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
本出願は、2017年11月1日出願に出願された米国特許出願第15/801,085号(これは、2017年7月25日に出願された国際特許出願番号PCT/US2017/043774の一部継続出願であり、この出願は、2016年7月25日に出願された米国仮特許出願第62/366,493号の利益を主張し、これらは全て、それらの全体において本明細書に参考として援用される)の利益を主張する。
本開示は、改変されたナチュラルキラー細胞を生成するための方法、上記改変されたナチュラルキラー細胞を含む組成物、およびそれらの使用法に関する。
抗原特異的細胞傷害性Tリンパ球の他に、先天性免疫系の細胞構成要素が、悪性の細胞増殖の免疫監視に寄与し得る。特に、ナチュラルキラー(NK)細胞は、初回刺激も感作もなしに異常な細胞を排除し得る。それらの活性は、阻害性および活性化NK細胞レセプターからのシグナルのバランスによって決定される。阻害性レセプター(例えば、キラー免疫グロブリンレセプター(KIR))は、自己の主要組織適合遺伝子複合体(MHC)クラスI抗原と相互作用し、NK細胞の攻撃から正常の細胞を保護する。
初代NK細胞において目的の遺伝子を有効に送達し、発現するために、単純かつ効率的な遺伝子移入法が必要である。導入遺伝子の安定しかつ堅固で、長期間の発現を示すNK細胞への遺伝子移入のための効率的なウイルスベクターベースの方法が本明細書で開示される。
本明細書でまたは添付の配列表に列挙される任意の核酸配列およびアミノ酸配列は、施行規則§1.822において規定されるように、ヌクレオチド塩基およびアミノ酸の標準的な文字略語を使用して示される。少なくともいくつかの場合では、各核酸配列の一方の鎖のみが示されるが、その相補鎖は、その示された鎖に対する何らかの言及によって含まれると理解される。
本明細書で開示されるのは、NK細胞において導入遺伝子を効率的にかつ安定して発現するための方法である。その方法は、NK細胞への遺伝子移入に効率的なウイルスベクターベースの方法を含み、導入遺伝子の安定してかつ長期間の堅固な発現を示す。形質転換されている初代細胞への高遺伝子移入率および患者細胞の大規模形質導入のための高力価のウイルス粒子を生成する能力は、臨床試験の重要な基準である。レンチウイルスベクター(例えば、本明細書中の実施例で利用されるもの)は、それらの形質導入効率を損なうことなく、高力価で生成され、濃縮され得る。さらに、現在記載される方法は、臨床適用するためにより安価かつ単純である。なぜならそれは、中程度の形質導入効率を得るために現在のレトロウイルスベクター媒介性遺伝子移入プロトコルにおいて適合されたいくつかの扱いづらい高価な工程(例えば、レトロネクチン、スピノキュレーション(spinoculation)、および形質導入されている初代NK細胞の生存度に対して顕著な有害な影響を有し得る反復/複数回の形質導入の使用)の必要性を要求しないからである。さらに、養子NK細胞ベースの免疫療法適用のための医薬品等の製造管理および品質管理に関する基準(GMP)条件の下でNK細胞の効率的エキソビボ拡大増殖のためのプロトコルが、適用可能である。本高効率レンチウイルスベクターベースの遺伝子移入プロトコルは、多くの現在のエキソビボNK細胞拡大増殖プロトコルを補完して、多数の遺伝的に再プログラムされたNK細胞を生成するために使用され得、潜在的には、がんまたはウイルス感染を有する患者においてそれらの抗腫瘍有効性を増強することによって、NK細胞ベースの免疫療法アプローチに変革を起こし得る。
CAR キメラ抗原レセプター
EBV−LCL エプスタイン・バーウイルスで形質転換したリンパ芽球系細胞株
eGFP 増強型緑色蛍光タンパク質
FACS 蛍光活性化セルソーティング
GMP 医薬品等の製造管理および品質管理に関する基準
IL インターロイキン
LTR 長末端反復
MOI 感染多重度
NK ナチュラルキラー細胞
PBMC 末梢血単球
shRNA 低分子ヘアピン型RNA
別段注記されなければ、技術用語は、従来の使用法に従って使用される。分子生物学における一般的用語の定義は、以下で見出され得る:Lewin’s Genes X, 編. Krebsら, Jones and Bartlett Publishers, 2009(ISBN 0763766321); Kendrewら(編), The Encyclopedia of Molecular Biology, Blackwell Publishersによって発行, 1994(ISBN 0632021829); Robert A. Meyers(編), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, Wiley, John & Sons, Inc.によって発行, 1995(ISBN 0471186341);およびGeorge P. Redei, Encyclopedic Dictionary of Genetics, Genomics, Proteomics and Informatics, 第3版, Springer, 2008(ISBN: 1402067534)、ならびに他の同様の参考文献。
本明細書で開示されるのは、改変されたNK細胞(例えば、1種もしくはこれより多くの異種核酸を含むかもしくは発現するか、または1種もしくはこれより多くの異種核酸を含むウイルスベクターの全てもしくは一部を含むNK細胞)を生成するための方法である。特定の例では、本明細書で開示される方法は、高効率においてウイルスベクターで形質導入するために以前は困難があった、(NK細胞株または拡大増殖されたNK細胞ではなく)休止中のまたは短期間の活性化NK細胞を形質導入するために利用される。
NK細胞のインビトロでの単離および富化に関する技術は、本明細書で記載される。例示的な手順は、米国特許出願公開番号2014/0086890(その全体において本明細書に参考として援用される)に記載される。当業者は、NK細胞を拡大増殖させるためのさらなる方法(例えば、Childsら, Hematol. The Education Program 2013:234−246, 2013(その全体において本明細書に参考として援用される)に記載されるとおり)を同定し得る。
開示される方法は、形質導入前のNK細胞の活性化(本明細書では「初回刺激(priming)ともいわれる)を含む。単離されたNK細胞(例えば、>95% CD3−および>85% CD56+または>99% CD3−および>90% CD56+)は、第IIA節に記載されるように調製されるか、または別の方法で得られる(例えば、低温保存された単離されたNK細胞調製物のような以前の調製物から)。サイトカイン刺激は、代謝的活性化を誘導し、他のリンパ球部分セットに類似のNK細胞における活性な遺伝子発現を可能にする。これは、効率的レンチウイルスベクター媒介性遺伝子形質導入で補助し得る。
その活性化(初回刺激)されたNK細胞(例えば、第IIB節に記載されるもの)は、1種またはこれより多くの異種核酸(例えば、目的のタンパク質をコードする1もしくはこれより多くの核酸、または目的の別の核酸(例えば、shRNA))を含むウイルスベクターで形質導入される。特定の非限定的例では、そのベクターは、レンチウイルスベクターである。
本明細書で開示されるのは、異種核酸を含むか、または目的の1種もしくはこれより多くの異種タンパク質もしくは核酸を発現するNK細胞(本明細書では「改変されたNK細胞」といわれる)である。1種またはこれより多くの異種核酸を含む改変されたまたは組換えNK細胞は、NK細胞を、1種またはこれより多くの異種核酸を有するベクター(例えば、レンチウイルスベクター)を含むウイルス粒子で、例えば、本明細書で開示される方法を使用して形質導入することによって生成され得る。その改変されたNK細胞は、被験体への投与のための治療用組成物へと、例えば、1種またはこれより多くの薬学的に受容可能なキャリアとともに製剤化され得る。治療用組成物およびそれらの使用法は、以下の第IV節で考察される。
本明細書で開示されるのは、本明細書で記載される改変されたNK細胞を被験体に投与することによって、疾患または障害を有する被験体を処置する方法である。本明細書で記載される改変されたNK細胞は、動物またはヒト被験体のいずれかに投与され得る。いくつかの実施形態において、その疾患または障害は、腫瘍または過剰増殖性疾患である。他の実施形態において、その疾患または障害は、ウイルス感染(サイトメガロウイルス、アデノウイルス、RSウイルス、エプスタイン・バーウイルス、またはヒト免疫不全ウイルスの感染が挙げられるが、これらに限定されない)である。
材料および方法
細胞株および試薬: ヒト骨髄性白血病株(赤白血病タイプ)K562(ATCC)および急性単球性白血病細胞株MOLM−14(ATCC)、およびEBV−SMI−LCLを、RPMI 1640(10% 熱非働化ウシ胎仔血清(FBS, Sigma−Aldrich)、2mM グルタミン、および100 U/mL ペニシリン、および100μg/mL ストレプトマイシン(Life Technologies)を補充)中で培養した。293T細胞株(SV40ラージT抗原を安定して発現するヒト胚性腎臓細胞株293)(ATCCから)を、ダルベッコ改変イーグル培地(DMEM; Invitrogen)(2mM L−グルタミン、100 U/mL ペニシリン、および100μg/mL ストレプトマイシン(Invitrogen)ならびに10% FBSを補充)中で培養した。それら細胞を、37℃および5% CO2において95% 湿度下で培養した。
NK細胞のレンチウイルス形質導入に対するIL−2初回刺激の効果
この実施例は、レンチウイルスベクターを使用するNK細胞の形質導入に対するIL−2での初回刺激の効果および形質導入されたNK細胞の特徴づけを記載する。
IL−2で形質導入前に1〜5日間初回刺激することによって評価した。形質導入の2日後に、ウイルス粒子を除去し、照射したLCLを10:1比(LCL:NK細胞)で添加し、細胞を、500 IU/ml IL−2を含む培地中で維持した。2日間またはこれより長い日数にわたるIL−2での初回刺激は、約25%またはこれより高い形質導入効率を生じた(図4)。NK細胞はまた、IL−2(500 IU/ml)を含む培地で、MOI 20での形質導入前に3日間、初回刺激した。形質導入の2日後に、ウイルス粒子を除去し、照射したLCL(10:1比のLCL:NK細胞)を添加し、細胞を、500 IU/ml IL−2を含む培地中で維持した。導入遺伝子発現は、形質導入後少なくとも40日間にわたって安定なままであり(図5A)、細胞生存度は、形質導入後少なくとも28日間にわたって非形質導入細胞に匹敵したままであった(図5B)。
NK細胞のレンチウイルス形質導入に対するIL−2およびIL−15初回刺激の効果
この実施例は、レンチウイルスベクターを使用するNK細胞の形質導入に対するIL−2およびIL−15での初回刺激の効果、ならびに形質導入されたNK細胞の特徴づけを記載する。
NK細胞表現型に対するレンチウイルス形質導入の効果
この実施例は、レンチウイルスで形質導入されたNK細胞の表現型を記載する。
培養および形質導入の条件のさらなる評価
この実施例は、NK細胞の活性化、形質導入、および拡大増殖のための条件を評価するさらなる実験を記載する。
さらなる導入遺伝子でのNK細胞の形質導入
この実施例は、目的のさらなる導入遺伝子でのNK細胞の形質導入を記載する。
マウスモデルにおける形質導入されたNK細胞の評価
この実施例は、過剰増殖性障害のマウスモデルにおいて異種核酸を発現する改変されたNK細胞の機能および有効性を評価するための方法を記載する。しかし、当業者は、これらの特定の方法から外れる方法がまた、動物モデルにおいて形質導入されたNK細胞を評価するために使用されうることを認識する。
過剰増殖性障害を有する被験体を処置するための方法
この実施例は、過剰増殖性障害を有する被験体を、異種核酸を発現する改変されたNK細胞で処置するための方法を記載する。しかし、当業者は、これらの特定の方法を外れる方法がまた、被験体において過剰増殖性障害を成功裡に処置または阻害するために使用されうることを理解する。
レンチウイルス発現ベクター
レンチウイルス発現ベクターを、Vectorbuilder design service(Cyagen Biosciences, Inc., Santa Clara, CA)を使用して構築した。そのベクターは、種々のプロモーターおよびEGFPまたはPGKプロモーターおよび種々のヒトタンパク質を含んだ。そのベクターは、配列番号8〜17の配列(表3に示されるとおり)を有する。さらなるベクター構成要素および各配列におけるそれらの位置は、表4に示される。
フィーダー細胞共培養でのNK細胞の活性化
ヒト末梢血から単離したNK細胞を、100Gy照射SMI−LCLありまたはなしで培養した。3日後に、細胞培養物を、Ficoll(登録商標)培地上で遠心分離して、死細胞を除去し、計数し、pLV[Exp]−PGK>EGFP:T2A:Luc(T2Aペプチドをコードし、コドン最適化ルシフェラーゼがさらに挿入された配列を有する配列番号14)で、Retronectin(登録商標)(Takara Clontech)被覆プレートを使用して、レンチウイルスで形質導入した。さらに3日後、細胞を再度計数し、10倍過剰のLCLとともに再度平板培養した。細胞を、10% 熱非働化ヒトAB血清、500 IU/ml IL−2、および2mM GlutaMAXTM補充物を補充したX−VIVOTM 20培地(Lonza)中で終始維持し、計数して、拡大増殖倍数を決定した。最初に、LCL(10:1比)とともにその後のLCL添加なしで培養した非形質導入NK細胞を、比較のために試験した。形質導入の前に10倍過剰のLCLとともに培養した細胞は、形質導入の前にLCLとともに培養しなかった細胞と比較して、改善された拡大増殖を有し、非形質導入細胞に類似の拡大増殖倍数を有した(図23)。
形質導入前のIL−2培養物での初代NK細胞のレンチウイルス形質導入
PBMCに由来するNK細胞を、RetroNectin被覆プレートにおいて、20:1 MOIでpLV[Exp]−PGK>EGFPベクターでの形質導入前に、500 U/ml IL−2とともに0〜5日間培養した。形質導入の3日後、細胞を、フローサイトメトリーによって、GFP発現および生存度に関してアッセイした。図24Aは、GFP+ NK細胞の代表的ゲーティングを示す。平均およびSEM(3名のドナーからの実験の幾何平均蛍光強度(GMFI)GFPのlog10変換した値についての)を示す(図24B)。これは、形質導入前のIL−2の存在下でのNK細胞の活性化が、効率的な形質導入を提供しかつNK細胞生存度を維持することを確認する。
Claims (32)
- 1種またはこれより多くの異種核酸を含むナチュラルキラー(NK)細胞を生成する方法であって、前記方法は、
活性化NK細胞の集団を生成するために、単離されたNK細胞の集団を、インターロイキン−2(IL−2)の存在下で少なくとも2日間培養する工程;
形質導入されたNK細胞の集団を生成するために、前記活性化NK細胞の集団を、1種またはこれより多くの異種核酸を含むウイルスベクターで形質導入する工程;ならびに
形質導入されたNK細胞の拡大増殖された集団を生成するために、前記形質導入されたNK細胞の集団を、IL−2および照射されたフィーダー細胞の存在下で培養する工程、
を包含する、方法。 - a)前記NK細胞の集団は、IL−2の存在下でかつ照射されたフィーダー細胞の非存在下で培養される、および/もしくは前記活性化NK細胞は、照射されたフィーダー細胞の非存在下で、前記ウイルスベクターで形質導入される;または
b)前記NK細胞の集団は、IL−2の存在下でかつ照射されたフィーダー細胞の存在下で培養される、および/もしくは前記活性化NK細胞は、照射されたフィーダー細胞の存在下で、前記ウイルスベクターで形質導入される、
請求項1に記載の方法。 - 前記単離されたNK細胞の集団を、1種またはこれより多くのサイトカインの存在下で培養する工程は、前記単離されたNK細胞の集団を、500 IU/ml IL−2を含む細胞培養培地中で培養することを包含する、請求項1または請求項2に記載の方法。
- 前記単離されたNK細胞の集団は、IL−2の存在下でかつ他のサイトカインは添加されずに培養される、請求項1〜3のいずれか1項に記載の方法。
- 前記活性化NK細胞の集団を形質導入する工程は、toll様レセプター(TLR)もしくはRIG−I様レセプター(RLR)の1種もしくはこれより多くのインヒビター、および/またはTBK1/IKKεの1種もしくはこれより多くのインヒビターの存在下で行われる、請求項1〜4のいずれか1項に記載の方法。
- TLRおよび/もしくはRLRの1種もしくはこれより多くのインヒビター、ならびに/またはTBK1/IKKεの1種もしくはこれより多くのインヒビターは、BX795、2−アミノプリン、BAY11−7082、セラストロール、CLI−095、H−89、ノルハルマン、IRAK1/4インヒビター、MRT67307、AZ13102909、MPI−0485520、アレキサノクス、化合物II、およびSR8185の1種もしくはこれより多くである、請求項5に記載の方法。
- TLRおよび/もしくはRLRの1種もしくはこれより多くのインヒビターならびに/またはTBK1/IKKεの1種もしくはこれより多くのインヒビターは、BX795である、請求項6に記載の方法。
- 前記1種またはこれより多くの異種核酸を含むウイルスベクターは、レンチウイルスベクターである、請求項1〜7のいずれか1項に記載の方法。
- 前記レンチウイルスベクターは、配列番号8〜19のいずれか1つと少なくとも90% 配列同一性を有する核酸配列を含むかまたはからなる、請求項8に記載の方法。
- 前記照射されたフィーダー細胞 対 前記形質導入されたNK細胞の比は、約10:1である、請求項1〜9のいずれか1項に記載の方法。
- 前記照射されたフィーダー細胞は、エプスタイン・バーウイルスで形質転換されたリンパ芽球系細胞株またはK562細胞を含む、請求項1〜10のいずれか1項に記載の方法。
- 前記異種核酸は、
高親和性CD16(CD16−V158)、CXCR4、CCR7、CXCR3、CD34、ダブルネガティブTGFβタイプIIレセプター、VLA−4、LFA−1、CD19、もしくはCD4;
腫瘍細胞上で発現される抗原に特異的に結合するキメラ抗原レセプター(CAR)であって、ここで前記異種核酸は、CD19、CD20、CD33、CD138、CS1、GD2、HER2、erbB2−、CEA、EpCAM、NKG2D−L、もしくはTRAIL−R1に特異的に結合するCARをコードするCAR;
細胞内ドメインを欠く短縮型CD34タンパク質をコードする核酸分子;および/または
低分子ヘアピン型RNA(shRNA)、低分子干渉RNA(siRNA)、もしくはアンチセンス核酸、
をコードする、請求項1〜11のいずれか1項に記載の方法。 - 前記NK細胞の集団は、IL−2の存在下かつ照射されたフィーダー細胞の存在下で培養されて、活性化NK細胞の集団を生成し、前記フィーダー細胞は、CD19免疫除去および/またはCD56免疫選択を使用して、前記活性化NK細胞から実質的に分離される、請求項2bに記載の方法。
- 腫瘍、過剰増殖性疾患、またはウイルス感染を有する被験体を処置する方法であって、前記方法は、
単離されたナチュラルキラー(NK)細胞の集団を、前記被験体またはドナーから得る工程;
活性化NK細胞の集団を生成するために、単離されたNK細胞の集団を、インターロイキン−2(IL−2)の存在下で少なくとも2日間培養する工程;
形質導入されたNK細胞の集団を生成するために、前記活性化NK細胞の集団を、1種またはこれより多くの異種核酸を含むウイルスベクターで形質導入する工程;
形質導入されたNK細胞の拡大増殖された集団を生成するために、前記形質導入されたNK細胞の集団を、IL−2および照射されたフィーダー細胞の存在下で培養する工程;ならびに
前記形質導入されたNK細胞の拡大増殖された集団を含む組成物を、前記被験体に投与する工程、
を包含する、方法。 - a)前記NK細胞の集団は、IL−2の存在下かつ照射されたフィーダー細胞の非存在下で培養される;および/もしくは前記活性化NK細胞は、照射されたフィーダー細胞の非存在下で、前記ウイルスベクターで形質導入される;または
b)前記NK細胞の集団は、IL−2の存在下かつ照射されたフィーダー細胞の存在下で培養される;および/もしくは前記活性化NK細胞は、照射されたフィーダー細胞の存在下で、前記ウイルスベクターで形質導入される、
請求項14に記載の方法。 - 前記単離されたNK細胞の集団を、1種またはこれより多くのサイトカインの存在下で培養する工程は、前記単離されたNK細胞の集団を、500 IU/ml IL−2を含む細胞培養培地中で培養することを包含する、請求項14または請求項15に記載の方法。
- 前記単離されたNK細胞の集団は、IL−2の存在下でかつ他のサイトカインは添加されずに培養される、請求項14〜16のいずれか1項に記載の方法。
- 前記活性化NK細胞の集団を形質導入する工程は、toll様レセプター(TLR)もしくはRIG−I様レセプター(RLR)の1種もしくはこれより多くのインヒビターおよび/またはTBK1/IKKεの1種もしくはこれより多くのインヒビターの存在下で行われる、請求項14〜17のいずれか1項に記載の方法。
- TLRおよび/もしくはRLRの1種もしくはこれより多くのインヒビターならびに/またはTBK1/IKKεの1種もしくはこれより多くのインヒビターは、BX795、2−アミノプリン、BAY11−7082、セラストロール、CLI−095、H−89、ノルハルマン、IRAK1/4インヒビター、MRT67307、AZ13102909、MPI−0485520、アレキサノクス、化合物II、およびSR8185の1種またはこれより多くである、請求項18に記載の方法。
- TLRおよび/もしくはRLRの1種もしくはこれより多くのインヒビターならびに/またはTBK1/IKKεの1種もしくはこれより多くのインヒビターは、BX795である、請求項19に記載の方法。
- 前記1種またはこれより多くの異種核酸を含むウイルスベクターは、レンチウイルスベクターである、請求項14〜20のいずれか1項に記載の方法。
- 前記レンチウイルスベクターは、配列番号8〜19のいずれか1つと少なくとも90% 配列同一性を有する核酸配列を含むかまたはからなる、請求項21に記載の方法。
- 前記レンチウイルスベクターは、PGK、EFS、またはSV40プロモーターに作動可能に連結された目的の核酸を含む、請求項21または請求項22に記載の方法。
- 前記照射されたフィーダー細胞 対 前記形質導入されたNK細胞の比は、10:1である、請求項14〜23のいずれか1項に記載の方法。
- 前記照射されたフィーダー細胞は、エプスタイン・バーウイルスで形質転換されたリンパ芽球系細胞株またはK562細胞を含む、請求項14〜24のいずれか1項に記載の方法。
- 前記異種核酸は、
高親和性CD16(CD16−V158)、CXCR4、CCR7、CXCR3、CD34、ダブルネガティブTGFβタイプIIレセプター、VLA−4、LFA−1、CD19、もしくはCD4;
腫瘍細胞上で発現される抗原に特異的に結合するキメラ抗原レセプター(CAR)であって、ここで前記異種核酸は、CD19、CD20、CD33、CD138、CS1、GD2、HER2、erbB2−、CEA、EpCAM、NKG2D−L、もしくはTRAIL−R1に特異的に結合するCARをコードするCAR;
細胞内ドメインを欠く短縮型CD34タンパク質をコードする核酸分子;および/または
低分子ヘアピン型RNA(shRNA)、低分子干渉RNA(siRNA)、もしくはアンチセンス核酸、
をコードする、請求項14〜25のいずれか1項に記載の方法。 - 前記NK細胞の集団は、IL−2の存在下かつ照射されたフィーダー細胞の存在下で培養されて、活性化NK細胞の集団を生成し、前記フィーダー細胞は、CD19免疫除去および/またはCD56免疫選択を使用して、前記活性化NK細胞から実質的に分離される、請求項15bに記載の方法。
- 前記形質導入されたNK細胞の拡大増殖された集団を含む組成物は、薬学的に受容可能なキャリアをさらに含む、請求項14〜27のいずれか1項に記載の方法。
- 請求項1〜13のいずれか1項に記載の方法によって生成される、1種またはこれより多くの異種核酸を含むナチュラルキラー細胞。
- 1種またはこれより多くの異種核酸を含むナチュラルキラー細胞および薬学的に受容可能なキャリアを含む組成物であって、ここで前記ナチュラルキラー細胞は、請求項1〜13のいずれか1項に記載の方法によって生成される、組成物。
- 1種またはこれより多くの異種核酸を含むナチュラルキラー(NK)細胞を生成する方法であって、前記方法は、
活性化NK細胞の集団を生成するために、単離されたNK細胞の集団を、インターロイキン−2(IL−2)および照射されたフィーダー細胞の存在下で少なくとも2日間培養する工程;
形質導入されたNK細胞の集団を生成するために、BX795の存在下で前記活性化NK細胞の集団を、1種またはこれより多くの異種核酸を含むウイルスベクターで形質導入する工程;ならびに
前記1種またはこれより多くの異種核酸を含む形質導入されたNK細胞の拡大増殖された集団を生成するために、前記形質導入されたNK細胞の集団を、IL−2および照射されたフィーダー細胞の存在下で培養する工程、
を包含する、方法。 - 前記単離されたNK細胞の集団は、IL−2の存在下でかつ他のサイトカインは添加されずに培養される、請求項31に記載の方法。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662366493P | 2016-07-25 | 2016-07-25 | |
US15/801,085 US11293010B2 (en) | 2016-07-25 | 2017-11-01 | Methods of producing modified natural killer cells and methods of use |
US15/801,085 | 2017-11-01 | ||
PCT/US2018/058747 WO2019089955A1 (en) | 2016-07-25 | 2018-11-01 | Methods of producing modified natural killer cells and methods of use |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2021501578A true JP2021501578A (ja) | 2021-01-21 |
JP2021501578A5 JP2021501578A5 (ja) | 2021-12-09 |
JP7364559B2 JP7364559B2 (ja) | 2023-10-18 |
Family
ID=59656171
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019503538A Active JP7086928B2 (ja) | 2016-07-25 | 2017-07-25 | 改変されたナチュラルキラー細胞を生成する方法および使用方法 |
JP2020524196A Active JP7364559B2 (ja) | 2016-07-25 | 2018-11-01 | 改変されたナチュラルキラー細胞を生成する方法および使用方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019503538A Active JP7086928B2 (ja) | 2016-07-25 | 2017-07-25 | 改変されたナチュラルキラー細胞を生成する方法および使用方法 |
Country Status (7)
Country | Link |
---|---|
US (2) | US11293010B2 (ja) |
EP (2) | EP3487991B1 (ja) |
JP (2) | JP7086928B2 (ja) |
CN (2) | CN109844099B (ja) |
IL (1) | IL273979B1 (ja) |
SG (2) | SG11201810871WA (ja) |
WO (2) | WO2018022646A1 (ja) |
Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106459914B (zh) | 2014-05-15 | 2020-11-06 | 新加坡国立大学 | 经修饰的自然杀伤细胞及其用途 |
WO2016077734A2 (en) * | 2014-11-14 | 2016-05-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Nk cells with an increased antibody-dependent cellular toxicity (adcc) against tumors |
CN109844099B (zh) * | 2016-07-25 | 2024-01-02 | 美国政府(由卫生和人类服务部的部长所代表) | 产生经修饰的自然杀伤细胞的方法及使用方法 |
WO2018104554A1 (en) * | 2016-12-09 | 2018-06-14 | Onkimmune Limited | Improved nk-based cell therapy |
RU2019128544A (ru) | 2017-03-27 | 2021-04-28 | Нэшнл Юниверсити Оф Сингапур | Линии стимулирующих клеток для ex vivo размножения и активации клеток-натуральных киллеров |
KR20240057444A (ko) | 2017-03-27 | 2024-05-02 | 내셔널 유니버시티 오브 싱가포르 | 절단된 nkg2d 키메라 수용체 및 자연 살해 세포 면역요법에서의 그의 용도 |
EP3746095A4 (en) | 2018-02-01 | 2021-04-21 | Nkmax Co., Ltd. | NATURAL KILLER CELL PRODUCTION PROCESS AND COMPOSITION FOR CANCER TREATMENT |
EP3749685A4 (en) * | 2018-02-09 | 2021-12-22 | National University of Singapore | ACTIVATOR CHEMERIC RECEPTORS AND THEIR USES IN NATURAL KILLING CELL IMMUNOTHERAPY |
TW202000214A (zh) * | 2018-02-21 | 2020-01-01 | 美國德克薩斯大學系統評議委員會 | 通用抗原呈現細胞及其用途 |
GB201804701D0 (en) * | 2018-03-23 | 2018-05-09 | Gammadelta Therapeutics Ltd | Lymphocytes expressing heterologous targeting constructs |
US20210228630A1 (en) * | 2018-05-16 | 2021-07-29 | Research Institute At Nationwide Children's Hospital | Generation of knock-out primary and expanded human nk cells using cas9 ribonucleoproteins |
WO2019226894A1 (en) * | 2018-05-23 | 2019-11-28 | Againchance Corporation Limited | Bispecific t cell engager and uses thereof |
JP2021525066A (ja) * | 2018-05-30 | 2021-09-24 | グリコステム セラピューティクス ベスローテン フェンノートシャップ | Car nk細胞 |
WO2019232631A1 (en) * | 2018-06-06 | 2019-12-12 | Stemcell Technologies Canada Inc. | Kits, compositions and methods for myeloid-derived suppressor cell enrichment |
AU2019314455B2 (en) * | 2018-08-01 | 2024-04-04 | Immunitybio, Inc. | A quadricistronic system comprising a homing receptor or a cytokine, and chimeric antigen receptor for genetic modification of immunotherapies |
CA3110926A1 (en) * | 2018-08-28 | 2020-03-05 | Pharos Vaccine Inc. | Improved lentiviral vector |
CN110863013A (zh) * | 2018-08-28 | 2020-03-06 | 北京永泰瑞科生物科技有限公司 | 改进的治疗性t细胞 |
CN110511912B (zh) * | 2018-08-30 | 2024-03-22 | 浙江煦顼技术有限公司 | 免疫细胞的功能调节 |
AU2019357602A1 (en) * | 2018-10-10 | 2021-05-13 | Wisconsin Alumni Research Foundation | Kir 7.1 gene therapy vectors and methods of using the same |
CN109402053A (zh) * | 2018-10-17 | 2019-03-01 | 广州元帅生物科技有限公司 | 一种外周血来源单个核细胞的分离及诱导培养方法 |
WO2020172328A1 (en) * | 2019-02-20 | 2020-08-27 | Rutgers, The State University Of New Jersey | Expansion of natural killer and chimeric antigen receptor-modified cells |
JP7487112B2 (ja) | 2019-03-05 | 2024-05-20 | ンカルタ・インコーポレイテッド | Cd19指向性キメラ抗原受容体および免疫療法におけるその使用 |
CN113710697A (zh) | 2019-03-15 | 2021-11-26 | 美国政府(由卫生和人类服务部的部长所代表) | 嵌合衔接子和激酶信号传导蛋白及其在免疫疗法中的用途 |
KR20200110576A (ko) * | 2019-03-15 | 2020-09-24 | 재단법인대구경북과학기술원 | 사이토카인 기반 면역세포 및 그의 면역 치료 용도 |
CN113677791A (zh) * | 2019-03-21 | 2021-11-19 | 昂克医疗有限公司 | 对细胞死亡具有增加的抗性的经修饰的免疫效应细胞 |
EP3712257A1 (en) * | 2019-03-21 | 2020-09-23 | ONK Therapeutics Limited | Modified natural killer cells with increased resistance to cell death |
CN110079529A (zh) * | 2019-04-28 | 2019-08-02 | 成都美杰赛尔生物科技有限公司 | 用于靶向敲除人NKG2A/KLRC1基因的sgRNA、表达载体、试剂盒及其用途 |
CN110106202A (zh) * | 2019-05-07 | 2019-08-09 | 杭州师范大学 | 抗肿瘤nk细胞的制备方法及其细胞与应用 |
CN110205293A (zh) * | 2019-06-25 | 2019-09-06 | 中冠赛尔生物科技(北京)有限公司 | 一种加强型高效治疗肺癌的nk免疫细胞的制备方法及应用 |
WO2021051088A1 (en) * | 2019-09-13 | 2021-03-18 | Ohio State Innovation Foundation | Nk cell immunotherapy compositions, methods of making and methods of using same |
US20210077527A1 (en) * | 2019-09-13 | 2021-03-18 | The Research Institute At Nationwide Children's Hospital | Universal donor selection method to identify nk-cell-donors |
US11230699B2 (en) | 2020-01-28 | 2022-01-25 | Immunitybio, Inc. | Chimeric antigen receptor-modified NK-92 cells targeting EGFR super-family receptors |
JP2023537799A (ja) | 2020-03-26 | 2023-09-06 | ザ ユナイテッド ステイツ オブ アメリカ, アズ リプレゼンテッド バイ ザ セクレタリー, デパートメント オブ ヘルス アンド ヒューマン サービシーズ | Cd28hドメイン含有キメラ抗原受容体および使用方法 |
CN113528452B (zh) * | 2020-07-06 | 2023-06-06 | 上海鑫湾生物科技有限公司 | 共表达IL-21和hrCD16嵌合受体的免疫细胞及其应用 |
CN112029721A (zh) * | 2020-09-09 | 2020-12-04 | 广东昭泰体内生物医药科技有限公司 | 一种活性增强型nk细胞的制备方法 |
KR102581230B1 (ko) * | 2020-10-16 | 2023-09-21 | 의료법인 성광의료재단 | 항암 관련 유전자 발현이 조절된 자연살해세포 및 이의 용도 |
CN116802273A (zh) | 2020-11-04 | 2023-09-22 | 美国政府(由卫生和人类服务部的部长所代表) | Ccr5表达减少的经修饰的nk细胞及其使用方法 |
WO2023034728A1 (en) * | 2021-08-30 | 2023-03-09 | Carrygenes Bioengineering, Llc | Synthetic chromosome encoding two or more chimeric antigen receptors binding to tumor associated antigens |
WO2023044304A1 (en) | 2021-09-15 | 2023-03-23 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric adaptor and kinase signaling proteins and their use in immunotherapy |
CN114306606B (zh) * | 2021-11-29 | 2023-05-26 | 江苏省人民医院(南京医科大学第一附属医院) | cGAS抑制剂在制备治疗T细胞淋巴瘤的药物中的应用 |
CN114381434A (zh) * | 2022-01-17 | 2022-04-22 | 华东师范大学 | 一种趋化型car-nk细胞及其制备方法和应用 |
CN114807237A (zh) * | 2022-05-12 | 2022-07-29 | 广东普罗凯融生物医药科技有限公司 | 一种过表达CD16a的NK细胞的制备方法及其应用 |
CN115074325A (zh) * | 2022-07-07 | 2022-09-20 | 广州希灵生物科技有限公司 | Herceptin联合4-1BBL体外扩增NK方法 |
CN115466726B (zh) * | 2022-09-05 | 2023-09-19 | 北京景达生物科技有限公司 | 一种nk细胞的高效基因转导方案 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017059177A2 (en) * | 2015-09-30 | 2017-04-06 | Vycellix, Inc. | Enhanced gene delivery to natural killer cells, hematopoietic stem cells and macrophages |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020177551A1 (en) * | 2000-05-31 | 2002-11-28 | Terman David S. | Compositions and methods for treatment of neoplastic disease |
DE10019075B4 (de) * | 2000-04-18 | 2007-01-18 | Vision 7 Gmbh | Verwendung von CD34 oder einem davon abgeleiteten Polypeptid als Zell-Oberflächen- bzw. Gentransfer-Marker |
US20130266551A1 (en) * | 2003-11-05 | 2013-10-10 | St. Jude Children's Research Hospital, Inc. | Chimeric receptors with 4-1bb stimulatory signaling domain |
EP1809738B1 (en) | 2004-11-02 | 2014-03-05 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by the Secretary, Department of Health and Human Services | Compositions and methods for treating hyperproliferative disorders |
CN101356679A (zh) * | 2005-10-31 | 2009-01-28 | 昂考梅德药品有限公司 | 用于诊断和治疗癌症的组合物和方法 |
US20070264687A1 (en) * | 2005-12-15 | 2007-11-15 | Min-Yuan Chou | Recombinant triplex scaffold-based polypeptides |
CN101684456A (zh) * | 2008-09-28 | 2010-03-31 | 江门罗森生物制药有限公司 | 一种体外培养条件下扩增人nk细胞的方法 |
ES2718546T3 (es) * | 2009-06-17 | 2019-07-02 | Tocagen Inc | Células productoras para vectores retrovirales de replicación competente |
CN104853766A (zh) * | 2012-10-02 | 2015-08-19 | 纪念斯隆-凯特琳癌症中心 | 用于免疫疗法的组合物和方法 |
EP2793026A1 (en) * | 2013-04-18 | 2014-10-22 | Centre National de la Recherche Scientifique (CNRS) | New method for monitoring cancer and/or inflammatory reaction based on relb phosphorylation |
WO2014179759A1 (en) * | 2013-05-03 | 2014-11-06 | Ohio State Innovation Foundation | Cs1-specific chimeric antigen receptor engineered immune effector cells |
US20170029777A1 (en) * | 2014-01-27 | 2017-02-02 | St. Jude Children's Research Hospital, Inc. | Methods of expanding ex vivo natural killer t (nkt) cells and therapeutic uses thereof |
WO2016073595A1 (en) | 2014-11-05 | 2016-05-12 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | T cells and dendritic cells for polyomavirus therapy |
WO2016077734A2 (en) | 2014-11-14 | 2016-05-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Nk cells with an increased antibody-dependent cellular toxicity (adcc) against tumors |
US10815457B2 (en) * | 2014-11-24 | 2020-10-27 | University Of Pittsburgh Of The Commonwealth Systems Of Higher Education | Active CXCR4+ immune cells and methods for their production and use |
CN105567634A (zh) * | 2016-01-27 | 2016-05-11 | 上海润泉生物技术有限公司 | 一种用于nk细胞体外扩增的培养基及nk细胞体外扩增的方法 |
CN109844099B (zh) | 2016-07-25 | 2024-01-02 | 美国政府(由卫生和人类服务部的部长所代表) | 产生经修饰的自然杀伤细胞的方法及使用方法 |
US20200392457A1 (en) * | 2016-07-25 | 2020-12-17 | The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services | Methods of producing modified natural killer cells and methods of use |
CN106350487B (zh) * | 2016-09-13 | 2019-01-25 | 北京多赢时代转化医学研究院 | 联合制备car-nk细胞和car-nkt细胞的方法 |
EP3545001A4 (en) * | 2016-11-22 | 2020-10-21 | Alloplex Biotherapeutics | ALLOGENIC TUMOR CELL VACCINE |
-
2017
- 2017-07-25 CN CN201780046354.1A patent/CN109844099B/zh active Active
- 2017-07-25 WO PCT/US2017/043774 patent/WO2018022646A1/en unknown
- 2017-07-25 SG SG11201810871WA patent/SG11201810871WA/en unknown
- 2017-07-25 EP EP17754517.5A patent/EP3487991B1/en active Active
- 2017-07-25 JP JP2019503538A patent/JP7086928B2/ja active Active
- 2017-11-01 US US15/801,085 patent/US11293010B2/en active Active
-
2018
- 2018-11-01 WO PCT/US2018/058747 patent/WO2019089955A1/en unknown
- 2018-11-01 EP EP18811415.1A patent/EP3704231A1/en active Pending
- 2018-11-01 IL IL273979A patent/IL273979B1/en unknown
- 2018-11-01 SG SG11202003201QA patent/SG11202003201QA/en unknown
- 2018-11-01 JP JP2020524196A patent/JP7364559B2/ja active Active
- 2018-11-01 CN CN201880071474.1A patent/CN111344395A/zh active Pending
-
2022
- 2022-03-07 US US17/688,435 patent/US20220228117A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017059177A2 (en) * | 2015-09-30 | 2017-04-06 | Vycellix, Inc. | Enhanced gene delivery to natural killer cells, hematopoietic stem cells and macrophages |
Non-Patent Citations (3)
Title |
---|
BLOOD, vol. 106, JPN6022044459, 2005, pages 376 - 383, ISSN: 0005036933 * |
HEMATOLOGY, vol. 2013, JPN6022044462, 2013, pages 234 - 246, ISSN: 0005036935 * |
HUMAN GENE THERAPY, vol. 23, JPN6022044461, 2012, pages 1090 - 1100, ISSN: 0005036934 * |
Also Published As
Publication number | Publication date |
---|---|
EP3487991B1 (en) | 2022-09-07 |
WO2018022646A1 (en) | 2018-02-01 |
IL273979B1 (en) | 2024-05-01 |
EP3704231A1 (en) | 2020-09-09 |
SG11202003201QA (en) | 2020-05-28 |
WO2019089955A1 (en) | 2019-05-09 |
CN109844099A (zh) | 2019-06-04 |
CN109844099B (zh) | 2024-01-02 |
EP3487991A1 (en) | 2019-05-29 |
US20180057795A1 (en) | 2018-03-01 |
IL273979A (en) | 2020-05-31 |
US11293010B2 (en) | 2022-04-05 |
JP2019523001A (ja) | 2019-08-22 |
JP7364559B2 (ja) | 2023-10-18 |
SG11201810871WA (en) | 2019-01-30 |
JP7086928B2 (ja) | 2022-06-20 |
US20220228117A1 (en) | 2022-07-21 |
CN111344395A (zh) | 2020-06-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7364559B2 (ja) | 改変されたナチュラルキラー細胞を生成する方法および使用方法 | |
Matosevic | Viral and nonviral engineering of natural killer cells as emerging adoptive cancer immunotherapies | |
US20200360436A1 (en) | Nk cells with an increased antibody-dependent cellular toxicity (adcc) against tumors | |
TWI788307B (zh) | 用於擴增腫瘤浸潤性淋巴細胞之工程化人造抗原呈現細胞 | |
KR102437015B1 (ko) | 유전자이식 t 세포 및 키메라 항원 수용체 t 세포 조성물 및 관련 방법 | |
CN107206024B (zh) | 改变cart细胞中的基因表达及其用途 | |
JP6203705B2 (ja) | 細胞免疫療法のための方法および組成物 | |
CN111566221B (zh) | 用于nk细胞转导的方法 | |
WO2019096115A1 (zh) | 分离的t细胞受体、其修饰的细胞、编码核酸、表达载体、制备方法、药物组合物和应用 | |
US20200392457A1 (en) | Methods of producing modified natural killer cells and methods of use | |
US20190389926A1 (en) | Mr1 restricted t cell receptors for cancer immunotherapy | |
JP6687246B2 (ja) | 改変型免疫細胞、改変型免疫細胞の製造方法、およびこれらの利用 | |
JP2023504075A (ja) | Car-nk細胞を得る方法 | |
US20240132841A1 (en) | Large scale car-t immune cell manufacturing method utilizing lentiviral vector transfection | |
WO2023070041A1 (en) | Enhanced immune cell therapy | |
WO2024007020A1 (en) | Combination of engineered natural killer (nk) cells and antibody therapy and related methods | |
CA3141210A1 (en) | Modified nk-92 cells, and therapeutic and diagnostic uses thereof | |
CN117915929A (zh) | 工程化自然杀伤(nk)细胞和相关方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211029 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211029 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220930 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221021 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230123 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230414 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230706 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230912 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231005 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7364559 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |