WO2008092153A2 - Modification of exosomal components for use as a vaccine - Google Patents
Modification of exosomal components for use as a vaccine Download PDFInfo
- Publication number
- WO2008092153A2 WO2008092153A2 PCT/US2008/052205 US2008052205W WO2008092153A2 WO 2008092153 A2 WO2008092153 A2 WO 2008092153A2 US 2008052205 W US2008052205 W US 2008052205W WO 2008092153 A2 WO2008092153 A2 WO 2008092153A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cell
- cancer cell
- exosome
- exosomes
- cancer
- Prior art date
Links
- 229960005486 vaccine Drugs 0.000 title description 13
- 230000004048 modification Effects 0.000 title description 7
- 238000012986 modification Methods 0.000 title description 7
- 210000004027 cell Anatomy 0.000 claims abstract description 288
- 210000001808 exosome Anatomy 0.000 claims abstract description 186
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 135
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 93
- 238000000034 method Methods 0.000 claims abstract description 91
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 88
- 229920001184 polypeptide Polymers 0.000 claims abstract description 83
- 230000001506 immunosuppresive effect Effects 0.000 claims abstract description 76
- 201000011510 cancer Diseases 0.000 claims description 75
- 239000000427 antigen Substances 0.000 claims description 71
- 108091007433 antigens Proteins 0.000 claims description 70
- 102000036639 antigens Human genes 0.000 claims description 70
- 108020004459 Small interfering RNA Proteins 0.000 claims description 50
- 230000014509 gene expression Effects 0.000 claims description 40
- 231100000617 superantigen Toxicity 0.000 claims description 28
- 231100000655 enterotoxin Toxicity 0.000 claims description 23
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- 230000002401 inhibitory effect Effects 0.000 claims description 21
- 102000040430 polynucleotide Human genes 0.000 claims description 21
- 108091033319 polynucleotide Proteins 0.000 claims description 21
- 206010033128 Ovarian cancer Diseases 0.000 claims description 20
- 239000002157 polynucleotide Substances 0.000 claims description 20
- 201000001441 melanoma Diseases 0.000 claims description 19
- 101000686985 Mouse mammary tumor virus (strain C3H) Protein PR73 Proteins 0.000 claims description 16
- 208000020816 lung neoplasm Diseases 0.000 claims description 14
- 206010009944 Colon cancer Diseases 0.000 claims description 13
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 13
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 13
- 201000005202 lung cancer Diseases 0.000 claims description 13
- OTLLEIBWKHEHGU-UHFFFAOYSA-N 2-[5-[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy]-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-4-phosphonooxyhexanedioic acid Chemical compound C1=NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COC1C(CO)OC(OC(C(O)C(OP(O)(O)=O)C(O)C(O)=O)C(O)=O)C(O)C1O OTLLEIBWKHEHGU-UHFFFAOYSA-N 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 12
- 208000026310 Breast neoplasm Diseases 0.000 claims description 12
- 206010060862 Prostate cancer Diseases 0.000 claims description 12
- 231100000776 exotoxin Toxicity 0.000 claims description 12
- 239000002095 exotoxin Substances 0.000 claims description 12
- 239000003053 toxin Substances 0.000 claims description 12
- 231100000765 toxin Toxicity 0.000 claims description 12
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 11
- 206010014733 Endometrial cancer Diseases 0.000 claims description 11
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 11
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 11
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 11
- 201000010881 cervical cancer Diseases 0.000 claims description 11
- 208000029742 colonic neoplasm Diseases 0.000 claims description 11
- 230000028993 immune response Effects 0.000 claims description 11
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 11
- 201000002528 pancreatic cancer Diseases 0.000 claims description 11
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 11
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 10
- 102100034256 Mucin-1 Human genes 0.000 claims description 10
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 10
- -1 EGFK Proteins 0.000 claims description 9
- 108010008707 Mucin-1 Proteins 0.000 claims description 9
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 claims description 9
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 claims description 9
- 210000004748 cultured cell Anatomy 0.000 claims description 9
- 108010079206 V-Set Domain-Containing T-Cell Activation Inhibitor 1 Proteins 0.000 claims description 8
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 claims description 8
- 102100038078 CD276 antigen Human genes 0.000 claims description 7
- 101710185679 CD276 antigen Proteins 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 claims description 6
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 claims description 6
- 102000015212 Fas Ligand Protein Human genes 0.000 claims description 6
- 108010039471 Fas Ligand Protein Proteins 0.000 claims description 6
- 101000794214 Staphylococcus aureus Toxic shock syndrome toxin-1 Proteins 0.000 claims description 6
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 6
- 206010044250 Toxic shock syndrome staphylococcal Diseases 0.000 claims description 6
- 230000002297 mitogenic effect Effects 0.000 claims description 6
- 108010028067 procathepsin D Proteins 0.000 claims description 6
- 102100038222 60 kDa heat shock protein, mitochondrial Human genes 0.000 claims description 5
- 101100136529 Bacillus cereus cerB gene Proteins 0.000 claims description 5
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 claims description 5
- 101710134395 Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1 Proteins 0.000 claims description 5
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 claims description 5
- 108010058432 Chaperonin 60 Proteins 0.000 claims description 5
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 claims description 5
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 claims description 5
- 108700041152 Endoplasmic Reticulum Chaperone BiP Proteins 0.000 claims description 5
- 102100021451 Endoplasmic reticulum chaperone BiP Human genes 0.000 claims description 5
- 101150032268 HOXB7 gene Proteins 0.000 claims description 5
- 108010045100 HSP27 Heat-Shock Proteins Proteins 0.000 claims description 5
- 101150112743 HSPA5 gene Proteins 0.000 claims description 5
- 101710113864 Heat shock protein 90 Proteins 0.000 claims description 5
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims description 5
- 102100039165 Heat shock protein beta-1 Human genes 0.000 claims description 5
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 claims description 5
- 101001024605 Homo sapiens Next to BRCA1 gene 1 protein Proteins 0.000 claims description 5
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 5
- 101150013773 Hoxa7 gene Proteins 0.000 claims description 5
- 102000003735 Mesothelin Human genes 0.000 claims description 5
- 108090000015 Mesothelin Proteins 0.000 claims description 5
- 102100023123 Mucin-16 Human genes 0.000 claims description 5
- 101710135898 Myc proto-oncogene protein Proteins 0.000 claims description 5
- 102100038895 Myc proto-oncogene protein Human genes 0.000 claims description 5
- 108010025568 Nucleophosmin Proteins 0.000 claims description 5
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 5
- 101100111629 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR2 gene Proteins 0.000 claims description 5
- 108010002687 Survivin Proteins 0.000 claims description 5
- 101710150448 Transcriptional regulator Myc Proteins 0.000 claims description 5
- 102000018252 Tumor Protein p73 Human genes 0.000 claims description 5
- 108010091356 Tumor Protein p73 Proteins 0.000 claims description 5
- 101150028578 grp78 gene Proteins 0.000 claims description 5
- PUPNJSIFIXXJCH-UHFFFAOYSA-N n-(4-hydroxyphenyl)-2-(1,1,3-trioxo-1,2-benzothiazol-2-yl)acetamide Chemical compound C1=CC(O)=CC=C1NC(=O)CN1S(=O)(=O)C2=CC=CC=C2C1=O PUPNJSIFIXXJCH-UHFFFAOYSA-N 0.000 claims description 5
- 108010044762 nucleolin Proteins 0.000 claims description 5
- 102000016914 ras Proteins Human genes 0.000 claims description 5
- 108010014186 ras Proteins Proteins 0.000 claims description 5
- 101150047061 tag-72 gene Proteins 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000004936 stimulating effect Effects 0.000 claims description 4
- 238000003306 harvesting Methods 0.000 claims description 3
- 101710114878 Phospholipase A-2-activating protein Proteins 0.000 claims 3
- 102100025483 Retinoid-inducible serine carboxypeptidase Human genes 0.000 claims 3
- BLFWHYXWBKKRHI-JYBILGDPSA-N plap Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)[C@@H](N)CCC(O)=O BLFWHYXWBKKRHI-JYBILGDPSA-N 0.000 claims 3
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims 2
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims 2
- 101100346932 Mus musculus Muc1 gene Proteins 0.000 claims 1
- 201000009030 Carcinoma Diseases 0.000 description 58
- 239000004055 small Interfering RNA Substances 0.000 description 42
- 108090000623 proteins and genes Proteins 0.000 description 41
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 40
- 102000004169 proteins and genes Human genes 0.000 description 31
- 235000018102 proteins Nutrition 0.000 description 28
- 210000004443 dendritic cell Anatomy 0.000 description 22
- 208000032839 leukemia Diseases 0.000 description 20
- 206010039491 Sarcoma Diseases 0.000 description 19
- 238000011282 treatment Methods 0.000 description 18
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 17
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 17
- 230000009368 gene silencing by RNA Effects 0.000 description 17
- 210000004881 tumor cell Anatomy 0.000 description 16
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 13
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 13
- 230000000295 complement effect Effects 0.000 description 13
- 241000282414 Homo sapiens Species 0.000 description 12
- 150000007523 nucleic acids Chemical class 0.000 description 12
- 210000001744 T-lymphocyte Anatomy 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 102000039446 nucleic acids Human genes 0.000 description 11
- 108020004707 nucleic acids Proteins 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 210000000987 immune system Anatomy 0.000 description 10
- 230000001629 suppression Effects 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 8
- 230000000692 anti-sense effect Effects 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000009169 immunotherapy Methods 0.000 description 8
- 125000003729 nucleotide group Chemical group 0.000 description 8
- 108700012359 toxins Proteins 0.000 description 8
- 241000700605 Viruses Species 0.000 description 7
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 7
- 239000000147 enterotoxin Substances 0.000 description 7
- 210000004698 lymphocyte Anatomy 0.000 description 7
- 239000002773 nucleotide Substances 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 102100024321 Alkaline phosphatase, placental type Human genes 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000003211 malignant effect Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 108010031345 placental alkaline phosphatase Proteins 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 101710146739 Enterotoxin Proteins 0.000 description 4
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 4
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 4
- 108091028664 Ribonucleotide Proteins 0.000 description 4
- 241000191940 Staphylococcus Species 0.000 description 4
- 108091008874 T cell receptors Proteins 0.000 description 4
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 4
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 208000003747 lymphoid leukemia Diseases 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000002336 ribonucleotide Substances 0.000 description 4
- 125000002652 ribonucleotide group Chemical group 0.000 description 4
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 3
- 208000009458 Carcinoma in Situ Diseases 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 3
- 101000907904 Homo sapiens Endoribonuclease Dicer Proteins 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 102000000574 RNA-Induced Silencing Complex Human genes 0.000 description 3
- 108010016790 RNA-Induced Silencing Complex Proteins 0.000 description 3
- 241000282898 Sus scrofa Species 0.000 description 3
- 230000006044 T cell activation Effects 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000006023 anti-tumor response Effects 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000003636 conditioned culture medium Substances 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000003119 immunoblot Methods 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 208000025113 myeloid leukemia Diseases 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 208000000649 small cell carcinoma Diseases 0.000 description 3
- 241000894007 species Species 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000002255 vaccination Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 206010058354 Bronchioloalveolar carcinoma Diseases 0.000 description 2
- 102100027668 Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1 Human genes 0.000 description 2
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 2
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 2
- 206010008583 Chloroma Diseases 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 108091033380 Coding strand Proteins 0.000 description 2
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 2
- 102100023387 Endoribonuclease Dicer Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 2
- 206010053574 Immunoblastic lymphoma Diseases 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 102100021010 Nucleolin Human genes 0.000 description 2
- 108700026244 Open Reading Frames Proteins 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 241000282849 Ruminantia Species 0.000 description 2
- 201000001542 Schneiderian carcinoma Diseases 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- 230000005867 T cell response Effects 0.000 description 2
- 102100027881 Tumor protein 63 Human genes 0.000 description 2
- 108090000848 Ubiquitin Proteins 0.000 description 2
- 102000044159 Ubiquitin Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 208000036676 acute undifferentiated leukemia Diseases 0.000 description 2
- 230000033289 adaptive immune response Effects 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 230000005975 antitumor immune response Effects 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000035572 chemosensitivity Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 2
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 230000001024 immunotherapeutic effect Effects 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 201000004933 in situ carcinoma Diseases 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 208000025036 lymphosarcoma Diseases 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 108091070501 miRNA Proteins 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 201000006894 monocytic leukemia Diseases 0.000 description 2
- 201000005987 myeloid sarcoma Diseases 0.000 description 2
- 239000007764 o/w emulsion Substances 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 208000031223 plasma cell leukemia Diseases 0.000 description 2
- 230000032361 posttranscriptional gene silencing Effects 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 235000013594 poultry meat Nutrition 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000000644 propagated effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940030325 tumor cell vaccine Drugs 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- JNYAEWCLZODPBN-KVTDHHQDSA-N (2r,3r,4r)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@@H](O)[C@H]1O JNYAEWCLZODPBN-KVTDHHQDSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- MRXDGVXSWIXTQL-HYHFHBMOSA-N (2s)-2-[[(1s)-1-(2-amino-1,4,5,6-tetrahydropyrimidin-6-yl)-2-[[(2s)-4-methyl-1-oxo-1-[[(2s)-1-oxo-3-phenylpropan-2-yl]amino]pentan-2-yl]amino]-2-oxoethyl]carbamoylamino]-3-phenylpropanoic acid Chemical compound C([C@H](NC(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C=O)C1NC(N)=NCC1)C(O)=O)C1=CC=CC=C1 MRXDGVXSWIXTQL-HYHFHBMOSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical class CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 1
- VGONTNSXDCQUGY-RRKCRQDMSA-N 2'-deoxyinosine Chemical group C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC2=O)=C2N=C1 VGONTNSXDCQUGY-RRKCRQDMSA-N 0.000 description 1
- UMHYVXGZRGOICM-AUYXYSRISA-N 2-[(z)-octadec-9-enoyl]oxypropyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC\C=C/CCCCCCCC UMHYVXGZRGOICM-AUYXYSRISA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- KIHBGTRZFAVZRV-UHFFFAOYSA-N 2-hydroxyoctadecanoic acid Chemical class CCCCCCCCCCCCCCCCC(O)C(O)=O KIHBGTRZFAVZRV-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 1
- 241000321096 Adenoides Species 0.000 description 1
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 1
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 1
- 208000035805 Aleukaemic leukaemia Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 208000037540 Alveolar soft tissue sarcoma Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 108010077805 Bacterial Proteins Proteins 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 241000283726 Bison Species 0.000 description 1
- 241000283725 Bos Species 0.000 description 1
- 208000013165 Bowen disease Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241001466804 Carnivora Species 0.000 description 1
- 108090000258 Cathepsin D Proteins 0.000 description 1
- 102000003908 Cathepsin D Human genes 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- OLVPQBGMUGIKIW-UHFFFAOYSA-N Chymostatin Natural products C=1C=CC=CC=1CC(C=O)NC(=O)C(C(C)CC)NC(=O)C(C1NC(N)=NCC1)NC(=O)NC(C(O)=O)CC1=CC=CC=C1 OLVPQBGMUGIKIW-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- 241000777300 Congiopodidae Species 0.000 description 1
- 102000000577 Cyclin-Dependent Kinase Inhibitor p27 Human genes 0.000 description 1
- 108010016777 Cyclin-Dependent Kinase Inhibitor p27 Proteins 0.000 description 1
- 101710087047 Cytoskeleton-associated protein 4 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 238000011510 Elispot assay Methods 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 206010057649 Endometrial sarcoma Diseases 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- 208000009331 Experimental Sarcoma Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 1
- 241000282818 Giraffidae Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 108010027992 HSP70 Heat-Shock Proteins Proteins 0.000 description 1
- 102000018932 HSP70 Heat-Shock Proteins Human genes 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 208000017662 Hodgkin disease lymphocyte depletion type stage unspecified Diseases 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 1
- 210000005131 Hürthle cell Anatomy 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 206010023256 Juvenile melanoma benign Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 206010024218 Lentigo maligna Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010053180 Leukaemia cutis Diseases 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010029488 Nodular melanoma Diseases 0.000 description 1
- 241000272458 Numididae Species 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001278385 Panthera tigris altaica Species 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 101150085390 RPM1 gene Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010042553 Superficial spreading melanoma stage unspecified Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 101710163806 Trypsin/chymotrypsin inhibitor Proteins 0.000 description 1
- 101710140697 Tumor protein 63 Proteins 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000012018 Yolk sac tumor Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 208000006336 acinar cell carcinoma Diseases 0.000 description 1
- 206010000583 acral lentiginous melanoma Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000006786 activation induced cell death Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000002534 adenoid Anatomy 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 208000008524 alveolar soft part sarcoma Diseases 0.000 description 1
- 208000006431 amelanotic melanoma Diseases 0.000 description 1
- 230000002707 ameloblastic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003302 anti-idiotype Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000014102 antigen processing and presentation of exogenous peptide antigen via MHC class I Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 108010014228 asialo-carcinoembryonic antigen Proteins 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 208000016894 basaloid carcinoma Diseases 0.000 description 1
- 201000000450 basaloid squamous cell carcinoma Diseases 0.000 description 1
- 208000003373 basosquamous carcinoma Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000010983 breast ductal carcinoma Diseases 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 230000000981 bystander Effects 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 230000008568 cell cell communication Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 229940030156 cell vaccine Drugs 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000002032 cellular defenses Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 108010086192 chymostatin Proteins 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
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 201000011050 comedo carcinoma Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000011229 conventional cytotoxic chemotherapy Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000011063 cribriform carcinoma Diseases 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002308 embryonic cell Anatomy 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 208000001991 endodermal sinus tumor Diseases 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 208000014804 familial ovarian cancer Diseases 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 108010017007 glucose-regulated proteins Proteins 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 208000017750 granulocytic sarcoma Diseases 0.000 description 1
- 210000002503 granulosa cell Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000035992 intercellular communication Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000001865 kupffer cell Anatomy 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 208000011080 lentigo maligna melanoma Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000610 leukopenic effect Effects 0.000 description 1
- 150000002632 lipids Chemical group 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 1
- 201000000966 lung oat cell carcinoma Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 201000010953 lymphoepithelioma-like carcinoma Diseases 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 206010061526 malignant mesenchymoma Diseases 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 230000000684 melanotic effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000002487 multivesicular body Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- AFFLGGQVNFXPEV-UHFFFAOYSA-N n-decene Natural products CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 description 1
- 208000014761 nasopharyngeal type undifferentiated carcinoma Diseases 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 201000000032 nodular malignant melanoma Diseases 0.000 description 1
- 208000029809 non-keratinizing sinonasal squamous cell carcinoma Diseases 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 229940060184 oil ingredients Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 201000007426 ovarian cystadenocarcinoma Diseases 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229940023041 peptide vaccine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000003169 placental effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940010310 propylene glycol dioleate Drugs 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical class CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 239000011546 protein dye Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 208000029817 pulmonary adenocarcinoma in situ Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 208000014212 sarcomatoid carcinoma Diseases 0.000 description 1
- 208000004259 scirrhous adenocarcinoma Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 208000011584 spitz nevus Diseases 0.000 description 1
- 230000003393 splenic effect Effects 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 208000028210 stromal sarcoma Diseases 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 201000010033 subleukemic leukemia Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 208000030457 superficial spreading melanoma Diseases 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 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
- 150000003505 terpenes Chemical class 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 208000022810 undifferentiated (embryonal) sarcoma Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 208000008662 verrucous carcinoma Diseases 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 229960000834 vinyl ether Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55544—Bacterial toxins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/57—Skin; melanoma
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/30—Special therapeutic applications
Definitions
- the presently disclosed subject matter relates to modified exosomes for use as vaccines.
- the presently disclosed subject matter relates to utilizing cell-produced exosomes modified to substantially lack one or more immunosuppressive polypeptides and methods of producing and using the exosomes as vaccines and treatments for disorders, including cancers.
- ovarian cancer remains the fourth leading cause of cancer-related deaths in women, resulting in more than 26,700 new cases and 14,800 deaths annually in the U.S.
- HERCEPTIN ® Trastuzumab
- RITUXAN ® rituximab
- CAMPATH ® alemtuzumab
- Peptide vaccines have been developed based on tumor associated antigens like carcinoembryonic antigen (CEA) or gpl OO, sometimes with epitope enhancement to enhance immunogenicity (S. A. Rosenberg et al., Nat. Med. 4:321 , 1998). Cytokines, chemokines, or costimulatory molecules have been used as potential adjuvants (J. A Berzofsky et al., Nat. Rev. Immunol. 1 :209, 2001 ; J. D. Ahlers et al., Proc. Nat. Acad. Sci. USA 99:13020, 2002).
- Tumor cell vaccines have also been based on tumor cells taken either from the patient being treated, or from an autologous source bearing a similar profile of tumor antigens. They are genetically modified to express a cytokine like GM-CSF or IL-4 that is thought to recruit the host immune system (J. W. Simons et al., Cancer Res. 59:5160, 1999; R. Soiffer et al., Proc. Natl. Acad. Sci. USA 95:13141 , 1998; E. M. Jaffee et al., J. Clin. Oncol. 19:145, 2001 ; R. Salgia et al., J. Clin. Oncol. 21 :624, 2003).
- a cytokine like GM-CSF or IL-4
- Transfected tumor cell vaccines are in late-stage clinical trials for prostate cancer, lung cancer, pancreatic cancer, and leukemia (R. Salgia et al., J. Clin. Oncol. 21 :624, 2003; K. M. Hege et al., Lung Cancer 41 :S103, 2003).
- An improved version of this approach is to isolate the patient's own tumor cells, and combine them with a cell line transfected to express a cytokine like GM-CSF in membranes form (U.S. Pat. No. 6,277,368).
- the transfected cells recruit the host immune system, which then initiates a CTL response against the tumor cells as bystanders.
- Another type of cellular vaccine comprises a patient's tumor cells combined with alloactivated T lymphocytes, which again play the role of recruiting the host immune system (U.S. Pat. Nos. 6,136,306; 6,203,787; and 6,207,147).
- dendritic cells play a central role in presenting tumor antigen to prime the CTL compartment, there has been considerable research interest in autologous dendritic cells as a tumor vaccine (G. Schuler et al., Curr. Opin. Immunol. 15:138, 2003; J. A. Berzofsky et al., J. Clin. Invest. 113:1515, 2004).
- Clinical trials have been based on dendritic cells from two sources: a) purified DC precursors from peripheral blood (L. Fong & E. G. Engleman, Annu. Rev. Immunol. 15:138, 2003); and b) ex vivo differentiation of DCs from peripheral blood monocytes (F. Sallusto et al., J. Exp.
- Exosome-based immunotherapy has also recently attracted much attention, since tumor-derived exosomes are a rich source of shared tumor rejection antigens for CTL cross-priming.
- tumor exosomes are usually loaded onto dendritic cells before administering in vivo. Novel approaches to bypass antigen loading onto DC either in vivo or in vitro have been investigated; however, to date, there are no reports regarding the modification of exosomes themselves to improve the antitumor effect of exosome-based immunotherapy.
- tumor exosomes appear to be enriched in potential antigenic targets, they also express immunosuppressive and apoptogenic activities. As a result, exosome-based immunotherapy for solid human cancers has exhibited at best marginal statistical success.
- an exosome isolated from a cell is provided.
- the exosome comprises one or more antigens and substantially lacks one or more immunosuppressive polypeptides normally found in the exosome.
- the cell has been modified to inhibit expression of the one or more immunosuppressive polypeptides.
- the exosome further comprises one or more exogenous antigens.
- the cell has been modified to comprise one or more inhibitory polynucleotides that specifically inhibit expression of the one or more immunosuppressive polypeptides.
- the one or more inhibitory polynucleotides comprise siRNA polynucleotides.
- the cell is a cultured cell.
- the cell is a cancer cell, such as for example, an ovarian cancer cell, a cervical cancer cell, a breast cancer cell, an endometrial cancer cell, a colon cancer cell, a prostate cancer cell, a lung cancer cell, a melanoma cell, or a pancreatic cancer cell.
- the cell is a UL-1 cell, a UL-2, a UL-3 cell, or a UL-6 cell.
- the one or more antigens are cancer cell antigens.
- the cancer cell antigen can be p53, p63, p73, mdm-2, procathepsin-D, B23, C23, PLAP, CA125, MUC-1 , cerB/HER2, NY-
- the one or more immunosuppressive polypeptides are selected from the group consisting of FasL, programmed death ligand-1 , programmed death ligand-2, B7-H3, B7-H4, and combinations thereof.
- the one or more exogenous antigens comprise superantigens.
- the superantigens can be staphylococcal enterotoxins (SEs), a Streptococcus pyogenes exotoxin (SPE), a Staphylococcus aureus toxic shock-syndrome toxin (TSST-1 ), a streptococcal mitogenic exotoxin (SME) or a streptococcal superantigen (SSA).
- SEs staphylococcal enterotoxins
- SPE Streptococcus pyogenes exotoxin
- TSST-1 Staphylococcus aureus toxic shock-syndrome toxin
- SME streptococcal mitogenic exotoxin
- SSA streptococcal superantigen
- a cell that produces the exosomes disclosed herein is provided.
- a composition comprising an exosome disclosed herein and a pharmaceutical carrier is provided.
- the presently-disclosed subject matter provides in some embodiments, a method of producing an exosome disclosed herein substantially lacking one or more immunosuppressive polypeptides.
- the method comprises providing a cell that can produce exosomes; inhibiting expression by the cell of one or more immunosuppressive polypeptides; and isolating exosomes produced by the cell, wherein the exosomes substantially lack the one or more immunosuppressive polypeptides.
- the method further comprises decorating the exosomes with one or more exogenous antigens.
- isolating the exosomes comprises harvesting a media in which the cells are cultured.
- a method of treating cancer in a subject comprises administering an effective amount of an exosome disclosed herein, which is produced by a cancer cell, to a subject in need thereof.
- the exosome can comprise one or more cancer antigens and is substantially lack one or more immunosuppressive polypeptides.
- the treated cancer is a solid tumor.
- the treated cancer is an ovarian cancer cell, a cervical cancer cell, a breast cancer cell, an endometrial cancer cell, a colon cancer cell, a prostate cancer cell, a lung cancer cell, a melanoma cell, or a pancreatic cancer cell.
- the exosome is administered intravenously, intratumorally, subcutaneously, transdermally, or intraperitoneally.
- the exosome comprises one or more exogenous antigens, such as for example, superantigens.
- the subject is a mammal.
- a method of stimulating an immune response in a subject against one or more antigens comprises administering an effective amount of an exosome disclosed herein, which is produced by a cell and comprising one or more antigens to a subject in need thereof.
- the exosome is substantially lacking one or more immunosuppressive polypeptides.
- FIG. 1 is a photograph showing the expression of Fas ligand (FasL) by four (4) ovarian tumor cell lines (UL1 , UL2, UL3, and UL6).
- Cell lines were either treated with mock siRNA or treated with siRNA primers specific for FasL.
- the expression of FasL was also assayed in expression of FasL on tumor- derived exosomes from siRNA treated cells.
- the levels of placental alkaline phosphatase (PLAP) was determined as a control for unaffected proteins.
- the gels define expression by western immunoblotting.
- Figure 2 is a pair of photographs of gels showing the consequences of co-incubated tumor-derived exosomes with T cells on the expression of the essential activation signal transducing proteins, CD3zeta and JAK3.
- the gels define the expression of the signaling molecules by western immunoblotting.
- the term "about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1 %, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1 % from the specified amount, as such variations are appropriate to perform the disclosed method.
- a general characteristic of activated cell types including lymphocytes, dendritic cells, and embryonic cells, is their ability to release vesicular membrane material (termed microvesicles or exosomes).
- exosomes vesicular membrane material
- the release of exosomes appears to be an important feature of intercellular communication.
- Exosomes from activated immune cells modulate lymphocyte and dendritic cell functions by eliciting "activation induced cell death" (AICD).
- Lymphocytes and dendritic cells appear to release exosomes following activation and these appear to play an essential role in immunoregulation, preventing of excessive immune responses, and the development of autoimmunity. Cancer cells have also been demonstrated to release exosomes.
- cancer cell exosomes may constitute a facsimile of the immune cell exosome pathway that can actually circumvent immunosurveillance and recognition of the tumor by the immune system through the inclusion of immunosuppressive polypeptides in the cancer cell exosomes.
- Production of exosomes by cancer cells may help to explain why many immunotherapies targeted to cancers have not been as therapeutically effective as desired.
- the presence of immunosuppressive polypeptides within cancer- derived exosomes can inhibit the effective use of immunotherapeutic exosome cancer treatments by dampening desired immune responses in subjects in need of treatment.
- the presently-disclosed subject matter provides at least two innovative approaches to improving exosomes for use in a therapeutic tumor antigen delivery system.
- one or more immunosuppressive polypeptides can be suppressed from expression and/or removed from exosomes derived from cells, e.g., cancer cells.
- siRNA suppression is utilized to reduce or eliminate expression of one or more tumor-derived immunosuppressive polypeptides.
- exosomes of the presently- disclosed subject matter can be modified to comprise one or more exogenous antigens (e.g., "superantigens") to enhance T cell-stimulating activity of the exosomes.
- protein transfer techniques can be utilized to introduce the exogenous antigens into the exosomes.
- siRNA suppression provides for the selective suppression of immunosuppressive polypeptides, while maintaining the tumor antigen-enriched nature of tumor exosomes.
- protein transfer can be used to express target proteins (e.g., superantigens) onto the cell surface.
- target proteins e.g., superantigens
- SEA staphylococcal enterotoxin A
- SEA-anchored tumor cells can induce an antitumor immune response. Since exosomes are tumor antigen-enriched microvesicles, exosomes are an optimal target for protein transfer.
- novel therapeutic exosomes disclosed herein combine target protein anchorage for enhanced immune system targeting and reduction or elimination of one or more immunosuppressive molecules, such as immunosuppressive polypeptides (e.g., by siRNA-suppression techniques), normally found in the naturally-produced exosomes.
- immunosuppressive polypeptides e.g., by siRNA-suppression techniques
- These novel immunotherapeutic exosomes provide optimal tools to induce regression of established tumors, as well as prevention of initial tumor development.
- Both CD4+ and CD8+ T cells have been shown to proliferate in response to SEA, resulting in increased production of cytokines such as IFN- ⁇ and IL-2.
- the use of cancer antigen-rich exosomes further provides the specificity necessary for an efficient therapy.
- the presently-disclosed tumor-derived exosomes surface anchored with exogenous superantigens and modified to lack immunosuppressive polypeptides can induce Th1 responses and tumor-specific CTL's more efficiently than any current approach
- an exosome isolated from a cell that produces the exosome comprises one or more antigens of interest and substantially lacks one or more immunosuppressive molecules that would otherwise be found in the exosome, including on the surface of the exosome, when produced by the cell.
- the immunosuppressive molecule is an miRNA or a polypeptide.
- isolated when used in the context of an isolated DNA molecule or an isolated polypeptide, is a DNA molecule or polypeptide that, by the hand of man, exists apart from its native environment and is therefore not a product of nature.
- An isolated DNA molecule or polypeptide can exist in a purified form or can exist in a non-native environment such as, for example, in a transgenic host cell.
- polypeptide polypeptide
- protein protein
- peptide which are used interchangeably herein, refer to a polymer of the 20 protein amino acids, or amino acid analogs, regardless of its size or function.
- polypeptide refers to peptides, polypeptides, and proteins, unless otherwise noted.
- protein refers to peptides, polypeptides, and proteins, unless otherwise noted.
- protein refers to peptides, polypeptides, and proteins, unless otherwise noted.
- protein refers to peptides, polypeptides, and proteins, unless otherwise noted.
- protein refers to peptides, polypeptides, and proteins, unless otherwise noted.
- protein polypeptide
- peptide are used interchangeably herein when referring to a gene product.
- exemplary polypeptides include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing.
- Exosomes are vesicles of endosomal origin that are secreted in the extracellular milieu following fusion of late endosomal multivesicular bodies with the plasma membrane.
- Cells from various tissue types have been shown to secrete exosomes, such as dendritic cells, B lymphocytes, tumor cells and mast cells, for instance.
- Exosomes from different origins exhibit discrete sets of proteins and lipid moieties. They notably contain proteins involved in antigen presentation and immunomodulation, suggesting that exosomes play a role in cell-cell communications leading to the modulation of immune responses.
- exosomes from dendritic cells (DC) pulsed with peptides derived from tumor antigens elicit anti-tumor responses in animal model using the matching tumor.
- exosomes derived from cancer cells comprising cancer antigens have been shown to comprise immunosuppressive polypeptides, making unmodified tumor-derived exosomes undesirable and potentially unsafe for use directly in vaccines.
- the exosomes of the presently disclosed subject matter are well-suited for producing antigens that can stimulate desirable immune responses in subjects because they are produced by cells, rather than artificially- synthesized, and therefore provide antigens that are "natural". That is, the antigens produced by the cells and found in the exosome can be full-length peptides that are processed (e.g., glycosylated, etc.) and folded by the cell to a similar extent as antigens experienced by immune cells in a subject. As such, the exosome antigens can be utilized in vaccines or treatments against, for example cancers. In some embodiments, therefore, the one or more antigens can each comprise a cancer cell antigen.
- the cancer cell antigen can be placental type alkaline phosphatase, p53, p63, p73, mdm-2, procathepsin-D, B23, C23, PLAP, CA125, MUC-1 , cerB/HER2, NY-ESO- 1.SCP1 , SSX-1 , SSX-2, SSX-4, HSP27, HSP60, HSP90, GRP78, TAG72,
- the exosomes are modified such that they substantially lack one or more immunosuppressive molecules, such as miRNAs or immunosuppressive polypeptides.
- immunosuppressive polypeptide is a polypeptide that reduces a normal immunological reaction by an immune system in a subject to a particular antigen.
- exosomes released by tumor cells can suppress immune responses in a subject and can induce apoptosis in lymphocytes due to the presence of immunosuppressive molecules in the exosomes, including immunosuppressive polypeptides. See Taylor & Gercel-Taylor (British Journal of Cancer (2005) 92:305-311 , herein incorporated by reference in its entirety).
- immunosuppressive molecules include, but are not limited to, microRNAs and immunosuppressive polypeptides, such as for example FasL, programmed death ligand-1 , programmed death ligand-2, B7-H3, B7-H4, and combinations thereof.
- substantially lacking refers to the selective removal of substantially all or at least a significant proportion of one or more immunosuppressive molecules resulting in an exosome that is significantly reduced or substantially lacking one or more selected immunosuppressive molecules.
- significantly reduced refers to a result that is reduced by more than the margin of error inherent in the measurement technique when comparing the modified exosome to a similar exosome produced by a comparable cell under otherwise comparable conditions.
- a decrease in presence in the modified exosome of a particular selected immunosuppressive molecule by about 10% or greater over a baseline presence.
- a decrease in activation or activity by about 20% or greater, in some embodiments a decrease in activation or activity by about 25% or greater, and in some embodiments a decrease in activation or activity by about 50% or greater is a significantly reduced presence of the immunosuppressive molecule.
- an exosome that is substantially lacking in one or more selected immunosuppressive molecules exhibits measurably reduced (as compared to the immunosuppressive capability of a comparable unmodified exosome) or absent capability to suppress one or more components of an animal immune system.
- Immunosuppressive capability of exosomes can be measured using any of several in vitro and in vivo assays generally known in the art. For example, and as described in detail in the Examples, expression of specific proteins associated with T cell activation can be measured and correlated with immunosuppressive activity (or lack thereof) in exosomes co- incubated with the T cells.
- the exosome further comprises one or more exogenous antigens.
- exogenous antigen refers to an antigenic polypeptide that is not typically coded for and/or expressed in the exosome-producing cell, is therefore not a native polypeptide of the cell or exosome and so is typically not found in exosomes produced by the cell.
- native refers to a polypeptide that is encoded by a native gene of an untransformed cell's genome and is therefore naturally present in the cell when expressed.
- Exogenous polypeptides can be included in the exosomes by a variety of techniques known in the art.
- exogenous polypeptides can be decorated on the surface of the exosomes after they are excreted by the cells using protein transfer techniques generally known to those of skill in the art. See, e.g., Nagarajan S, Selvaraj P. Glycolipid-anchored IL-12 expressed on tumor cell surface induces antitumor immune response. Cancer Res 2002;62:2869-74; McHugh RS, Nagarajan S, Wang Y, Sell KW, Selvaraj P. Protein transfer of glycosyl-phosphatidylinositol-137-1 into tumor cell membranes: a novel approach to tumor immunotherapy.
- exogenous polypeptides can be incorporated into exosomes using recombinant expression techniques.
- Recombinant exosomes have been described in the art, which derive from cells transfected with plasmids encoding the recombinant polypeptides. Such recombinant exosomes contain the plasmid-encoded recombinant peptide (see e.g., PCT Published Application No. WO00/28001 , herein incorporated by reference).
- Exogenous polypeptides that can be incorporated into exosomes of the present subject matter are polypeptides that can provide additional desirable functionality to the exosomes, such as for example polypeptides that provide increased immunogenic properties to the exosomes.
- SAgs superantigens
- SAgs can comprise a group of bacterial and viral proteins that are extremely efficient in activating a large fraction of the T-cell population.
- SAgs can bind directly to the major histocompatibility complex (MHC) without being processed.
- MHC major histocompatibility complex
- SAgs can bind unprocessed outside the antigen-binding groove on the MHC class Il molecules, thereby avoiding most of the polymorphism in the conventional peptide-binding site.
- the mechanism of binding depends on the SAgs binding to the T-cell receptor (TCR) in the V ⁇ chain, instead of binding to the hypervahable loops of the T-cell receptor (TCR).
- superantigens that can be incorporated into exosomes as exogenous polypeptides include, but are not limited to staphylococcal enterotoxins (SEs), a Streptococcus pyogenes exotoxin (SPE), a
- SEs Staphylococcus aureus toxic shock-syndrome toxin (TSST-1 ), a streptococcal mitogenic exotoxin (SME) and a streptococcal superantigen (SSA). SEs are a homologous group of superantigens, with regard to both structure and function.
- the exogenous polypeptide is staphylococcal enterotoxin A (SEA) or staphylococcal enterotoxin E (SEE). See, e.g., SEA or staphylococcal enterotoxin A (SEA) or staphylococcal enterotoxin E (SEE). See, e.g., SEA or staphylococcal enterotoxin E (SEE). See, e.g., SEA or staphylococcal enterotoxin E (SEE). See, e.g., SEA or staphylococcal enterotoxin E (SEE). See, e.g., SEA or staphylococcal enterotoxin E (SEE).
- the cell that produces the exosomes disclosed herein is provided.
- the cell is a cultured cell, that is, a cell propagated ex vivo in culture media.
- the culture cell can be immortalized to facilitate continuous propagation.
- the cell is a cancer cell, such as for example a cancer cell originally isolated from a tumor and then propagated in culture, as is generally known in the art.
- the cancer cell can be an ovarian cancer cell, a cervical cancer cell, a breast cancer cell, an endometrial cancer cell, a colon cancer cell, a prostate cancer cell, a lung cancer cell, a melanoma cell, or a pancreatic cancer cell.
- the cell is a cultured cell line selected from the group consisting of a UL-1 cell, UL-2 cell, a UL-3 cell, and UL-6. All of these primary human ovarian tumor cell lines were established in our laboratory, from women with Stage IMc cyst adenocarcinoma of the ovary (designated UL-1 , UL-2, UL-3, and UL-6). UL-2 and UL-3 were derived from hereditary ovarian cancer, while UL-1 and UL-6 were derived from spontaneous cancers.
- UL-1 cells were derived from a 63 year old female
- UL-2 cells were derived from a 34 year old female
- UL-3 cells were derived from a 42 year old female
- UL-6 cells were derived from a 72 year old female patient.
- These cell lines are tumorigenic in nude mice, giving rise to tumors that are consistent with cyst adenocarcinomas.
- These cell lines are all positive for EpCAM, PLAP, FasL PD-L1 and class Il MHC.
- a pharmaceutical composition comprising an exosome disclosed herein and a pharmaceutical carrier.
- the pharmaceutical composition is pharmaceutically acceptable in humans.
- the pharmaceutical composition can be formulated as a therapeutic composition for delivery to a subject in some embodiments.
- a pharmaceutical composition as described herein preferably comprises a composition that includes pharmaceutical carrier such as aqueous and nonaqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and nonaqueous sterile suspensions, which can include suspending agents and thickening agents.
- pharmaceutical carrier such as aqueous and nonaqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient
- aqueous and nonaqueous sterile suspensions which can include suspending agents and thickening agents.
- compositions used can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a frozen or freeze-dried (lyophilized) condition requiring only the addition of sterile liquid carrier immediately prior to use.
- Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations can be prepared by conventional techniques with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
- suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
- emulsifying agents e.g. lecithin or acacia
- non-aqueous vehicles e.g., almond oil, oily esters, ethyl alcohol
- compositions can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
- Preparations for oral administration can be suitably formulated to give controlled release of the active compound.
- buccal administration the compositions can take the form of capsules, tablets or lozenges formulated in conventional manner.
- the compositions can also be formulated as a preparation for implantation or injection.
- the compositions can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
- the compounds can also be formulated in rectal compositions (e.g., suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides), creams or lotions, or transdermal patches.
- exosomes comprising one or more antigens and exogenous peptides within the exosomes
- other components such as a vehicle for exosome delivery and additional immunostimulatory substances within the vehicle designed to enhance the polypeptide's immunogenicity can be included in the pharmaceutical composition.
- the immunogenic compositions and vaccines according to the presently disclosed subject matter can further comprise or consist essentially of one or more adjuvants.
- Suitable adjuvants for use in the practice of the present subject matter include, but are not limited to (1 ) polymers of acrylic or methacrylic acid, maleic anhydride and alkenyl derivative polymers, (2) immunostimulating sequences (ISS), such as oligodeoxyhbonucleotide sequences having one ore more non-methylated CpG units (Klinman et al., Proc. Natl. Acad. Sci., USA, 1996, 93, 2879-2883; WO98/16247), (3) an oil in water emulsion, such as the SPT emulsion described on page 147 of "Vaccine Design, The Subunit and Adjuvant Approach" published by M. Powell, M.
- the oil in water emulsion (3) can be based on: light liquid paraffin oil (European pharmacopoeia type), isoprenoid oil such as squalane, squalene, oil resulting from the oligomerization of alkenes, e.g.
- esters of acids or alcohols having a straight-chain alkyl group such as vegetable oils, ethyl oleate, propylene glycol, di(caprylate/caprate), glycerol tri(caprylate/caprate) and propylene glycol dioleate, or esters of branched, fatty alcohols or acids, especially isostearic acid esters.
- the oil can be used in combination with emulsifiers to form an emulsion.
- the emulsifiers can be nonionic surfactants, such as: esters of, on the one hand, sorbitan, mannide (e.g.
- anhydromannitol oleate glycerol, polyglycerol or propylene glycol and, on the other hand, oleic, isostearic, ricinoleic or hydroxystearic acids, the esters being optionally ethoxylated, or polyoxypropylene-polyoxyethylene copolymer blocks, such as Pluronic, e.g., L121.
- polymers of cross-linked acrylic or methacrylic acid especially cross-linked by polyalkenyl ethers of sugars or polyalcohols. These compounds are known under the name carbomer (Pharmeuropa, vol. 8, no. 2, June 1996).
- carbomer Pharmeuropa, vol. 8, no. 2, June 1996.
- One skilled in the art can also refer to U.S. Pat. No. 2,909,462, which provides such acrylic polymers cross-linked by a polyhydroxyl compound having at least three hydroxyl groups, preferably no more than eight such groups, the hydrogen atoms of at least three hydroxyl groups being replaced by unsaturated, aliphatic radicals having at least two carbon atoms.
- the preferred radicals are those containing 2 to 4 carbon atoms, e.g.
- the unsaturated radicals can also contain other substituents, such as methyl.
- Products sold under the name CARBOPOLTM (BF Goodrich, Ohio, U.S.A.) can be suitable. They are cross-linked by allyl saccharose or by allyl pentaerythhtol. Among them, reference is made to CARBOPOLTM 974P, 934P and 971 P.
- EMA Monsanto, St. Louis, Missouri, U.S.A.
- EMA Monsanto, St. Louis, Missouri, U.S.A.
- They are straight-chain or cross-linked ethylene-maleic anhydride copolymers and they are, for example, cross-linked by divinyl ether.
- J. Fields et al. Nature 186: 778-780, Jun. 4, 1960.
- the presently disclosed subject matter further provides methods of using the exosomes disclosed herein. In some embodiments, a method of producing an exosome substantially lacking one or more immunosuppressive polypeptides is provided.
- the method comprises providing a cell, such as the cells disclosed hereinabove, that can produce exosomes; inhibiting expression by the cell of one or more immunosuppressive polypeptides; and isolating exosomes produced by the cell, wherein the exosomes substantially lack the one or more immunosuppressive polypeptides.
- the method can further comprise stimulating the cell to produce the exosomes.
- stimulation is generally not required.
- the method further comprises decorating the exosomes (e.g., by protein transfer or by recombinant expression in the cells producing the exosomes, as disclosed herein and as is generally known in the art) with one or more exogenous antigens (e.g., superantigens).
- decorating the exosomes e.g., by protein transfer or by recombinant expression in the cells producing the exosomes, as disclosed herein and as is generally known in the art
- one or more exogenous antigens e.g., superantigens
- "isolating the exosomes” comprises harvesting a media in which the cells are cultured and selectively removing the exosomes from the media, such as for example by centrifugation.
- inhibiting expression by the cell of the one or more immunosuppressive polypeptides comprises introducing into the cell one or more inhibitory polynucleotides that specifically inhibit expression of the one or more immunosuppressive polypeptides.
- the one or more inhibitory polynucleotides comprise small interfering RNA (siRNA) polynucleotides.
- siRNA small interfering RNA
- nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
- a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof ⁇ e.g., degenerate codon substitutions) and complementary sequences and as well as the sequence explicitly indicated.
- degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer ef a/. (1991 )
- polynucleotide or “nucleic acid sequence” can also be used interchangeably with gene, open reading frame (ORF), cDNA, and mRNA encoded by a gene.
- small interfering RNA small interfering RNA
- short interfering RNA small hairpin
- RNA RNA
- shRNA RNA interference
- RNAi RNA interference
- gene silencing RNA interference
- the siRNA comprises a double stranded polynucleotide molecule comprising complementary sense and antisense regions, wherein the antisense region comprises a sequence complementary to a region of a target nucleic acid molecule encoding an immunosuppressive polypeptide.
- the siRNA comprises a single stranded polynucleotide having self- complementary sense and antisense regions, wherein the antisense region comprises a sequence complementary to a region of the target nucleic acid molecule.
- the siRNA comprises a single stranded polynucleotide having one or more loop structures and a stem comprising self complementary sense and antisense regions, wherein the antisense region comprises a sequence complementary to a region of the target nucleic acid molecule, and wherein the polynucleotide can be processed either in vivo or in vitro to generate an active siRNA capable of mediating RNAi.
- siRNA molecules need not be limited to those molecules containing only RNA, but further encompass chemically modified nucleotides and non-nucleotides. The presently disclosed subject matter takes advantage of the ability of short, double stranded RNA molecules to cause the down regulation of cellular genes, a process referred to as RNA interference.
- RNA interference refers to a process of sequence-specific post- transcriptional gene silencing mediated by a small interfering RNA (siRNA). See generally Fire et al., Nature 391 :806-811 , 1998. The process of post- transcriptional gene silencing is thought to be an evolutionarily conserved cellular defense mechanism that has evolved to prevent the expression of foreign genes (Fire, Trends Genet 15:358-363, 1999).
- RNAi might have evolved to protect cells and organisms against the production of double stranded RNA (dsRNA) molecules resulting from infection by certain viruses (particularly the double stranded RNA viruses or those viruses for which the life cycle includes a double stranded RNA intermediate) or the random integration of transposon elements into the host genome via a mechanism that specifically degrades single stranded RNA or viral genomic RNA homologous to the double stranded RNA species.
- dsRNA double stranded RNA
- RNA-induced silencing complex RISC
- the RISC is capable of mediating cleavage of single stranded RNA present within the cell that is complementary to the antisense strand of the siRNA duplex. According to Elbashir et al., cleavage of the target RNA occurs near the middle of the region of the single stranded RNA that is complementary to the antisense strand of the siRNA duplex (Elbashir et al., Genes Dev 15:188-200, 2001 b).
- RNAi has been described in several cell types and organisms. Fire et al., 1998 described RNAi in C. elegans. Wianny & Zernicka-Goetz, Nature Cell Biol 2:70-75, 1999 disclose RNAi mediated by dsRNA in mouse embryos. Hammond et al., Nature 404:293-296, 2000 were able to induce RNAi in Drosophila cells by transfecting dsRNA into these cells. Elbashir et al. Nature 411 :494-498, 2001 demonstrated the presence of RNAi in cultured mammalian cells including human embryonic kidney and HeLa cells by the introduction of duplexes of synthetic 21 nucleotide RNAs.
- WO 00/44914 and WO 01/68836 and certain nucleotide modifications that might inhibit the activation of double stranded RNA-dependent protein kinase (PKR), specifically 2'-amino or 2'-O-methyl nucleotides, and nucleotides containing a 2'-O or 4'-C methylene bridge (Canadian Patent Application No. 2,359,180).
- PLR RNA-dependent protein kinase
- dsRNA and RNAi include PCT International Publication Nos. WO 01/75164 (in vitro RNAi system using cells from Drosophila and the use of specific siRNA molecules for certain functional genomic and certain therapeutic applications); WO 01/36646 (methods for inhibiting the expression of particular genes in mammalian cells using dsRNA molecules); WO 99/32619 (methods for introducing dsRNA molecules into cells for use in inhibiting gene expression); WO 01/92513 (methods for mediating gene suppression by using factors that enhance RNAi); WO 02/44321 (synthetic siRNA constructs); WO 00/63364 and WO 01/04313 (methods and compositions for inhibiting the function of polynucleotide sequences); and WO 02/055692 and WO 02/055693 (methods for inhibiting gene expression using RNAi), each of which is incorporated herein by reference.
- the presently disclosed subject matter utilizes RNAi to at least partially inhibit expression of one or more immunosuppressive polypeptides of interest, for example but not limited to, FasL, programmed death ligand-1 , programmed death ligand-2, B7-H3, B7-H4, or combinations thereof. In some embodiments, inhibition is at least about 10% of normal expression amounts.
- the method comprises introducing an RNA to a target cell in an amount sufficient to inhibit expression of the one or more immunosuppressive polypeptides, wherein the RNA comprises a ribonucleotide sequence which corresponds to a coding strand of a gene of interest.
- the RNA can have a double-stranded region comprising a first strand comprising a ribonucleotide sequence that corresponds to the coding strand of the gene encoding the target immunosuppressive polypeptide and a second strand comprising a ribonucleotide sequence that is complementary to the first strand.
- the first strand and the second strand hybridize to each other to form the double-stranded molecule.
- the double stranded region can be at least 15 basepairs in length, and in some embodiments, between 15 and 50 basepairs in length, and in some embodiments the double stranded region is between 15 and 30 basepairs in length.
- the RNA comprises one strand that forms a double-stranded region by intramolecular self-hybridization, which is preferably complementary over at least 19 bases. In some embodiments, the RNA comprises two separate strands that form a double-stranded region by intermolecular hybridization that is complementary over at least 19 bases.
- a vector encoding the RNA is introduced to the target cell. For example, the vector encoding the RNA can be transfected into the target cell and the RNA is then transcribed by cellular polymerases. See, e.g., Koyanagi et al.
- a recombinant virus comprising nucleic acid encoding the RNA can be produced.
- Introducing the RNA into a target cell then comprises infecting the target cell with the recombinant virus.
- Cellular polymerases transcribe the RNA resulting in expression of the RNA within the target cell.
- Engineering recombinant viruses is well known to those having ordinary skill in the art. See, e.g., Tritto et al. The acquired immune response to the mucosal adjuvant LTK63 imprints the mouse lung with a protective signature. Journal of Immunology. 179(8):5346-57, 2007 Oct 15, herein incorporated by reference.
- One of skill would readily appreciate the multiple factors involved in selecting the appropriate virus and vector components needed to optimize recombinant virus production for use with the presently disclosed subject matter without the necessity of further detailed discussion herein.
- a method of treating cancer in a subject comprises administering an effective amount of an exosome produced by a cancer cell, such as cancer cells and exosomes disclosed herein, to a subject in need thereof, wherein the exosome comprises one or more cancer antigens and is substantially lacking one or more immunosuppressive polypeptides.
- the administered exosome can act as a "vaccine” with regard to the antigens provided on the exosomes and thereby promotes an immune response against the antigens by the subject's immune system.
- the term "vaccine” as used herein is not intended to limit the present subject matter to methods of preventing disorders only, but is inclusive of therapies for treating disorders already present in a subject.
- the stimulated immune system is then capable of mounting a response against cells comprising the antigens, including for example cancer cells.
- the presently disclosed subject matter further provides in some embodiments a method of stimulating an immune response in a subject against one or more antigens, comprising administering an effective amount of an exosome produced by a cell and comprising one or more antigens to a subject in need thereof, wherein the exosome is substantially lacking one or more immunosuppressive polypeptides.
- treatment relate to any treatment of a condition of interest (e.g., a cancer), including but not limited to prophylactic treatment and therapeutic treatment.
- treatment or “treating” include, but are not limited to: preventing a condition of interest or the development of a condition of interest; inhibiting the progression of a condition of interest; arresting or preventing the development of a condition of interest; reducing the severity of a condition of interest; ameliorating or relieving symptoms associated with a condition of interest; and causing a regression of the condition of interest or one or more of the symptoms associated with the condition of interest.
- cancer refers to all types of cancer or neoplasm or malignant tumors found in animals, including leukemias, carcinomas and sarcomas.
- leukemia is meant broadly progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow.
- Leukemia diseases include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell
- carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
- exemplary carcinomas include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebhform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma
- sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
- Sarcomas include, for example, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilns' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell
- melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
- Melanomas include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma subungal melanoma, and superficial spreading melanoma.
- Additional cancers include, for example, Hodgkin's Disease, Non-
- Hodgkin's Lymphoma multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, and adrenal cortical cancer.
- the treated cancer is a solid tumor.
- the treated cancer is an ovarian cancer cell, a cervical cancer cell, a breast cancer cell, an endometrial cancer cell, colon cancer cell, a prostate cancer cell, a lung cancer cell, a melanoma cells, or a pancreatic cancer cell.
- an amount of the therapeutic composition e.g., a composition comprising an exosome disclosed herein
- a measurable biological response e.g., an immune response (e.g., antibody production and/or T cell activation) by the subject against antigens contained on the exosome and/or a measurable decrease in tumor size, activity, etc.
- an immune response e.g., antibody production and/or T cell activation
- a therapeutic composition of the presently disclosed subject matter can be varied so as to administer an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular subject and/or application.
- the selected dosage level will depend upon a variety of factors including the activity of the therapeutic composition, formulation, the route of administration, combination with other drugs or treatments, severity of the condition being treated, and the physical condition and prior medical history of the subject being treated.
- a minimal dose is administered, and the dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of a therapeutically effective dose, as well as evaluation of when and how to make such adjustments, are known to those of ordinary skill in the art of medicine.
- Administration may be, for example, intravenously, intratumorally, subcutaneously, transdermal ⁇ , or intraperitoneal ⁇ .
- the exosomes can be employed in an amount ranging from about 0.005 mg/kg to about 100 mg/kg, preferably about 10 to 50 or 10 to 70 mg/kg, and more preferably from about 10 mg/kg to about 30 mg/kg.
- formulation and dose see U.S. Patent Nos. 5,326,902; 5,234,933; PCT International Publication No. WO 93/25521 ; Berkow et a!.. (1997) The Merck Manual of Medical Information, Home ed.
- Suitable methods for administering to a subject a composition comprising exosomes disclosed herein in accordance with the methods of the present subject matter include but are not limited to systemic administration, intravenous administration, intratumoral administration, intramuscular administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, inhalation, intratracheal installation, surgical implantation, transdermal delivery, local injection, and hyper-velocity injection/bombardment.
- continuous infusion can enhance drug accumulation at a target site, if desired (see, e.g., U.S. Patent No. 6,180,082).
- the particular mode of drug administration used in accordance with the methods of the present subject matter depends on various factors, including but not limited to the particular exosome composition (e.g., antigen characteristics and concentration, presence of additional antigenic molecules such as SAgs, etc.), carrier employed, the severity of the condition to be treated, and mechanisms for metabolism or removal of the drug following administration.
- a preferred subject is a vertebrate subject.
- a preferred vertebrate is warm-blooded; a preferred warm-blooded vertebrate is a mammal.
- a preferred mammal is most preferably a human.
- the term "subject" includes both human and animal subjects.
- veterinary therapeutic uses are provided in accordance with the presently disclosed subject matter.
- the presently disclosed subject matter provides for the treatment of mammals such as humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and/or animals of social importance to humans, such as animals kept as pets or in zoos.
- Examples of such animals include but are not limited to: carnivores such as cats and dogs; swine, including pigs, hogs, and wild boars; ruminants and/or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels; and horses. Also provided is the treatment of birds, including the treatment of those kinds of birds that are endangered and/or kept in zoos, as well as fowl, and more particularly domesticated fowl, i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economic importance to humans.
- carnivores such as cats and dogs
- swine including pigs, hogs, and wild boars
- ruminants and/or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and came
- livestock including, but not limited to, domesticated swine, ruminants, ungulates, horses (including race horses), poultry, and the like.
- livestock including, but not limited to, domesticated swine, ruminants, ungulates, horses (including race horses), poultry, and the like.
- Fas Ligand Fas Ligand
- the present methodology can function equally well in the suppression of one or more other immunosuppressive polypeptides found on tumor-derived exosomes, including but not limited to programmed death ligand-1 , programmed death ligand-2, B7- H3, and B7-H4.
- tumor-derived cells (2x10 5 cells/well) were plated onto six-well tissue culture plates in 2 ml antibiotic-free Roswell Park Memorial Institute (RPMI) media supplemented with ultracenthfuged FBS.
- RPMI Roswell Park Memorial Institute
- the siRNA duplex solution (2-8 ⁇ l of siRNA duplex: 0.25-1 ⁇ g siRNA into 10O ⁇ l siRNA Transfection mediumTM (Santa Cruz Biotechnology, Inc, Santa Cruz, CA, cat no. sc-36868) was added directly to dilute Transfection Reagent (Santa Cruz Biotechnology, Inc, cat no. sc-29528).
- the cells were incubated for 18hrs, the medium removed and replaced with complete medium with 10% ultracentrifuged FBS and 1X antibiotics. After 72 hours, the conditioned medium was removed and exosomes isolated.
- Antibody and siRNA pairs are commercially available for the known immunosuppressive polypeptides.
- the exemplary antibody and siRNAs utilized in the present examples were purchased from Santa Cruz Biotechnology, Inc, Santa Cruz, CA and are as follows: Protein siRNA Antibody
- Exosomes were isolated from the conditioned media of siRNA-treated tumor cells. Conditioned media from ovarian cancer cell lines were used to isolate the exosomes. The >500kD material was concentrated by ultrafiltration and applied to a SEPHAROSE ® 2B column (Sigma Chemical Co., St. Louis, Missouri, U.S.A.). The >5x10 7 Da material was subjected to floatation on a discontinuous sucrose gradient and the quantity of isolated exosomes determined by the Bradford microassay method (Bradford, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding, Anal Biochem, 72, 248-254 (1976)).
- IL-2 human T-cell lymphoma with a functional TcR/CD3 complex capable of synthesizing IL-2 was obtained from the American Type Culture Collection (Rockville, MD). These cells were utilized as an in vitro assay for lymphocyte modulation by ascites-dehved MF. These T cell lines were grown in RPM1 1640 medium supplemented with 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 20OmM L-glutamate, 100 ⁇ g/ml streptomycin and 100 IU/ml penicillin in a humidified 5% CO2 chamber at 37 0 C. Cell viability was evaluated by trypan blue exclusion. All cultures utilized for this study were >95% viable.
- viable Jurkat cells (10 6 cells/ml) were incubated in a medium supplemented with 400 ⁇ g/ml isolated exosomes, modified with siRNA or unmodified, for 4 days and were compared with unexposed Jurkat cells or Jurkat cells exposed to the analogous chromatographic fractions from control sera. After 4 days, the cells were centrifuged, the cell pellet washed, and used for either protein or mRNA analysis. To assess CD3-zeta protein, the cell pellet was lysed using 5OmM
- HEPES pH7.2, 15OmM NaCI, 5mM EDTA, 1 mM sodium orthovanadate, 2.5% Triton X-100, 200 ⁇ g/ml trypsin/chymotrypsin inhibitor, 200 ⁇ g/ml chymostatin and 2mM PMSF.
- the cell lysate was assayed for protein by the BioRad protein assay (Bio-Rad Laboratories, Hercules, CA).
- CD3-zeta The modulation of CD3-zeta was analyzed by western immunoblot using a 15% SDS-PAGE gel, as described above with mouse monoclonal anti-CD3-zeta and rabbit polyclonal anti-JAK3 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) as the primary antibody (Figure 2).
- Exosomes derived from tumor cell cultures treated with siRNA for FasL and thus not expressing FasL failed to inhibit the expressions of CD3-zeta or JAK3 within the T cell cultures. Since the suppression of CD3-zeta and JAK3 have been correlated with the presence of ovarian cancer, the extent of disease, and overall patient survival, the reversal of this exosome-derived suppression can result in increased patient T cell responses and improved patient survival.
- exosomes can be isolated from B16-F10 cells, which will suppress T cell activation.
- the exosomal FasL1 expression can be modified by treatment of the B16-F10 cells with siRNA from FasL.
- the modified exosomes can be labeled with SEA.
- 100 ⁇ l of SEA 50 ⁇ g/ml
- PBS phosphate-buffered saline
- Unincorporated SEA can be removed with by chromatographing on Sepharose 2B.
- mice can be immunized sc with 10 ⁇ g exosome/SEA complex, three times at 7-day intervals.
- B16-F10 cells (1 *10 5 ) can then be injected sc, 1 week after the last injection.
- the tumor sizes can be measured every 2 days, and the long-term survival was observed daily up to 90 days.
- Mice can be euthanized when tumors reached 3cm in diameter. Each group can contain 10 mice, for example.
- the splenic T cells can be isolated using pan-T-cell magnetic beads to 95% purity as confirmed by flow cytometry.
- These CD3+ T cells, 1 ⁇ 10 5 obtained from treated mice can be co-incubated with 2*10 4 inactivated B16-F10 cells (inactivated by treatment with 50 ⁇ g/ml mitomycin C) in 96-well plates for 5 days.
- T-cell proliferation can be determined after 72 hours using the CellTiter Aqueous cell proliferation assay (Promega).
- IFN- ⁇ To assess immunologic activity, the production of IFN- ⁇ can be defined.
- splenocytes For IFN-Y enzyme-linked immunospot (ELISPOT) assay, 7 days after the last immunization, splenocytes can be isolated and assayed at 5 ⁇ 10 6 /ml.
- the lymphocytes can be stimulated with 10 ⁇ g/ml of the labeled, modified exosomes versus unlabeled, unmodified exosomes or 5 ⁇ g/ml Concanavalin A for 3 days.
- the treated lymphocytes will be transferred to the ELISPOT plate, and the IFN- ⁇ -specific secreting colonies will be counted using a dissecting microscope.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Cell Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009547455A JP2010516786A (en) | 2007-01-26 | 2008-01-28 | Modification of exosome components for use as a vaccine |
US12/524,432 US8455188B2 (en) | 2007-01-26 | 2008-01-28 | Modification of exosomal components for use as a vaccine |
EP08728400A EP2117305A4 (en) | 2007-01-26 | 2008-01-28 | Modification of exosomal components for use as a vaccine |
CA002676143A CA2676143A1 (en) | 2007-01-26 | 2008-01-28 | Modification of exosomal components for use as a vaccine |
BRPI0806436-9A BRPI0806436A2 (en) | 2007-01-26 | 2008-01-28 | modification of exosomal components for use as a vaccine |
AU2008207735A AU2008207735B2 (en) | 2007-01-26 | 2008-01-28 | Modification of exosomal components for use as a vaccine |
IL200027A IL200027A0 (en) | 2007-01-26 | 2009-07-23 | Modification of exosomal components for use as a vaccine |
US13/875,392 US20130243820A1 (en) | 2007-01-26 | 2013-05-02 | Modification of exosomal components for use as a vaccine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US89764507P | 2007-01-26 | 2007-01-26 | |
US60/897,645 | 2007-01-26 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/875,392 Continuation US20130243820A1 (en) | 2007-01-26 | 2013-05-02 | Modification of exosomal components for use as a vaccine |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2008092153A2 true WO2008092153A2 (en) | 2008-07-31 |
WO2008092153A3 WO2008092153A3 (en) | 2008-11-20 |
Family
ID=39645226
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2008/052205 WO2008092153A2 (en) | 2007-01-26 | 2008-01-28 | Modification of exosomal components for use as a vaccine |
Country Status (10)
Country | Link |
---|---|
US (1) | US8455188B2 (en) |
EP (1) | EP2117305A4 (en) |
JP (1) | JP2010516786A (en) |
CN (1) | CN101641010A (en) |
AU (1) | AU2008207735B2 (en) |
BR (1) | BRPI0806436A2 (en) |
CA (1) | CA2676143A1 (en) |
IL (1) | IL200027A0 (en) |
WO (1) | WO2008092153A2 (en) |
ZA (1) | ZA200905005B (en) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011080271A2 (en) | 2009-12-28 | 2011-07-07 | Centre De Recerca En Salut Internacional De Barcelona | Exosomes derived from reticulocytes infected with plasmodium sp., method for obtaining them and uses thereof |
US8217149B2 (en) | 2008-12-09 | 2012-07-10 | Genentech, Inc. | Anti-PD-L1 antibodies, compositions and articles of manufacture |
WO2013025779A1 (en) | 2011-08-15 | 2013-02-21 | Amplimmune, Inc. | Anti-b7-h4 antibodies and their uses |
US8652465B2 (en) | 2005-06-08 | 2014-02-18 | Emory University | Methods and compositions for the treatment of persistent infections |
WO2014049125A1 (en) * | 2012-09-28 | 2014-04-03 | Fundación Centro Nacional De Investigaciones Cardiovasculares Carlos Iii (Cnic) | Nucleotide sequence motifs directing nucleic acid location to extracellular vesicles |
WO2014100483A1 (en) | 2012-12-19 | 2014-06-26 | Amplimmune, Inc. | Anti-human b7-h4 antibodies and their uses |
EP2742154A4 (en) * | 2011-08-08 | 2015-08-12 | Caris Life Sciences Switzerland Holdings Gmbh | Biomarker compositions and methods |
WO2015110957A3 (en) * | 2014-01-21 | 2015-12-03 | De Beer Joel | Hybridosomes, compositions comprising the same, processes for their production and uses thereof |
US9598491B2 (en) | 2008-11-28 | 2017-03-21 | Emory University | Methods for the treatment of infections and tumors |
US10144917B2 (en) | 2014-08-29 | 2018-12-04 | Calixar | Method for preparing a vaccine antigen, resulting vaccine antigen and uses |
US10799457B2 (en) | 2010-02-05 | 2020-10-13 | University Of Louisville Research Foundation, Inc. | Exosomal compositions and methods for the treatment of disease |
US10815520B2 (en) | 2017-04-07 | 2020-10-27 | University Of Louisville Research Foundation, Inc. | Nanovesicles, methods, and systems for diagnosis and prognosis of cancer |
US11103586B2 (en) * | 2011-12-07 | 2021-08-31 | Oxford University Innovation Limited | Exosomes for delivery of biotherapeutics |
US11230715B2 (en) | 2009-04-17 | 2022-01-25 | Oxford University Innovation Limited | Composition for delivery of genetic material |
US11274139B2 (en) | 2013-04-12 | 2022-03-15 | Evox Therapeutics Ltd | Therapeutic delivery vesicles |
US11890382B2 (en) | 2011-11-07 | 2024-02-06 | University Of Louisville Research Foundation, Inc. | Edible plant-derived microvesicle compositions for diagnosis and treatment of disease |
US12036262B2 (en) | 2017-11-22 | 2024-07-16 | University Of Louisville Research Foundation, Inc. | Edible plant-derived nanoparticles for regulation of gut microbiota |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3517151B1 (en) * | 2006-03-09 | 2021-04-21 | Aethlon Medical, Inc. | Extracorporeal removal of microvesicular particles |
US8768629B2 (en) * | 2009-02-11 | 2014-07-01 | Caris Mpi, Inc. | Molecular profiling of tumors |
IL301804A (en) * | 2006-05-18 | 2023-05-01 | Caris Mpi Inc | System and method for determining individualized medical intervention for a disease state |
CN103276062A (en) | 2007-07-25 | 2013-09-04 | 路易斯维尔大学研究基金会公司 | Exosome-associated microRNA as a diagnostic marker |
EP2347009A4 (en) * | 2008-10-14 | 2012-05-30 | Caris Mpi Inc | Gene and gene expressed protein targets depicting biomarker patterns and signature sets by tumor type |
EP2358912B1 (en) * | 2008-10-30 | 2016-10-12 | Caris Life Sciences Switzerland Holdings GmbH | Methods for assessing rna patterns |
JP2012508577A (en) * | 2008-11-12 | 2012-04-12 | カリス ライフ サイエンシズ ルクセンブルク ホールディングス | Method and system for using exosomes to determine phenotype |
CN103237901B (en) | 2010-03-01 | 2016-08-03 | 卡里斯生命科学瑞士控股有限责任公司 | For treating the biomarker of diagnosis |
KR20130043104A (en) | 2010-04-06 | 2013-04-29 | 카리스 라이프 사이언스 룩셈부르크 홀딩스 | Circulating biomarkers for disease |
US11497733B2 (en) * | 2015-02-09 | 2022-11-15 | Synta Pharmaceuticals Corp. | Combination therapy of HSP90 inhibitors and PD-1 inhibitors for treating cancer |
EP3515453A1 (en) * | 2016-09-22 | 2019-07-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for reprograming immune environment in a subject in need thereof |
WO2018085275A1 (en) * | 2016-11-02 | 2018-05-11 | The Regents Of The University Of California | Targeting lats1/2 and the hippo intracellular signaling pathway for cancer immunotherapy |
KR102048228B1 (en) * | 2016-12-02 | 2019-11-25 | 가톨릭대학교 산학협력단 | Exosome for stimulating T cell and pharmaceutical use thereof |
EP3600254A4 (en) | 2017-03-21 | 2020-10-21 | Exoprother Medical Ltd. | Native cell derived vesicles containing tumor suppressor proteins for therapy |
CN107875376A (en) * | 2017-10-18 | 2018-04-06 | 深圳先进技术研究院 | Microvesicle, preparation method and the usage comprising NY ESO 1 |
US11510876B2 (en) * | 2019-03-29 | 2022-11-29 | Mayo Foundation For Medical Education And Research | In vivo targeting of extracellular vesicles |
CN115919798A (en) * | 2022-11-14 | 2023-04-07 | 华中科技大学同济医学院附属协和医院 | Tumor vaccine based on tumor extracellular particles and preparation method and application thereof |
Citations (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2909462A (en) | 1955-12-08 | 1959-10-20 | Bristol Myers Co | Acrylic acid polymer laxative compositions |
US5234933A (en) | 1991-10-31 | 1993-08-10 | Board Of Governors Of Wayne State University And Vanderbilt University | Cyclic hydroxamic acids |
WO1993025521A1 (en) | 1992-06-08 | 1993-12-23 | Board Of Governors Of Wayne State University | Aryl aliphatic acids |
US5326902A (en) | 1992-03-30 | 1994-07-05 | Gruenenthal Gmbh | Oxyalkyne compounds, pharmaceutical compositions containing them and processes for preparing such compounds and compositions |
US5612030A (en) | 1995-01-17 | 1997-03-18 | University Of Kentucky Research Foundation | Anti-idiotype monoclonal antibody 1A7 and use for the treatment of melanoma and small cell carcinoma |
WO1998016247A1 (en) | 1996-10-11 | 1998-04-23 | The Regents Of The University Of California | Immunostimulatory polynucleotide/immunomodulatory molecule conjugates |
WO1999007409A1 (en) | 1997-08-04 | 1999-02-18 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Product comprising at least a double stranded rna combined with at least an antiviral agent |
WO1999032619A1 (en) | 1997-12-23 | 1999-07-01 | The Carnegie Institution Of Washington | Genetic inhibition by double-stranded rna |
WO2000001846A2 (en) | 1998-07-03 | 2000-01-13 | Devgen N.V. | Characterisation of gene function using double stranded rna inhibition |
WO2000028001A1 (en) | 1998-11-05 | 2000-05-18 | Institut National De La Sante Et De La Recherche Medicale | Modified exosomes and uses |
WO2000044895A1 (en) | 1999-01-30 | 2000-08-03 | Roland Kreutzer | Method and medicament for inhibiting the expression of a defined gene |
WO2000044914A1 (en) | 1999-01-28 | 2000-08-03 | Medical College Of Georgia Research Institute, Inc. | Composition and method for in vivo and in vitro attenuation of gene expression using double stranded rna |
US6136306A (en) | 1995-03-17 | 2000-10-24 | The Regents Of The University Of California | Method for treating tumors |
WO2000063364A2 (en) | 1999-04-21 | 2000-10-26 | American Home Products Corporation | Methods and compositions for inhibiting the function of polynucleotide sequences |
WO2001004313A1 (en) | 1999-07-09 | 2001-01-18 | American Home Products Corporation | Methods and compositions for preventing the formation of aberrant rna during transcription of a plasmid sequence |
US6180082B1 (en) | 1997-11-24 | 2001-01-30 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Method to enhance tissue accumulation of radiolabeled compounds |
US6203787B1 (en) | 1997-10-10 | 2001-03-20 | The Regents Of The University Of California | Treating tumors using implants comprising combinations of allogeneic cells |
US6207147B1 (en) | 1996-10-11 | 2001-03-27 | The Regents Of The University Of California | Cancer immunotherapy using tumor cells combined with mixed lymphocytes |
WO2001029058A1 (en) | 1999-10-15 | 2001-04-26 | University Of Massachusetts | Rna interference pathway genes as tools for targeted genetic interference |
US6235280B1 (en) | 1996-04-12 | 2001-05-22 | Malaya Chatterjee | Methods of delaying development of CEA-associated tumors using anti-idiotype antibody 3H1 |
WO2001036646A1 (en) | 1999-11-19 | 2001-05-25 | Cancer Research Ventures Limited | Inhibiting gene expression with dsrna |
US6277368B1 (en) | 1996-07-25 | 2001-08-21 | The Regents Of The University Of California | Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokine |
WO2001068836A2 (en) | 2000-03-16 | 2001-09-20 | Genetica, Inc. | Methods and compositions for rna interference |
WO2001075164A2 (en) | 2000-03-30 | 2001-10-11 | Whitehead Institute For Biomedical Research | Rna sequence-specific mediators of rna interference |
WO2001092513A1 (en) | 2000-05-30 | 2001-12-06 | Johnson & Johnson Research Pty Limited | METHODS FOR MEDIATING GENE SUPPRESION BY USING FACTORS THAT ENHANCE RNAi |
WO2002044321A2 (en) | 2000-12-01 | 2002-06-06 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Rna interference mediating small rna molecules |
WO2002055693A2 (en) | 2001-01-09 | 2002-07-18 | Ribopharma Ag | Method for inhibiting the expression of a target gene |
WO2002055692A2 (en) | 2001-01-09 | 2002-07-18 | Ribopharma Ag | Method for inhibiting the expression of a target gene and medicament for treating a tumor disease |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030198642A1 (en) | 1995-08-03 | 2003-10-23 | Johannes J. Geuze | Cell derived antigen presenting vesicles |
WO1998026747A2 (en) * | 1996-12-17 | 1998-06-25 | Terman David S | Superantigen based methods and compositions for treatment of diseases |
FR2766205B1 (en) | 1997-07-16 | 2002-08-30 | Inst Nat Sante Rech Med | NOVEL METHOD FOR SENSITIZING ANTIGEN PRESENTING CELLS AND NOVEL MEANS FOR IMPLEMENTING THE METHOD |
FR2788780B1 (en) | 1999-01-27 | 2001-03-30 | Ap Cells Inc | PROCESS FOR THE PREPARATION OF MEMBRANE VESICLES |
US20040241176A1 (en) * | 2000-04-27 | 2004-12-02 | Ap Cells. Inc. | Method of producing membrane vesicles |
US6812023B1 (en) | 2000-04-27 | 2004-11-02 | Anosys, Inc. | Methods of producing membrane vesicles |
SE0102327D0 (en) * | 2001-06-28 | 2001-06-28 | Active Biotech Ab | A novel engineered superantigen for human therapy |
EP1417229B1 (en) | 2001-08-17 | 2011-06-15 | Exothera L.L.C. | Methods and compounds for the targeting of protein to exosomes |
NZ519371A (en) * | 2002-06-04 | 2004-11-26 | Auckland Uniservices Ltd | Immunomodulatory constructs and their uses |
JP4939926B2 (en) | 2003-02-14 | 2012-05-30 | アノシス・インコーポレーテッド | Methods and compounds for generating antibodies and screening antibody repertoires |
EP1766053A4 (en) * | 2004-06-02 | 2007-12-12 | Sourcepharm Inc | Rna-containing microvesicles and methods therefor |
JP2008505104A (en) * | 2004-07-01 | 2008-02-21 | ユニヴァーシティ オヴ ピッツバーグ オヴ ザ コモンウェルス システム オヴ ハイアー エデュケーション | Immunosuppressive exosomes |
CA2504279A1 (en) * | 2005-04-15 | 2006-10-15 | University Of Saskatchewan | Materials and method of modulating the immune response using t helper-antigen presenting cells |
CN101842484B (en) | 2007-09-14 | 2015-07-29 | 俄亥俄州立大学研究基金会 | MIRNA in human peripheral blood microvesicles expresses and its purposes |
JP2012508577A (en) * | 2008-11-12 | 2012-04-12 | カリス ライフ サイエンシズ ルクセンブルク ホールディングス | Method and system for using exosomes to determine phenotype |
-
2008
- 2008-01-28 US US12/524,432 patent/US8455188B2/en not_active Expired - Fee Related
- 2008-01-28 WO PCT/US2008/052205 patent/WO2008092153A2/en active Application Filing
- 2008-01-28 AU AU2008207735A patent/AU2008207735B2/en not_active Ceased
- 2008-01-28 CA CA002676143A patent/CA2676143A1/en not_active Abandoned
- 2008-01-28 CN CN200880009056A patent/CN101641010A/en active Pending
- 2008-01-28 JP JP2009547455A patent/JP2010516786A/en active Pending
- 2008-01-28 EP EP08728400A patent/EP2117305A4/en not_active Withdrawn
- 2008-01-28 BR BRPI0806436-9A patent/BRPI0806436A2/en not_active IP Right Cessation
-
2009
- 2009-07-17 ZA ZA200905005A patent/ZA200905005B/en unknown
- 2009-07-23 IL IL200027A patent/IL200027A0/en unknown
Patent Citations (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2909462A (en) | 1955-12-08 | 1959-10-20 | Bristol Myers Co | Acrylic acid polymer laxative compositions |
US5234933A (en) | 1991-10-31 | 1993-08-10 | Board Of Governors Of Wayne State University And Vanderbilt University | Cyclic hydroxamic acids |
US5326902A (en) | 1992-03-30 | 1994-07-05 | Gruenenthal Gmbh | Oxyalkyne compounds, pharmaceutical compositions containing them and processes for preparing such compounds and compositions |
WO1993025521A1 (en) | 1992-06-08 | 1993-12-23 | Board Of Governors Of Wayne State University | Aryl aliphatic acids |
US5612030A (en) | 1995-01-17 | 1997-03-18 | University Of Kentucky Research Foundation | Anti-idiotype monoclonal antibody 1A7 and use for the treatment of melanoma and small cell carcinoma |
US6136306A (en) | 1995-03-17 | 2000-10-24 | The Regents Of The University Of California | Method for treating tumors |
US6235280B1 (en) | 1996-04-12 | 2001-05-22 | Malaya Chatterjee | Methods of delaying development of CEA-associated tumors using anti-idiotype antibody 3H1 |
US6277368B1 (en) | 1996-07-25 | 2001-08-21 | The Regents Of The University Of California | Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokine |
US6207147B1 (en) | 1996-10-11 | 2001-03-27 | The Regents Of The University Of California | Cancer immunotherapy using tumor cells combined with mixed lymphocytes |
WO1998016247A1 (en) | 1996-10-11 | 1998-04-23 | The Regents Of The University Of California | Immunostimulatory polynucleotide/immunomodulatory molecule conjugates |
WO1999007409A1 (en) | 1997-08-04 | 1999-02-18 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Product comprising at least a double stranded rna combined with at least an antiviral agent |
US6203787B1 (en) | 1997-10-10 | 2001-03-20 | The Regents Of The University Of California | Treating tumors using implants comprising combinations of allogeneic cells |
US6180082B1 (en) | 1997-11-24 | 2001-01-30 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Method to enhance tissue accumulation of radiolabeled compounds |
WO1999032619A1 (en) | 1997-12-23 | 1999-07-01 | The Carnegie Institution Of Washington | Genetic inhibition by double-stranded rna |
WO2000001846A2 (en) | 1998-07-03 | 2000-01-13 | Devgen N.V. | Characterisation of gene function using double stranded rna inhibition |
WO2000028001A1 (en) | 1998-11-05 | 2000-05-18 | Institut National De La Sante Et De La Recherche Medicale | Modified exosomes and uses |
WO2000044914A1 (en) | 1999-01-28 | 2000-08-03 | Medical College Of Georgia Research Institute, Inc. | Composition and method for in vivo and in vitro attenuation of gene expression using double stranded rna |
CA2359180A1 (en) | 1999-01-30 | 2000-08-03 | Roland Kreutzer | Method and medicament for inhibiting the expression of a given gene |
WO2000044895A1 (en) | 1999-01-30 | 2000-08-03 | Roland Kreutzer | Method and medicament for inhibiting the expression of a defined gene |
WO2000063364A2 (en) | 1999-04-21 | 2000-10-26 | American Home Products Corporation | Methods and compositions for inhibiting the function of polynucleotide sequences |
WO2001004313A1 (en) | 1999-07-09 | 2001-01-18 | American Home Products Corporation | Methods and compositions for preventing the formation of aberrant rna during transcription of a plasmid sequence |
WO2001029058A1 (en) | 1999-10-15 | 2001-04-26 | University Of Massachusetts | Rna interference pathway genes as tools for targeted genetic interference |
WO2001036646A1 (en) | 1999-11-19 | 2001-05-25 | Cancer Research Ventures Limited | Inhibiting gene expression with dsrna |
WO2001068836A2 (en) | 2000-03-16 | 2001-09-20 | Genetica, Inc. | Methods and compositions for rna interference |
WO2001075164A2 (en) | 2000-03-30 | 2001-10-11 | Whitehead Institute For Biomedical Research | Rna sequence-specific mediators of rna interference |
WO2001092513A1 (en) | 2000-05-30 | 2001-12-06 | Johnson & Johnson Research Pty Limited | METHODS FOR MEDIATING GENE SUPPRESION BY USING FACTORS THAT ENHANCE RNAi |
WO2002044321A2 (en) | 2000-12-01 | 2002-06-06 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Rna interference mediating small rna molecules |
WO2002055693A2 (en) | 2001-01-09 | 2002-07-18 | Ribopharma Ag | Method for inhibiting the expression of a target gene |
WO2002055692A2 (en) | 2001-01-09 | 2002-07-18 | Ribopharma Ag | Method for inhibiting the expression of a target gene and medicament for treating a tumor disease |
Non-Patent Citations (65)
Title |
---|
A. HEISER ET AL., CANCER RES., vol. 61, 2001, pages 338 |
A. MAKENSEN ET AL., INT. J. CANCER, vol. 86, 2000, pages 385 |
B. THURNER ET AL., J. EXP. MED., vol. 190, 1999, pages 16169 |
BASS, NATURE, vol. 411, 2001, pages 428 - 429 |
BATZER ET AL., NUCLEIC ACID RES, vol. 19, 1991, pages 5081 |
BAZZETT ET AL.: "Modulation of proliferation and chemosensitivity by procathepsin D in ovarian cancer", GYNECOLOGIC ONCOLOGY, vol. 74, 1999, pages 181 - 187 |
BERKOW ET AL.: "The Merck Manual of Medical Information", 1997, MERCK RESEARCH LABORATORIES |
BERNSTEIN ET AL., NATURE, vol. 409, 2001, pages 363 - 366 |
BR SINGH; MJ BETLEY: "Comparative structural analysis of staphylococcal enterotoxins A and E", J BIOL CHEM, vol. 264, 1989, pages 4404 - 4411 |
BRADFORD: "A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding", ANAL BIOCHEM, vol. 72, 1976, pages 248 - 254, XP025650297, DOI: doi:10.1016/0003-2697(76)90527-3 |
C. MILAZZO ET AL., BLOOD, vol. 101, 2002, pages 977 |
CHINNI ET AL.: "Cathepsin D and glucose-regulated protein 78 recognized by the humoral response of ovarian cancer patients", CLINICAL CANCER RESEARCH, vol. 3, 1997, pages 1557 - 1564 |
D. BOCZKOWSKI ET AL., J. EXP. MED., vol. 184, 1996, pages 465 |
DUCH ET AL., TOXICOL. LETT., vol. 100-101, 1998, pages 255 - 263 |
EBADI: "CRC Desk Reference of Clinical Pharmacoloqy", 1998, CRC PRESS |
ELBASHIR ET AL., GENES DEV, vol. 15, 2001, pages 188 - 200 |
ELBASHIR ET AL., NATURE, vol. 411, 2001, pages 494 - 498 |
F. O. NESTLE ET AL., NAT. MED., vol. 4, 1998, pages 328 |
F. SALLUSTO ET AL., J. EXP. MED., vol. 179, 1994, pages 1109 |
FIRE ET AL., NATURE, vol. 391, 1998, pages 806 - 811 |
FIRE, TRENDS GENET, vol. 15, 1999, pages 358 - 363 |
FREIREICH ET AL., CANCER CHEMOTHER REP., vol. 50, 1966, pages 219 - 244 |
G. SCHULER ET AL., CURR. OPIN. IMMUNOL., vol. 15, 2003, pages 138 |
GIBB, R. K. ET AL.: "Apoptosis as a measure of chemosensitivity to cisplatin and Taxol therapy in ovarian cancer cell lines", GYNECOLOGIC ONCOLOGY, vol. 65, 1997, pages 13 - 22 |
GOODMAN ET AL.: "Goodman & Gilman's the Pharmacological Basis of Therapeutics", 1996, MCGRAW-HILL HEALTH PROFESSIONS DIVISION |
HAMMOND ET AL., NATURE, vol. 404, 2000, pages 293 - 296 |
HUANG C; YU H; WANG Q; YANG G; MA W; XIA D; CHEN X; YI P; SHEN F; ZHENG H: "A novel antitumor approach: SEA-anchored tumor cells expressing heat shock protein 70 onto the surface elicit strong antitumor efficacy", IMMUNOL LETT, vol. 101, 2005, pages 71 - 80 |
I. M. BELYAKOV ET AL., PROC. NATL. ACAD. SCI. USA, vol. 96, 1999, pages 4512 |
J. A BERZOFSKY ET AL., NAT. REV. IMMUNOL., vol. 1, 2001, pages 209 |
J. A. BERZOFSKY ET AL., J. CLIN. INVEST., vol. 113, 2004, pages 1515 |
J. BANCHEREAU ET AL., CANCER RES., vol. 61, 2001, pages 6451 |
J. D. AHLERS ET AL., PROC. NAT. ACAD. SCI. USA, vol. 99, 2002, pages 13020 |
J. FIELDS ET AL., NATURE, vol. 186, 4 June 1960 (1960-06-04), pages 778 - 780 |
J. IMMUNOL., vol. 166, 2001, pages 2953 |
J. L. MARSHALL ET AL., J. CLIN. ONCOL., vol. 18, 2000, pages 3964 |
J. W. SIMONS ET AL., CANCER RES., vol. 59, 1999, pages 5160 |
JOURNAL OF IMMUNOLOGY, vol. 179, no. 8, 15 October 2007 (2007-10-15), pages 5346 - 57 |
K. M. HEGE ET AL., LUNG CANCER, vol. 41, 2003, pages 5103 |
KATZUNQ: "Basic & Clinical Pharmacoloqy", 2001, LANGE MEDICAL BOOKS/MCGRAW-HILL MEDICAL PUB |
KLINMAN ET AL., PROC. NATL. ACAD. SCI., USA, vol. 93, 1996, pages 2879 - 2883 |
KOYANAGI E: "Long-term exposure to superantigen induces p27Kip1 and Bcl-2 expression in effector memory CD4+ T cells", CELLULAR IMMUNOLOGY, vol. 248, no. 2, August 2007 (2007-08-01), pages 77 - 85, XP022401826, DOI: doi:10.1016/j.cellimm.2007.09.002 |
L. FONG ET AL., J. IMMUNOL., vol. 167, 2001, pages 7150 |
L. FONG; E. G. ENGLEMAN, ANNU. REV. IMMUNOL., vol. 15, 2003, pages 138 |
M. JAFFEE ET AL., J. CLIN. ONCOL., vol. 19, 2001, pages 145 |
M. POWELL; M. NEWMAN: "Vaccine Design, The Subunit and Adjuvant Approach", 1995, PLENUM PRESS, pages: 147 |
M. Z. ZHU ET AL., CLIN. CANCER RES., vol. 6, 2000, pages 24 |
MAKHIJA ET AL.: "Regulation of chemotherapy induced apoptosis in ovarian cancer cell spheroids", INTERNATIONAL JOURNAL OF ONCOLOGY, vol. 14, 1999, pages 515 - 521 |
MCHUGH RS; NAGARAJAN S; WANG Y; SELL KW; SELVARAJ P: "Protein transfer of glycosyl-phosphatidylinositol-137- 1 into tumor cell membranes: a novel approach to tumor immunotherapy", CANCER RES, vol. 59, 1999, pages 2433 - 7, XP002973300 |
NAGARAJAN S; SELVARAJ P.: "Glycolipid-anchored IL-12 expressed on tumor cell surface induces antitumor immune response", CANCER RES, vol. 62, 2002, pages 2869 - 74, XP002320354 |
NYKANEN ET AL., CELL, vol. 107, 2001, pages 309 - 321 |
OHTSUKA ET AL., J BIOL CHEM, vol. 260, 1985, pages 2605 - 2608 |
PHARMEUROPA, vol. 8, no. 2, June 1996 (1996-06-01) |
R. SALGIA ET AL., J. CLIN. ONCOL., vol. 21, 2003, pages 624 |
R. SOIFFER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 95, 1998, pages 13141 |
REMINQTON ET AL.: "Reminqton's Pharmaceutical Sciences", 1975, MACK PUB. CO. |
ROSSOLINI ET AL., MOL CELL PROBES, vol. 8, 1994, pages 91 - 98 |
S. A. ROSENBERG ET AL., NAT. MED., vol. 4, 1998, pages 321 |
S. K. NAIR ET AL., EUR. J. IMMUNOL., vol. 27, 1997, pages 589 |
See also references of EP2117305A4 |
SPEIQHT: "Averv's Drug Treatment: A Guide to the Properties. Choice. Therapeutic Use and Economic Value of Drugs in Disease Management", 1997, ADIS INTERNATIONAL |
TAYLOR; GERCEL-TAYLOR, BRITISH JOURNAL OF CANCER, vol. 92, 2005, pages 305 - 311 |
TRITTO ET AL.: "The acquired immune response to the mucosal adjuvant LTK63 imprints the mouse lung with a protective signature", JOURNAL OF IMMUNOLOGY, vol. 179, no. 8, 15 October 2007 (2007-10-15), pages 5346 - 57 |
WIANNY; ZERNICKA-GOETZ, NATURE CELL BIOL, vol. 2, 1999, pages 70 - 75 |
Z. SU ET AL., CANCER RES., vol. 63, 2003, pages 2127 |
ZHOU ET AL.: "Induction of CML28 - specific cytotoxic T cell responses using co-transfected dendritic cells with CML28 DNA vaccine and SOCS1 small interfering RNA expression vector", BIOCHEMICAL & BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 347, 2006, pages 200 - 207, XP024925487, DOI: doi:10.1016/j.bbrc.2006.06.093 |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9457080B2 (en) | 2005-06-08 | 2016-10-04 | Emory University | Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway |
US11359013B2 (en) | 2005-06-08 | 2022-06-14 | Emory University | Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway |
US10370446B2 (en) | 2005-06-08 | 2019-08-06 | Emory University | Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway |
US8652465B2 (en) | 2005-06-08 | 2014-02-18 | Emory University | Methods and compositions for the treatment of persistent infections |
US9598491B2 (en) | 2008-11-28 | 2017-03-21 | Emory University | Methods for the treatment of infections and tumors |
US8217149B2 (en) | 2008-12-09 | 2012-07-10 | Genentech, Inc. | Anti-PD-L1 antibodies, compositions and articles of manufacture |
US9920123B2 (en) | 2008-12-09 | 2018-03-20 | Genentech, Inc. | Anti-PD-L1 antibodies, compositions and articles of manufacture |
US11230715B2 (en) | 2009-04-17 | 2022-01-25 | Oxford University Innovation Limited | Composition for delivery of genetic material |
ES2362589A1 (en) * | 2009-12-28 | 2011-07-08 | Centre De Recerca En Salut Internacional De Barcelona | Exosomes derived from reticulocytes infected with plasmodium sp., method for obtaining them and uses thereof |
WO2011080271A2 (en) | 2009-12-28 | 2011-07-07 | Centre De Recerca En Salut Internacional De Barcelona | Exosomes derived from reticulocytes infected with plasmodium sp., method for obtaining them and uses thereof |
US10799457B2 (en) | 2010-02-05 | 2020-10-13 | University Of Louisville Research Foundation, Inc. | Exosomal compositions and methods for the treatment of disease |
EP2742154A4 (en) * | 2011-08-08 | 2015-08-12 | Caris Life Sciences Switzerland Holdings Gmbh | Biomarker compositions and methods |
US9676854B2 (en) | 2011-08-15 | 2017-06-13 | Medimmune, Llc | Anti-B7-H4 antibodies and their uses |
WO2013025779A1 (en) | 2011-08-15 | 2013-02-21 | Amplimmune, Inc. | Anti-b7-h4 antibodies and their uses |
US11890382B2 (en) | 2011-11-07 | 2024-02-06 | University Of Louisville Research Foundation, Inc. | Edible plant-derived microvesicle compositions for diagnosis and treatment of disease |
US11103586B2 (en) * | 2011-12-07 | 2021-08-31 | Oxford University Innovation Limited | Exosomes for delivery of biotherapeutics |
WO2014049125A1 (en) * | 2012-09-28 | 2014-04-03 | Fundación Centro Nacional De Investigaciones Cardiovasculares Carlos Iii (Cnic) | Nucleotide sequence motifs directing nucleic acid location to extracellular vesicles |
WO2014100483A1 (en) | 2012-12-19 | 2014-06-26 | Amplimmune, Inc. | Anti-human b7-h4 antibodies and their uses |
US11274139B2 (en) | 2013-04-12 | 2022-03-15 | Evox Therapeutics Ltd | Therapeutic delivery vesicles |
US11649272B2 (en) | 2013-04-12 | 2023-05-16 | Evox Therapeutics Ltd. | Therapeutic delivery vesicles |
AU2015208837B2 (en) * | 2014-01-21 | 2020-06-18 | Anjarium Biosciences Ag | Hybridosomes, compositions comprising the same, processes for their production and uses thereof |
US11944706B2 (en) | 2014-01-21 | 2024-04-02 | Anjarium Biosciences Ag | Hybridosomes, compositions comprising the same, processes for their production and uses thereof |
EA037503B1 (en) * | 2014-01-21 | 2021-04-05 | Анджариум Байосайенсиз Аг | Process for manufacturing a hybridosome, hybridosome manufactureed by the process and method for delivering a therapeutic or diagnostic agent |
US10561610B2 (en) | 2014-01-21 | 2020-02-18 | Anjarium Biosciences Ag | Hybridosomes, compositions comprising the same, processes for their production and uses thereof |
WO2015110957A3 (en) * | 2014-01-21 | 2015-12-03 | De Beer Joel | Hybridosomes, compositions comprising the same, processes for their production and uses thereof |
US11484500B2 (en) | 2014-01-21 | 2022-11-01 | Anjarium Biosciences Ag | Hybridosomes, compositions comprising the same, processes for their production and uses thereof |
US10144917B2 (en) | 2014-08-29 | 2018-12-04 | Calixar | Method for preparing a vaccine antigen, resulting vaccine antigen and uses |
US10815520B2 (en) | 2017-04-07 | 2020-10-27 | University Of Louisville Research Foundation, Inc. | Nanovesicles, methods, and systems for diagnosis and prognosis of cancer |
US12036262B2 (en) | 2017-11-22 | 2024-07-16 | University Of Louisville Research Foundation, Inc. | Edible plant-derived nanoparticles for regulation of gut microbiota |
Also Published As
Publication number | Publication date |
---|---|
US20100092524A1 (en) | 2010-04-15 |
US8455188B2 (en) | 2013-06-04 |
AU2008207735A1 (en) | 2008-07-31 |
EP2117305A4 (en) | 2011-03-30 |
ZA200905005B (en) | 2010-04-28 |
JP2010516786A (en) | 2010-05-20 |
WO2008092153A3 (en) | 2008-11-20 |
AU2008207735B2 (en) | 2013-10-03 |
BRPI0806436A2 (en) | 2011-09-06 |
EP2117305A2 (en) | 2009-11-18 |
CN101641010A (en) | 2010-02-03 |
CA2676143A1 (en) | 2008-07-31 |
IL200027A0 (en) | 2010-04-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8455188B2 (en) | Modification of exosomal components for use as a vaccine | |
US20130243820A1 (en) | Modification of exosomal components for use as a vaccine | |
Hatfield et al. | Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy | |
Ho et al. | An immunomodulatory GpG oligonucleotide for the treatment of autoimmunity via the innate and adaptive immune systems | |
Marshall et al. | Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+ IL-17+ polyfunctional T cells that mediate rejection of murine tumors | |
Daniels et al. | A simple method to cure established tumors by inflammatory killing of normal cells | |
Rochlitz et al. | Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen‐specific immunotherapy in patients with MUC1‐positive advanced cancer | |
Rovere‐Querini et al. | HMGB1 is an endogenous immune adjuvant released by necrotic cells | |
Walker et al. | Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-12-and IFN-γ-dependent mechanisms | |
Lovett-Racke et al. | Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes | |
Chiche et al. | The role of natural killer cells in sepsis | |
Kelly et al. | Targeting the immune system in non–small-cell lung cancer: bridging the gap between promising concept and therapeutic reality | |
Buttari et al. | Resveratrol prevents dendritic cell maturation in response to advanced glycation end products | |
AU2009201222A1 (en) | Immunomodulation using altered dendritic cells | |
US20230210971A1 (en) | Edible plant exosome-like nanovectors for vaccination | |
Tian et al. | Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC | |
Melisi et al. | Toll-like receptor 9 agonists for cancer therapy | |
CN109069604A (en) | Neoantigen composition and its application method in immune oncotherapy | |
Flatekval et al. | Modulation of dendritic cell maturation and function with mono‐and bifunctional small interfering RNAs targeting indoleamine 2, 3‐dioxygenase | |
Kawamura et al. | Dendritic cells that endocytosed antigen-containing IgG-liposomes elicit effective antitumor immunity | |
Zhu et al. | The involvement of endoplasmic reticulum stress response in immune dysfunction of dendritic cells after severe thermal injury in mice | |
Kang et al. | Enhancing dendritic cell vaccine potency by combining a BAK/BAX siRNA‐mediated antiapoptotic strategy to prolong dendritic cell life with an intracellular strategy to target antigen to lysosomal compartments | |
Li et al. | Caveolin-1–mediated negative signaling plays a critical role in the induction of regulatory dendritic cells by DNA and protein coimmunization | |
Du et al. | CD38 deficiency downregulates the onset and pathogenesis of collagen‐induced arthritis through the NF‐κB pathway | |
Babaer et al. | Oligodeoxynucleotides ODN 2006 and M362 exert potent adjuvant effect through TLR-9/-6 synergy to exaggerate mammaglobin-A peptide specific cytotoxic CD8+ T lymphocyte responses against breast cancer cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200880009056.6 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08728400 Country of ref document: EP Kind code of ref document: A2 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 578546 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008207735 Country of ref document: AU Ref document number: 2676143 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200027 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 2009547455 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12524432 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008728400 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2008207735 Country of ref document: AU Date of ref document: 20080128 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 5484/DELNP/2009 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: PI0806436 Country of ref document: BR Kind code of ref document: A2 Effective date: 20090727 |