JP7429539B2 - 薬効を評価するためのシステム及び方法 - Google Patents
薬効を評価するためのシステム及び方法 Download PDFInfo
- Publication number
- JP7429539B2 JP7429539B2 JP2019566271A JP2019566271A JP7429539B2 JP 7429539 B2 JP7429539 B2 JP 7429539B2 JP 2019566271 A JP2019566271 A JP 2019566271A JP 2019566271 A JP2019566271 A JP 2019566271A JP 7429539 B2 JP7429539 B2 JP 7429539B2
- Authority
- JP
- Japan
- Prior art keywords
- expression
- feature
- training
- machine learning
- trained
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims description 72
- 239000003814 drug Substances 0.000 title 1
- 229940079593 drug Drugs 0.000 title 1
- 230000014509 gene expression Effects 0.000 claims description 182
- 238000010801 machine learning Methods 0.000 claims description 162
- 230000004043 responsiveness Effects 0.000 claims description 162
- 238000012549 training Methods 0.000 claims description 161
- 206010028980 Neoplasm Diseases 0.000 claims description 125
- 238000011282 treatment Methods 0.000 claims description 116
- 108090000623 proteins and genes Proteins 0.000 claims description 89
- 210000004027 cell Anatomy 0.000 claims description 70
- 230000005746 immune checkpoint blockade Effects 0.000 claims description 70
- 230000036438 mutation frequency Effects 0.000 claims description 45
- 239000000427 antigen Substances 0.000 claims description 44
- 108091007433 antigens Proteins 0.000 claims description 44
- 102000036639 antigens Human genes 0.000 claims description 44
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 27
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 27
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims description 26
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 23
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 23
- 238000007637 random forest analysis Methods 0.000 claims description 16
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 14
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 14
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims description 14
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 12
- 102100027581 Forkhead box protein P3 Human genes 0.000 claims description 12
- 101000861452 Homo sapiens Forkhead box protein P3 Proteins 0.000 claims description 12
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 claims description 12
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 claims description 12
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 12
- 102000004503 Perforin Human genes 0.000 claims description 12
- 108010056995 Perforin Proteins 0.000 claims description 12
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 claims description 12
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 12
- 101710084225 Proteasome subunit beta type-10 Proteins 0.000 claims description 12
- 102100029081 Proteasome subunit beta type-10 Human genes 0.000 claims description 12
- 108010044012 STAT1 Transcription Factor Proteins 0.000 claims description 12
- 102100029904 Signal transducer and activator of transcription 1-alpha/beta Human genes 0.000 claims description 12
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 claims description 12
- 101710090983 T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 claims description 12
- 102000015736 beta 2-Microglobulin Human genes 0.000 claims description 12
- 108010081355 beta 2-Microglobulin Proteins 0.000 claims description 12
- 230000008595 infiltration Effects 0.000 claims description 12
- 238000001764 infiltration Methods 0.000 claims description 12
- 230000015654 memory Effects 0.000 claims description 11
- 102000001398 Granzyme Human genes 0.000 claims description 10
- 108060005986 Granzyme Proteins 0.000 claims description 10
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 claims description 10
- 101000986086 Homo sapiens HLA class I histocompatibility antigen, A alpha chain Proteins 0.000 claims description 10
- 102000005962 receptors Human genes 0.000 claims description 9
- 108020003175 receptors Proteins 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- HBBOZFUQJDYASD-LPHOMBEVSA-N alpha-L-Fucp-(1->3)-[beta-D-Galp-(1->4)]-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O HBBOZFUQJDYASD-LPHOMBEVSA-N 0.000 claims description 8
- 101000979599 Homo sapiens Protein NKG7 Proteins 0.000 claims description 7
- 102100023370 Protein NKG7 Human genes 0.000 claims description 7
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 claims description 7
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 102100030346 Antigen peptide transporter 1 Human genes 0.000 claims description 6
- 102100027207 CD27 antigen Human genes 0.000 claims description 6
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 claims description 6
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 claims description 6
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 claims description 6
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 claims description 6
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 6
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 claims description 6
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 claims description 6
- 101001100327 Homo sapiens RNA-binding protein 45 Proteins 0.000 claims description 6
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 claims description 6
- 108010032774 Interleukin-2 Receptor alpha Subunit Proteins 0.000 claims description 6
- 102000007351 Interleukin-2 Receptor alpha Subunit Human genes 0.000 claims description 6
- 102000043131 MHC class II family Human genes 0.000 claims description 6
- 108091054438 MHC class II family Proteins 0.000 claims description 6
- 108010023335 Member 2 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 claims description 6
- 102100038823 RNA-binding protein 45 Human genes 0.000 claims description 6
- 108010029180 Sialic Acid Binding Ig-like Lectin 3 Proteins 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 102100030343 Antigen peptide transporter 2 Human genes 0.000 claims description 5
- 108010023338 Member 3 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 claims description 5
- 238000010199 gene set enrichment analysis Methods 0.000 claims description 5
- 230000000890 antigenic effect Effects 0.000 claims description 4
- 239000003086 colorant Substances 0.000 claims description 4
- 230000034994 death Effects 0.000 claims description 2
- 102000019034 Chemokines Human genes 0.000 claims 4
- 108010012236 Chemokines Proteins 0.000 claims 4
- 108700018351 Major Histocompatibility Complex Proteins 0.000 claims 4
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 claims 4
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 claims 4
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 claims 2
- 102000009410 Chemokine receptor Human genes 0.000 claims 2
- 108050000299 Chemokine receptor Proteins 0.000 claims 2
- 102100030386 Granzyme A Human genes 0.000 claims 2
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 claims 2
- 101001009599 Homo sapiens Granzyme A Proteins 0.000 claims 2
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims 2
- 230000035772 mutation Effects 0.000 description 52
- 230000004044 response Effects 0.000 description 47
- 239000000523 sample Substances 0.000 description 34
- 210000004881 tumor cell Anatomy 0.000 description 33
- 102000004169 proteins and genes Human genes 0.000 description 29
- 238000002560 therapeutic procedure Methods 0.000 description 29
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 28
- 230000000670 limiting effect Effects 0.000 description 28
- 230000037361 pathway Effects 0.000 description 27
- 230000002596 correlated effect Effects 0.000 description 21
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 19
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 19
- 230000004048 modification Effects 0.000 description 18
- 238000012986 modification Methods 0.000 description 18
- 230000030741 antigen processing and presentation Effects 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 16
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 16
- 210000001744 T-lymphocyte Anatomy 0.000 description 15
- 210000004698 lymphocyte Anatomy 0.000 description 15
- 210000000987 immune system Anatomy 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 12
- 238000010586 diagram Methods 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 102000008070 Interferon-gamma Human genes 0.000 description 9
- 108010074328 Interferon-gamma Proteins 0.000 description 9
- 229960003130 interferon gamma Drugs 0.000 description 9
- 230000005055 memory storage Effects 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 8
- 102100025618 C-X-C chemokine receptor type 6 Human genes 0.000 description 8
- 102000016937 Chemokine CXCL9 Human genes 0.000 description 8
- 108010014231 Chemokine CXCL9 Proteins 0.000 description 8
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 8
- 101000856683 Homo sapiens C-X-C chemokine receptor type 6 Proteins 0.000 description 8
- 102000043129 MHC class I family Human genes 0.000 description 8
- 108091054437 MHC class I family Proteins 0.000 description 8
- 102000043850 Programmed Cell Death 1 Ligand 2 Human genes 0.000 description 8
- 238000009825 accumulation Methods 0.000 description 8
- 125000003275 alpha amino acid group Chemical group 0.000 description 8
- 230000000875 corresponding effect Effects 0.000 description 8
- 238000003066 decision tree Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 210000000822 natural killer cell Anatomy 0.000 description 8
- 239000002773 nucleotide Substances 0.000 description 8
- 125000003729 nucleotide group Chemical group 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 7
- 238000013518 transcription Methods 0.000 description 7
- 230000035897 transcription Effects 0.000 description 7
- 102100031011 Chemerin-like receptor 1 Human genes 0.000 description 6
- 108700038876 Chemerin-like receptor 1 Proteins 0.000 description 6
- 101150001828 Cmklr1 gene Proteins 0.000 description 6
- 230000005975 antitumor immune response Effects 0.000 description 6
- 238000002619 cancer immunotherapy Methods 0.000 description 6
- 230000001461 cytolytic effect Effects 0.000 description 6
- 238000009169 immunotherapy Methods 0.000 description 6
- 238000007481 next generation sequencing Methods 0.000 description 6
- 210000003289 regulatory T cell Anatomy 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000007482 whole exome sequencing Methods 0.000 description 6
- 238000002790 cross-validation Methods 0.000 description 5
- 210000002865 immune cell Anatomy 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000013519 translation Methods 0.000 description 5
- 108020004705 Codon Proteins 0.000 description 4
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 4
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 4
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 4
- 238000003559 RNA-seq method Methods 0.000 description 4
- 108091081024 Start codon Proteins 0.000 description 4
- 206010064390 Tumour invasion Diseases 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000009400 cancer invasion Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 230000037433 frameshift Effects 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 208000021039 metastatic melanoma Diseases 0.000 description 4
- 210000004882 non-tumor cell Anatomy 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108020004485 Nonsense Codon Proteins 0.000 description 3
- 108700009124 Transcription Initiation Site Proteins 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000004640 cellular pathway Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 230000008004 immune attack Effects 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 229960005386 ipilimumab Drugs 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 238000001565 modulated differential scanning calorimetry Methods 0.000 description 3
- 230000003990 molecular pathway Effects 0.000 description 3
- 229960003301 nivolumab Drugs 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- HOZCHTFDGMSKNK-UHFFFAOYSA-N 6-methylspiro[4.5]dec-9-ene-10-carboxylic acid Chemical compound CC1CCC=C(C(O)=O)C11CCCC1 HOZCHTFDGMSKNK-UHFFFAOYSA-N 0.000 description 2
- 206010057248 Cell death Diseases 0.000 description 2
- 230000008836 DNA modification Effects 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- 206010062049 Lymphocytic infiltration Diseases 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 101100182935 Penicillium citrinum MSDC gene Proteins 0.000 description 2
- 108020004566 Transfer RNA Proteins 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960003852 atezolizumab Drugs 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 231100000221 frame shift mutation induction Toxicity 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000037434 nonsense mutation Effects 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229960002621 pembrolizumab Drugs 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000037436 splice-site mutation Effects 0.000 description 2
- 238000013456 study Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 101000665442 Homo sapiens Serine/threonine-protein kinase TBK1 Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 101000760337 Homo sapiens Urokinase plasminogen activator surface receptor Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 108091092724 Noncoding DNA Proteins 0.000 description 1
- 102000004020 Oxygenases Human genes 0.000 description 1
- 108090000417 Oxygenases Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 108091006593 SLC15A2 Proteins 0.000 description 1
- 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 102100021488 Solute carrier family 15 member 2 Human genes 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102100024689 Urokinase plasminogen activator surface receptor Human genes 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 229940121420 cemiplimab Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013500 data storage Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005315 distribution function Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000556 factor analysis Methods 0.000 description 1
- 238000003500 gene array Methods 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 230000008826 genomic mutation Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000000059 patterning Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000003498 protein array Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012706 support-vector machine Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000012070 whole genome sequencing analysis Methods 0.000 description 1
- 238000012049 whole transcriptome sequencing Methods 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- G16B40/20—Supervised data analysis
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N20/00—Machine learning
- G06N20/20—Ensemble learning
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N5/00—Computing arrangements using knowledge-based models
- G06N5/01—Dynamic search techniques; Heuristics; Dynamic trees; Branch-and-bound
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B45/00—ICT specially adapted for bioinformatics-related data visualisation, e.g. displaying of maps or networks
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N20/00—Machine learning
- G06N20/10—Machine learning using kernel methods, e.g. support vector machines [SVM]
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N3/00—Computing arrangements based on biological models
- G06N3/02—Neural networks
Landscapes
- Engineering & Computer Science (AREA)
- Theoretical Computer Science (AREA)
- Physics & Mathematics (AREA)
- Software Systems (AREA)
- Data Mining & Analysis (AREA)
- Medical Informatics (AREA)
- Artificial Intelligence (AREA)
- Evolutionary Computation (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Mathematical Physics (AREA)
- General Engineering & Computer Science (AREA)
- Computing Systems (AREA)
- Computer Vision & Pattern Recognition (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Evolutionary Biology (AREA)
- Biotechnology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Bioinformatics & Computational Biology (AREA)
- Computational Linguistics (AREA)
- Bioethics (AREA)
- Databases & Information Systems (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Image Analysis (AREA)
- Measuring And Recording Apparatus For Diagnosis (AREA)
- Peptides Or Proteins (AREA)
Description
本出願は、2017年12月1日出願の米国仮特許出願第62/593,802号の優先権を主張し、その全内容をこれにより本明細書に組み込む。
SRA SRP067938
SRA SRP090294
dbGaP phs000452.v2.pl
Claims (27)
- 訓練した機械学習分類器に非訓練対象のゲノム情報を入力する工程であって、非訓練対象のゲノム情報が、非訓練対象から得られる腫瘍プロファイル由来の特徴を含み、
訓練した機械学習分類器が、複数の訓練対象のゲノム情報、及びチェックポイント阻害を含む治療に対する複数の訓練対象のそれぞれの応答性について訓練され、複数の訓練対象のゲノム情報が、複数の訓練対象のそれぞれから得られる腫瘍プロファイルの特徴を含み、機械学習分類器が、治療に対する応答性を予測するように訓練される、工程と、
訓練した機械学習分類器を使用して、非訓練対象についてチェックポイント阻害応答性分類を生成する工程であって、チェックポイント阻害応答性分類が、非訓練対象がチェックポイント阻害に対して応答することを予測する、工程と、
非訓練対象のチェックポイント阻害応答性分類を、グラフィカルユーザインターフェースを使用してレポートする工程と
を含む、コンピュータ実行方法であって、
非訓練対象から得られる腫瘍プロファイル由来の特徴の少なくとも一部、又は訓練対象の1人又は複数から得られる腫瘍プロファイル由来の特徴の少なくとも一部が、すべての変異からなる総変異頻度、非同義変異からなる総変異頻度、ベータ2ミクログロブリン(B2M)発現、プロテアソームサブユニットベータ10(PSMB10)発現、抗原ペプチドトランスミッター1(TAP1)発現、抗原ペプチド輸送体2(TAP2)発現、ヒト白血球抗原A(HLA-A)発現、主要組織適合複合体クラスI B(HLA-B)発現、主要組織適合複合体クラスI C(HLA-C)発現、主要組織適合複合体クラスII DQアルファ1(HLA-DQA1)発現、HLAクラスII組織適合抗原DRB1ベータ鎖(HLA-DRB1)発現、HLAクラスI組織適合抗原アルファ鎖E(HLA-E)発現、ナチュラルキラー細胞顆粒タンパク質7(NKG7)発現、ケモカイン様受容体(CMKLR1)発現、表面抗原分類8(CD8)を発現する細胞による腫瘍浸潤、表面抗原分類4(CD4)を発現する細胞による腫瘍浸潤、表面抗原分類19(CD19)を発現する細胞による腫瘍浸潤、グランザイムA(GZMA)発現、パーフォリン1(PRF1)発現、プログラム細胞死1リガンド2(PDL2)発現、リンパ球活性化遺伝子3(LAG3)発現、Ig及びITIMドメインを有するT細胞免疫受容体(TIGIT)発現、表面抗原分類276(CD276)発現、ケモカイン(C-Cモチーフ)リガンド5(CCL5)、CD27発現、ケモカイン(C-X-Cモチーフ)リガンド9(CXCL9)発現、C-X-Cモチーフケモカイン受容体6(CXCR6)、インドールアミン2,3-ジオキシゲナーゼ(IDO)発現、シグナル伝達兼転写活性化因子1(STAT1)発現、3-フコシル-N-アセチル-ラクトサミン(CD15)発現、インターロイキン2受容体アルファ鎖(CD25)発現、siglec-3(CD33)、表面抗原分類39(CD39)発現、表面抗原分類118(CD118)発現、フォークヘッドボックスP3(FOXP3)発現、及び前述の2つ以上の任意の組合せからなる群から選択される、コンピュータ実行方法。 - 非訓練対象から得られる腫瘍プロファイル由来の特徴の少なくとも一部、又は訓練対象の1人又は複数から得られる腫瘍プロファイル由来の特徴の少なくとも一部が、細胞傷害性Tリンパ球関連タンパク質4(CTLA4)発現、プログラム細胞死タンパク質1(PD1)発現、もしくはプログラム死リガンド1(PDL1)発現の一つ又は複数をさらに含む、請求項1に記載の方法。
- 訓練特徴の少なくとも一部、又は非訓練特徴の少なくとも一部が、遺伝子セットを含む、請求項1に記載の方法。
- 遺伝子セットが、単一サンプル遺伝子セットの濃縮解析を使用して選択された、請求項3に記載の方法。
- 機械学習分類器が、ランダムフォレストである、請求項1に記載の方法。
- 少なくとも50,000の木が、機械学習分類器の訓練において使用される、請求項5に記載の方法。
- チェックポイント阻害応答性分類が、予測スコア及び1つ又は複数の特徴識別子を含み、1つ又は複数の特徴識別子が、特徴価、特徴重要度、及び特徴重みからなる群から選択される、請求項1に記載の方法。
- グラフィカルユーザインターフェースが、特徴識別子を環状扇形の各側面としてレポートし、環状扇形の角度が特徴重要度をレポートし、環状扇形の外半径が特徴重みをレポートし、環状扇形の色が特徴価をレポートする、請求項7に記載の方法。
- 特徴の特徴重要度が、特徴のジニ指数の減少を含む、請求項8に記載の方法。
- グラフィカルユーザインターフェースが、特徴の特徴重要度が閾値を超える場合かつその場合に限り、特徴の識別子をレポートする、請求項9に記載の方法。
- 特徴の特徴重要度が、特徴の特徴重要度の2乗が0.1を超えない場合、閾値を超えない、請求項10に記載の方法。
- 各環状扇形が内弧を含み、環状扇形の内弧が円を形成するように配置される、請求項10に記載の方法。
- 治療に対する非訓練対象の応答性を、訓練した機械学習分類器に入力する工程と、機械学習分類器を更に訓練する工程とを更に含み、更に訓練する工程が、訓練した機械学習分類器を、非訓練対象から得られる腫瘍試料の特徴、及び治療に対する非訓練対象の応答性について訓練することを含む、請求項1に記載の方法。
- 生成されたチェックポイント阻害応答性分類に基づいて治療を選択する工程を更に含む、請求項1に記載の方法。
- 1つ又は複数のマイクロプロセッサと、
訓練した機械学習分類器、及び非訓練対象のゲノム情報を記憶するための1つ又は複数のメモリであって、訓練した機械学習分類器が、複数の訓練対象のゲノム情報、及びチェックポイント阻害を含む治療に対する複数の訓練対象のそれぞれの応答性について訓練され、複数の訓練対象のゲノム情報が、複数の訓練対象のそれぞれから得られる腫瘍プロファイルの特徴を含み、機械学習分類器が、治療に対する応答性を予測するように訓練され、非訓練対象のゲノム情報が、非訓練対象から得られる腫瘍プロファイル由来の特徴を含む、メモリと
を含むコンピュータシステムであって、
1つ又は複数のメモリが、1つ又は複数のマイクロプロセッサにより実行される場合、コンピュータシステムに、訓練した機械学習分類器を使用してチェックポイント阻害応答性分類を非訓練対象について生成させ、非訓練対象のチェックポイント阻害応答性分類を、グラフィカルユーザインターフェースを使用してレポートさせる、命令を記憶し、前記チェックポイント阻害応答性分類が、非訓練対象がチェックポイント阻害に対して応答することを予測し、
非訓練対象から得られる腫瘍プロファイル由来の特徴の少なくとも一部、又は訓練対象の1人又は複数から得られる腫瘍プロファイル由来の特徴の少なくとも一部が、すべての変異からなる総変異頻度、非同義変異からなる総変異頻度、ベータ2ミクログロブリン(B2M)発現、プロテアソームサブユニットベータ10(PSMB10)発現、抗原ペプチドトランスミッター1(TAP1)発現、抗原ペプチド輸送体2(TAP2)発現、ヒト白血球抗原A(HLA-A)発現、主要組織適合複合体クラスI B(HLA-B)発現、主要組織適合複合体クラスI C(HLA-C)発現、主要組織適合複合体クラスII DQアルファ1(HLA-DQA1)発現、HLAクラスII組織適合抗原DRB1ベータ鎖(HLA-DRB1)発現、HLAクラスI組織適合抗原アルファ鎖E(HLA-E)発現、ナチュラルキラー細胞顆粒タンパク質7(NKG7)発現、ケモカイン様受容体(CMKLR1)発現、表面抗原分類8(CD8)を発現する細胞による腫瘍浸潤、表面抗原分類4(CD4)を発現する細胞による腫瘍浸潤、表面抗原分類19(CD19)を発現する細胞による腫瘍浸潤、グランザイムA(GZMA)発現、パーフォリン1(PRF1)発現、プログラム細胞死1リガンド2(PDL2)発現、リンパ球活性化遺伝子3(LAG3)発現、Ig及びITIMドメインを有するT細胞免疫受容体(TIGIT)発現、表面抗原分類276(CD276)発現、ケモカイン(C-Cモチーフ)リガンド5(CCL5)、CD27発現、ケモカイン(C-X-Cモチーフ)リガンド9(CXCL9)発現、C-X-Cモチーフケモカイン受容体6(CXCR6)、インドールアミン2,3-ジオキシゲナーゼ(IDO)発現、シグナル伝達兼転写活性化因子1(STAT1)発現、3-フコシル-N-アセチル-ラクトサミン(CD15)発現、インターロイキン2受容体アルファ鎖(CD25)発現、siglec-3(CD33)、表面抗原分類39(CD39)発現、表面抗原分類118(CD118)発現、フォークヘッドボックスP3(FOXP3)発現、及び前述の2つ以上の任意の組合せからなる群から選択される、コンピュータシステム。 - 非訓練対象から得られる腫瘍プロファイル由来の特徴の少なくとも一部、又は訓練対象の1人若しくは複数から得られる腫瘍プロファイル由来の特徴の少なくとも一部が、細胞傷害性Tリンパ球関連タンパク質4(CTLA4)発現、プログラム細胞死タンパク質1(PD1)発現、もしくはプログラム死リガンド1(PDL1)発現の一つ又は複数をさらに含む、請求項15に記載のシステム。
- 訓練特徴の少なくとも一部、又は非訓練特徴の少なくとも一部が、遺伝子セットを含む、請求項15に記載のシステム。
- 遺伝子セットが、単一サンプル遺伝子セットの濃縮解析を使用して選択された、請求項17に記載のシステム。
- 機械学習分類器が、ランダムフォレストである、請求項15に記載のシステム。
- 少なくとも50,000の木が、機械学習分類器の訓練において使用される、請求項19に記載のシステム。
- チェックポイント阻害応答性分類が、予測スコア及び1つ又は複数の特徴識別子を含み、1つ又は複数の特徴識別子が、特徴価、特徴重要度、及び特徴重みからなる群から選択される、請求項15に記載のシステム。
- 命令が、1つ又は複数のマイクロプロセッサにより実行される場合、グラフィカルユーザインターフェースに特徴識別子を環状扇形の各側面としてレポートさせ、環状扇形の角度が特徴重要度をレポートし、環状扇形の外半径が特徴重みをレポートし、環状扇形の色が特徴価をレポートする、請求項21に記載のシステム。
- 特徴の特徴重要度が、特徴のジニ指数の減少を含む、請求項22に記載のシステム。
- 命令が、1つ又は複数のマイクロプロセッサにより実行される場合、グラフィカルユーザインターフェースに、特徴の特徴重要度が閾値を超える場合かつその場合に限り、特徴の識別子をレポートさせる、請求項23に記載のシステム。
- 特徴の特徴重要度が、特徴の特徴重要度の2乗が0.1を超えない場合、閾値を超えない、請求項24に記載のシステム。
- 命令が、1つ又は複数のマイクロプロセッサにより実行される場合、グラフィカルユーザインターフェースに、各環状扇形の内弧、及び環状扇形の内弧を含む円をレポートさせる、請求項24に記載のシステム。
- 命令が、1つ又は複数のマイクロプロセッサにより実行される場合、コンピュータシステムに機械学習分類器を更に訓練させ、更に訓練させることが、訓練した機械学習分類器を、非訓練対象から得られる腫瘍試料の特徴、及び治療に対する非訓練対象の応答性について訓練することを含む、請求項15に記載のシステム。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762593802P | 2017-12-01 | 2017-12-01 | |
US62/593,802 | 2017-12-01 | ||
PCT/US2018/063658 WO2019109089A1 (en) | 2017-12-01 | 2018-12-03 | Systems and methods for assessing drug efficacy |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021505976A JP2021505976A (ja) | 2021-02-18 |
JP7429539B2 true JP7429539B2 (ja) | 2024-02-08 |
Family
ID=64734247
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019566271A Active JP7429539B2 (ja) | 2017-12-01 | 2018-12-03 | 薬効を評価するためのシステム及び方法 |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP3616205A1 (ja) |
JP (1) | JP7429539B2 (ja) |
KR (1) | KR20200093437A (ja) |
CN (1) | CN110678930B (ja) |
AU (1) | AU2018375214A1 (ja) |
BR (1) | BR112019024537A2 (ja) |
CA (1) | CA3061736A1 (ja) |
MX (1) | MX2019014285A (ja) |
SG (1) | SG11201910041WA (ja) |
WO (1) | WO2019109089A1 (ja) |
ZA (1) | ZA201907298B (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111640508B (zh) * | 2020-05-28 | 2023-08-01 | 上海市生物医药技术研究院 | 基于高通量测序数据和临床表型构建的泛肿瘤靶向药敏感性状态评估模型的方法及应用 |
CN111863126B (zh) * | 2020-05-28 | 2024-03-26 | 上海市生物医药技术研究院 | 构建结直肠肿瘤状态评估模型的方法及应用 |
CN111755073B (zh) * | 2020-05-31 | 2022-11-15 | 复旦大学 | 基于转录组的pd-1疗法治疗效果预测系统 |
CN113095440B (zh) * | 2020-09-01 | 2022-05-17 | 电子科技大学 | 基于元学习者的训练数据生成方法及因果效应异质反应差异估计方法 |
AU2022327751A1 (en) * | 2021-08-11 | 2024-03-21 | OncoHost Ltd. | Predicting patient response |
CN114694745A (zh) * | 2022-03-24 | 2022-07-01 | 至本医疗科技(上海)有限公司 | 预测免疫疗效的方法、装置、计算机设备和存储介质 |
WO2023230321A1 (en) * | 2022-05-27 | 2023-11-30 | Cofactor Genomics, Inc. | Machine learning systems and methods for gene set enrichment analysis and scoring |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015184061A2 (en) | 2014-05-28 | 2015-12-03 | Dana-Farber Cancer Institute, Inc. | Activating jak kinase biomarkers predictive of anti-immune checkpoint inhibitor response |
WO2017167942A1 (en) | 2016-03-31 | 2017-10-05 | Pamgene Bv | Method for predicting the response of melanoma patients to a medicament |
WO2017201165A1 (en) | 2016-05-17 | 2017-11-23 | Genecentric Diagnostics, Inc. | Methods for subtyping of lung adenocarcinoma |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110106740A1 (en) * | 2002-05-24 | 2011-05-05 | University Of South Florida | Tissue classification method for diagnosis and treatment of tumors |
CN104573410A (zh) * | 2015-01-20 | 2015-04-29 | 合肥工业大学 | 基于分子子网与随机森林分类器的癌症化疗敏感性预测方法 |
-
2018
- 2018-12-03 CA CA3061736A patent/CA3061736A1/en active Pending
- 2018-12-03 BR BR112019024537A patent/BR112019024537A2/pt unknown
- 2018-12-03 EP EP18821929.9A patent/EP3616205A1/en active Pending
- 2018-12-03 WO PCT/US2018/063658 patent/WO2019109089A1/en unknown
- 2018-12-03 KR KR1020197035545A patent/KR20200093437A/ko active Search and Examination
- 2018-12-03 MX MX2019014285A patent/MX2019014285A/es unknown
- 2018-12-03 CN CN201880036325.1A patent/CN110678930B/zh active Active
- 2018-12-03 AU AU2018375214A patent/AU2018375214A1/en active Pending
- 2018-12-03 SG SG11201910041W patent/SG11201910041WA/en unknown
- 2018-12-03 JP JP2019566271A patent/JP7429539B2/ja active Active
-
2019
- 2019-11-04 ZA ZA2019/07298A patent/ZA201907298B/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015184061A2 (en) | 2014-05-28 | 2015-12-03 | Dana-Farber Cancer Institute, Inc. | Activating jak kinase biomarkers predictive of anti-immune checkpoint inhibitor response |
WO2017167942A1 (en) | 2016-03-31 | 2017-10-05 | Pamgene Bv | Method for predicting the response of melanoma patients to a medicament |
WO2017201165A1 (en) | 2016-05-17 | 2017-11-23 | Genecentric Diagnostics, Inc. | Methods for subtyping of lung adenocarcinoma |
JP2019516407A (ja) | 2016-05-17 | 2019-06-20 | ジーンセントリック セラピューティクス, インコーポレイテッド | 肺腺癌のサブタイピングのための方法 |
Also Published As
Publication number | Publication date |
---|---|
BR112019024537A2 (pt) | 2020-06-09 |
WO2019109089A1 (en) | 2019-06-06 |
RU2019135697A (ru) | 2022-01-04 |
NZ759413A (en) | 2022-03-25 |
CA3061736A1 (en) | 2019-06-06 |
MX2019014285A (es) | 2020-01-27 |
EP3616205A1 (en) | 2020-03-04 |
SG11201910041WA (en) | 2019-11-28 |
KR20200093437A (ko) | 2020-08-05 |
CN110678930B (zh) | 2023-06-20 |
CN110678930A (zh) | 2020-01-10 |
ZA201907298B (en) | 2023-06-28 |
AU2018375214A1 (en) | 2019-12-12 |
JP2021505976A (ja) | 2021-02-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7429539B2 (ja) | 薬効を評価するためのシステム及び方法 | |
Kardos et al. | Claudin-low bladder tumors are immune infiltrated and actively immune suppressed | |
Karasaki et al. | An immunogram for the cancer-immunity cycle: towards personalized immunotherapy of lung cancer | |
Charoentong et al. | Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade | |
Griffiths et al. | Circulating immune cell phenotype dynamics reflect the strength of tumor–immune cell interactions in patients during immunotherapy | |
Lee et al. | Comprehensive immunoproteogenomic analyses of malignant pleural mesothelioma | |
CN111164700A (zh) | 使用下一代测序的免疫-肿瘤学应用 | |
AU2020251324A1 (en) | Aryl hydrocarbon receptor (AHR) activation signature and methods for determining AHR signaling status | |
McCoach et al. | The evolving understanding of immunoediting and the clinical impact of immune escape | |
Zhao et al. | Identification of immune cell infiltration landscape and their prognostic significance in uveal melanoma | |
McCann et al. | Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer | |
US20200176083A1 (en) | Systems and methods for assessing drug efficacy | |
CA3227993A1 (en) | Predicting patient response | |
Kim et al. | MHC II immunogenicity shapes the neoepitope landscape in human tumors | |
US20230160009A1 (en) | Predictive response biomarker discovery process | |
Bendall et al. | Specific human endogenous retroviruses predict metastatic potential in uveal melanoma | |
Noviello et al. | Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial | |
Liu et al. | Landscape of immune microenvironment in epithelial ovarian cancer and establishing risk model by machine learning | |
Naulaerts et al. | Immunogenomic, single-cell and spatial dissection of CD8+ T cell exhaustion reveals critical determinants of cancer immunotherapy | |
Shin et al. | IL-7 receptor alpha defines heterogeneity and signature of human effector memory CD8+ T cells in high dimensional analysis | |
RU2797170C9 (ru) | Системы и способы оценки эффективности лекарственного средства | |
RU2797170C2 (ru) | Системы и способы оценки эффективности лекарственного средства | |
Zhang et al. | Pan-cancer evaluation of regulated cell death to predict overall survival and immune checkpoint inhibitor response | |
NZ759413B2 (en) | Systems and methods for assessing drug efficacy | |
Feng et al. | Identification and validation of an emt-related lncrna signature for hnscc to predict survival and immune landscapes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211115 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221128 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230227 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230424 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230719 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230925 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231110 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20231120 |
|
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: 20240122 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240129 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7429539 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |