JP2018530747A - 肺ガンを患っている患者の生存時間を予測するための方法 - Google Patents
肺ガンを患っている患者の生存時間を予測するための方法 Download PDFInfo
- Publication number
- JP2018530747A JP2018530747A JP2018510472A JP2018510472A JP2018530747A JP 2018530747 A JP2018530747 A JP 2018530747A JP 2018510472 A JP2018510472 A JP 2018510472A JP 2018510472 A JP2018510472 A JP 2018510472A JP 2018530747 A JP2018530747 A JP 2018530747A
- Authority
- JP
- Japan
- Prior art keywords
- cells
- density
- treg
- tls
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000004083 survival effect Effects 0.000 title claims abstract description 55
- 238000000034 method Methods 0.000 title claims abstract description 37
- 208000020816 lung neoplasm Diseases 0.000 title claims abstract description 27
- 206010058467 Lung neoplasm malignant Diseases 0.000 title claims abstract description 25
- 201000005202 lung cancer Diseases 0.000 title claims abstract description 24
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 186
- 210000004027 cell Anatomy 0.000 claims abstract description 125
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 94
- 210000003289 regulatory T cell Anatomy 0.000 claims abstract description 91
- 210000002865 immune cell Anatomy 0.000 claims abstract description 20
- 102000001398 Granzyme Human genes 0.000 claims abstract description 13
- 108060005986 Granzyme Proteins 0.000 claims abstract description 13
- 230000001105 regulatory effect Effects 0.000 claims abstract description 13
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 46
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 46
- 238000011002 quantification Methods 0.000 claims description 22
- 208000033878 Tertiary Lymphoid Structures Diseases 0.000 description 73
- 210000001519 tissue Anatomy 0.000 description 55
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 50
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 50
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 48
- 239000000523 sample Substances 0.000 description 47
- 201000011510 cancer Diseases 0.000 description 37
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 29
- 230000014509 gene expression Effects 0.000 description 28
- 108090000623 proteins and genes Proteins 0.000 description 26
- 210000004369 blood Anatomy 0.000 description 21
- 239000008280 blood Substances 0.000 description 21
- -1 benzodopa Chemical class 0.000 description 20
- 230000027455 binding Effects 0.000 description 18
- 210000003719 b-lymphocyte Anatomy 0.000 description 17
- 238000010186 staining Methods 0.000 description 17
- 238000011282 treatment Methods 0.000 description 17
- 239000003550 marker Substances 0.000 description 16
- 238000009169 immunotherapy Methods 0.000 description 15
- 210000001165 lymph node Anatomy 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 14
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 14
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 14
- 239000002955 immunomodulating agent Substances 0.000 description 14
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 11
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 11
- 230000004913 activation Effects 0.000 description 11
- 230000004069 differentiation Effects 0.000 description 11
- 102000004127 Cytokines Human genes 0.000 description 10
- 108090000695 Cytokines Proteins 0.000 description 10
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 10
- 210000000987 immune system Anatomy 0.000 description 10
- 229940045513 CTLA4 antagonist Drugs 0.000 description 9
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 9
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 9
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 9
- 230000000875 corresponding effect Effects 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 9
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 9
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 7
- 102100038078 CD276 antigen Human genes 0.000 description 7
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 7
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 7
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000000427 antigen Substances 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000001325 log-rank test Methods 0.000 description 7
- 238000001959 radiotherapy Methods 0.000 description 7
- 230000035945 sensitivity Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 6
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 6
- 108010050904 Interferons Proteins 0.000 description 6
- 102000014150 Interferons Human genes 0.000 description 6
- 102100033467 L-selectin Human genes 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 229940127089 cytotoxic agent Drugs 0.000 description 6
- 230000034994 death Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 229940047124 interferons Drugs 0.000 description 6
- 208000037841 lung tumor Diseases 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 6
- 238000004393 prognosis Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 5
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 5
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 5
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 5
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 5
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 5
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 5
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 5
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 5
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 5
- 102100038213 Lysosome-associated membrane glycoprotein 3 Human genes 0.000 description 5
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 5
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 5
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 5
- 208000009956 adenocarcinoma Diseases 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 239000002458 cell surface marker Substances 0.000 description 5
- 229940047120 colony stimulating factors Drugs 0.000 description 5
- 230000002596 correlated effect Effects 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 5
- 230000001506 immunosuppresive effect Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 229960003301 nivolumab Drugs 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 4
- 102100032976 CCR4-NOT transcription complex subunit 6 Human genes 0.000 description 4
- 101710185679 CD276 antigen Proteins 0.000 description 4
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 4
- 102000003951 Erythropoietin Human genes 0.000 description 4
- 108090000394 Erythropoietin Proteins 0.000 description 4
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 4
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 4
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 4
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 108010066979 Interleukin-27 Proteins 0.000 description 4
- 102100036678 Interleukin-27 subunit alpha Human genes 0.000 description 4
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 4
- 230000006044 T cell activation Effects 0.000 description 4
- 108091023040 Transcription factor Proteins 0.000 description 4
- 102000040945 Transcription factor Human genes 0.000 description 4
- 101710187830 Tumor necrosis factor receptor superfamily member 1B Proteins 0.000 description 4
- 102100033733 Tumor necrosis factor receptor superfamily member 1B Human genes 0.000 description 4
- 239000000090 biomarker Substances 0.000 description 4
- 230000005907 cancer growth Effects 0.000 description 4
- 239000002771 cell marker Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 210000004443 dendritic cell Anatomy 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229940105423 erythropoietin Drugs 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 238000012744 immunostaining Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 238000010837 poor prognosis Methods 0.000 description 4
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 206010041823 squamous cell carcinoma Diseases 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 4
- 229960000241 vandetanib Drugs 0.000 description 4
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 4
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 3
- 108010074604 Epoetin Alfa Proteins 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 3
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 3
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 3
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 3
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 3
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 3
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 3
- 101000819111 Homo sapiens Trans-acting T-cell-specific transcription factor GATA-3 Proteins 0.000 description 3
- 102100034980 ICOS ligand Human genes 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 102000003814 Interleukin-10 Human genes 0.000 description 3
- 108090000174 Interleukin-10 Proteins 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 102000015696 Interleukins Human genes 0.000 description 3
- 108010063738 Interleukins Proteins 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- 108010009489 Lysosomal-Associated Membrane Protein 3 Proteins 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000005867 T cell response Effects 0.000 description 3
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 3
- 210000000662 T-lymphocyte subset Anatomy 0.000 description 3
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 3
- 101001062349 Xenopus tropicalis Forkhead box protein A1 Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229930195731 calicheamicin Natural products 0.000 description 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 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 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 230000003325 follicular Effects 0.000 description 3
- 210000001280 germinal center Anatomy 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 229940047122 interleukins Drugs 0.000 description 3
- 230000002601 intratumoral effect Effects 0.000 description 3
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 3
- 230000004807 localization Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 229960002621 pembrolizumab Drugs 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 3
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 2
- 102100036305 C-C chemokine receptor type 8 Human genes 0.000 description 2
- 108010029697 CD40 Ligand Proteins 0.000 description 2
- 102100032937 CD40 ligand Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 102100032768 Complement receptor type 2 Human genes 0.000 description 2
- 101710093674 Cyclic nucleotide-gated cation channel beta-1 Proteins 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 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 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
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- 102100020997 Fractalkine Human genes 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 101150046249 Havcr2 gene Proteins 0.000 description 2
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 2
- 101000716063 Homo sapiens C-C chemokine receptor type 8 Proteins 0.000 description 2
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 description 2
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 2
- 101000854520 Homo sapiens Fractalkine Proteins 0.000 description 2
- 101001011441 Homo sapiens Interferon regulatory factor 4 Proteins 0.000 description 2
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 2
- 102000026633 IL6 Human genes 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 102100026720 Interferon beta Human genes 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 102100030126 Interferon regulatory factor 4 Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 2
- 238000000585 Mann–Whitney U test Methods 0.000 description 2
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 102100028762 Neuropilin-1 Human genes 0.000 description 2
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108010019992 STAT4 Transcription Factor Proteins 0.000 description 2
- 102000005886 STAT4 Transcription Factor 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
- 102100021386 Trans-acting T-cell-specific transcription factor GATA-3 Human genes 0.000 description 2
- 102100025946 Transforming growth factor beta activator LRRC32 Human genes 0.000 description 2
- 101710169732 Transforming growth factor beta activator LRRC32 Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000001815 biotherapy Methods 0.000 description 2
- 229940022399 cancer vaccine Drugs 0.000 description 2
- 238000009566 cancer vaccine Methods 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000035605 chemotaxis Effects 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 230000004186 co-expression Effects 0.000 description 2
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 2
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 230000004547 gene signature Effects 0.000 description 2
- 238000003881 globally optimized alternating phase rectangular pulse Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 230000028996 humoral immune response Effects 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 210000003563 lymphoid tissue Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 229940127084 other anti-cancer agent Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 108010044644 pegfilgrastim Proteins 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 238000007447 staining method Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 1
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- NOPNWHSMQOXAEI-PUCKCBAPSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-(2,3-dihydropyrrol-1-yl)-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCC=C1 NOPNWHSMQOXAEI-PUCKCBAPSA-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
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-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
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- VPBYZLCHOKSGRX-UHFFFAOYSA-N 1-[2-chloro-4-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-propylurea Chemical compound C1=C(Cl)C(NC(=O)NCCC)=CC=C1OC1=NC=NC2=CC(OC)=C(OC)C=C12 VPBYZLCHOKSGRX-UHFFFAOYSA-N 0.000 description 1
- NCYCYZXNIZJOKI-IOUUIBBYSA-N 11-cis-retinal Chemical compound O=C/C=C(\C)/C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-IOUUIBBYSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-QLKYHASDSA-N 3'-deamino-3'-(3-cyanomorpholin-4-yl)doxorubicin Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-QLKYHASDSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AXRCEOKUDYDWLF-UHFFFAOYSA-N 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1=CC=CC=N1 AXRCEOKUDYDWLF-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 1
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 1
- HHFBDROWDBDFBR-UHFFFAOYSA-N 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC1=NC=C(CN=C(C=2C3=CC=C(Cl)C=2)C=2C(=CC=CC=2F)F)C3=N1 HHFBDROWDBDFBR-UHFFFAOYSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 1
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 description 1
- YCWQAMGASJSUIP-YFKPBYRVSA-N 6-diazo-5-oxo-L-norleucine Chemical compound OC(=O)[C@@H](N)CCC(=O)C=[N+]=[N-] YCWQAMGASJSUIP-YFKPBYRVSA-N 0.000 description 1
- 102100021206 60S ribosomal protein L19 Human genes 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- OONFNUWBHFSNBT-HXUWFJFHSA-N AEE788 Chemical compound C1CN(CC)CCN1CC1=CC=C(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)C=C1 OONFNUWBHFSNBT-HXUWFJFHSA-N 0.000 description 1
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 102100021631 B-cell lymphoma 6 protein Human genes 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 1
- 102100036848 C-C motif chemokine 20 Human genes 0.000 description 1
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 description 1
- 102100036150 C-X-C motif chemokine 5 Human genes 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- LLVZBTWPGQVVLW-SNAWJCMRSA-N CP-724714 Chemical compound C12=CC(/C=C/CNC(=O)COC)=CC=C2N=CN=C1NC(C=C1C)=CC=C1OC1=CC=C(C)N=C1 LLVZBTWPGQVVLW-SNAWJCMRSA-N 0.000 description 1
- 108090000835 CX3C Chemokine Receptor 1 Proteins 0.000 description 1
- 102100039196 CX3C chemokine receptor 1 Human genes 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- BYOYVFXXYLKUIQ-UHFFFAOYSA-N Cl.N=1CC(C=C2C=NC=CC12)=O Chemical compound Cl.N=1CC(C=C2C=NC=CC12)=O BYOYVFXXYLKUIQ-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 102100023362 Elongation factor 1-gamma 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
- 230000010665 Enzyme Interactions Effects 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 description 1
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 description 1
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 229930189413 Esperamicin Natural products 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 108010039471 Fas Ligand Protein Proteins 0.000 description 1
- 102100031512 Fc receptor-like protein 3 Human genes 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 102100021186 Granulysin Human genes 0.000 description 1
- 101710168479 Granulysin Proteins 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 101001105789 Homo sapiens 60S ribosomal protein L19 Proteins 0.000 description 1
- 101000971234 Homo sapiens B-cell lymphoma 6 protein Proteins 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 1
- 101000713099 Homo sapiens C-C motif chemokine 20 Proteins 0.000 description 1
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 description 1
- 101000947186 Homo sapiens C-X-C motif chemokine 5 Proteins 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101001050451 Homo sapiens Elongation factor 1-gamma Proteins 0.000 description 1
- 101000846910 Homo sapiens Fc receptor-like protein 3 Proteins 0.000 description 1
- 101001076418 Homo sapiens Interleukin-1 receptor type 1 Proteins 0.000 description 1
- 101001076422 Homo sapiens Interleukin-1 receptor type 2 Proteins 0.000 description 1
- 101001098352 Homo sapiens OX-2 membrane glycoprotein Proteins 0.000 description 1
- 101000594698 Homo sapiens Ornithine decarboxylase antizyme 1 Proteins 0.000 description 1
- 101000713602 Homo sapiens T-box transcription factor TBX21 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 102100026016 Interleukin-1 receptor type 1 Human genes 0.000 description 1
- 102100026017 Interleukin-1 receptor type 2 Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 108010047357 Luminescent Proteins Proteins 0.000 description 1
- 102000006830 Luminescent Proteins Human genes 0.000 description 1
- 206010050017 Lung cancer metastatic Diseases 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 229940124640 MK-2206 Drugs 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OUSFTKFNBAZUKL-UHFFFAOYSA-N N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide Chemical compound O1C(C(C)(C)C)=CN=C1CSC(S1)=CN=C1NC(=O)C1CCNCC1 OUSFTKFNBAZUKL-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 101710204212 Neocarzinostatin Proteins 0.000 description 1
- 108090000772 Neuropilin-1 Proteins 0.000 description 1
- 102100037589 OX-2 membrane glycoprotein Human genes 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 102100036199 Ornithine decarboxylase antizyme 1 Human genes 0.000 description 1
- SUDAHWBOROXANE-VIFPVBQESA-N PD 0325901-Cl Chemical compound OC[C@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-VIFPVBQESA-N 0.000 description 1
- PBBRWFOVCUAONR-UHFFFAOYSA-N PP2 Chemical compound C12=C(N)N=CN=C2N(C(C)(C)C)N=C1C1=CC=C(Cl)C=C1 PBBRWFOVCUAONR-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 241001600434 Plectroglyphidodon lacrymatus Species 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Porfiromycine Chemical compound O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 108091008778 RORγ2 Proteins 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- 102100040756 Rhodopsin Human genes 0.000 description 1
- 108090000820 Rhodopsin Proteins 0.000 description 1
- 229920002305 Schizophyllan Polymers 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 102100035721 Syndecan-1 Human genes 0.000 description 1
- 230000006043 T cell recruitment Effects 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 102100036840 T-box transcription factor TBX21 Human genes 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 1
- 210000000447 Th1 cell Anatomy 0.000 description 1
- 210000000068 Th17 cell Anatomy 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
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- SPJCRMJCFSJKDE-ZWBUGVOYSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-[4-[bis(2-chloroethyl)amino]phenyl]acetate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 SPJCRMJCFSJKDE-ZWBUGVOYSA-N 0.000 description 1
- XZSRRNFBEIOBDA-CFNBKWCHSA-N [2-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethyl] 2,2-diethoxyacetate Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)C(OCC)OCC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 XZSRRNFBEIOBDA-CFNBKWCHSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 description 1
- 229930188522 aclacinomycin Natural products 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 238000012152 algorithmic method Methods 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 238000011316 allogeneic transplantation Methods 0.000 description 1
- WLDHEUZGFKACJH-UHFFFAOYSA-K amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1N=NC1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-UHFFFAOYSA-K 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000013059 antihormonal agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000003995 blood forming stem cell Anatomy 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 229950005993 brivanib alaninate Drugs 0.000 description 1
- LTEJRLHKIYCEOX-OCCSQVGLSA-N brivanib alaninate Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@@H](C)OC(=O)[C@H](C)N)=C1 LTEJRLHKIYCEOX-OCCSQVGLSA-N 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 238000004422 calculation algorithm Methods 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin 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=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- USVCWSAJUAARAL-MEMLXQNLSA-N chembl551064 Chemical compound C1=2C(N)=NC=NC=2N([C@@H]2C[C@H](C2)N2CCC2)C=C1C(C=1)=CC=CC=1OCC1=CC=CC=C1 USVCWSAJUAARAL-MEMLXQNLSA-N 0.000 description 1
- 239000005081 chemiluminescent agent Substances 0.000 description 1
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@@H](C)[C@H](OC(C)=O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1C[C@@H](O)[C@@H](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 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
- 230000002301 combined effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000004940 costimulation Effects 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 108010006226 cryptophycin Proteins 0.000 description 1
- 108010089438 cryptophycin 1 Proteins 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229950003913 detorubicin Drugs 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- 238000011496 digital image analysis Methods 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229940056913 eftilagimod alfa Drugs 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 229950002189 enzastaurin Drugs 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229950002973 epitiostanol Drugs 0.000 description 1
- 229960003388 epoetin alfa Drugs 0.000 description 1
- 229940089118 epogen Drugs 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin 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[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 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
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 239000000834 fixative 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
- ZFKJVJIDPQDDFY-UHFFFAOYSA-N fluorescamine Chemical compound C12=CC=CC=C2C(=O)OC1(C1=O)OC=C1C1=CC=CC=C1 ZFKJVJIDPQDDFY-UHFFFAOYSA-N 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000001102 germinal center b cell Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 150000002309 glutamines Chemical class 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 231100000508 hormonal effect Toxicity 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000031261 interleukin-10 production Effects 0.000 description 1
- 238000010212 intracellular staining Methods 0.000 description 1
- 229940065638 intron a Drugs 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 229940087875 leukine Drugs 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- MPVGZUGXCQEXTM-UHFFFAOYSA-N linifanib Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C(N)=NNC=3C=CC=2)=C1 MPVGZUGXCQEXTM-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 210000005210 lymphoid organ Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- 229950003968 motesanib Drugs 0.000 description 1
- RAHBGWKEPAQNFF-UHFFFAOYSA-N motesanib Chemical compound C=1C=C2C(C)(C)CNC2=CC=1NC(=O)C1=CC=CN=C1NCC1=CC=NC=C1 RAHBGWKEPAQNFF-UHFFFAOYSA-N 0.000 description 1
- ZTFBIUXIQYRUNT-MDWZMJQESA-N mubritinib Chemical compound C1=CC(C(F)(F)F)=CC=C1\C=C\C1=NC(COC=2C=CC(CCCCN3N=NC=C3)=CC=2)=CO1 ZTFBIUXIQYRUNT-MDWZMJQESA-N 0.000 description 1
- WPOXAFXHRJYEIC-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2C3=CC(OC)=C(OCC4CCN(C)CC4)C=C3N=CN=2)=C1 WPOXAFXHRJYEIC-UHFFFAOYSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 238000011227 neoadjuvant chemotherapy Methods 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 description 1
- 229940071846 neulasta Drugs 0.000 description 1
- 229940082926 neumega Drugs 0.000 description 1
- 229940029345 neupogen Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 239000012740 non-selective inhibitor Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950005848 olivomycin Drugs 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 108010046821 oprelvekin Proteins 0.000 description 1
- 238000012634 optical imaging Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- HQQSBEDKMRHYME-UHFFFAOYSA-N pefloxacin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 HQQSBEDKMRHYME-UHFFFAOYSA-N 0.000 description 1
- 229960001373 pegfilgrastim 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
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 230000030786 positive chemotaxis Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000007112 pro inflammatory response Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940029359 procrit Drugs 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 238000011362 radionuclide therapy Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009919 saracatinib Drugs 0.000 description 1
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 210000005212 secondary lymphoid organ Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229950003647 semaxanib Drugs 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CCEKAJIANROZEO-UHFFFAOYSA-N sulfluramid Chemical group CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F CCEKAJIANROZEO-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- LZAJKCZTKKKZNT-PMNGPLLRSA-N trichothecene Chemical compound C12([C@@]3(CC[C@H]2OC2C=C(CCC23C)C)C)CO1 LZAJKCZTKKKZNT-PMNGPLLRSA-N 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 230000005641 tunneling Effects 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57423—Specifically defined cancers of lung
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Medicinal Chemistry (AREA)
- Analytical Chemistry (AREA)
- Biotechnology (AREA)
- Hospice & Palliative Care (AREA)
- Oncology (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Description
本発明は、肺ガンを患っている患者の生存時間を予測するための方法に関する。
Dieu-Nosjean et al. (J Clin Oncol 26:4410-4417. 2008)に示されているように、肺ガンは、世界で最も一般的なガン関連死の原因である。症例の約80%〜90%は、腺ガン及び扁平上皮細胞ガンを含む非小細胞肺ガン(NSCLC)を伴う。その腫瘍を完全に切除し得る患者のみが、生存増加の有意な可能性を有する。しかしながら、ステージIの疾患を有する患者の30%もの数が、術後に再発を経験する。腫瘍浸潤免疫細胞と、肺ガンを有する患者の予後との間の相関関係は議論の余地がある。腫瘍は、不均一なネットワークを形成して複雑な相互作用を示す悪性細胞、間質細胞、内皮細胞及び免疫細胞から構成される。多くの場合、免疫系による腫瘍根絶は非効率であるが、多くの発達中のガンは免疫系から無視されないという証拠がある。自己免疫の発現と同時に起こる自然腫瘍退縮と、免疫抑制患者におけるより高い腫瘍発生率とは、腫瘍拒絶における免疫系の関与を示すものである。免疫機能欠損マウスは、自然に腫瘍を発達させる。細胞傷害性表現型及び記憶表現型を有する腫瘍浸潤リンパ球(TIL)の密度は、多くの固形腫瘍における臨床転帰良好をよく予測するものである。
本発明の第1の目的は、肺ガンを患っている被験体の生存時間を予測するための方法であって、i)該被験体から得られた腫瘍組織サンプルにおける制御性T(Treg)細胞の密度を定量する工程、ii)前記腫瘍組織サンプルにおけるTLS−成熟DC又はTLS−B細胞又はCD3+Tconv細胞、CD8+T細胞又はCD8+グランザイム−B+T細胞からなる群より選択される免疫細胞の1つのさらなる集団の密度を定量する工程、iii)工程i)及びii)において定量した密度と、それらの対応する所定の基準値とを比較する工程、並びにiv)Treg細胞の密度がその対応する所定の基準値よりも高く、免疫細胞のさらなる集団の密度がその対応する所定の基準値よりも低い場合には、該被験体が短い生存時間を有すると結論するか、又はTreg細胞の密度がその対応する所定の基準値よりも低く、免疫細胞のさらなる集団の密度がその対応する所定の基準値よりも高い場合には、該被験体が長い生存時間を有すると結論する工程を含む方法に関する。
a)肺ガンを患っている被験体由来の腫瘍組織サンプルのコレクションを提供する工程;
b)工程a)において提供した各腫瘍組織サンプルについて、対応する被験体の実際の臨床転帰に関する情報(すなわち、無病生存(DFS)及び/又は全生存(OS)の期間)を提供する工程;
c)一連の任意の定量値を提供する工程;
d)工程a)において提供したコレクションに含まれる各腫瘍組織サンプルの細胞密度を定量する工程;
e)工程c)において提供した1つの特定の任意の定量値について、前記腫瘍組織サンプルを2つの群((i)前記一連の定量値に含まれる前記任意の定量値よりも低いレベルで定量値を示す腫瘍組織サンプルを含む第1の群;(ii)前記一連の定量値に含まれる前記任意の定量値よりも高い前記レベルについての定量値を示す腫瘍組織サンプルを含む第2の群)にそれぞれ分類し、それにより、前記特定の定量値について、2つの腫瘍組織サンプル群を得、各群の腫瘍組織サンプルを別々に計数する工程;
f)(i)工程e)において得た定量値と(ii)工程f)において定義した第1の群及び第2の群に含まれる腫瘍組織サンプルが由来する被験体の実際の臨床転帰との間の統計的有意性を計算する工程;
g)工程d)において提供したあらゆる任意の定量値を試験するまで、工程f)及びg)を反復する工程;
h)前記所定の基準値を、工程g)において最も高い統計的有意性(ログランク検定で得られた最も有意なP値、P<0.05の場合に有意)が計算された任意の定量値からなるように設定する工程
を含む方法を行うことによって決定され得る。
患者:
外科的完全切除後、Institut Mutualiste Montsouris, Hotel Dieu and Cochin hospitals (Paris, France)のNSCLC患者から、原発性肺腫瘍サンプルを得た。2001〜2005年に手術を受けたHotel Dieu Hospital (Paris)のNSCLC患者243人のレトロスペクティブコホートが本研究に参加した。ネオアジュバント化学療法及び放射線療法で処置された患者は、このコホートから除外した。手術と最終経過観察又は死亡との間の時間をこのコホートの観察時間とみなす。対話後に、当局の記録簿又は患者の家族から、長期転帰のデータを得た。このプロトコールは、フランス国法の第L.1121−1条を適用して地方倫理委員会(n° 2008-133及びn° 2012-0612)によって承認された。プロスペクティブコホートについては、NSCLC患者55人から、新鮮腫瘍生検を得た。手術を受けた患者から、非腫瘍遠隔肺標本(NTDL)及びリンパ節(LN)標本も得た。書面による同意を得た患者から、サンプルを得た。レトロスペクティブコホート及びプロスペクティブコホートの患者の主な臨床的及び病理学的特徴は、それぞれ表2及び3に示されている。
表2:レトロスペクティブコホートのNSCLC患者の臨床的及び病理学的特徴。NSCLC患者243人において、全てのパラメータを評価した。新たなTNM病期分類46にしたがって、肺ガンの病期を決定した。WHO47の分類にしたがって、組織学的サブタイプを決定した。略語:ADC、腺ガン;ND、未決定;SCC、扁平上皮細胞ガン
表2:プロスペクティブコホートのNSCLC患者の臨床的及び病理学的特徴。NSCLC患者55人において、全てのパラメータを評価した。新たなTNM病期分類46にしたがって、肺ガンの病期を決定した。WHO47の分類にしたがって、組織学的サブタイプを決定した。略語:ADC、腺ガン;ND、未決定;SCC、扁平上皮細胞ガン
CD3、FoxP3、DC−Lamp、CD8、CD20、CD21及びパンサイトケラチンの免疫組織化学二重染色のために、厚さ5μmのホルマリン固定パラフィン包埋連続組織切片を使用した。簡潔に言えば、組織切片を脱パラフィン処理し、水で元に戻し、抗原回復バッファーTRS(Dako)で処置した。protein bloc (Dako)中で切片を30分間インキュベーションしてから、適切な一次抗体及び二次抗体を追加した。基質キットを使用して、酵素活性を実施した。NDPviewソフトウェアを備えるNanozoomer (Hamamatsu)を使用して、画像を取得した。
Calopixソフトウェア(Tribvn)を使用して全腫瘍切片において、免疫細胞を定量し、目的の領域1mm2当たりの細胞数として表した。同じソフトウェアを使用して、目的の領域の表面積も決定した。二重DC−Lamp/CD3(TLSのT細胞領域)及びCD20/CD21(TLSのB細胞領域)染色を参照して、TLSの領域を手動で決定した。自動計数を用いて、TLSにおけるCD3+FoxP3+細胞の密度を決定した。以前に記載されているように7,(22)、TLS−DC−Lamp+DC、CD3+T細胞、CD8+T細胞、TLS−CD20+B細胞の定量を決定した。
合計34個のNSCLC新鮮腫瘍サンプルが本研究に参加した。腫瘍組織標本及び非腫瘍組織標本を機械的に細断し、非酵素溶液(細胞回収溶液、BD Biosciences)で消化した。フィコール勾配の後、全単核細胞を得た。蛍光標識抗体及びそれらのマッチアイソタイプコントロールの複数のパネルで、単核細胞を染色した。さらに、細胞内染色のための固定/パーマキット(ebioscience)を使用して、細胞を固定及び透過処理した。細胞を洗浄し、Fortessa cytometer (BD Biosciences)によってデータを取得した。flow Jo 9.7.6 (Tree Star Inc, Ashland, OR)及びSpice 5.3.5 (Mario Roederer, Vaccine Research Center, NIAID, NIHによる開発)ソフトウェアプログラムを使用して、データを分析した。
4つの細胞集団(すなわち、CD62L+及びCD62L−Treg、CD62L+及びCD62L−CD4+従来型T細胞(Tconv))について、インハウス設計のプロトコールを使用して、新鮮腫瘍標本及び非腫瘍組織標本(n=20)からを選別した。簡潔に言えば、Easysep(商標)untouched human CD4+ T cell kit (stem cell technologies Ref. No.)とフローサイトメトリー細胞選別との組み合わせを使用して、高純度の細胞サブセットを達成した。最高の品質及び量のmRNAを得るために、RLT+10%β−メルカプトエタノールを含有するバイアルに細胞を直接選別した。
製造業者の説明書にしたがってRNeasy micro kit (Qiagen)を用いて、選別細胞由来の全mRNAを抽出し、2100 Bioanalyzer (Agilent Technologies)を使用してRNAの量及び品質を決定した。superscript VILO kit (Life Technologies)を使用して、mRNAをcDNAに逆転写した。Taqman PreAmp 2x及びMTEプライマー(NanoString technologies, Seatle, USA)を使用して、mRNAが1ng未満のサンプルを9サイクル増幅し、mRNA 1ng超を有するサンプルを7サイクルのPCRによって増幅した。
nCounter analysis system (Nanostring Technologies)を使用して、遺伝子発現を実施した。目的の各遺伝子のための2つの特異的プローブ(キャプチャ及びレポーター)を適用した。製造業者の説明書(Nanostring Technologies, Seattle, USA)にしたがって、5つのハウスキーピングコントロール(β−アクチン、GAPDH、EEF1G、OAZ1及びRPL19)及び細胞系統コントロール(CD3、CD4、CD8、CD19、CD138及びEpCAM)を含む選択遺伝子125個の特注レポータープローブ及びキャプチャプローブコードセットをハイブリダイゼーションに使用した。水をネガティブコントロールとして使用して、バックグラウンドノイズをチェックした。NanoString Prep-stationを使用して、ハイブリダイゼーションしたサンプルを回収し、デジタルnCounterを用いてmRNA分子を計数した。計数の数は、遺伝子の発現を表していた。ポジティブコントロール及びネガティブコントロールと、内部コントロールとして1つの患者RNAサンプルとを使用して、異なるバッチの実験中の技術的整合性をチェックした。
マンホイットニーU検定及びウィルコクスン順位検定(P<0.05*、P<0.01**、P<0.001***)を使用して、異なる腫瘍における細胞の密度を比較した。カプラン・マイヤー法によって全生存(OS)曲線を推定し、ログランク検定を使用して患者群間の差異を計算した。以前に公開されているように(7、22)、「最小P値」アプローチを使用して、高密度及び低密度の免疫細胞によって患者を2つの群に分類した。最適なカットオフ値は、898.793 CD3+FoxP3−Tconv、21.997 CD3+FoxP3+Treg、127.0348 TLS Treg、1.248 DC−Lamp+DC、226.5 CD8+T細胞/mm2であり、腫瘍領域のTLS−CD20+B細胞は0.3256%である(図2)。Prism 5 (GraphPad)、Statview (Abacus system)及びR (http: //www.r-project.org/)ソフトウェアを用いて、全ての分析を実施した。遺伝子発現研究及びヒートマップデモンストレーションのために、ソフトウェア「nSolver」(Nanostring Technologies)及びRを使用した。「nSolver」ソフトウェアを使用して、5つのハウスキーピング遺伝子の平均数によって、生データを正規化した。スチューデントT検定及びANOVA検定を使用して、それぞれデータ群間の遺伝子発現を比較した。偽陽性結果が含まれることを回避するために、本発明者らは、偽発見率(FDR)法を用いてP値を算出した。ヒートマップ、ボルケーノプロット及び相関マトリックス形式で、データを表した。
Tregは、TLSを含む異なる肺腫瘍領域に浸潤し、活性化記憶表現型を示す。
本発明者らは、NSCLC患者における腫瘍浸潤Tregの存在、局在性及び頻度を評価した。免疫組織化学によって、CD3+FoxP3+T細胞の存在が異なる腫瘍領域において検出された。CD8+T細胞のような他のT細胞サブセットについては、珍しいCD3+FoxP3+T細胞が腫瘍母地において観察された。実際、腫瘍間質では、T細胞の大部分は、CD3+FoxP3+及びCD8+T細胞と共に検出された。間質反応によるより深い特性評価により、本発明者らは、DC−Lamp+成熟DC及びCD3+T細胞クラスタの存在によって実証されているように、TLSのT細胞リッチ領域におけるTregを視覚化することができた。
異なる分化段階のTregが異なる腫瘍領域に存在することから、本発明者らは、それらの活性化、免疫抑制及び免疫チェックポイント(ICP)状態の性質を調査した。したがって、Tregにおいて分子(n=169)及びタンパク質(n=14)レベルで、活性化マーカー及び免疫調節マーカーの発現を調査し、それらの表現型と、腫瘍におけるCD4+Tconvのものとを比較した。FoxP3、IL2Rα及びIL2Rβと一緒に、腫瘍浸潤Tregは、CD4+Tconvと比較して、いくつかの転写因子(Helios及びIRF4)、ケモカイン(CCL22)及びレセプター(CXCR3、CCR4及びCCR8)、サイトカイン(IL10、IL27及びIFNα)及びレセプター(TNFR2、IL1R1及びIL1R2)、活性化レセプター(GITR、4−1BB、ICOS及びOX40)及びいくつかのICP分子(膜及び可溶性CTLA−4、LAG−3、Tim−3、TIGIT、CD39、B7H3、GARP及びPDL2)を有意に過剰発現していた。遺伝子発現レベルによれば、タンパク質レベルでGITR、ICOS、4−1BB、OX40、CTLA−4、Tim−3及びTIGITについて陽性のTregの割合は、CD4+Tconvよりも顕著に高かったのに対して、2つのT細胞サブセット間では、LAG−3に関する統計的差異は測定されなかった。
ほとんどのTregは、異なる部位において推定エフェクター機能を有する記憶表現型であったが、それらは腫瘍に広く浸潤していたので、本発明者らは、それらの局在性が何であっても、それらが同じ分子パターンを示すかを決定した。以前に実施されているように、本発明者らは、NSCLC患者のTreg浸潤腫瘍、NTDL、LN及び血液における活性化マーカー、免疫抑制マーカー及びICPマーカーの遺伝子及びタンパク質発現レベルを比較した。驚くべきことに、腫瘍では、NTDLと対比して、非常にわずかな遺伝子(試験した遺伝子120個のうちの11個)がTregによってディファレンシャルに発現されていたが、これは、それらが、腫瘍性肺及び非腫瘍性肺において同様の遺伝子発現シグネチャーを示すことを示している。これらの遺伝子のほとんどは、走化性及びICP(PD−1、BTLA、B7−H3、IL−27、BCL6、STAT4、CD44)に関係する。腫瘍及びLNにおけるTregを比較したところ、本発明者らは、より過剰発現されている遺伝子を観察し(n=21、そのうち腫瘍において17個及びLNにおいて4個)、それらのほとんどは腫瘍におけるTreg及びCD4+Tconvを比較したときに既に同定されていた。Treg上でディファレンシャルに発現される最も重要な遺伝子の数は、腫瘍と血液との間であった。1個を除いて、それらの全てが腫瘍において過剰発現されており、以前に強調されていた遺伝子を含む(腫瘍とLNとの対比)。腫瘍Tregにおける腫瘍関連遺伝子は、転写因子(FoxP3、FoxA1、STAT4)、活性化(ICOS、GITR、Ox−40、4−1BB、TNFR2、CD26)、ICP(mCTLA4、PD1、PDL1、B7−H3、BTLA、TIGIT、Tim3、LAG−3)、走化性(CCL20、CCL22、CXCL5、CX3CL1、CXCR3、CD200、CX3CR1、LTβR)、免疫抑制(IL−10、CD39、GARP)及び細胞傷害性(グランザイムB、グラニュリシン、FasL)分子に関係する。タンパク質レベルにおいて、本発明者らは、異なる部位におけるTregが、活性化分子及びICP分子の同じセットを発現せず、血液が、腫瘍と最も重要な差異を示すことを確認した。フローサイトメトリー分析により、本発明者らは、研究したマーカーの潜在的な同時発現を研究することができた。したがって、CD38、CD40L、CD69及びGITR発現の多重分析は、これらの分子全てについて陰性のTregの割合が、血液における80%から腫瘍における8%に大きく減少したことを示している。1個又は2個のマーカーを発現するTregの割合は、それが20%に低下した血液を除いて、全ての部位において非常に安定していた(約60%)。したがって、3〜4個のマーカーについて陽性のTregの頻度は、血液における0%から腫瘍における35%に劇的に増加した。少なくとも2個の分子を発現する細胞の分析は、ほとんどの場合において、単一陽性細胞が主にCD69であり(優先的CD38発現を有する血液を除く)、二重陽性細胞がCD69及びGITRであり、三重陽性細胞がCD69、GITR及びCD38であることを示している。4.1BB、ICOS及びOX40の発現についても、同じ状況が生じた。三重陰性Tregの割合は、血液における65%から腫瘍における26%に有意に減少したのに対して、三重陽性Tregについては、それは2%から22%に増加した。ほとんどの場合において、単一陽性細胞から三重陽性細胞に、最初にICOSが発現され、続いてOX40が発現され、次いで4.1BBが発現された。活性化マーカーについては、ICPを全く発現しないTregの割合は、血液における56%から腫瘍における10%に劇的に低下した。1個のマーカーのみを発現するTregについても同じ結果である。対照的に、少なくとも2個のマーカーについて陽性の細胞の頻度は、血液における8%から腫瘍における70%に有意に増加した。TIGIT、次いでTim−3又はCTLA−4がTregによって連続的に発現された。
カプラン・マイヤー曲線は、高密度の腫瘍内Tregが、NSCLC患者の臨床転帰不良と相関していたことを表している(「Treg低」では、平均OSが達成されなかったのに対して、「Treg高」患者では、それは51カ月間であった。P=0.0049、図1A)。高密度のTLS−成熟DC、TLS−B細胞及びエフェクターCD8+T細胞は、NSCLCを有する患者の長い生存に関連していたので(4、7、22、図1C、E、G)、本発明者らはさらに患者の生存に対するこれらの免疫細胞とTregとの複合的な影響を試験した。本発明者らは、成熟DC、TLS−B細胞又はCD8+T細胞の密度が何であっても、低密度のTregが好ましい臨床転帰に関連していたことを観察した。対照的に、高密度のTregと、低密度の成熟DC(平均OS=25カ月間;P<0.0001、図1D)、TLS−B細胞(平均OS=24カ月間;P<0.0001、図1F)又はCD8+T細胞(平均OS=40カ月間;P=0.0002、図1H)とを有する患者は最悪の転帰を有しており、各変数のみの場合と比較して、平均生存が最短であった。「Treg高/成熟DC、TLS−B又はCD8+T高」の患者は、中程度の死亡リスクを有していたが、これは、一方では成熟DC、TLS−B及びCD8+T細胞、そして他方ではTregが、NSCLC患者の転帰に対して二重の影響を有することを示唆している。異なる腫瘍領域におけるTregが、乳ガン患者の生存に対して異なる影響を有することが示されているので(16)、本発明者らは、NSCLC患者100人のTLS領域及び非TLS領域におけるTregを別々に計算した。高密度のTLS−Treg及び非TLS−Tregは、全Tregと同様に、臨床転帰不良と相関していたことが観察された(それぞれ「TLS−Treg低」及び「TLS−Treg高」患者について、平均OS=57カ月間対34カ月間;P=0.0245、図1B)。本発明者らはまた、全CD3+T細胞又はCD8+T細胞又は成熟DC/Tregの密度の比率を決定したところ、「高比率」のこれらのマーカーは全て、「低比率」と比較してNSCLC患者に有益であったことが見出された(図3)。
文献には、異なる固形ガンにおけるTregの予後関連性について議論されている多くの研究があるが、不一致の原因となる様々な要因により、それは常に論争中であった。腫瘍の種類、病期及び組織型に応じて、Tregの予後的重要性が異なることが見出された(15)。それらの局所性に基づいて、Tregは、抗腫瘍応答を抑制又は支援し得る。最近、胚中心において、Tregは、Tfh分化を支援し得ることが観察されている(26)。したがって、異なる腫瘍領域におけるTregの異なる役割及び表現型を推測することは興味深いものであった。利用可能な先進技術を用いて、本発明者らは、総数としての、さらには、異なる肺腫瘍サブ領域におけるそれらの局在性に応じたTregの予後的価値を再検討した。
Claims (8)
- 肺ガンを患っている被験体の生存時間を予測するための方法であって、
i)該被験体から得られた腫瘍組織サンプルにおける制御性T(Treg)細胞の密度を定量する工程、
ii)前記腫瘍組織サンプルにおけるTLS−成熟DC又はTLS−B細胞又はTconv細胞又はCD8+T細胞又はCD8+Gran−B+T細胞からなる群より選択される免疫細胞の1つのさらなる集団の密度を定量する工程、
iii)工程i)及びii)において定量した密度と、それらの対応する所定の基準値とを比較する工程、並びに
iv)Treg細胞の密度がその対応する所定の基準値よりも高く、免疫細胞のさらなる集団の密度がその対応する所定の基準値よりも低い場合には、該被験体が短い生存時間を有すると結論するか、又はTreg細胞の密度がその対応する所定の基準値よりも低く、免疫細胞のさらなる集団の密度がその対応する所定の基準値よりも高い場合には、該被験体が長い生存時間を有すると結論する工程
を含む、方法。 - それぞれ工程i)及びii)において、制御性T(Treg)細胞の密度及びTLS−成熟DCの密度を定量する、請求項1に記載の方法。
- それぞれ工程i)及びii)において、制御性T(Treg)細胞の密度及びTLS−B細胞の密度を定量する、請求項1に記載の方法。
- それぞれ工程i)及びii)において、制御性T(Treg)細胞の密度及びTconv細胞の密度を定量する、請求項1に記載の方法。
- それぞれ工程i)及びii)において、制御性T(Treg)細胞の密度及びCD8+T細胞の密度を定量する、請求項1に記載の方法。
- それぞれ工程i)及びii)において、制御性T(Treg)細胞の密度及びCD8+グランザイム−B+T細胞の密度を定量する、請求項1に記載の方法。
- IHCによって密度の定量を決定する、請求項1に記載の方法。
- 被験体が非小細胞肺ガン(NSCLC)を患っている、請求項1に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15306318 | 2015-08-27 | ||
EP15306318.5 | 2015-08-27 | ||
PCT/EP2016/070158 WO2017032867A1 (en) | 2015-08-27 | 2016-08-26 | Methods for predicting the survival time of patients suffering from a lung cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018530747A true JP2018530747A (ja) | 2018-10-18 |
JP6791951B2 JP6791951B2 (ja) | 2020-11-25 |
Family
ID=54064252
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018510472A Active JP6791951B2 (ja) | 2015-08-27 | 2016-08-26 | 肺ガンを患っている患者の生存時間を予測するための方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US11385231B2 (ja) |
EP (1) | EP3341732B1 (ja) |
JP (1) | JP6791951B2 (ja) |
ES (1) | ES2955775T3 (ja) |
WO (1) | WO2017032867A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020171141A1 (ja) * | 2019-02-20 | 2020-08-27 | 学校法人 埼玉医科大学 | がん免疫療法における長期生存を予測するための方法および組成物 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20200085299A (ko) * | 2017-11-07 | 2020-07-14 | 코이뮨, 인크. | 수지상 세포 요법을 위한 방법 및 용도 |
US20240044901A1 (en) * | 2021-02-09 | 2024-02-08 | Institut National de la Santé et de la Recherche Médicale | New method to pronostic lung cancer |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012038068A2 (en) * | 2010-09-24 | 2012-03-29 | Niels Grabe | Means and methods for the prediction of treatment response of a cancer patient |
WO2015007625A1 (en) * | 2013-07-15 | 2015-01-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for the prognosis of survival time of a patient suffering from a solid cancer |
JP2015505607A (ja) * | 2012-01-20 | 2015-02-23 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | B細胞の密度に基づいて、固形癌に苦しむ患者の生存時間を予測するための方法 |
JP2015505608A (ja) * | 2012-01-20 | 2015-02-23 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 固形ガンを患う患者の生存期間の予後診断のための方法 |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5618829A (en) | 1993-01-28 | 1997-04-08 | Mitsubishi Chemical Corporation | Tyrosine kinase inhibitors and benzoylacrylamide derivatives |
KR960703622A (ko) | 1993-07-15 | 1996-08-31 | 수잔 포오덴 | 단백질 티로신 키나아제 억제제의 프로드러그(prodrugs of protein tyrosine kinase inhibitors) |
US5804396A (en) | 1994-10-12 | 1998-09-08 | Sugen, Inc. | Assay for agents active in proliferative disorders |
US5639757A (en) | 1995-05-23 | 1997-06-17 | Pfizer Inc. | 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors |
US5811097A (en) | 1995-07-25 | 1998-09-22 | The Regents Of The University Of California | Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling |
US5855887A (en) | 1995-07-25 | 1999-01-05 | The Regents Of The University Of California | Blockade of lymphocyte down-regulation associated with CTLA-4 signaling |
US6051227A (en) | 1995-07-25 | 2000-04-18 | The Regents Of The University Of California, Office Of Technology Transfer | Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling |
EP0892789B2 (en) | 1996-04-12 | 2009-11-18 | Warner-Lambert Company LLC | Irreversible inhibitors of tyrosine kinases |
US6207157B1 (en) | 1996-04-23 | 2001-03-27 | The United States Of America As Represented By The Department Of Health And Human Services | Conjugate vaccine for nontypeable Haemophilus influenzae |
ZA986732B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
US6100254A (en) | 1997-10-10 | 2000-08-08 | Board Of Regents, The University Of Texas System | Inhibitors of protein tyrosine kinases |
EE05627B1 (et) | 1998-12-23 | 2013-02-15 | Pfizer Inc. | CTLA-4 vastased inimese monoklonaalsed antikehad |
US6740665B1 (en) | 1999-02-10 | 2004-05-25 | Ramachandran Murali | Tyrosine kinase inhibitors and methods of using the same |
US6245759B1 (en) | 1999-03-11 | 2001-06-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
US6329380B1 (en) | 1999-06-30 | 2001-12-11 | Merck & Co., Inc. | SRC kinase inhibitor compounds |
CA2383546A1 (en) | 1999-06-30 | 2001-01-04 | William H. Parsons | Src kinase inhibitor compounds |
JP2003503354A (ja) | 1999-06-30 | 2003-01-28 | メルク エンド カムパニー インコーポレーテッド | Srcキナーゼ阻害剤化合物 |
US7605238B2 (en) | 1999-08-24 | 2009-10-20 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
EP1792991A1 (en) | 1999-08-24 | 2007-06-06 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
KR20020027635A (ko) | 1999-09-10 | 2002-04-13 | 폴락 돈나 엘. | 티로신 키나제 억제제 |
US6794393B1 (en) | 1999-10-19 | 2004-09-21 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
JP2003512353A (ja) | 1999-10-19 | 2003-04-02 | メルク エンド カムパニー インコーポレーテッド | チロシンキナーゼ阻害剤 |
DE60017179T2 (de) | 1999-10-19 | 2006-01-05 | Merck & Co., Inc. | Tyrosin kinaseinhibitoren |
US6420382B2 (en) | 2000-02-25 | 2002-07-16 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
US6313138B1 (en) | 2000-02-25 | 2001-11-06 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
US7219016B2 (en) | 2001-04-20 | 2007-05-15 | Yale University | Systems and methods for automated analysis of cells and tissues |
US20030049696A1 (en) * | 2001-06-07 | 2003-03-13 | Norment Anne M. | Regulatory T cells and uses thereof |
ES2255621T3 (es) | 2001-06-22 | 2006-07-01 | MERCK & CO., INC. | Inhibidores de tirosina quinasa. |
WO2003011836A1 (en) | 2001-08-01 | 2003-02-13 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
WO2003020276A1 (en) | 2001-08-30 | 2003-03-13 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
CA2466279A1 (en) | 2001-11-13 | 2003-05-22 | Dana-Farber Cancer Institute, Inc. | Agents that modulate immune cell activation and methods of use thereof |
CA2508660C (en) | 2002-12-23 | 2013-08-20 | Wyeth | Antibodies against pd-1 and uses therefor |
GB0229734D0 (en) | 2002-12-23 | 2003-01-29 | Qinetiq Ltd | Grading oestrogen and progesterone receptors expression |
US7257268B2 (en) | 2003-02-28 | 2007-08-14 | Aperio Technologies, Inc. | Systems and methods for image pattern recognition |
SI2439273T1 (sl) | 2005-05-09 | 2019-05-31 | Ono Pharmaceutical Co., Ltd. | Človeška monoklonska protitelesa za programirano smrt 1 (PD-1) in postopki za zdravljenje raka z uporabo protiteles proti PD-1 samostojno ali v kombinaciji z ostalimi imunoterapevtiki |
CN101248089A (zh) | 2005-07-01 | 2008-08-20 | 米德列斯公司 | 抗程序性死亡配体1(pd-l1)的人单克隆抗体 |
WO2007109571A2 (en) | 2006-03-17 | 2007-09-27 | Prometheus Laboratories, Inc. | Methods of predicting and monitoring tyrosine kinase inhibitor therapy |
US8023714B2 (en) | 2007-06-06 | 2011-09-20 | Aperio Technologies, Inc. | System and method for assessing image interpretability in anatomic pathology |
KR101586617B1 (ko) | 2007-06-18 | 2016-01-20 | 머크 샤프 앤 도메 비.브이. | 사람 프로그램된 사멸 수용체 pd-1에 대한 항체 |
EP2262837A4 (en) | 2008-03-12 | 2011-04-06 | Merck Sharp & Dohme | PD-1 BINDING PROTEINS |
CA2737116C (en) | 2008-09-16 | 2019-01-15 | Historx, Inc. | Reproducible quantification of biomarker expression |
SI2342226T1 (sl) | 2008-09-26 | 2016-11-30 | Dana-Farber Cancer Institute Inc. | Humana protitelesa proti PD-1, PD-L1 in PD-L2 in njihove uporabe |
UA109108C2 (uk) | 2008-12-09 | 2015-07-27 | Дженентек, Інк. | Антитіло до pd-l1 та його застосування для посилення функції t-клітин |
ES2629337T3 (es) | 2009-02-09 | 2017-08-08 | Inserm - Institut National De La Santé Et De La Recherche Médicale | Anticuerpos contra PD-1 y anticuerpos contra PD-L1 y usos de los mismos |
US20110111435A1 (en) | 2009-11-06 | 2011-05-12 | SlidePath Limited | Detecting Cell Surface Markers |
US20130017199A1 (en) | 2009-11-24 | 2013-01-17 | AMPLIMMUNE ,Inc. a corporation | Simultaneous inhibition of pd-l1/pd-l2 |
US20130022629A1 (en) | 2010-01-04 | 2013-01-24 | Sharpe Arlene H | Modulators of Immunoinhibitory Receptor PD-1, and Methods of Use Thereof |
JP2013532153A (ja) | 2010-06-18 | 2013-08-15 | ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッド | 慢性免疫病に対する免疫治療のためのtim−3およびpd−1に対する二重特異性抗体 |
US8907053B2 (en) | 2010-06-25 | 2014-12-09 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
-
2016
- 2016-08-26 US US15/754,640 patent/US11385231B2/en active Active
- 2016-08-26 ES ES16757251T patent/ES2955775T3/es active Active
- 2016-08-26 WO PCT/EP2016/070158 patent/WO2017032867A1/en active Application Filing
- 2016-08-26 JP JP2018510472A patent/JP6791951B2/ja active Active
- 2016-08-26 EP EP16757251.0A patent/EP3341732B1/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012038068A2 (en) * | 2010-09-24 | 2012-03-29 | Niels Grabe | Means and methods for the prediction of treatment response of a cancer patient |
JP2015505607A (ja) * | 2012-01-20 | 2015-02-23 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | B細胞の密度に基づいて、固形癌に苦しむ患者の生存時間を予測するための方法 |
JP2015505608A (ja) * | 2012-01-20 | 2015-02-23 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 固形ガンを患う患者の生存期間の予後診断のための方法 |
WO2015007625A1 (en) * | 2013-07-15 | 2015-01-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for the prognosis of survival time of a patient suffering from a solid cancer |
Non-Patent Citations (8)
Title |
---|
C GERMAIN ET AL.: "Presence of B Cells in Tertiary Lymphoid Structures Is Associated with a Protective Immunity in Pati", AM. J. RESPIR. CRIT. CARE MED., vol. 189, no. 7, JPN6020012952, 2014, pages 832 - 844, XP093064331, ISSN: 0004247178, DOI: 10.1164/rccm.201309-1611OC * |
CATHERINE SAUTES-FRIDMAN ET AL.: "TUMOR MICROENVIRONMENT IS MULTIFACETED", CANCER AND METASTASIS REVIEWS, vol. VOL:30, NR:1, JPN5018005385, 28 January 2011 (2011-01-28), DO, pages 13 - 25, ISSN: 0004247177 * |
GEREMY GOC ET AL.: "Dendric Cells in Tumor-Associated Tertiary lymphoid Structures Signal a Th1 Cytotoxic Immune Context", CANCER RES., vol. 74, no. 3, JPN6020012944, 2014, pages 705 - 715, ISSN: 0004247181 * |
HIROYUKI TAO ET AL.: "Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-inf", LUNG CANCER, vol. 75, no. 1, JPN6020012950, 2012, pages 95 - 101, XP028393812, ISSN: 0004247176, DOI: 10.1016/j.lungcan.2011.06.002 * |
K HIRAOKA ET AL.: "Concurrent infiltraion by CD8+ T Cells and CD4+ T Cells is a favourable prognostic factor in non-sma", BRITISH JOURNAL OF CANCER, vol. 94, no. 2, JPN6020012942, 2006, pages 275 - 280, ISSN: 0004247180 * |
KATSUHIKO SHIMIZU ET AL.: "Tumor-Infiltrating Foxp3+ Regulatory T cells are Correlated with Cyclooxygenase-2 Expression and are", J. THORAC. ONCOL., vol. 5, JPN6020012948, 2010, pages 585 - 590, ISSN: 0004247175 * |
W.H.FRIDMAN ET AL.: "Immune Infiltration in Human Cancer: Prognostic Significance and Disease Control", CURR. TOP. MICROBIOL. IMMUNOL., vol. 344, JPN6020012953, 2011, pages 1 - 24, XP009158913, ISSN: 0004247179 * |
木下智成ほか: "肺腺癌における間質に浸潤する制御性T細胞の意義", 肺癌, vol. 52, no. 5, JPN6020012946, 5 October 2012 (2012-10-05), pages 624, ISSN: 0004247174 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020171141A1 (ja) * | 2019-02-20 | 2020-08-27 | 学校法人 埼玉医科大学 | がん免疫療法における長期生存を予測するための方法および組成物 |
Also Published As
Publication number | Publication date |
---|---|
ES2955775T3 (es) | 2023-12-07 |
WO2017032867A1 (en) | 2017-03-02 |
EP3341732B1 (en) | 2023-07-12 |
JP6791951B2 (ja) | 2020-11-25 |
EP3341732A1 (en) | 2018-07-04 |
US20180252720A1 (en) | 2018-09-06 |
US11385231B2 (en) | 2022-07-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Gide et al. | Distinct immune cell populations define response to anti-PD-1 monotherapy and anti-PD-1/anti-CTLA-4 combined therapy | |
Gorchs et al. | Human pancreatic carcinoma-associated fibroblasts promote expression of co-inhibitory markers on CD4+ and CD8+ T-cells | |
Tobin et al. | IL-6 and IL-8 are linked with myeloid-derived suppressor cell accumulation and correlate with poor clinical outcomes in melanoma patients | |
Huang et al. | S100A9 regulates MDSCs-mediated immune suppression via the RAGE and TLR4 signaling pathways in colorectal carcinoma | |
Halama et al. | Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients | |
Outh-Gauer et al. | Immunotherapy in head and neck cancers: a new challenge for immunologists, pathologists and clinicians | |
US20220041994A1 (en) | Methods to preserve tumor-stromal interactions in culture and therapeutic predictive applications thereof | |
Levitsky et al. | Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients | |
CN109844536B (zh) | 预测对pd-1轴抑制剂的响应 | |
US10969392B2 (en) | Methods and systems for predicting response to immunotherapies for treatment of cancer | |
CN110678750A (zh) | 用于癌症治疗的生物标志物 | |
US20190284640A1 (en) | Methods and Systems for Predicting Response to Immunotherapies for Treatment of Cancer | |
JP6791951B2 (ja) | 肺ガンを患っている患者の生存時間を予測するための方法 | |
EP3400443B1 (en) | Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma | |
Xu et al. | Biochanin A suppresses tumor progression and PD-L1 expression via inhibiting ZEB1 expression in colorectal cancer | |
Somasundaram et al. | Systemic immune dysfunction in cancer patients driven by IL6 induction of LAG3 in peripheral CD8+ T cells | |
Page et al. | A phase Ib study of preoperative, locoregional IRX-2 cytokine immunotherapy to prime immune responses in patients with early-stage breast cancer | |
Heger et al. | Unbiased high-dimensional flow cytometry identified NK and DC immune cell signature in Luminal A-type and triple negative breast cancer | |
Qin et al. | Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: Challenges and opportunities | |
Yang | Upregulation of CD112R (PVRIG) and PD-1 on cytotoxic T-cells located in T-cell niche of colorectal cancer | |
US11573234B2 (en) | Predicting responders to cyclophosphamide therapy | |
Menjivar | Arginase 1 is a Key Driver of Immune Suppression and a Therapeutic Target of Pancreatic Cancer | |
Melero et al. | Neutralizing GDF-15 can overcome anti-PD-(L) 1 resistance in late-stage cancer | |
CN116710475A (zh) | Sqstm1及其在癌症疗法中的用途 | |
SAKREF et al. | IFN-III primes pDCs for TLR7 activation and antagonizes TGF-β mediated-immune suppression in tumors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190617 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20200325 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200407 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200706 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20201006 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20201105 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6791951 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313115 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
S633 | Written request for registration of reclamation of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313633 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |