TW202313966A - 表現免疫機能控制因子之免疫活性細胞及表現載體 - Google Patents
表現免疫機能控制因子之免疫活性細胞及表現載體 Download PDFInfo
- Publication number
- TW202313966A TW202313966A TW111147302A TW111147302A TW202313966A TW 202313966 A TW202313966 A TW 202313966A TW 111147302 A TW111147302 A TW 111147302A TW 111147302 A TW111147302 A TW 111147302A TW 202313966 A TW202313966 A TW 202313966A
- Authority
- TW
- Taiwan
- Prior art keywords
- cells
- nucleic acid
- ccl19
- cell
- acid encoding
- Prior art date
Links
- 239000013604 expression vector Substances 0.000 title claims abstract description 90
- 230000036737 immune function Effects 0.000 title abstract description 15
- 102000037983 regulatory factors Human genes 0.000 title abstract 2
- 108091008025 regulatory factors Proteins 0.000 title abstract 2
- 210000004027 cell Anatomy 0.000 claims abstract description 213
- 108010002586 Interleukin-7 Proteins 0.000 claims abstract description 159
- 102000000704 Interleukin-7 Human genes 0.000 claims abstract description 159
- 229940100994 interleukin-7 Drugs 0.000 claims abstract description 159
- 102100036842 C-C motif chemokine 19 Human genes 0.000 claims abstract description 142
- 101000713106 Homo sapiens C-C motif chemokine 19 Proteins 0.000 claims abstract description 142
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 137
- 201000011510 cancer Diseases 0.000 claims abstract description 116
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 112
- 239000000427 antigen Substances 0.000 claims abstract description 91
- 108091007433 antigens Proteins 0.000 claims abstract description 91
- 102000036639 antigens Human genes 0.000 claims abstract description 91
- 102000039446 nucleic acids Human genes 0.000 claims description 162
- 108020004707 nucleic acids Proteins 0.000 claims description 162
- 150000007523 nucleic acids Chemical class 0.000 claims description 162
- 108090000623 proteins and genes Proteins 0.000 claims description 37
- 101800001318 Capsid protein VP4 Proteins 0.000 claims description 26
- 239000002246 antineoplastic agent Substances 0.000 claims description 21
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 16
- 210000000822 natural killer cell Anatomy 0.000 claims description 15
- -1 URLC10 Proteins 0.000 claims description 9
- 210000000612 antigen-presenting cell Anatomy 0.000 claims description 6
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 claims description 5
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims description 5
- 102000010956 Glypican Human genes 0.000 claims description 5
- 108050001154 Glypican Proteins 0.000 claims description 5
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims description 5
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 claims description 5
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 claims description 5
- 101800001271 Surface protein Proteins 0.000 claims description 5
- 108010002687 Survivin Proteins 0.000 claims description 5
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 5
- 210000003714 granulocyte Anatomy 0.000 claims description 5
- SSOORFWOBGFTHL-OTEJMHTDSA-N (4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SSOORFWOBGFTHL-OTEJMHTDSA-N 0.000 claims description 4
- 102100024153 Cadherin-15 Human genes 0.000 claims description 4
- 102100037753 DEP domain-containing protein 1A Human genes 0.000 claims description 4
- 102100036109 Dual specificity protein kinase TTK Human genes 0.000 claims description 4
- 102100028773 Endonuclease 8-like 3 Human genes 0.000 claims description 4
- 108010008599 Forkhead Box Protein M1 Proteins 0.000 claims description 4
- 102100023374 Forkhead box protein M1 Human genes 0.000 claims description 4
- 101000762242 Homo sapiens Cadherin-15 Proteins 0.000 claims description 4
- 101000714553 Homo sapiens Cadherin-3 Proteins 0.000 claims description 4
- 101000950642 Homo sapiens DEP domain-containing protein 1A Proteins 0.000 claims description 4
- 101000659223 Homo sapiens Dual specificity protein kinase TTK Proteins 0.000 claims description 4
- 101001123819 Homo sapiens Endonuclease 8-like 3 Proteins 0.000 claims description 4
- 101100452137 Homo sapiens IGF2BP3 gene Proteins 0.000 claims description 4
- 101001027621 Homo sapiens Kinesin-like protein KIF20A Proteins 0.000 claims description 4
- 101001027631 Homo sapiens Kinesin-like protein KIF20B Proteins 0.000 claims description 4
- 101000762967 Homo sapiens Lymphokine-activated killer T-cell-originated protein kinase Proteins 0.000 claims description 4
- 101000801539 Homo sapiens Mitochondrial import receptor subunit TOM34 Proteins 0.000 claims description 4
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 4
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 claims description 4
- 101000817237 Homo sapiens Protein ECT2 Proteins 0.000 claims description 4
- 101000837581 Homo sapiens Ubiquitin-conjugating enzyme E2 T Proteins 0.000 claims description 4
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims description 4
- 102100037920 Insulin-like growth factor 2 mRNA-binding protein 3 Human genes 0.000 claims description 4
- 102100037694 Kinesin-like protein KIF20A Human genes 0.000 claims description 4
- 102100037691 Kinesin-like protein KIF20B Human genes 0.000 claims description 4
- 102100026753 Lymphokine-activated killer T-cell-originated protein kinase Human genes 0.000 claims description 4
- 102000003735 Mesothelin Human genes 0.000 claims description 4
- 108090000015 Mesothelin Proteins 0.000 claims description 4
- 102100033583 Mitochondrial import receptor subunit TOM34 Human genes 0.000 claims description 4
- 102100034256 Mucin-1 Human genes 0.000 claims description 4
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 claims description 4
- 102100040437 Protein ECT2 Human genes 0.000 claims description 4
- 102100027244 U4/U6.U5 tri-snRNP-associated protein 1 Human genes 0.000 claims description 4
- 101710155955 U4/U6.U5 tri-snRNP-associated protein 1 Proteins 0.000 claims description 4
- 102100028705 Ubiquitin-conjugating enzyme E2 T Human genes 0.000 claims description 4
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 4
- 102000040856 WT1 Human genes 0.000 claims description 4
- 108700020467 WT1 Proteins 0.000 claims description 4
- 101150084041 WT1 gene Proteins 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 102000005962 receptors Human genes 0.000 claims description 4
- 108020003175 receptors Proteins 0.000 claims description 4
- 108050007237 Glypican-3 Proteins 0.000 claims description 3
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 claims description 3
- 101001044869 Shewanella frigidimarina (strain NCIMB 400) Ice-binding protein 1 Proteins 0.000 claims description 3
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 claims description 3
- 238000012737 microarray-based gene expression Methods 0.000 claims description 2
- 238000012243 multiplex automated genomic engineering Methods 0.000 claims description 2
- 108091008874 T cell receptors Proteins 0.000 abstract description 71
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 abstract description 69
- 230000035899 viability Effects 0.000 abstract description 7
- 230000002062 proliferating effect Effects 0.000 abstract description 5
- 238000009825 accumulation Methods 0.000 abstract description 4
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 239000013598 vector Substances 0.000 description 47
- 238000000034 method Methods 0.000 description 44
- 108090000765 processed proteins & peptides Proteins 0.000 description 24
- 241000699670 Mus sp. Species 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 230000004083 survival effect Effects 0.000 description 16
- 108020004414 DNA Proteins 0.000 description 12
- 239000012634 fragment Substances 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108700031361 Brachyury Proteins 0.000 description 10
- 238000002659 cell therapy Methods 0.000 description 10
- 230000001939 inductive effect Effects 0.000 description 10
- 210000004698 lymphocyte Anatomy 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 241001430294 unidentified retrovirus Species 0.000 description 10
- 108010002350 Interleukin-2 Proteins 0.000 description 9
- 238000009169 immunotherapy Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 241000700605 Viruses Species 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 230000006698 induction Effects 0.000 description 7
- 229940127084 other anti-cancer agent Drugs 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 210000004443 dendritic cell Anatomy 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000002773 nucleotide Substances 0.000 description 6
- 125000003729 nucleotide group Chemical group 0.000 description 6
- 238000003752 polymerase chain reaction Methods 0.000 description 6
- 238000011144 upstream manufacturing Methods 0.000 description 6
- 102100036846 C-C motif chemokine 21 Human genes 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 description 5
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000012292 cell migration Effects 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000833 heterodimer Substances 0.000 description 5
- 108091033319 polynucleotide Proteins 0.000 description 5
- 102000040430 polynucleotide Human genes 0.000 description 5
- 239000002157 polynucleotide Substances 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 5
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 4
- 102000004039 Caspase-9 Human genes 0.000 description 4
- 108090000566 Caspase-9 Proteins 0.000 description 4
- 108020004705 Codon Proteins 0.000 description 4
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 4
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 4
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 4
- 102100040247 Tumor necrosis factor Human genes 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 201000000053 blastoma Diseases 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 201000008184 embryoma Diseases 0.000 description 4
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 4
- 230000002068 genetic effect Effects 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 210000003563 lymphoid tissue Anatomy 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000001177 retroviral effect Effects 0.000 description 4
- 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 4
- 238000010361 transduction Methods 0.000 description 4
- 230000026683 transduction Effects 0.000 description 4
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 4
- 239000013603 viral vector Substances 0.000 description 4
- 108091026890 Coding region Proteins 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000700584 Simplexvirus Species 0.000 description 3
- 238000010459 TALEN Methods 0.000 description 3
- 102000006601 Thymidine Kinase Human genes 0.000 description 3
- 108020004440 Thymidine kinase Proteins 0.000 description 3
- 108010009583 Transforming Growth Factors Proteins 0.000 description 3
- 102000009618 Transforming Growth Factors Human genes 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 229960002963 ganciclovir Drugs 0.000 description 3
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 3
- 238000010362 genome editing Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 3
- 230000003394 haemopoietic effect Effects 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108091008146 restriction endonucleases Proteins 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 210000004989 spleen cell Anatomy 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 102100023635 Alpha-fetoprotein Human genes 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010029704 Constitutive Androstane Receptor Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 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 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102100020715 Fms-related tyrosine kinase 3 ligand protein Human genes 0.000 description 2
- 101710162577 Fms-related tyrosine kinase 3 ligand protein Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229930186217 Glycolipid Natural products 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 101001043808 Mus musculus Interleukin-7 Proteins 0.000 description 2
- 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 2
- 102100038512 Nuclear receptor subfamily 1 group I member 3 Human genes 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 2
- 241000709664 Picornaviridae Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 108091007416 X-inactive specific transcript Proteins 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 206010052015 cytokine release syndrome Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 210000001671 embryonic stem cell Anatomy 0.000 description 2
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 210000004263 induced pluripotent stem cell Anatomy 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 210000002706 plastid Anatomy 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- 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 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010068873 Adenosquamous cell carcinoma Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 108010031480 Artificial Receptors Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 108700012434 CCL3 Proteins 0.000 description 1
- 102000004631 Calcineurin Human genes 0.000 description 1
- 108010042955 Calcineurin Proteins 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000000013 Chemokine CCL3 Human genes 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 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 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101100495232 Homo sapiens MS4A1 gene Proteins 0.000 description 1
- 101001094545 Homo sapiens Retrotransposon-like protein 1 Proteins 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 1
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 101100005547 Mus musculus Ccl19 gene Proteins 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 208000007027 Oral Candidiasis Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 201000008199 Pleuropulmonary blastoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 208000000277 Splenic Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 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
- 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 1
- 241000287411 Turdidae Species 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 108091035715 XIST (gene) Proteins 0.000 description 1
- 108010017070 Zinc Finger Nucleases Proteins 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 201000008395 adenosquamous carcinoma Diseases 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 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
- 229960000997 bicalutamide Drugs 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 201000005200 bronchus cancer Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000019975 dosage compensation by inactivation of X chromosome Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000008846 dynamic interplay Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 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 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000012637 gene transfection Methods 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 229940099279 idamycin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 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 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000005210 lymphoid organ Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000010232 migration assay Methods 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000581 natural killer T-cell Anatomy 0.000 description 1
- 208000029974 neurofibrosarcoma Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 210000004967 non-hematopoietic stem cell Anatomy 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 108010056030 retronectin Proteins 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 201000002471 spleen cancer Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000009258 tissue cross reactivity Effects 0.000 description 1
- 206010044285 tracheal cancer Diseases 0.000 description 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 1
- 229960004066 trametinib Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 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 1
- 208000010576 undifferentiated carcinoma Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- 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
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- 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
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4632—T-cell receptors [TCR]; antibody T-cell receptor constructs
-
- 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
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4635—Cytokines
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5418—IL-7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 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
- 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
-
- 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
-
- 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
-
- 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
- C12N5/0636—T 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cell Biology (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Mycology (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Developmental Biology & Embryology (AREA)
- Virology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本發明之課題在於提供一種於免疫活性細胞中表現免疫活性細胞之免疫機能控制因子，兼具增生能力、生存能力、及T細胞之集聚能力之免疫活性細胞、及用以製作該表現免疫活性細胞之免疫機能控制因子載體。
製作免疫活性細胞，該免疫活性細胞表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19。較佳的是特異性地識別癌抗原之細胞表面分子為特異性地識別癌抗原之T細胞受體，或免疫活性細胞為T細胞。
Description
本發明係關於一種表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19之免疫活性細胞、及含有該免疫活性細胞之抗癌劑、及用以製作該表現免疫活性細胞之載體。
癌症係全世界罹患者眾多之疾病，一般而言，業界廣泛採用化學療法、放射線療法、或外科療法。然而，存在產生副作用、或喪失一部分機能、或難以對轉移進行治療等各種問題。
因此，為了進一步將患者之QOL(Quality Of Life，生活品質)維持為較高，近年來進行了免疫療法之開發。於該免疫療法中，免疫細胞療法係從患者採集免疫活性細胞，將該免疫活性細胞以提高其免疫機能之方式加以處置並擴增，再次移入至患者體內之療法。具體而言，已知有從患者採集T細胞，向該T細胞中導入編碼CAR(Constitutive Androstane Receptor，組成雄甾烷受體)之基因進行擴增，再次移入至患者體內之療法(參照非專利文獻1)。該療法目前正於全世界進行臨床試驗，獲得了於白血病及淋巴瘤等造血器官惡性腫瘤等中顯示出有效性之結果。
又，作為T細胞等免疫活性細胞之免疫機能控制因子，已知有細胞激素、趨化激素、訊息控制蛋白質等至少數百種因子。其中，已知介白素7(IL-7)係T細胞生存所必須之細胞激素，其係由骨髄、胸腺、淋巴器官/組織之基質細胞等非造血細胞所產生。作為該利用IL-7之機能之T細胞，揭示有表現將IL-7與IL-7Rα融合而成之嵌合體細胞激素受體的T細胞(參照專利文獻1)。然而，該T細胞中之嵌合體細胞激素受體不過是作為一個融合蛋白，限定於所導入之T細胞之膜表面進行表現，僅對自體之細胞不依賴配體而傳遞IL-7R等細胞激素訊息，無法提高未導入上述受體之T細胞之機能。
又，揭示有CCL19或CCL21、IL-7之表現降低會導致SIRP(Signal Regulatory Protein，訊息調節蛋白)α變異小鼠之脾臟中之T細胞區之維持缺陷(參照非專利文獻2)，及CCL19或CCL21、IL-7具有於二次淋巴組織(脾臟或淋巴結)中維持T細胞之恆常性之作用(參照非專利文獻3)。然而，上述非專利文獻2、3係顯示出對於恆常地存在於二次淋巴組織之T細胞區中之非活化T細胞之作用，並非顯示出與抗腫瘤免疫應答之直接關聯性。進而，上述非專利文獻2、3中之CCL19或CCL21、IL-7表現細胞係存在於二次淋巴組織中之網狀內皮系統之細胞而非T細胞。
另一方面，T細胞受體(T cell receptor，以下，亦稱為「TCR」)係於T細胞之細胞膜上表現之抗原受體分子。已知係以包含α鏈與β鏈、或γ鏈與Δ鏈之異型二聚物之形式存在，藉由對與主要組織相容性因複合體(MHC)分子結合而成之抗原分子進行識別，而將T細胞活化。
業界不斷進行如下免疫療法之開發，即，應用該TCR之機能，將可識別於癌細胞中進行表現之腫瘤抗原之TCR基因導入至從癌症患者獲得之T細胞中，於擴增後再次移入至患者體內。具體而言，揭示有一種腦膜瘤治療用醫藥組合物，其含有表現特異性地識別WT1表現細胞之TCR之細胞(參照專利文獻2)。
於上述技術之一部分中雖然存在確認到具有針對造血器官惡性腫瘤之抗腫瘤效果者，但尚無對實體癌顯示出顯著效果之例。考慮到所移入之免疫活性細胞於活體內之生存效率較低、或者由所移入之免疫活性細胞誘導之內源性免疫活性細胞之活化、或向腫瘤局部之集聚不充分之問題，而謀求開發出解決該等之技術。
[先前技術文獻]
[專利文獻]
專利文獻1：國際公開第2013/123061號說明書
專利文獻2：日本專利特開2013-116891號公報
非專利文獻1：中澤洋三 信州醫志 61 (4)： 197～203 (2013)
非專利文獻2：SATO-HASHIMOTO M. et al., J. Immunol., 2011, vol. 187, no. 1, 291-7
非專利文獻3：SIEGERT S. et al., Front. Immunol., 2012, vol. 3, article 285
[發明所欲解決之問題]
於先前之免疫療法中所使用之免疫活性細胞中，內源性免疫活性細胞之免疫誘導效果、或免疫活性細胞之增生能力、生存能力、或T細胞之集聚能力未得到充分地增強。因此，本發明之課題在於提供一種於免疫活性細胞中表現免疫活性細胞之免疫機能控制因子，兼具增生能力、生存能力、及T細胞之集聚能力之免疫活性細胞、及用以製作該免疫活性細胞之免疫機能控制因子表現載體。
[解決問題之技術手段]
發明者等人為了於利用免疫活性細胞之癌症免疫療法中，達成更優異之免疫誘導效果或抗腫瘤活性，而嘗試改良表現免疫機能控制因子之細胞。於該過程中，著眼於作為控制免疫活性細胞之免疫機能之因子的細胞激素、趨化激素、訊息控制蛋白質，而構建表現上述控制免疫活性細胞之免疫機能之因子的載體。將該表現載體導入至免疫活性細胞中，結果發現，可製作具有較先前之免疫活性細胞更優異之免疫誘導效果、增生能力、生存能力以及T細胞之集聚能力的免疫活性細胞，從而完成本發明。
即，本發明如以下之(1)至(9)所揭示。
(1)一種免疫活性細胞，其表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19。
(2)如上述(1)中所記載之免疫活性細胞，其特徵在於：特異性地識別癌抗原之細胞表面分子為特異性地識別癌抗原之T細胞受體。
(3)如上述(1)或(2)中所記載之免疫活性細胞，其特徵在於：免疫活性細胞為T細胞。
(4)如上述(1)至(3)之任一項中所記載之免疫活性細胞，其特徵在於：癌抗原為WT1、MART-1、NY-ESO-1、MAGE(Melanoma antigen，黑色素瘤抗原)-A1、MAGE-A3、MAGE-A4、磷脂醯肌醇蛋白聚糖(Glypican)-3、KIF20A、存活蛋白(Survivin)、AFP(Alpha Fetal Protein，α-胎蛋白)-1、gp100、MUC1、PAP-10、PAP-5、TRP2-1、SART-1、VEGFR(Vascular Endothelial Growth Facotr Receptor，血管內皮生長因子受體)1、VEGFR2、NEIL3、MPHOSPH1、DEPDC1、FOXM1、CDH3、TTK、TOMM34、URLC10、KOC1、UBE2T、TOPK、ECT2、間皮素(MESOTHELIN)、NKG2D、P1A、GD2、或GM2。
(5)一種表現載體，其係用以製作如上述(1)至(4)之任一項中所記載之免疫活性細胞的以下之(a)至(e)中之任一種：
(a)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、編碼IL-7之核酸、及編碼CCL19之核酸之表現載體；
(b)以下之(b-1)及(b-2)之2種表現載體：
(b-1)含有編碼特異性地識別癌抗原之細胞表面分子之核酸之表現載體；
(b-2)含有編碼IL-7之核酸、及編碼CCL19之核酸之表現載體；
(c)以下之(c-1)及(c-2)之2種表現載體：
(c-1)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、及編碼IL-7之核酸之表現載體；
(c-2)含有編碼CCL19之核酸之表現載體；
(d)以下之(d-1)及(d-2)之2種表現載體：
(d-1)含有編碼IL-7之核酸之表現載體；
(d-2)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、及編碼CCL19之核酸之表現載體；
(e)以下之(e-1)、(e-2)及(e-3)之3種表現載體：
(e-1)含有編碼特異性地識別癌抗原之細胞表面分子之核酸之表現載體；
(e-2)含有編碼IL-7之核酸之表現載體；
(e-3)含有編碼CCL19之核酸之表現載體。
(6)如上述(5)中所記載之表現載體，其特徵在於：特異性地識別癌抗原之細胞表面分子為特異性地識別癌抗原之T細胞受體。
(7)如上述(5)或(6)中所記載之表現載體，其特徵在於：(a)之表現載體中之編碼特異性地識別癌抗原之細胞表面分子之核酸、編碼IL-7之核酸、及編碼CCL19之核酸，
(b-2)之表現載體中之編碼IL-7之核酸、及編碼CCL19之核酸，
(c-1)之表現載體中之編碼特異性地識別癌抗原之細胞表面分子之核酸、及編碼IL-7之核酸，或
(d-2)之表現載體中之編碼特異性地識別癌抗原之細胞表面分子之核酸、及編碼CCL19之核酸係經由自裂解型肽而連結。
(8)如上述(5)至(7)之任一項中所記載之表現載體，其特徵在於：含有編碼自殺基因之核酸。
(9)一種抗癌劑，其含有如上述(1)至(4)之任一項中所記載之免疫活性細胞與藥學上所容許之添加劑。
[發明之效果]
若使用本發明之表現特異性地識別癌抗原之細胞表面分子、IL-7、及CCL19之免疫活性細胞(以下，亦稱為「IL-7×CCL19表現免疫活性細胞」)，則具有抗腫瘤活性，可抑制由具有細胞表面分子特異性地識別之抗原的癌細胞所形成之腫瘤所引起之生存率降低。又，若使用本發明之表現載體，則可製作兼具增生能力、生存能力及T細胞集聚能力之免疫活性細胞。
本發明之IL-7×CCL19表現免疫活性細胞只要表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19，則無特別限制，進而亦可表現IL-15、CCL21、IL-2、IL-4、IL-12、IL-13、IL-17、IL-18、IP-10、CCL4、Flt3L、干擾素-γ、MIP(Macrophage Inflammatory Protein，巨噬細胞炎性蛋白)-1α、GM-CSF(Granulocyte Macrophage-Colony Stimulating Factor，顆粒球巨噬細胞群落刺激因子)、M-CSF(Macrophage Colony Stimulating Factor，巨噬細胞群落刺激因子)、TGF(Transforming Growth Factor，轉化生長因子)-β、TNF(Tumor Necrosis Factor，腫瘤壞死因子)-α等其他免疫機能控制因子。
所謂癌抗原係指於在癌細胞中較正常細胞更高地進行表現、或者於癌細胞中特異性地進行表現之蛋白質、糖脂質等物質，作為該癌抗原，可列舉：腫瘤相關抗原或癌睾丸抗原、血管新生相關抗原、因基因變異而產生之癌新生抗原(新抗原)之抗原決定肽，具體而言，可列舉：WT1、MART-1、NY-ESO-1、MAGE-A1、MAGE-A3、MAGE-A4、磷脂醯肌醇蛋白聚糖-3、KIF20A、存活蛋白、AFP-1、gp100、MUC1、PAP-10、PAP-5、TRP2-1、SART-1、VEGFR1、VEGFR2、NEIL3、MPHOSPH1、DEPDC1、FOXM1、CDH3、TTK、TOMM34、URLC10、KOC1、UBE2T、TOPK、ECT2、間皮素、NKG2D、P1A等蛋白質、或GD2、GM2等糖脂質，但並不限定於此。
作為特異性地識別癌抗原之細胞表面分子，可列舉特異性地識別癌抗原之細胞表面受體、人工受體、黏著因子，可適宜地列舉特異性地識別癌抗原之T細胞受體或特異性地識別癌抗原之嵌合體抗原受體(CAR，constitutive androstane receptor)等藉由在細胞表面進行表現而賦予針對癌症之特異性之識別能力之分子，可更適宜地列舉TCR。作為TCR，只要特異性地識別癌抗原，則可為包含α鏈及β鏈之異型二聚物(α/β-TCR)，亦可為包含γ鏈及Δ鏈之異型二聚物(γ/Δ-TCR)。再者，關於特異性地識別癌抗原之細胞表面分子，只要癌抗原之識別為特異性，則可為間接地進行識別者。例如，與本發明之免疫活性細胞同時或連續地向對象投予特異性地識別癌抗原之抗體等分子，對該抗體等分子進行識別、或對抗體等分子上所標記之標籤進行識別，藉此本發明之免疫活性細胞可間接地特異性地識別癌抗原。作為識別抗體之情形之例，作為細胞表面分子，可列舉CD16等，作為抗體等分子上所標記之標籤之例，可列舉FITC(fluorescein isothiocyanate，螢光異硫氰酸鹽)等。
作為本發明之IL-7×CCL19表現免疫活性細胞中之免疫活性細胞之種類，只要為與免疫應答相關之細胞即可，可列舉：T細胞、自然殺手細胞(NK細胞)、B細胞等淋巴球系細胞、或單核球、巨噬細胞、樹狀細胞等抗原呈現細胞、或嗜中性球、嗜酸性球、嗜鹼性球、肥胖細胞等粒細胞，可適宜地列舉源自人類、狗、貓、豬、小鼠等哺乳動物之T細胞，較佳為源自人類之T細胞。又，T細胞可從浸潤於血液、骨髄液等體液、或脾臟、胸腺、淋巴結等組織、或者原發腫瘤、轉移性腫瘤、癌性腹水等癌組織中之免疫細胞進行單離、精製而獲得，又，亦可利用由ES細胞(embryonic stem cells，胚胎幹細胞)或iPS細胞(induced pluripotent stem cells，誘導性多功能幹細胞)製作而成者。作為該T細胞，可列舉：α/β-T細胞、γ/Δ-T細胞、CD8
+T細胞、CD4
+T細胞、腫瘤浸潤T細胞、記憶T細胞、初始T細胞、NKT細胞。
作為本發明之IL-7×CCL19表現免疫活性細胞之製作方法，可列舉下述將本發明之表現載體導入至免疫活性細胞中而製作之方法。或者，亦可列舉對於受精卵、ES細胞、或iPS細胞，導入表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及/或CCL19之載體後進行誘導而製作之方法；或從藉由基因導入特異性地識別癌抗原之細胞表面分子而表現之基因轉殖哺乳動物分離得之免疫活性細胞，對該免疫活性細胞進而視需要導入表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及/或CCL19的載體而製作之方法。
作為將下述本發明之表現載體導入至上述免疫活性細胞中而製作之方法，並無特別限制，可列舉藉由病毒感染法、磷酸鈣法、脂質體轉染法、顯微注射法、電穿孔法等公知方法進行導入之方法，可適宜地列舉藉由病毒感染法進行導入之方法。
作為病毒感染法，可列舉使本發明之表現載體與包裝質體轉染至GP2-293細胞(TAKARA BIO公司製造)、Plat-GP細胞(Cosmobio公司製造)、PG13細胞(ATCC CRL-10686)、PA317細胞(ATCC CRL-9078)等包裝細胞而製作重組病毒，並使免疫活性細胞感染該重組病毒之方法，可使用Retrovirus packagin Kit Eco(反轉錄病毒包裝套組Eco)(TAKARA BIO公司製造)等市售之套組而進行。
又，本發明之免疫活性細胞可藉由如下方法而製作：使用公知之基因編輯技術，以於適當之啟動子之控制下能夠進行表現之方式將包含編碼特異性地識別癌抗原之細胞表面分子、IL-7、及CCL19之鹼基序列之聚核苷酸組入至細胞之基因組中。作為公知之基因編輯技術，可列舉使用鋅指核酸酶、TALEN(Transcription Activator-like Effector Nuclease，類轉錄活化因子效應物核酸酶)、CRISPR(Clustered Regularly Interspaced Short Palindromic Repeat，成簇規律間隔短回文重複)-Cas系統等內核酸酶之技術。於本發明之免疫活性細胞中表現其他外來蛋白質之情形亦同樣地可使用基因編輯技術，以於適當之啟動子之控制下能夠進行表現之方式將包含編碼其他外來蛋白質之鹼基序列之聚核苷酸組入至細胞之基因組中。作為以於適當之啟動子之控制下能夠進行表現之方式將聚核苷酸組入至細胞基因組中之方法，可列舉：將編碼特異性地識別癌抗原之細胞表面分子、IL-7、及CCL19(或其他蛋白質)之鹼基序列機能性地連結於適當之啟動子之下游，將所獲得之聚核苷酸(即，以於該啟動子之控制下能夠進行表現之方式連結編碼序列之聚核苷酸)組入至細胞基因組之非編碼區等之方法；將包含編碼特異性地識別癌抗原之細胞表面分子、IL-7、及CCL19(或其他蛋白質)之鹼基序列的聚核苷酸組入至細胞基因組之內源性啟動子之下游之方法等。作為內源性啟動子，例如可列舉TCRα、TCRβ之啟動子等。
又，亦可設法於本發明之IL-7×CCL19表現免疫活性細胞中，表現下述單純疱疹病毒之胸苷激酶(HSV-TK)或誘導性半胱天冬酶9(inducible caspase 9)。
本發明之IL-7×CCL19表現免疫活性細胞由於表現特異性地識別癌抗原之細胞表面分子、IL-7、及CCL19，故而增生能力、生存能力、及內源性T細胞之集聚能力較高，可應用於使用有各種免疫活性細胞之過繼免疫療法。作為過繼免疫療法之例，可列舉：樹狀細胞療法、NK細胞療法、γ/Δ-T細胞療法、α/β-T細胞療法、CTL(Cytotoxic T Lymphocyte，細胞毒性T淋巴細胞)療法、TIL(Tumor Infiltrating Lymphocyte，腫瘤浸潤T淋巴細胞)療法等，但並不限定於此。可列舉向從患者採集之免疫活性細胞中導入下述本發明之表現載體進行擴增，並投予患者之方法。以下，列舉具體之例，但並不限定於此。樹狀細胞療法包括向由從患者採集之單核球分化之樹狀細胞中，導入手術摘取之癌組織或其溶菌產物，並向患者之體內投予之步驟，但亦可包括將本發明之表現載體導入至樹狀細胞中之步驟。此處，亦可人工地合成並利用癌抗原分子之抗原決定肽代替上述癌組織或溶菌產物。NK細胞療法包括對從患者採集之淋巴球，利用IL-2等複數種刺激物質使NK細胞活化並增生，再向患者投予之步驟，但亦可包括將本發明之載體導入至NK細胞中之步驟。再者，藉由將針對癌症之抗體醫藥與活化之NK細胞併用，可期待高效率地進攻癌細胞之效果。γ/Δ-T細胞療法包括利用IL-2或唑來膦酸對從患者採集之淋巴球進行培養刺激，使γ/Δ-T細胞增生，再向患者投予之步驟，但亦可包括將本發明之表現載體導入至γ/Δ-T細胞中之步驟。α/β-T細胞療法包括利用抗CD3抗體或IL-2培養從患者採集之淋巴球，並進行活化，向患者投予所獲得之α/β-T細胞之步驟，但亦可包括將本發明之表現載體導入至α/β-T細胞中之步驟。CTL療法包括利用從患者採集之癌細胞刺激從患者採集之淋巴球，並添加抗CD3抗體或IL-2進行培養，於癌細胞中使特異性之CTL增生，再向患者投予之步驟，但亦可包括將本發明之表現載體導入至CTL中之步驟。又，亦可利用呈現癌抗原抗原決定肽之抗原呈現細胞代替上述癌細胞。TIL療法包括從自患者採集之癌組織採集淋巴球，利用IL-2等進行刺激、培養，再向患者投予之步驟，但亦可包括將本發明之表現載體導入至淋巴球中之步驟。
本發明之表現載體為用以製作上述本發明之IL-7×CCL19表現免疫活性細胞的以下之(a)至(e)中之任一種。
(a)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、編碼IL-7之核酸、及編碼CCL19之核酸之表現載體；
(b)以下之(b-1)及(b-2)之2種表現載體：
(b-1)含有編碼特異性地識別癌抗原之細胞表面分子之核酸之表現載體；
(b-2)含有編碼IL-7之核酸、及編碼CCL19之核酸之表現載體；
(c)以下之(c-1)及(c-2)之2種表現載體：
(c-1)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、及編碼IL-7之核酸之表現載體；
(c-2)含有編碼CCL19之核酸之表現載體；
(d)以下之(d-1)及(d-2)之2種表現載體：
(d-1)含有編碼IL-7之核酸之表現載體；
(d-2)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、及編碼CCL19之核酸之表現載體；
(e)以下之(e-1)、(e-2)及(e-3)之3種表現載體：
(e-1)含有編碼特異性地識別癌抗原之細胞表面分子之核酸之表現載體；
(e-2)含有編碼IL-7之核酸之表現載體；
(e-3)含有編碼CCL19之核酸之表現載體。
本發明之表現載體亦可進而含有編碼IL-15、CCL21、IL-2、IL-4、IL-12、IL-13、IL-17、IL-18、IP-10、CCL4、Flt3L、干擾素(Interferon)-γ、MIP-1α、GM-CSF、M-CSF、TGF-β、TNF-α等其他免疫機能控制因子之核酸。
上述編碼特異性地識別癌抗原之細胞表面分子之核酸、編碼介白素7(IL-7)之核酸、及編碼CCL19之核酸分別可列舉源自哺乳動物之核酸，可適宜地列舉源自人類之核酸。上述各核酸可根據導入本發明之表現載體之細胞之種類而適當加以選擇，該各核酸之序列資訊可檢索公知之文獻或NCBI(National Center of Biotechnology Information，美國國家生物技術信息中心)(http：//www.ncbi.nlm.nih.gov/guide/)等資料庫而適當獲取。
作為上述編碼特異性地識別癌抗原之細胞表面分子之核酸，可適宜地列舉源自人類之核酸。該編碼特異性地識別癌抗原之細胞表面分子之核酸可列舉編碼T細胞受體(TCR)之核酸或編碼嵌合體抗原受體(CAR)之核酸，可為源自天然之核酸，亦可為人工合成之核酸，可根據導入本發明之表現載體之細胞之種類而適當加以選擇，序列資訊可檢索公知之文獻或NCBI(http：//www.ncbi.nlm.nih.gov/guide/)等資料庫而適當獲取。
編碼特異性地識別癌抗原之細胞表面分子之核酸、編碼IL-7之核酸及編碼CCL19之核酸可藉由基於編碼各者之核酸之鹼基序列之資訊進行化學合成之方法、或藉由PCR(Polymerase Chain Reaction，聚合酶鏈反應)進行擴增之方法等公知之技術而製作。再者，用以編碼胺基酸之所選擇之密碼子可為了使目標之宿主細胞中之核酸之表現最佳化而進行改形。
作為上述編碼TCR之核酸中之TCR，可為包含α鏈及β鏈之異型二聚物(α/β-TCR)，亦可為包含γ鏈及Δ鏈之異型二聚物(γ/Δ-TCR)。再者，編碼α/β-TCR之核酸包括編碼TCR之α鏈之核酸與編碼β鏈之核酸之兩者，編碼γ/Δ-TCR之核酸包括編碼TCR之γ鏈之核酸與編碼Δ鏈之核酸之兩者。
上述編碼TCR之核酸之序列資訊可藉由使用該技術領域中之公知方法，根據作為使用特定抗原肽而誘導之CTL之TCR次單元的α鏈及β鏈之核酸進行鑑定(國際公開第2007/032255號說明書、及Morgan et al., J Immunol, 171, 3288 (2003))。例如，為了分析TCR，較佳為PCR法。用於分析之PCR引子例如可為作為5'側引子之5'-R引子(5'-gtctaccaggcattcgcttcat-3'：序列編號3)、及作為3'側引子之對TCRα鏈C區具有特異性之3-TRa-C引子(5'-tcagctggaccacagccgcagcgt-3'：序列編號4)、對TCRβ鏈C1區具有特異性之3-TRb-C1引子(5'-tcagaaatcctttctcttgac-3'：序列編號5)、或對TCRβ鏈C2區具有特異性之3-TRβ-C2引子(5'-ctagcctctggaatcctttctctt-3'：序列編號6)，但並不限定於該等。TCR衍生物可以較高之結合力與呈現抗原肽之靶細胞結合，且可任意地於活體內(in vivo)及活體外(in vitro)介導呈現抗原肽之靶細胞之有效率之殺傷。
作為上述編碼TCR之核酸，例如只要可識別MART1特異性TCR(Cancer Res. 54, 5265-5268 (1994))、MAGE-A3特異性TCR(Anticancer Res., 20, 1793-1799 (2000))、gp100特異性TCR(J. Immunol. 170, 2186-2194 (2003))、NY-ESO-1特異性TCR(J. Immunol., 174, 4415-4423 (2005))、WT1特異性TCR(Blood, 106, 470-476 (2005))、MAGE-A1特異性TCR(Int. Immunol., 8, 1463-1466 (1996))、P1A特異性TCR(Sarma, S., Y. Guo, Y. Guilloux, C. Lee, X. -F. Bai, Y. Liu. 1999. Cytotoxic T lymphocytes to an unmutated tumor antigen P1A： normal development but restrained effector function. J. Exp. Med. 189： 811.)等編碼TCR之核酸、或結合於MHC分子之抗原分子，且使T細胞活化，則可為與上述文獻中所記載之編碼TCR之鹼基序列具有80%以上、較佳為85%以上、更佳為90%以上、進而較佳為95%以上、最佳為98%以上之同一性的鹼基序列。進而，亦可為於上述文獻中所記載之編碼TCR之鹼基序列中特定出編碼CDR之序列，維持該編碼CDR之序列，且於編碼CDR之序列以外之序列中與上述文獻中所記載之編碼TCR之鹼基序列具有60%以上、較佳為70%以上、更佳為80%以上、進而較佳為90%以上、最佳為95%以上之同一性的鹼基序列。
作為編碼IL-7之核酸，可列舉編碼序列編號1所示之胺基酸序列之鹼基序列，只要具有IL-7之細胞增生率或細胞生存率之亢進作用，則可為與編碼序列編號1所示之胺基酸序列之鹼基序列具有80%以上、較佳為85%以上、更佳為90%以上、進而較佳為95%以上、最佳為98%以上之同一性的鹼基序列。作為編碼CCL19之核酸，可列舉編碼序列編號2所示之胺基酸序列之鹼基序列，只要具有CCL19之細胞遷移作用，則亦可使用與編碼序列編號2所示之胺基酸序列之鹼基序列具有80%以上、較佳為85%以上、更佳為90%以上、進而較佳為95%以上、最佳為98%以上之同一性的鹼基序列。
又，於本發明之表現載體中亦可含有編碼自殺基因之核酸。所謂自殺基因係指具有如下機能之基因，即，藉由進行表現而直接地、或二次地誘導具有細胞毒性之物質，使自身之細胞死亡。藉由使本發明之表現載體中包含編碼自殺基因之核酸，根據癌症之治療過程，例如於腫瘤消失之情形時投予使自殺基因之機能活化之藥劑，可控制活體內之免疫活性細胞。又，IL-7或CCL19與其他細胞激素不同，引起作為副作用之細胞激素釋出症候群或基因導入細胞之腫瘤化之可能性較低。然而，藉由使導入有本發明之表現載體之免疫活性細胞之機能提高，於進攻目標之癌組織時釋出之細胞激素等有可能會出乎意料地對周邊組織產生影響。於該情形時，藉由使本發明之表現載體中包含編碼自殺基因之核酸，可確實地減少成為細胞激素釋出症候群之風險。
作為自殺基因，可列舉以下之文獻中所記載之編碼單純疱疹病毒之胸苷激酶(HSV-TK)或誘導性半胱天冬酶9(inducible caspase 9)之基因等，作為使該基因之機能活化之藥劑，對於前者可列舉更昔洛韋(Ganciclovir)，對於後者可列舉作為二聚物誘導化合物(CID，chemical induction of dimerization)之AP1903(Cooper LJ., et. al. Cytotherapy. 2006; 8 (2)： 105-17., Jensen M. C. et. al. Biol Blood Marrow Transplant. 2010 Sep; 16 (9)： 1245-56., Jones BS. Front Pharmacol. 2014 Nov 27; 5： 254., Minagawa K., Pharmaceuticals (Basel). 2015 May 8; 8 (2)： 230-49., Bole-Richard E., Front Pharmacol. 2015 Aug 25; 6： 174)。
本發明之載體中之(a)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、編碼IL-7之核酸、及編碼CCL19之核酸的表現載體中，任一種核酸可配置於任一上游或下游。具體而言，若以含有編碼TCR之核酸作為編碼特異性地識別癌抗原之細胞表面分子之核酸之情形為例，則從上游起依序可為編碼TCR之核酸、編碼IL-7之核酸及編碼CCL19之核酸，亦可為編碼TCR之核酸、編碼CCL19之核酸及編碼IL-7之核酸，亦可為編碼IL-7之核酸、編碼CCL19之核酸及編碼TCR之核酸，亦可為編碼IL-7之核酸、編碼TCR之核酸及編碼CCL19之核酸，亦可為編碼CCL19之核酸、編碼TCR之核酸、及編碼IL-7之核酸，亦可為編碼CCL19之核酸、編碼IL-7之核酸及編碼TCR之核酸。
於本發明之載體中之(b-2)含有編碼IL-7之核酸、及編碼CCL19之核酸之表現載體中，編碼IL-7之核酸及編碼CCL19之核酸之配置並無特別限制，相對於編碼IL-7之核酸，編碼CCL19之核酸可配置於上游，亦可配置於下游。
於本發明之載體中之(c-1)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、及編碼IL-7之核酸之表現載體中，編碼特異性地識別癌抗原之細胞表面分子之核酸及編碼IL-7之核酸之配置並無特別限制，相對於編碼特異性地識別癌抗原之細胞表面分子之核酸，編碼IL-7之核酸可配置於上游，亦可配置於下游。
於本發明之載體中之(d-2)含有編碼特異性地識別癌抗原之細胞表面分子之核酸、及編碼CCL19之核酸之表現載體中，編碼特異性地識別癌抗原之細胞表面分子之核酸及編碼CCL19之核酸之配置並無特別限制，相對於編碼特異性地識別癌抗原之細胞表面分子之核酸，編碼CCL19之核酸可配置於上游，亦可配置於下游。
再者，編碼特異性地識別癌抗原之細胞表面分子之核酸、編碼IL-7之核酸及編碼CCL19之核酸可分別利用其他啟動子進行轉錄，亦可使用內部核糖體進入位點(IRES，internal ribozyme entry site)或自裂解型2A肽並利用一個啟動子進行轉錄。
於使用內部核糖體進入位點(IRES)或自裂解型2A肽，利用一個啟動子轉錄編碼IL-7之核酸及編碼CCL19之核酸之情形時之上述各核酸之間、或包含上述編碼特異性地識別癌抗原之細胞表面分子之核酸之情形時之該核酸與編碼IL-7之核酸及編碼CCL19之核酸之間、或包含編碼α/β-TCR之核酸之情形時之編碼α鏈之核酸與編碼β鏈之核酸之間、或編碼γ/Δ-TCR之核酸之情形時之編碼Δ鏈之核酸與編碼Δ鏈之核酸之間，只要能夠表現各核酸，則可含有任意之核酸，但較佳為經由自裂解型肽(2A肽)、或編碼IRES之序列、較佳為編碼2A肽之序列進行連結。藉由使用該序列進行連結，可高效率地表現各核酸。
又，於含有編碼自殺基因之核酸之情形時，自殺基因之位置並無特別限制，例如可於用以使編碼特異性地識別癌抗原之細胞表面分子之核酸、編碼IL-7之核酸、或編碼CCL19之核酸進行表現之啟動子之下游，經由編碼2A肽或IRES之序列而配置於上述各核酸之上游或下游，亦可配置於其他啟動子之下游。
所謂2A肽係源自病毒之自裂解型肽，具有序列編號7所表示之胺基酸序列中之G-P間(距C末端1個殘基之位置)被內質網切斷之特徵(Szymczak et al., Expert Opin. Biol. Ther. 5 (5)： 627-638 (2005))。因此，經由2A肽而組入至其前後之核酸於細胞內相互獨立地進行表現。
作為上述2A肽，較佳為源自小核糖核酸病毒、輪狀病毒、昆蟲病毒、鵝口瘡病毒或錐體蟲病毒之2A肽，更佳為序列編號8所示之源自小核糖核酸病毒之2A肽(F2A)。
作為本發明之表現載體中之載體，可為直鏈狀亦可為環狀，可為質體等非病毒載體，可為病毒載體，亦可為轉位子之載體。又，於該載體中可含有啟動子或終止子等控制序列、或耐藥劑性基因、報導基因等選擇標記物序列。藉由在啟動子序列之下游可促效地配置編碼IL-7之核酸及編碼CCL19之核酸，可高效率地轉錄各核酸。
作為上述啟動子，可列舉：反轉錄病毒之LTR(Long Terminal Repeat，長末端重複序列)啟動子、SV40初始啟動子、巨細胞病毒啟動子、單純疱疹病毒之胸苷激酶啟動子等源自病毒之啟動子；磷酸甘油酸激酶(PGK，Phosphoglycerate kinase)啟動子、Xist(X-inactive specific transcript，X染色體失活特異轉錄因子)啟動子、β-肌動蛋白啟動子、RNA(Ribonucleic Acid，核糖核酸)聚合酶II啟動子等源自哺乳類之啟動子。又，亦可使用由四環素所誘導之四環素應答型啟動子、由干擾素所誘導之Mx1啟動子等。藉由在本發明之表現載體中使用由上述特定之物質所誘導之啟動子，可根據癌症之治療過程而控制IL-7及CCL19之表現之誘導。
作為上述病毒載體，可列舉：反轉錄病毒載體、慢病毒載體、腺病毒載體、腺相關病毒載體，可適宜地列舉反轉錄病毒載體，可更適宜地列舉pMSGV載體(Tamada k et al., Clin Cancer Res 18： 6436-6445 (2002))或pMSCV載體(TAKARA BIO公司製造)。若使用反轉錄病毒載體，則導入基因被取入宿主細胞之基因組中，故而可長期且穩定地進行表現。
確認於免疫活性細胞中含有本發明之表現載體，例如於含有編碼TCR之核酸之情形時，可藉由流式細胞儀、北方墨點法(Northern Blotting)、南方墨點法(Southern Blotting)、RT-PCR(Reverse Transcription-Polymerase Chain Reaction，反轉錄酶-聚合酶鏈反應)等PCR、ELISA(Enzyme Linked Immunosorbent Assay，酶結合免疫吸附分析)、西方墨點法而對TCR之表現進行調查，於本發明之表現載體中含有標記物基因之情形時，可藉由調查插入至該表現載體中之標記物基因之表現而加以確認。
於本發明之IL-7×CCL19表現免疫活性細胞中所含之表現載體中含有編碼TCR之核酸之情形時，進行表現之TCR之可變區位於細胞外，藉由具備該TCR之可變區，TCR表現免疫活性細胞可識別結合於MHC分子之抗原分子。
本發明之抗癌劑若含有本發明之IL-7×CCL19表現免疫活性細胞與藥學上所容許之添加劑，則無特別限制，作為上述添加劑，可列舉：生理鹽水、緩衝生理鹽水、細胞培養培養基、葡萄糖、注射用水、甘油、乙醇及該等之組合、穩定劑、助溶劑及界面活性劑、緩衝劑及防腐劑、等張劑、填充劑、以及潤滑劑。
本發明之抗癌劑可使用本領域業者已知之方法，投予需要癌症之治療之受驗體，作為投予方法，可列舉向靜脈內、腫瘤內、皮內、皮下、肌內、腹腔內、動脈內、髄內、心臟內、關節內、黏液囊內、顱內、脊椎內、及蛛網膜下(髄液)之注射。
所投予之抗癌劑中所含之本發明之IL-7×CCL19表現免疫活性細胞之量可根據癌症之種類、位置、嚴重程度、接受治療之受驗體之年齡、體重及狀態等而適當加以調整，較佳為於一次之投予中可列舉1×10
4～1×10
10個、較佳為1×10
5～1×10
9個、更佳為5×10
6～5×10
8個。
可列舉所投予之抗癌劑為1天4次、3次、2次或1次、每隔1天、每隔2天、每隔3天、每隔4天、每隔5天、一週1次、每隔7天、每隔8天、每隔9天、一週2次、一月1次或一月2次獨立地投予之方法。
作為本發明之抗癌劑、或下述癌症之治療方法中之癌症，可為實體癌亦可為血液癌，可列舉腺癌、鱗狀細胞癌、腺鱗狀細胞癌、未分化癌、大細胞癌、小細胞癌、皮膚癌、乳癌、攝護腺癌、膀胱癌、陰道癌、子宮頸癌、子宮癌、肝癌、腎癌、胰腺癌、脾臟癌、肺癌、氣管癌、支氣管癌、結腸癌、小腸癌、胃癌、食道癌、膽嚢癌、睾丸癌、卵巢癌等癌、或骨組織、軟骨組織、脂肪組織、肌肉組織、血管組織及造血組織之癌，此外亦可列舉軟骨肉瘤、尤因氏肉瘤、惡性血管內皮瘤、惡性神經鞘瘤、骨肉瘤、軟組織肉瘤等肉瘤、或肝胚細胞瘤、神經管胚細胞瘤、腎胚細胞瘤、神經胚細胞瘤、胰胚細胞瘤、胸膜肺胚細胞瘤、視網膜胚細胞瘤等胚細胞瘤、或胚細胞腫瘤、或淋巴瘤、或白血病。
本發明之抗癌劑可與其他抗癌劑併用而使用。作為其他抗癌劑，可列舉：環磷醯胺、苯達莫司汀、異環磷醯胺、達卡巴𠯤等烷基化藥，噴司他丁、氟達拉濱、克拉屈濱、甲胺喋呤、5-氟尿嘧啶、6-巰基嘌呤、依諾他濱等代謝拮抗藥，利妥昔單抗、西妥昔單抗、曲妥珠單抗等分子靶向藥，伊馬替尼、吉非替尼、埃羅替尼、阿法替尼、達沙替尼、舒尼替尼、曲美替尼等激酶抑制劑，硼替佐米等蛋白酶體抑制劑，環孢靈、他克莫司等鈣調神經磷酸酶抑制藥，艾達黴素、多柔比星、絲裂黴素C等抗癌性抗生素，伊立替康、依託泊苷等植物生物鹼，順鉑、奧沙利鉑、卡鉑等鉑製劑，他莫昔芬、比卡魯胺等激素療法藥，干擾素、納武單抗、派姆單抗等免疫控制藥，可適宜地列舉烷基化藥或代謝拮抗藥。
作為上述「將本發明之抗癌劑與其他抗癌劑併用而使用」之方法，可列舉：使用其他抗癌劑進行處理，其後使用本發明之抗癌劑之方法；或同時使用本發明之抗癌劑與其他抗癌劑之方法；或使用本發明之抗癌劑進行處理，其後使用其他抗癌劑之方法；可適宜地列舉使用其他抗癌劑進行處理，其後使用本發明之抗癌劑之方法。又，於將本發明之抗癌劑與其他抗癌劑併用之情形時，進一步提高癌症之治療效果，並且減少各抗癌劑之投予次數或投予量，藉此可減少因各抗癌劑引起之副作用。又，於本發明之抗癌劑中亦可包含上述其他抗癌劑。
作為本發明之另一態樣1，可列舉：1)一種癌症之治療方法，其特徵在於向需要癌症之治療之患者投予表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19之免疫活性細胞；或2)一種免疫活性細胞，其用作抗癌劑，且表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19；或3)一種免疫活性細胞之用途，其用於製備抗癌劑，且該免疫活性細胞表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19。
進而，作為本發明之另一態樣2，可列舉一種套組，其係用以製作上述具備本發明之表現載體之表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19之免疫活性細胞，作為該套組，只要具備本發明之表現載體，則無特別限制，亦可包含用以製作本發明之IL-7×CCL19表現免疫活性細胞之說明書、或用以將本發明之表現載體導入至免疫活性細胞中之試劑。
實施例1
(免疫機能控制因子之選擇)
可控制T細胞之機能的分子於生物體內至少存在數百種。發明者等人基於迄今為止之見解及經驗，作為用以進一步提高免疫活性細胞之免疫機能控制效果的控制分子，首先從大量之組合中選擇IL-7與CCL19，且選擇兩者之組合、即IL-7與CCL19之組合而非各自單獨，而製作該表現免疫活性細胞之免疫機能控制因子之載體。
(表現IL-7及CCL19之載體之製作-1)
人工合成編碼包含抗FITC scFv(Single Chain Fragment Variable，單鏈可變區片段)、小鼠CD8跨膜區、小鼠CD28-4-1BB-CD3ζ細胞內訊息基元之抗FITC CAR的抗FITC CAR DNA(Deoxyribonucleic Acid，去氧核糖核酸)片段(序列編號9)、編碼序列編號8所示之2A肽(F2A)與繼該肽之後之限制酶部位(MCS(Multiple Cloning Site，多選殖位點))之F2A-MCS DNA片段(序列編號10)、編碼小鼠IL-7(無終止密碼子)、與繼其之後之F2A及小鼠CCL19之IL-7-F2A-CCL19 DNA片段(序列編號11)(Life Technology公司製造)。
為了製作表現IL-7及CCL19之載體，將上述抗FITC CAR DNA片段與上述F2A-MCS DNA片段連結而製作抗FITC CAR-F2A-MCS構建物。其次，將所製作之構建物選殖至pMSGV反轉錄病毒表現載體(Tamada k et al., Clin Cancer Res 18： 6436-6445 (2002))而製作包含抗FITC CAR-F2A-MCS之pMSGV載體。於該pMSGV載體之MCS上，藉由限制酶(NsiI及SalI)處理及連接而插入上述IL-7-F2A-CCL19 DNA片段，從而獲得包含抗FITC CAR-F2A-IL-7-F2A-CCL19之pMSGV載體(IL-7×CCL19表現載體(1))。將所獲得之載體之基因圖示於圖1。又，作為對照，將上述抗FITC CAR DNA片段選殖至上述pMSGV反轉錄病毒表現載體，而製作不含IL-7及CCL19之pMSGV載體(對照載體(1))。
(導入有IL-7×CCL19表現載體之反轉錄病毒之製作)
為了進行小鼠T細胞之轉導，而製作反轉錄病毒。使用Lipofectamine 2000或3000(Life Technology公司製造)，將上述IL-7×CCL19表現載體(1)或對照載體(1)與pCL-Eco質體(Imgenex公司製造)轉染至GP2-293包裝細胞株(TAKARA BIO公司製造)，藉此製作導入有IL-7×CCL19表現載體(1)或對照載體(1)之反轉錄病毒。
使用添加有10%FCS(Fetal Calf Serum，胎牛血清)、100 U/ml之青黴素、100 mg/ml之鏈黴素的DMEM(Dulbecco Modified Eagle Medium，杜貝可改良伊格爾培養基)作為上述GP2-293細胞之培養液。又，使用添加有10%FCS、100 U/ml之青黴素、100 mg/ml之鏈黴素、50 mM之2-巰基乙醇、2 mM之L-麩醯胺的RPMI-1640作為下述實施例中所使用之T細胞之培養液。
(小鼠T細胞之轉導)
為了進行小鼠T細胞之轉導，利用經固相化之抗CD3mAb(3 μg/ml)及IL-2(100 IU/ml)將源自脾臟及淋巴結之3×10
6個精製後之小鼠T細胞活化48小時。其次，將含有上述中所製作之導入有IL-7×CCL19表現載體(1)或對照載體(1)之反轉錄病毒的上清液與於塗佈有25 μg/ml之RetroNectin(註冊商標：TAKARA BIO公司製造)之培養盤中進行活化之上述小鼠T細胞(1×10
6cells/ml)加以混合，於1500 rpm下離心2小時後，於IL-2(100 IU/ml)之存在下培養6小時。為了從培養液去除反轉錄病毒，回收小鼠T細胞，並轉移至含有IL-2(100 IU/ml)之新的增生培養液(RPMI)中，進而培養42小時，而獲得導入有IL-7×CCL19表現載體(1)之小鼠T細胞(IL-7/CCL19表現T細胞(1))或導入有對照載體(1)之小鼠T細胞(對照T細胞(1))。
(表現IL-7及CCL19之表現載體之製作-2)
於上述中之IL-7×CCL19表現載體(1)之製作中，將序列編號9所示之序列中所含之抗FITC scFv區之序列置換為Life Technology公司基於利妥昔單抗之序列而合成之抗人類CD20 scFv(序列編號12)之序列，除此以外，藉由與上述「表現IL-7及CCL19之表現載體之製作-1」相同之方法，而製作包含抗人類CD20 CAR-F2A-IL-7-F2A-CCL19之pMSGV載體(IL-7×CCL19表現載體(2))。同樣地，於上述中之對照載體(1)之製作中，將序列編號9所示之序列中所含之抗FITC scFv區之序列置換為上述抗人類CD20 scFv(序列編號12)之序列，除此以外，藉由與上述「表現IL-7及CCL19之表現載體之製作-1」相同之方法，而製作不含IL-7及CCL19之pMSGV載體(對照載體(2))。藉由與上述相同之方法，使用反轉錄病毒，將該IL-7×CCL19表現載體(2)或對照載體(2)導入至小鼠T細胞中，而製作IL-7/CCL19表現T細胞(2)或對照T細胞(2)。
實施例2
(IL-7/CCL19表現T細胞之細胞數及生存率)
對由IL-7/CCL19表現T細胞所產生之IL-7或CCL19是否發揮生物機能而顯示出免疫誘導效果進行研究。將所製作之含有IL-7/CCL19表現T細胞(2)(4×10
5個)或對照T細胞(2)之樣品培養5天。上述培養係為了於IL-7及CCL19之表現中排除因人類CD20 CAR產生之影響，而於不利用CD20進行抗原刺激之情況下進行。其次，利用台盼藍而調查細胞數與生存率。將結果示於圖2A、圖2B。圖2A為細胞數，圖2B為生存率，黑柱表示IL-7/CCL19表現T細胞，白柱表示對照T細胞。
(結果)
如圖2A、圖2B所示，於IL-7/CCL19表現T細胞(2)中，與對照T細胞(2)相比，細胞數增高約5倍，生存率增高約2倍。因此明確，藉由使用將本發明之表現載體導入至T細胞中而成之IL-7/CCL19表現T細胞，發揮IL-7或CCL19生物機能，而顯示出免疫誘導效果。
實施例3
[T細胞遷移試驗]
(利用IL-7/CCL19表現T細胞所進行之T細胞遷移試驗)
藉由使用有Transwell之細胞遷移試驗，對CCL19之遷移引發效果進行研究。應答側T細胞之遷移性係藉由使用96孔之Transwell(註冊商標)小室(Cornig Costar公司製造)，使之通過孔徑5 μm之聚碳酸酯過濾器進行遷移而加以測定。具體而言，於小室之下層中培養IL-7/CCL19表現T細胞(1)或對照T細胞(1)。上述培養係為了於IL-7及CCL19之表現中排除因FITC CAR產生之影響，而於不利用FITC進行抗體刺激之情況下進行。應答側T細胞係藉由MACS(Magnetic Activated Cell Sorter，磁性激活細胞分選儀)(Miltenyi Biotec公司製造)之負選擇，由脾臟或淋巴結而製備。應答側T細胞係利用CytoTell blue(AAT Bioquest公司製造)進行標記，並於上層中培養3小時。從小室之上層向下層之遷移係利用流式細胞儀(EC800：Sony公司製造)進行調查，資料分析係使用FlowJo軟體(Tree Star公司製造)。將結果示於圖3。圖3中，黑柱表示IL-7/CCL19表現T細胞(1)，白柱表示對照T細胞(1)，縱軸表示遷移至下層之小室之應答側T細胞之絕對數。又，統計學上之有意義差係藉由學生t檢定(Student's t-test)進行研究。
(結果)
如圖3所示，IL-7/CCL19表現T細胞(1)係使與對照T細胞(1)相比為約1.8倍之T細胞遷移至下層。於T細胞等淋巴球移入療法中，因所投予之T細胞引起之癌細胞傷害當然重要，但此外將原本存在於癌症患者體內之內源性T細胞(＝宿主側免疫細胞)活化而動員為進攻癌細胞之細胞亦重要。因此，就免疫治療效果之方面而言，較佳為不僅從外部移入具有抗腫瘤活性之淋巴球，亦利用某些方法，引發所移入之T細胞與內源性T細胞之能動性相互作用，使內源性T細胞集聚於癌局部。由圖3之結果表明，IL-7/CCL19表現T細胞(1)由於具有使內源性T細胞集聚之能力，故而可誘導所移入之T細胞與內源性T細胞之能動性相互作用。
又，由圖2A、圖2B、圖3之結果表明，表現IL-7及CCL19之T細胞藉由IL-7有效地增生，生存率亦較高，且具備藉由CCL19集聚T細胞之對免疫誘導必不可少之重要效果，具有優異之免疫誘導效果。即，表明於免疫活性細胞中，表現「IL-7」與「CCL19」之2種控制分子，藉此可提高該免疫活性細胞之增生能力、生存率、免疫誘導效果。進而，如上所述般表現IL-7及CCL19之T細胞由於兼具增生能力、生存能力、及T細胞集聚能力，故而提示具有T細胞或樹狀細胞於癌組織中之滲透效果、或腫瘤增生抑制效果之可能性。
實施例4
[IL-7×CCL19×HSV-TK表現載體之製作]
藉由在pMSGV1載體之多選殖位點，選殖如下鹼基序列，可製作表現IL-7、CCL19、及HSV-TK之載體，該鹼基序列係將編碼IL-7、CCL19及作為自殺基因之HSV-TK之各基因的鹼基序列夾著編碼作為自裂解型肽之2A肽之鹼基序列串聯排列而成。將該載體之基因圖示於圖4。
導入有藉由上述方法所製作之IL-7×CCL19×HSV-TK表現載體的免疫活性細胞藉由向投予有上述免疫活性細胞之受驗體投予更昔洛韋，可控制受驗體內之免疫活性細胞。
實施例5
[TCR×IL-7×CCL19表現載體之製作]
藉由在pMSGV1載體之多選殖位點，選殖如下鹼基序列，可製作表現TCR、IL-7及CCL19之載體，該鹼基序列係將編碼TCR、IL-7及CCL19之各基因之鹼基序列夾著編碼作為自裂解型肽之2A肽之鹼基序列串聯排列而成。將該載體之基因圖示於圖5。
導入有藉由上述方法所製作之TCR×IL-7×CCL19表現載體之免疫活性細胞不僅能夠與癌細胞之表面所存在之癌抗原特異性地結合，亦能夠與源自癌細胞內之癌抗原之肽呈現於MHC之複合體特異性地結合，而變得能夠進行針對更廣範圍之腫瘤相關靶分子的特異性T細胞之誘導。
實施例6
[表現IL-7、CCL19及eGFP之表現載體之製作]
人工合成編碼小鼠IL-7(無終止密碼子)、與繼其之後之F2A、小鼠CCL19之IL-7-F2A-CCL19 DNA片段(Life Technology公司製造)。
為了製作表現IL-7、CCL19及eGFP之載體，藉由限制酶(NCOI及ECORI)處理及連接，將上述所合成之IL-7-F2A-CCL19 DNA片段插入至具有F2A-eGFP序列之pMSGV反轉錄病毒表現載體(Tamada k et al., Clin Cancer Res 18： 6436-6445 (2002))之MCS，而獲得包含IL-7-F2A-CCL19-F2A-eGFP DNA片段(序列編號13)之pMSGV載體(IL-7×CCL19表現載體(3))。將所獲得之載體之基因圖示於圖6。又，作為對照，製作包含eGFP且不含IL-7及CCL19之pMSGV載體(對照載體(3))。再者，於序列編號13中，第1號～第462號鹼基為IL-7(第1號～第75號鹼基為IL-7之訊息序列)，第463號～第537號鹼基為F2A，第538號～第861號鹼基為CCL19(第538號～第612號鹼基為CCL19之訊息序列)，868～942為F2A，第946號～第1662號鹼基為編碼eGFP之核酸，第1663～1665號鹼基為終止密碼子。又，將與上述鹼基序列13對應之胺基酸序列示於序列編號14。再者，為了使用限制酶NcoI，而將序列編號13中之第4號鹼胸腺嘧啶(t)置換為鳥嘌呤(g)(將序列編號14中之第2號胺基酸苯丙胺酸(F)置換為纈胺酸(V))。
[表現P815腫瘤抗原P1A特異性TCR、IL-7、CCL19、及eGFP之T細胞之製作]
從自Y. Liu取得之表現H-2L
d限制性之P815腫瘤抗原P1A特異性TCR的基因轉殖小鼠(Sarma, S., Y. Guo, Y. Guilloux, C. Lee, X. -F. Bai, Y. Liu. 1999. J. Exp. Med. 189： 811.)採集脾臟細胞，而獲得表現源自脾臟細胞之P815腫瘤抗原P1A特異性TCR之小鼠T細胞(P1A特異性TCR-T細胞)。其次，藉由與實施例1相同之方法，製作導入有IL-7×CCL19表現載體(3)及對照載體(3)之反轉錄病毒，並轉導至利用P1A肽將包含上述P1A特異性TCR-T細胞之脾臟細胞(3×10
6個/孔)活化48小時而獲得之細胞中，而獲得P1A特異性TCR/IL-7/CCL19/eGFP表現T細胞或P1A特異性TCR/eGFP表現T細胞。各表現載體之轉導係藉由檢測作為替代標記之eGFP之流式細胞儀分析而確認。所獲得之各T細胞之eGFP之表現量於任一實驗中均為70～80%。
於第0天，對於6～10週齡之雄DBA/2小鼠(n＝30)，將懸浮於0.1 ml之HBSS(Hank's Balanced Salt Solution，漢克平衡鹽溶液)中之5×10
5個P815肥胖細胞瘤皮下接種至側腹。於第6天，對小鼠進行進行次致死量(3-5 Gy)之照射，以進行預處理。於第7天，將小鼠(n＝10)分成3個群，分別靜脈投予1×10
6個P1A特異性TCR/IL-7/CCL19/eGFP表現T細胞、或P1A特異性TCR/eGFP表現T細胞(任一種細胞均為70～80%eGFP陽性)。其後，分析各小鼠之生存率，並且測定死亡小鼠之腫瘤體積。將各小鼠之生存率之分析結果示於圖7，將測定死亡小鼠之腫瘤體積之結果示於圖8。
於圖7中，▲為未處理小鼠之結果，■為投予有P1A特異性TCR/eGFP表現T細胞之小鼠之結果，●為投予有P1A特異性TCR/IL-7/CCL19/eGFP表現T細胞之小鼠之結果，橫軸為皮下接種P815肥胖細胞瘤後之天數(day)，縱軸為生存率(%)。投予有P1A特異性TCR/IL-7/CCL19/eGFP表現T細胞之小鼠於第60天仍生存80%，即便超過100天仍生存50%。因此表明，藉由使用表現P1A特異性TCR、IL-7及CCL19之免疫活性細胞，發揮出抗腫瘤效果，而抑制因腫瘤引起之生存率降低。
又，於圖8中，橫軸為皮下接種P815肥胖細胞瘤後之天數(day)，縱軸為腫瘤體積(mm
3)。由圖8表明，對於投予有P1A特異性TCR/IL-7/CCL19/eGFP表現T細胞之小鼠，腫瘤體積之增加顯著得到抑制，P1A特異性TCR/IL-7/CCL19/eGFP表現T細胞具有優異之抗腫瘤活性，及發揮出針對實體癌之治療效果。
[產業上之可利用性]
本發明之IL-7×CCL19表現免疫活性細胞由於兼具增生能力、生存能力及淋巴球集聚能力，故而能夠利用於免疫療法領域。
圖1係表示IL-7×CCL19表現載體之遺傳圖的圖。
圖2A係表示調查IL-7/CCL19表現T細胞之細胞數所獲得之結果的圖。
圖2B係表示調查IL-7/CCL19表現T細胞之生存率所獲得之結果的圖。
圖3係表示利用IL-7/CCL19表現T細胞所進行之T細胞遷移試驗之結果的圖。
圖4係表示IL-7×CCL19×HSV-TK表現載體之遺傳圖的圖。
圖5係表示TCR×IL-7×CCL19表現載體之遺傳圖的圖。
圖6係表示IL-7×CCL19×eGFP(enhanced green fluorescent protein，強化型綠色螢光蛋白)表現載體之遺傳圖的圖。
圖7係表示未處理小鼠、投予有P1A特異性TCR/eGFP表現T細胞之小鼠、及投予有P1A特異性TCR/IL-7/CCL19/eGFP表現T細胞之小鼠之生存率的圖。
圖8係表示調查未處理小鼠、投予有P1A特異性TCR/eGFP表現T細胞之小鼠、及投予有P1A特異性TCR/IL-7/CCL19/eGFP表現T細胞之小鼠之腫瘤體積所獲得之結果的圖。
Claims (10)
- 一種自然殺手細胞(NK細胞)、B細胞、抗原呈現細胞或粒細胞，其表現特異性地識別癌抗原之嵌合體抗原受體(CAR)、介白素7(IL-7)、及CCL19。
- 如請求項1之自然殺手細胞(NK細胞)、B細胞、抗原呈現細胞或粒細胞，其中含有自細胞外導入之編碼CAR之核酸、自細胞外導入之編碼IL-7之核酸、及自細胞外導入之編碼CCL19之核酸。
- 如請求項1或2之自然殺手細胞(NK細胞)、B細胞、抗原呈現細胞或粒細胞，其中癌抗原為WT1、MART-1、NY-ESO-1、MAGE-A1、MAGE-A3、MAGE-A4、磷脂醯肌醇蛋白聚糖-3、KIF20A、存活蛋白、AFP-1、gp100、MUC1、PAP-10、PAP-5、TRP2-1、SART-1、VEGFR1、VEGFR2、NEIL3、MPHOSPH1、DEPDC1、FOXM1、CDH3、TTK、TOMM34、URLC10、KOC1、UBE2T、TOPK、ECT2、間皮素、NKG2D、P1A、GD2、或GM2。
- 一種抗癌劑，其含有如請求項1或2之自然殺手細胞(NK細胞)、B細胞、抗原呈現細胞或粒細胞、與藥學上所容許之添加劑。
- 一種編碼IL-7之核酸、及編碼CCL19之核酸之用途，其係用以導入至表現特異性地識別癌抗原之細胞表面分子之免疫活性細胞中，而製作表現特異性地識別癌抗原之細胞表面分子、介白素7(IL-7)、及CCL19之免疫活性細胞。
- 如請求項5之用途，其中使用表現載體將編碼IL-7之核酸、及編碼CCL19之核酸導入至免疫活性細胞中。
- 如請求項6之用途，其中使用含有編碼IL-7之核酸、及編碼CCL19之核酸之表現載體而導入至免疫活性細胞中。
- 如請求項5至7中任一項之用途，其中特異性地識別癌抗原之細胞表面分子為特異性地識別癌抗原之嵌合體抗原受體(CAR)、特異性地識別癌抗原之T細胞受體、或特異性地識別癌抗原之抗體。
- 如請求項5至7中任一項之用途，其含有編碼自殺基因之核酸。
- 如請求項5至7中任一項之用途，其中癌抗原為WT1、MART-1、NY-ESO-1、MAGE-A1、MAGE-A3、MAGE-A4、磷脂醯肌醇蛋白聚糖-3、KIF20A、存活蛋白、AFP-1、gp100、MUC1、PAP-10、PAP-5、TRP2-1、SART-1、VEGFR1、VEGFR2、NEIL3、MPHOSPH1、DEPDC1、FOXM1、CDH3、TTK、TOMM34、URLC10、KOC1、UBE2T、TOPK、ECT2、間皮素、NKG2D、P1A、GD2、或GM2。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2016053913 | 2016-03-17 | ||
| JP??2016-053913 | 2016-03-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW202313966A true TW202313966A (zh) | 2023-04-01 |
Family
ID=59851517
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW111147302A TW202313966A (zh) | 2016-03-17 | 2017-03-16 | 表現免疫機能控制因子之免疫活性細胞及表現載體 |
| TW106108741A TWI789348B (zh) | 2016-03-17 | 2017-03-16 | 表現免疫機能控制因子之免疫活性細胞及表現載體 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW106108741A TWI789348B (zh) | 2016-03-17 | 2017-03-16 | 表現免疫機能控制因子之免疫活性細胞及表現載體 |
Country Status (18)
| Country | Link |
|---|---|
| US (4) | US11337997B2 (zh) |
| EP (1) | EP3431597A4 (zh) |
| JP (5) | JP6561372B2 (zh) |
| KR (5) | KR102495308B1 (zh) |
| CN (2) | CN115896120A (zh) |
| AU (1) | AU2017235116B2 (zh) |
| BR (1) | BR112018068314A2 (zh) |
| CA (1) | CA3017442A1 (zh) |
| IL (1) | IL261707B2 (zh) |
| MX (2) | MX2018010974A (zh) |
| MY (1) | MY190565A (zh) |
| NZ (1) | NZ746168A (zh) |
| PH (1) | PH12018550156A1 (zh) |
| RU (1) | RU2770812C2 (zh) |
| SG (1) | SG11201807857PA (zh) |
| TW (2) | TW202313966A (zh) |
| WO (1) | WO2017159736A1 (zh) |
| ZA (1) | ZA201805913B (zh) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY190565A (en) * | 2016-03-17 | 2022-04-27 | Univ Yamaguchi | Immunocompetent cell and expression vector expressing regulatory factors of immune function |
| US11447562B2 (en) | 2017-01-01 | 2022-09-20 | Chi-Yu Gregory Lee | RP215 chimeric antigen receptor construct and methods of making and using same |
| AU2018242408B2 (en) * | 2017-03-27 | 2022-08-04 | Noile-Immune Biotech, Inc. | Chimeric antigen receptor |
| WO2019073973A1 (ja) | 2017-10-10 | 2019-04-18 | 国立大学法人山口大学 | メモリー機能を有するｔ細胞又はｂ細胞の増強剤、悪性腫瘍再発抑制剤、及びｔ細胞又はｂ細胞にメモリー機能を誘導する誘導剤 |
| US20200323920A1 (en) | 2017-12-24 | 2020-10-15 | Noile-Immune Biotech, Inc. | Immunocompetent cell that expresses a cell surface molecule specifically recognizing human mesothelin, il-7 and ccl19 |
| EP3822345B1 (en) * | 2018-05-15 | 2024-10-16 | CRAGE medical Co., Limited | Genetically engineered cell and application thereof |
| US20220401480A1 (en) * | 2019-10-28 | 2022-12-22 | Noile-Immune Biotech Inc. | Drug for Treating Cancer, Combination Drug, Drug Composition, Immune Responsive Cell, Nucleic Acid Delivery Vehicle, and Product |
| CN111849910B (zh) | 2020-05-27 | 2021-06-15 | 南京北恒生物科技有限公司 | 工程化免疫细胞及其用途 |
| TW202307009A (zh) | 2021-07-16 | 2023-02-16 | 日商諾伊爾免疫生物科技股份有限公司 | 嵌合抗原受體、表現前述受體之細胞、含有前述細胞之醫藥組成物、前述細胞之製造方法、及含有編碼前述嵌合抗原受體之鹼基序列之聚核苷酸或載體 |
| CA3225682A1 (en) | 2021-07-16 | 2023-01-19 | Koji Tamada | Anti-egfrviii antibody, polypeptide, cell capable of expressing said polypeptide, pharmaceutical composition comprising said cell, method for producing said cell, and polynucleotide or vector comprising nucleotide sequence encoding said polypeptid |
| EP4377335A1 (en) | 2021-07-29 | 2024-06-05 | Takeda Pharmaceutical Company Limited | Engineered immune cell that specifically targets mesothelin and uses thereof |
| CN115704010A (zh) * | 2021-08-11 | 2023-02-17 | 南京北恒生物科技有限公司 | 工程化免疫细胞及其用途 |
| GB202205572D0 (en) * | 2022-04-14 | 2022-06-01 | Adaptimmune Ltd | Engineered T cells |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0920679A2 (pt) * | 2008-10-08 | 2022-05-17 | Intrexon Corp | Células construídas expressando múltiplos imunomoduladores e usos das mesmas |
| TW201823463A (zh) | 2010-03-23 | 2018-07-01 | 美商英翠克頌公司 | 條件性表現治療性蛋白質之載體、包含該載體之宿主細胞及彼等之用途 |
| CN103492406B (zh) | 2010-12-09 | 2022-07-26 | 宾夕法尼亚大学董事会 | 嵌合抗原受体-修饰的t细胞治疗癌症的用途 |
| ES2791716T3 (es) | 2010-12-14 | 2020-11-05 | Univ Maryland | Células T que expresan al receptor de antígeno quimérico antietiqueta universal y métodos para el tratamiento del cáncer |
| CN102539745B (zh) * | 2010-12-31 | 2013-03-06 | 中国人民解放军第三〇九医院 | 移植肾排斥反应早期诊断及预警试剂盒 |
| DK2755487T3 (en) | 2011-09-16 | 2019-04-08 | Baylor College Medicine | TARGETATION OF THE TUMORMICROMY ENVIRONMENT USING MANIPULATED NKT CELLS |
| JP6117515B2 (ja) | 2011-11-01 | 2017-04-19 | 国立大学法人名古屋大学 | 髄膜腫治療用医薬組成物 |
| AU2013221672B2 (en) | 2012-02-13 | 2017-11-09 | Seattle Children's Hospital D/B/A Seattle Children's Research Institute | Bispecific chimeric antigen receptors and therapeutic uses thereof |
| EP2827879B1 (en) * | 2012-03-21 | 2019-05-08 | Dana-Farber Cancer Institute, Inc. | Isolation and use of human lymphoid organ-derived suppressive stromal cells |
| PT3597742T (pt) | 2014-10-09 | 2022-08-30 | Univ Yamaguchi | Vetor de expressão de car e células t que expressam car |
| MY190565A (en) * | 2016-03-17 | 2022-04-27 | Univ Yamaguchi | Immunocompetent cell and expression vector expressing regulatory factors of immune function |
| CN112226462A (zh) * | 2020-10-12 | 2021-01-15 | 广东昭泰体内生物医药科技有限公司 | 共表达分泌型il-7和选择性ccl19的表达载体及其应用 |
-
2017
- 2017-03-15 MY MYPI2018703180A patent/MY190565A/en unknown
- 2017-03-15 EP EP17766732.6A patent/EP3431597A4/en active Pending
- 2017-03-15 US US16/084,503 patent/US11337997B2/en active Active
- 2017-03-15 CN CN202211222315.1A patent/CN115896120A/zh active Pending
- 2017-03-15 MX MX2018010974A patent/MX2018010974A/es unknown
- 2017-03-15 JP JP2018505978A patent/JP6561372B2/ja active Active
- 2017-03-15 CN CN201780029948.1A patent/CN109153989B/zh active Active
- 2017-03-15 CA CA3017442A patent/CA3017442A1/en active Pending
- 2017-03-15 KR KR1020207034092A patent/KR102495308B1/ko active IP Right Grant
- 2017-03-15 KR KR1020237001960A patent/KR20230017358A/ko not_active IP Right Cessation
- 2017-03-15 KR KR1020247023377A patent/KR20240116832A/ko active Search and Examination
- 2017-03-15 NZ NZ746168A patent/NZ746168A/en unknown
- 2017-03-15 RU RU2018135652A patent/RU2770812C2/ru active
- 2017-03-15 BR BR112018068314A patent/BR112018068314A2/pt active Search and Examination
- 2017-03-15 AU AU2017235116A patent/AU2017235116B2/en active Active
- 2017-03-15 WO PCT/JP2017/010437 patent/WO2017159736A1/ja active Application Filing
- 2017-03-15 IL IL261707A patent/IL261707B2/en unknown
- 2017-03-15 KR KR1020247023376A patent/KR20240115908A/ko active Search and Examination
- 2017-03-15 SG SG11201807857PA patent/SG11201807857PA/en unknown
- 2017-03-15 KR KR1020187029397A patent/KR102186180B1/ko active IP Right Grant
- 2017-03-16 TW TW111147302A patent/TW202313966A/zh unknown
- 2017-03-16 TW TW106108741A patent/TWI789348B/zh active
-
2018
- 2018-09-04 ZA ZA2018/05913A patent/ZA201805913B/en unknown
- 2018-09-11 MX MX2023005317A patent/MX2023005317A/es unknown
- 2018-09-12 PH PH12018550156A patent/PH12018550156A1/en unknown
-
2019
- 2019-07-01 JP JP2019122746A patent/JP6884423B2/ja active Active
-
2021
- 2021-04-30 JP JP2021077128A patent/JP2021121198A/ja active Pending
-
2022
- 2022-05-19 US US17/748,889 patent/US11931381B2/en active Active
-
2023
- 2023-01-11 JP JP2023002047A patent/JP7479082B2/ja active Active
-
2024
- 2024-01-26 US US18/424,245 patent/US20240226157A1/en active Pending
- 2024-04-16 JP JP2024066097A patent/JP2024096903A/ja active Pending
- 2024-06-07 US US18/737,778 patent/US20240307451A1/en active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI789348B (zh) | 表現免疫機能控制因子之免疫活性細胞及表現載體 | |
| RU2670147C1 (ru) | Вектор экспрессии car и car-экспрессирующие т-клетки | |
| CN109803983B (zh) | 靶向nkg2dl的特异性嵌合抗原受体t细胞，其制备方法和应用 | |
| AU2016253549A1 (en) | Reversing the effects of the tumor microenvironment using chimeric cytokine receptors | |
| TWI811278B (zh) | 表現特異性辨識人類間皮素之細胞表面分子、il-7、及ccl19之免疫活性細胞 | |
| JP2021512637A (ja) | サイクリンａ１特異的ｔ細胞受容体およびその使用 | |
| CN110819596A (zh) | 具有增强的迁移能力的修饰的细胞 | |
| TW202140790A (zh) | 病毒載體轉導細胞的方法 |