CN109310746B - 过继细胞转移与溶瘤病毒组合疗法 - Google Patents
过继细胞转移与溶瘤病毒组合疗法 Download PDFInfo
- Publication number
- CN109310746B CN109310746B CN201780038919.1A CN201780038919A CN109310746B CN 109310746 B CN109310746 B CN 109310746B CN 201780038919 A CN201780038919 A CN 201780038919A CN 109310746 B CN109310746 B CN 109310746B
- Authority
- CN
- China
- Prior art keywords
- cells
- cancer
- tumor
- pharmaceutical combination
- virus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 244000309459 oncolytic virus Species 0.000 title claims abstract description 75
- 238000012546 transfer Methods 0.000 title abstract description 19
- 238000002648 combination therapy Methods 0.000 title description 37
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 271
- 239000000427 antigen Substances 0.000 claims abstract description 176
- 108091007433 antigens Proteins 0.000 claims abstract description 176
- 102000036639 antigens Human genes 0.000 claims abstract description 176
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 118
- 201000011510 cancer Diseases 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 50
- 229960005486 vaccine Drugs 0.000 claims abstract description 11
- 210000004027 cell Anatomy 0.000 claims description 153
- 102100030704 Interleukin-21 Human genes 0.000 claims description 59
- 108010074108 interleukin-21 Proteins 0.000 claims description 59
- 241000700605 Viruses Species 0.000 claims description 54
- 108090000172 Interleukin-15 Proteins 0.000 claims description 53
- 102000003812 Interleukin-15 Human genes 0.000 claims description 53
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 53
- 229960002930 sirolimus Drugs 0.000 claims description 53
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 53
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 37
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 34
- 230000000174 oncolytic effect Effects 0.000 claims description 28
- 210000004443 dendritic cell Anatomy 0.000 claims description 27
- 210000000612 antigen-presenting cell Anatomy 0.000 claims description 25
- 241000700618 Vaccinia virus Species 0.000 claims description 24
- 238000012258 culturing Methods 0.000 claims description 23
- 108010002350 Interleukin-2 Proteins 0.000 claims description 22
- 230000010076 replication Effects 0.000 claims description 21
- 102100031413 L-dopachrome tautomerase Human genes 0.000 claims description 20
- 241001372913 Maraba virus Species 0.000 claims description 11
- -1 NY-ESO1 Proteins 0.000 claims description 10
- 238000011124 ex vivo culture Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 9
- 108090000623 proteins and genes Proteins 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 claims description 6
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 claims description 6
- 102000013529 alpha-Fetoproteins Human genes 0.000 claims description 6
- 108010026331 alpha-Fetoproteins Proteins 0.000 claims description 6
- 108010051081 dopachrome isomerase Proteins 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 5
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims description 5
- 108090000978 Interleukin-4 Proteins 0.000 claims description 5
- 102000000440 Melanoma-associated antigen Human genes 0.000 claims description 5
- 108050008953 Melanoma-associated antigen Proteins 0.000 claims description 5
- 102000006601 Thymidine Kinase Human genes 0.000 claims description 5
- 108020004440 Thymidine kinase Proteins 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 claims description 3
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 claims description 3
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 101800003344 Vaccinia growth factor Proteins 0.000 claims description 3
- 230000001464 adherent effect Effects 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 102100035526 B melanoma antigen 1 Human genes 0.000 claims description 2
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 claims description 2
- 108090001005 Interleukin-6 Proteins 0.000 claims description 2
- 102000003425 Tyrosinase Human genes 0.000 claims description 2
- 108060008724 Tyrosinase Proteins 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 208000037819 metastatic cancer Diseases 0.000 claims description 2
- 208000011575 metastatic malignant neoplasm Diseases 0.000 claims description 2
- 230000007812 deficiency Effects 0.000 claims 2
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 claims 1
- 102000008160 Cyclin A1 Human genes 0.000 claims 1
- 108010060267 Cyclin A1 Proteins 0.000 claims 1
- 102000010956 Glypican Human genes 0.000 claims 1
- 108050001154 Glypican Proteins 0.000 claims 1
- 108050007237 Glypican-3 Proteins 0.000 claims 1
- 101001027621 Homo sapiens Kinesin-like protein KIF20A Proteins 0.000 claims 1
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 claims 1
- 101000972282 Homo sapiens Mucin-5AC Proteins 0.000 claims 1
- 101001024605 Homo sapiens Next to BRCA1 gene 1 protein Proteins 0.000 claims 1
- 101000880770 Homo sapiens Protein SSX2 Proteins 0.000 claims 1
- 101000621309 Homo sapiens Wilms tumor protein Proteins 0.000 claims 1
- 102100034872 Kallikrein-4 Human genes 0.000 claims 1
- 102100037694 Kinesin-like protein KIF20A Human genes 0.000 claims 1
- 102100024144 Lengsin Human genes 0.000 claims 1
- 101710113750 Lengsin Proteins 0.000 claims 1
- 241001482085 Meloe Species 0.000 claims 1
- 102100022496 Mucin-5AC Human genes 0.000 claims 1
- 102100037686 Protein SSX2 Human genes 0.000 claims 1
- 108010002687 Survivin Proteins 0.000 claims 1
- 101150033527 TNF gene Proteins 0.000 claims 1
- 102100022748 Wilms tumor protein Human genes 0.000 claims 1
- 230000001678 irradiating effect Effects 0.000 claims 1
- 108010024383 kallikrein 4 Proteins 0.000 claims 1
- 230000008685 targeting Effects 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 49
- 210000004698 lymphocyte Anatomy 0.000 description 32
- 230000004044 response Effects 0.000 description 28
- 238000011282 treatment Methods 0.000 description 27
- 208000015181 infectious disease Diseases 0.000 description 23
- 238000002347 injection Methods 0.000 description 21
- 239000007924 injection Substances 0.000 description 21
- 239000013598 vector Substances 0.000 description 21
- 102000000588 Interleukin-2 Human genes 0.000 description 20
- 101800001466 Envelope glycoprotein E1 Proteins 0.000 description 16
- 241000711975 Vesicular stomatitis virus Species 0.000 description 16
- 210000003071 memory t lymphocyte Anatomy 0.000 description 16
- 238000001990 intravenous administration Methods 0.000 description 15
- 210000001519 tissue Anatomy 0.000 description 15
- 101710093778 L-dopachrome tautomerase Proteins 0.000 description 14
- 230000000259 anti-tumor effect Effects 0.000 description 14
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
- 230000000638 stimulation Effects 0.000 description 14
- 201000006625 congenital myasthenic syndrome 5 Diseases 0.000 description 11
- 210000004881 tumor cell Anatomy 0.000 description 11
- 241000124008 Mammalia Species 0.000 description 10
- 229940038426 oncolytic vaccine Drugs 0.000 description 10
- 230000035755 proliferation Effects 0.000 description 10
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 10
- 102100032912 CD44 antigen Human genes 0.000 description 9
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 9
- 108700019146 Transgenes Proteins 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 230000001461 cytolytic effect Effects 0.000 description 9
- 230000004069 differentiation Effects 0.000 description 9
- 238000001802 infusion Methods 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 8
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 8
- 102000004877 Insulin Human genes 0.000 description 8
- 108090001061 Insulin Proteins 0.000 description 8
- 102000008070 Interferon-gamma Human genes 0.000 description 8
- 108010074328 Interferon-gamma Proteins 0.000 description 8
- 102100033467 L-selectin Human genes 0.000 description 8
- 108091008874 T cell receptors Proteins 0.000 description 8
- 230000005867 T cell response Effects 0.000 description 8
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 229960003130 interferon gamma Drugs 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 7
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 7
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 238000007912 intraperitoneal administration Methods 0.000 description 7
- 230000002601 intratumoral effect Effects 0.000 description 7
- 230000003836 peripheral circulation Effects 0.000 description 7
- 230000003362 replicative effect Effects 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 206010039491 Sarcoma Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 238000011830 transgenic mouse model Methods 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- 238000002255 vaccination Methods 0.000 description 6
- 201000009030 Carcinoma Diseases 0.000 description 5
- 102000003886 Glycoproteins Human genes 0.000 description 5
- 108090000288 Glycoproteins Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 230000036755 cellular response Effects 0.000 description 5
- 238000007918 intramuscular administration Methods 0.000 description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 5
- 229960004854 viral vaccine Drugs 0.000 description 5
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 4
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- 229930182816 L-glutamine Natural products 0.000 description 4
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 4
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 4
- 108700020796 Oncogene Proteins 0.000 description 4
- 102000043276 Oncogene Human genes 0.000 description 4
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- 230000008029 eradication Effects 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 4
- 238000003364 immunohistochemistry Methods 0.000 description 4
- 230000001506 immunosuppresive effect Effects 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 230000001394 metastastic effect Effects 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 210000001550 testis Anatomy 0.000 description 4
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 3
- 238000011725 BALB/c mouse Methods 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 201000008808 Fibrosarcoma Diseases 0.000 description 3
- 241000711950 Filoviridae Species 0.000 description 3
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- 108010065805 Interleukin-12 Proteins 0.000 description 3
- 102000013462 Interleukin-12 Human genes 0.000 description 3
- 101710085938 Matrix protein Proteins 0.000 description 3
- 101710127721 Membrane protein Proteins 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 241001506137 Rapa Species 0.000 description 3
- 206010041067 Small cell lung cancer Diseases 0.000 description 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- 206010046865 Vaccinia virus infection Diseases 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 238000003501 co-culture Methods 0.000 description 3
- 210000004748 cultured cell Anatomy 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 230000001627 detrimental effect Effects 0.000 description 3
- 210000003162 effector t lymphocyte Anatomy 0.000 description 3
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000004923 pancreatic tissue Anatomy 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 208000007089 vaccinia Diseases 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 241000701242 Adenoviridae Species 0.000 description 2
- 241000712892 Arenaviridae Species 0.000 description 2
- 241001533362 Astroviridae Species 0.000 description 2
- 241000711404 Avian avulavirus 1 Species 0.000 description 2
- 241000701412 Baculoviridae Species 0.000 description 2
- 241000255797 Bahia Grande virus Species 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 241000702628 Birnaviridae Species 0.000 description 2
- 241000238097 Callinectes sapidus Species 0.000 description 2
- 241000520666 Carmotetraviridae Species 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 108091006027 G proteins Proteins 0.000 description 2
- 102000030782 GTP binding Human genes 0.000 description 2
- 108091000058 GTP-Binding Proteins 0.000 description 2
- 241000700739 Hepadnaviridae Species 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 108010066719 Interleukin Receptor Common gamma Subunit Proteins 0.000 description 2
- 102000018682 Interleukin Receptor Common gamma Subunit Human genes 0.000 description 2
- 108010002586 Interleukin-7 Proteins 0.000 description 2
- 102100022430 Melanocyte protein PMEL Human genes 0.000 description 2
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 2
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 241000172092 New Minto virus Species 0.000 description 2
- 241000712464 Orthomyxoviridae Species 0.000 description 2
- 241000711504 Paramyxoviridae Species 0.000 description 2
- 241000701945 Parvoviridae Species 0.000 description 2
- 241000150350 Peribunyaviridae Species 0.000 description 2
- 241001533393 Potyviridae Species 0.000 description 2
- 239000012979 RPMI medium Substances 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 241000702247 Reoviridae Species 0.000 description 2
- 201000000582 Retinoblastoma Diseases 0.000 description 2
- 241000712907 Retroviridae Species 0.000 description 2
- 241000711931 Rhabdoviridae Species 0.000 description 2
- 241000961587 Secoviridae Species 0.000 description 2
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101800001271 Surface protein Proteins 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 241000710924 Togaviridae Species 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 108700010877 adenoviridae proteins Proteins 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 210000005210 lymphoid organ Anatomy 0.000 description 2
- 230000001048 lympholytic effect Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 238000001370 static light scattering Methods 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 230000002463 transducing effect Effects 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000010472 type I IFN response Effects 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SSOORFWOBGFTHL-OTEJMHTDSA-N (4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SSOORFWOBGFTHL-OTEJMHTDSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- 102100039583 116 kDa U5 small nuclear ribonucleoprotein component Human genes 0.000 description 1
- LKKMLIBUAXYLOY-UHFFFAOYSA-N 3-Amino-1-methyl-5H-pyrido[4,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C=C(N)N=C2C LKKMLIBUAXYLOY-UHFFFAOYSA-N 0.000 description 1
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 description 1
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 1
- 102100021222 ATP-dependent Clp protease proteolytic subunit, mitochondrial Human genes 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 241001428876 Adelaide River virus Species 0.000 description 1
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 1
- 102100032959 Alpha-actinin-4 Human genes 0.000 description 1
- 241000252085 Anguilla rostrata Species 0.000 description 1
- 101710145634 Antigen 1 Proteins 0.000 description 1
- 241000473391 Archosargus rhomboidalis Species 0.000 description 1
- 241000172103 Aruac virus Species 0.000 description 1
- CBHVAFXKOYAHOY-NHCYSSNCSA-N Asn-Val-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O CBHVAFXKOYAHOY-NHCYSSNCSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 101150006352 B18R gene Proteins 0.000 description 1
- 101150118897 B8R gene Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 241001674104 Bangoran virus Species 0.000 description 1
- 241001533460 Barnaviridae Species 0.000 description 1
- 241000479165 Barur virus Species 0.000 description 1
- 241001331006 Berrimah virus Species 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 241001674102 Bimbo virus Species 0.000 description 1
- 241000897511 Bivens Arm virus Species 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241001674094 Boteke virus Species 0.000 description 1
- 241000712462 Bovine ephemeral fever virus Species 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 241000219076 Calchaqui virus Species 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000702749 Carajas virus Species 0.000 description 1
- 102000004091 Caspase-8 Human genes 0.000 description 1
- 108090000538 Caspase-8 Proteins 0.000 description 1
- 102000016362 Catenins Human genes 0.000 description 1
- 108010067316 Catenins Proteins 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- 241001435774 Chaco virus Species 0.000 description 1
- 101710181340 Chaperone protein DnaK2 Proteins 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 241001533399 Circoviridae Species 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100037238 E3 ubiquitin-protein ligase UBR4 Human genes 0.000 description 1
- 101150021140 EFTUD2 gene Proteins 0.000 description 1
- 102100031334 Elongation factor 2 Human genes 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 101710165567 Extracellular signal-regulated kinase 1 Proteins 0.000 description 1
- 241000644768 Farmington virus Species 0.000 description 1
- 241001470863 Flanders hapavirus Species 0.000 description 1
- 241000710781 Flaviviridae Species 0.000 description 1
- 241001331001 Fukuoka virus Species 0.000 description 1
- AKDOUBMVLRCHBD-SIUGBPQLSA-N Gln-Tyr-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AKDOUBMVLRCHBD-SIUGBPQLSA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 102100031493 Growth arrest-specific protein 7 Human genes 0.000 description 1
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 1
- 108010075704 HLA-A Antigens Proteins 0.000 description 1
- 102000025850 HLA-A2 Antigen Human genes 0.000 description 1
- 108010074032 HLA-A2 Antigen Proteins 0.000 description 1
- 241001144654 Hart Park virus Species 0.000 description 1
- 102100040407 Heat shock 70 kDa protein 1B Human genes 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 241001122120 Hepeviridae Species 0.000 description 1
- 241000700586 Herpesviridae Species 0.000 description 1
- KAXZXLSXFWSNNZ-XVYDVKMFSA-N His-Ser-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KAXZXLSXFWSNNZ-XVYDVKMFSA-N 0.000 description 1
- 101000750222 Homo sapiens ATP-dependent Clp protease proteolytic subunit, mitochondrial Proteins 0.000 description 1
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 1
- 101000797282 Homo sapiens Alpha-actinin-4 Proteins 0.000 description 1
- 101000807547 Homo sapiens E3 ubiquitin-protein ligase UBR4 Proteins 0.000 description 1
- 101000866749 Homo sapiens Elongation factor 2 Proteins 0.000 description 1
- 101000923044 Homo sapiens Growth arrest-specific protein 7 Proteins 0.000 description 1
- 101001053790 Homo sapiens Integrator complex subunit 1 Proteins 0.000 description 1
- 101000998146 Homo sapiens Interleukin-17A Proteins 0.000 description 1
- 101001005719 Homo sapiens Melanoma-associated antigen 3 Proteins 0.000 description 1
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 1
- 101000978949 Homo sapiens NADP-dependent malic enzyme Proteins 0.000 description 1
- 101000619805 Homo sapiens Peroxiredoxin-5, mitochondrial Proteins 0.000 description 1
- 101001130763 Homo sapiens Protein OS-9 Proteins 0.000 description 1
- 101001067951 Homo sapiens Protein phosphatase 1 regulatory subunit 3B Proteins 0.000 description 1
- 101000842302 Homo sapiens Protein-cysteine N-palmitoyltransferase HHAT Proteins 0.000 description 1
- 101000613391 Homo sapiens Protocadherin beta-16 Proteins 0.000 description 1
- 101000665150 Homo sapiens Small nuclear ribonucleoprotein Sm D1 Proteins 0.000 description 1
- 101000665250 Homo sapiens Small nuclear ribonucleoprotein Sm D2 Proteins 0.000 description 1
- 101000648075 Homo sapiens Trafficking protein particle complex subunit 1 Proteins 0.000 description 1
- 101000904724 Homo sapiens Transmembrane glycoprotein NMB Proteins 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- 241000702394 Inoviridae Species 0.000 description 1
- 102100024061 Integrator complex subunit 1 Human genes 0.000 description 1
- 102100033461 Interleukin-17A Human genes 0.000 description 1
- 102000000704 Interleukin-7 Human genes 0.000 description 1
- 241000701377 Iridoviridae Species 0.000 description 1
- 241001109688 Isfahan virus Species 0.000 description 1
- 241001481498 Jurona vesiculovirus Species 0.000 description 1
- 241001331013 Kimberley virus Species 0.000 description 1
- 241000897510 Klamath virus Species 0.000 description 1
- 241000182270 Koolpinyah virus Species 0.000 description 1
- 241000479160 Kotonkon virus Species 0.000 description 1
- 241000172088 Kwatta virus Species 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 241000172089 La Joya virus Species 0.000 description 1
- 241000172086 Landjia virus Species 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 206010024612 Lipoma Diseases 0.000 description 1
- 241000701365 Lipothrixviridae Species 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 108010029973 Lymphocytic choriomeningitis virus glycoprotein peptide Proteins 0.000 description 1
- 241000172085 Manitoba virus Species 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 241001435771 Marco virus Species 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 102100025082 Melanoma-associated antigen 3 Human genes 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 241001144665 Mosqueiro virus Species 0.000 description 1
- 241001144667 Mossuril virus Species 0.000 description 1
- 241000479161 Mount Elgon bat virus Species 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 241000701553 Myoviridae Species 0.000 description 1
- 102100023175 NADP-dependent malic enzyme Human genes 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 241000172094 Navarro virus Species 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- 241000479169 Nkolbisson virus Species 0.000 description 1
- 241000723741 Nodaviridae Species 0.000 description 1
- 102100031719 Nuclear transcription factor Y subunit gamma Human genes 0.000 description 1
- 101710150472 Nuclear transcription factor Y subunit gamma Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 241001331020 Oak-Vale virus Species 0.000 description 1
- 241000468053 Obodhiang virus Species 0.000 description 1
- 241000172093 Oita virus Species 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001674105 Ouango virus Species 0.000 description 1
- 102100034640 PWWP domain-containing DNA repair factor 3A Human genes 0.000 description 1
- 108050007154 PWWP domain-containing DNA repair factor 3A Proteins 0.000 description 1
- 241001330997 Parry Creek virus Species 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 102100022078 Peroxiredoxin-5, mitochondrial Human genes 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 241000701253 Phycodnaviridae Species 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 241000711965 Piry virus Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000701369 Plasmaviridae Species 0.000 description 1
- 241000702072 Podoviridae Species 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 241000700625 Poxviridae Species 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 102100031492 Protein OS-9 Human genes 0.000 description 1
- 102100034504 Protein phosphatase 1 regulatory subunit 3B Human genes 0.000 description 1
- 102100030616 Protein-cysteine N-palmitoyltransferase HHAT Human genes 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 241000702263 Reovirus sp. Species 0.000 description 1
- 241000220010 Rhode Species 0.000 description 1
- 241000479163 Sandjimba virus Species 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 241000801924 Sena Species 0.000 description 1
- 101710173693 Short transient receptor potential channel 1 Proteins 0.000 description 1
- 240000004672 Sigmavirus Species 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 241000702202 Siphoviridae Species 0.000 description 1
- 108010041216 Sirtuin 2 Proteins 0.000 description 1
- 102000000477 Sirtuin 2 Human genes 0.000 description 1
- 102100038685 Small nuclear ribonucleoprotein Sm D2 Human genes 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- 241000172096 Sweetwater Branch virus Species 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 101150003725 TK gene Proteins 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 241001330998 Tibrogargan virus Species 0.000 description 1
- 241001435769 Timbo virus Species 0.000 description 1
- 241001533336 Tombusviridae Species 0.000 description 1
- 102100025256 Trafficking protein particle complex subunit 1 Human genes 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 101000980463 Treponema pallidum (strain Nichols) Chaperonin GroEL Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- LVTKHGUGBGNBPL-UHFFFAOYSA-N Trp-P-1 Chemical compound N1C2=CC=CC=C2C2=C1C(C)=C(N)N=C2C LVTKHGUGBGNBPL-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010079351 Tumor Suppressor Protein p14ARF Proteins 0.000 description 1
- 241001329715 Tupaia virus Species 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 241000172097 Xiburema virus Species 0.000 description 1
- 241000172105 Yata virus Species 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 238000011467 adoptive cell therapy Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 201000007180 bile duct carcinoma Diseases 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- KQNZDYYTLMIZCT-KQPMLPITSA-N brefeldin A Chemical compound O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](O)C[C@H]21 KQNZDYYTLMIZCT-KQPMLPITSA-N 0.000 description 1
- JUMGSHROWPPKFX-UHFFFAOYSA-N brefeldin-A Natural products CC1CCCC=CC2(C)CC(O)CC2(C)C(O)C=CC(=O)O1 JUMGSHROWPPKFX-UHFFFAOYSA-N 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000012578 cell culture reagent Substances 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 201000002660 colon sarcoma Diseases 0.000 description 1
- 238000011220 combination immunotherapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 201000010918 connective tissue cancer Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000024558 digestive system cancer Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 201000010231 gastrointestinal system cancer Diseases 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000025750 heavy chain disease Diseases 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000008004 immune attack Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000013115 immunohistochemical detection Methods 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 231100000405 induce cancer Toxicity 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 208000020082 intraepithelial neoplasia Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000016847 malignant urinary system neoplasm Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- CWEFIMQKSZFZNY-UHFFFAOYSA-N pentyl 2-[4-[[4-[4-[[4-[[4-(pentoxycarbonylamino)phenyl]methyl]phenyl]carbamoyloxy]butoxycarbonylamino]phenyl]methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OCCCCC)=CC=C1CC(C=C1)=CC=C1NC(=O)OCCCCOC(=O)NC(C=C1)=CC=C1CC1=CC=C(NC(=O)OCCCCC)C=C1 CWEFIMQKSZFZNY-UHFFFAOYSA-N 0.000 description 1
- 108010042234 peptide SVYDFFVWL Proteins 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000008943 replicative senescence Effects 0.000 description 1
- 201000007048 respiratory system cancer Diseases 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 201000010965 sweat gland carcinoma Diseases 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 201000004435 urinary system cancer Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001174—Proteoglycans, e.g. glypican, brevican or CSPG4
-
- 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
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4614—Monocytes; Macrophages
-
- 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
- A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
- A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
-
- 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
- A61K39/46433—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
-
- 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
- A61K39/464401—Neoantigens
-
- 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
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464403—Receptors for growth factors
- A61K39/464406—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4
-
- 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
- A61K39/464448—Regulators of development
- A61K39/46445—Apoptosis related proteins, e.g. survivin or livin
-
- 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
- A61K39/464452—Transcription factors, e.g. SOX or c-MYC
- A61K39/464453—Wilms tumor 1 [WT1]
-
- 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
- A61K39/464474—Proteoglycans, e.g. glypican, brevican or CSPG4
-
- 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
- A61K39/46448—Cancer antigens from embryonic or fetal origin
- A61K39/464482—Carcinoembryonic antigen [CEA]
-
- 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
- A61K39/464484—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/464486—MAGE
-
- 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
- A61K39/464484—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/464488—NY-ESO
-
- 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
- A61K39/464499—Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor
-
- 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
- A61K39/464838—Viral 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5256—Virus expressing foreign proteins
-
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/20—Cytokines; Chemokines
- C12N2501/23—Interleukins [IL]
- C12N2501/2302—Interleukin-2 (IL-2)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/20—Cytokines; Chemokines
- C12N2501/23—Interleukins [IL]
- C12N2501/2315—Interleukin-15 (IL-15)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/20—Cytokines; Chemokines
- C12N2501/23—Interleukins [IL]
- C12N2501/2321—Interleukin-21 (IL-21)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/24011—Poxviridae
- C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
- C12N2710/24141—Use of virus, viral particle or viral elements as a vector
- C12N2710/24143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/20011—Rhabdoviridae
- C12N2760/20211—Vesiculovirus, e.g. vesicular stomatitis Indiana virus
- C12N2760/20241—Use of virus, viral particle or viral elements as a vector
- C12N2760/20243—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- Virology (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Developmental Biology & Embryology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Hospice & Palliative Care (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Reproductive Health (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明描述了一种治疗癌症的方法,包括过继转移肿瘤抗原特异性CD8+ T细胞和靶向相同抗原的溶瘤病毒疫苗。
Description
相关申请的交叉引用
本申请要求2016年6月24日提交的美国临时专利申请62/354,506号的权益,通过引用将其全部公开内容合并至本文中。
发明领域
本申请涉及癌症的组合免疫治疗方法。
发明背景
癌症和常规癌症治疗剂目前造成很大的社会经济负担,表现在精神/身体压力、失去生命和增加的医疗保健成本方面。常规疗法显示出一些有益的临床结果,但具有往往会降低患者的生活质量的有害副作用[1]。需要更有效的癌症疗法,其具有更少和更轻的有害副作用。
众所周知,免疫系统可以有效地消除恶性肿瘤,而免疫疗法代表了一种有前景的癌症替代疗法[2]。
免疫细胞(例如对肿瘤相关抗原(TAA)具有特异性的T细胞)具有摧毁肿瘤的潜力。由于天然肿瘤细胞更新或通过施用治疗性疫苗,可以在癌症患者中诱导这些细胞。但是,当这些细胞渗入肿瘤时经常被证明是无效的,并且它们通常表现出耗尽的(exhausted)和/或功能失调的表型,并且由于肿瘤诱导的局部免疫抑制而缺乏减少或破坏肿瘤所必需的细胞溶解功能[3-5]。因此,免疫抑制性肿瘤环境仍然是阻碍常规癌症免疫治疗剂诱导的反应的重要障碍。
基于检查点抑制剂的疗法已被用来减轻对肿瘤浸润淋巴细胞(TIL)的抑制性信号传导并激活内源性抗肿瘤反应[6,7]。检查点抑制剂在临床试验中已显示出疗效,但未在所有治疗的受试者中均观察到反应[8]。检查点抑制剂治疗依赖于既有的TAA特异性T细胞的活化,但一些患者没有足够的既有TAA特异性T细胞以在治疗诱导的再激活后导致肿瘤完全消退[9,10]。
TAA特异性T细胞的过继细胞转移(ACT)是用于治疗恶性肿瘤的检查点抑制剂疗法的优异替代方案(见综述[11])。ACT用从癌症患者分离并离体生长的肿瘤反应性T细胞进行。当从肿瘤施加的免疫抑制环境中移除后,这些细胞在转移回患者之前被激活并增殖至高数量。实质上,离体培养将少量具有很少或没有细胞溶解活性的功能失调的T细胞转化为数十亿个能够有效归巢和破坏同源肿瘤细胞的全功能T细胞。ACT的淋巴细胞来源于包括外周血单核细胞(PBMC)和TIL在内的一系列来源。ACT是灵活的,因为它可以利用通过其天然受体识别TAA的淋巴细胞,或者淋巴细胞可以通过用编码TAA特异性T细胞受体(TCR)或嵌合抗原受体(CAR)的转基因转导来修饰[12,13]。
临床证据表明ACT在非实体癌(如B细胞淋巴瘤)中具有良好的抗肿瘤功效。 事实上,人乳头瘤病毒反应性T细胞的输注也可以诱导HPV阳性转移性宫颈癌的消退[14]。该策略正在扩展至靶向非病毒肿瘤相关抗原,但仍有待改善以提高肿瘤浸润和实体瘤消退。
先前涉及ACT的工作已经表明,ACT的治愈潜力要求转移的细胞以足够的量和长期持久性渗入肿瘤才能杀死所有恶性细胞。临床证据表明,这些要求可以通过高剂量的过继转移的细胞(数十亿)来实现,这些细胞具有维持复制能力的最小分化表型[15]。但是,这两个目标相互冲突;产生高剂量的T细胞需要大量的体外扩增,这也会导致T细胞的终末分化和复制衰老[16]。实际上,常规ACT疗法使用终末分化的效应T细胞,并且需要对患者进行预先放疗或化疗以耗竭淋巴细胞群并允许更好地移植需要输注的数十亿细胞[17,18]。此外,需要进行IL2治疗,以维持输注细胞的持久性和活化[19]。
最近的研究表明,较低分化的细胞(如中枢记忆T细胞)在ACT中显示出更好的成功率,表现在移植细胞的持久性和临床结果方面[15,20]。已经发表了一种从PBMC样品中产生TAA特异性中枢记忆T细胞培养物的方法[21],但该方案需要临床级细胞分选仪(这是劳动力密集型的和资源密集型的)以富集抗原特异性细胞(也参见美国专利申请公开号US2015/0023938)。本发明提供了一种产生抗原特异性中枢记忆T细胞的大的离体扩增的方法和一种从针对表达该抗原的肿瘤细胞的该抗原特异性中枢记忆T细胞引起侵袭性细胞溶解反应的体内方法。结合起来,这些方法构成了用于治疗癌症的过继性细胞疗法,其不需要使用细胞分选器或耗尽受试者的内源性T细胞群,因此代表了对现有疗法的显著改善。
发明概述
本发明提供一种治疗哺乳动物(例如人)的癌症的方法,其包括过继性细胞转移以及随后进行的溶瘤病毒疫苗施用。在一些实施方案中,本发明提供了在有需要的受试者中治疗癌症的组合疗法,其包括(i)将肿瘤抗原特异性中枢记忆T(Tcm)细胞过继细胞转移到受试者中,然后(ii)用表达被过继细胞转移(ACT)T细胞靶向的相同抗原的重组溶瘤病毒(OV)疫苗接种受试者,以诱导癌症破坏和消除。在优选的实施方案中,对ACT T细胞进行遗传修饰以表达对肿瘤抗原特异的一种或多种重组T细胞受体(TCR)或嵌合抗原受体(CAR)。在一些实施方案中,ACT T细胞是源自待治疗受试者的自体T细胞。优选地,该组合疗法不包括受试者被免疫耗竭(immunodepleted)的步骤。
本文描述的方法可用于治疗哺乳动物的癌症。本文所用的术语“癌症”包括任何癌症,包括但不限于黑素瘤、肉瘤、淋巴瘤、癌、脑癌(例如神经胶质瘤)、乳腺癌、肝癌、肺癌、肾癌、胰腺癌、食道癌、胃癌、结肠癌、结直肠癌、膀胱癌、前列腺癌和白血病。在一些方面,所述癌症是实体瘤。在其他方面,癌症是转移癌。
本文所使用的术语“哺乳动物”是指人类以及非人类哺乳动物,术语“过继性细胞转移”意在包括通过离体培养从外周血或肿瘤组织样本中提取的淋巴细胞而产生的细胞产物的输注。
在一个实施方案中,提供了产生肿瘤抗原特异性中枢记忆CD8+ T细胞的方法,其包括离体细胞培养步骤,该步骤包括在存在肿瘤抗原、抗原呈递细胞(如树突细胞)、IL21、IL15和雷帕霉素并且优选不存在IL12的条件下,培养来自PBMC或TIL的淋巴细胞。优选地,在培养之前从PBMC中除去CD25 +细胞(调节性T细胞和活化的T细胞和B细胞)。肿瘤抗原可以是例如肿瘤相关抗原(TAA),它是肿瘤细胞中产生的在哺乳动物中引发免疫应答的物质。在一些实施方案中,肿瘤抗原是自身抗原。在其他实施方案中,肿瘤抗原是肿瘤特异性抗原,其对于该肿瘤是独特的并且不在正常细胞中表达或在正常细胞中以非常低的量表达(例如新生抗原(neo-antigen))。
在相关实施方案中,肿瘤抗原是组织特异性肿瘤抗原,与正常细胞相比,其在癌细胞中具有更高的表达,其非限制性实例包括酪氨酸酶、MART-1、gp100、TRP-1/gp75和TRP-2蛋白。在其他实施方案中,肿瘤抗原是肿瘤特异性共有抗原,其在肿瘤和睾丸中表达但在其他正常组织中不表达或以非常少的量表达(肿瘤睾丸抗原或CT抗原),其非限制性实例包括BAGE、CAMEL、MAGE-A1和NY-ESO-1。在其他实施方案中,肿瘤抗原是肿瘤特异性独特抗原(新生抗原),其仅在肿瘤细胞中表达,其非限制性实例包括CDK4、连环蛋白、半胱天冬酶-8、MUM-1、MUM-2、MUM-3、MART-2、OS-9、p14ARF、GAS7、GAPDH、SIRT2、GPNMB、SNRP116、RBAF600、SNRPD1、PRDX5、CLPP、PPP1R3B、EF2、ACTN4、ME1、NF-YC、HLA-A2、HSP70-2和KIAA1440。在其他实施方案中,肿瘤抗原是与正常细胞相比在癌细胞中过表达的过表达肿瘤抗原。肿瘤相关抗原的实例包括癌胚抗原(如甲胎蛋白(AFP)和癌胚抗原(CEA))、表面糖蛋白(如CA 125)、癌基因(如Her2)、黑素瘤相关抗原(如多巴色素互变异构酶(DCT)、GP100和MART1)、肿瘤睾丸抗原(如MAGE蛋白和NY-ESO1)、病毒癌基因(如HPV E6和E7)、在肿瘤中异位表达且通常限于胚胎或胚外组织的蛋白(如PLAC1)。如本领域技术人员将理解的,可以基于使用本发明方法治疗的癌症类型选择抗原,因为一种或多种抗原可能特别适合用于治疗某些癌症。例如,对于黑素瘤的治疗,可以使用黑素瘤相关抗原(如DCT)。
在一些优选的实施方案中,为了产生肿瘤抗原(例如TAA)特异性CD8+ T细胞,本方法包括对离体培养的细胞(例如从受试者获得的自体PBMC或具有与受试者组织相容性表型的PBMC)进行遗传修饰以表达一种或多种重组TCR或CAR以赋予肿瘤抗原特异性。在存在肿瘤抗原、抗原呈递细胞(如树突细胞)、IL21、IL15和雷帕霉素的条件下离体培养转导的细胞。CAR是由抗体衍生的胞外单链可变片段(scFv)与抗原识别部分和胞内T细胞激活结构域组成的融合蛋白。重组TCR包含α链和β链,并且可以识别例如HLA-A2 /肽复合物。细胞可以用携带支持所选的TCR/CAR表达的转基因盒的载体(如慢病毒载体或逆转录病毒载体)转导。将转基因盒引入载体的方法是本领域普通技术人员所熟知的。通常,修饰载体以表达TCR/CAR。在这方面,使用公认的重组技术将编码所选择的TCR/CAR的核酸序列引入所选择的载体中。在一些实施方案中,TCR或CAR特异于MART-1、gp100、NY-ESO-1或MAGE家族的成员(例如MAGE-A3)。有利的是,通过本文描述的方法产生的肿瘤抗原(例如TAA)特异性CD8+ T细胞不需要纯化(或进一步富集),例如在扩增(例如用抗CD3抗体、抗CD28抗体和IL2进行快速扩增)前使用四聚体标记和临床级分选器。因此,在优选的实施方案中,提供了过继细胞转移的方法,包括(i)在存在肿瘤抗原负载的抗原呈递细胞(APC,例如自体树突细胞)、IL21、IL15和雷帕霉素并且优选不存在IL12的情况下,培养从患有癌症的受试者获得的PBMC或TIL,以产生富含肿瘤抗原特异性CD8+ T细胞的细胞群,(ii)用抗CD3抗体、抗CD28抗体和IL2扩增肿瘤抗原特异性CD8+ T细胞,和(iii)将细胞重新引入该受试者,其中该方法不包括在步骤(i)和(ii)之间进行纯化(或进一步富集)T细胞的步骤,例如分选四聚体+细胞。
在优选的实施方案中,来自PBMC或TIL的淋巴细胞在存在肿瘤抗原、APC(例如树突细胞)、IL21、IL15和雷帕霉素且优选不存在IL12的条件下离体培养约1至约4周,例如, 约一周、约两周、约三周、约四周或其间的任何范围,可在之后在存在IL21、IL15和雷帕霉素而不存在肿瘤抗原和抗原呈递细胞的情况下,培养约1周至约2周、约1周或约2周。在一个特别优选的实施方案中,在存在肿瘤抗原肽负载的树突细胞、IL21、IL15和雷帕霉素的情况下,将来自PBMC的淋巴细胞离体培养约2周,并在存在IL21、IL15和雷帕霉素且不存在肿瘤抗原肽负载的树突状细胞的情况下培养约1周。有利的是,可以将根据本文所述方法产生的肿瘤抗原特异性CD8+ T细胞引入哺乳动物中,而不需要淋巴细胞耗竭(lymphodepletion),并且不需要向受试者施用IL-2。 因此,在一些实施方案中,提供了过继细胞转移的方法,其包括(i)在存在肿瘤抗原、抗原呈递细胞(如树突细胞)、IL21、IL15和雷帕霉素的情况下离体培养来自PBMC或TIL的淋巴细胞以及(ii)将所产生的肿瘤抗原(例如TAA)特异性CD8+ T细胞施用至哺乳动物,而不通过化疗或放疗方法破坏该哺乳动物中的现有淋巴细胞(淋巴细胞耗竭或淋巴细胞清除(lymphoablation)),并且不向受试者施用IL-2。
根据本文所述的组合疗法,在过继转移肿瘤抗原特异性CD8+ T细胞后,将表达肿瘤抗原的溶瘤病毒施用于受试者。肿瘤抗原特异性CD8+ T细胞的过继转移可以通过任何合适的方法完成,包括本文所述的方法和美国专利申请公开号US 2015/0023938中描述的方法,其内容通过引用并入本文。
在一些实施方案中,所述组合疗法包括(i)在存在载有肿瘤抗原肽的抗原呈递细胞(APC)和IL21的条件下离体培养来自患有肿瘤的受试者的TILS,在培养物中扩增所述细胞并将它们重新引入受试者,以及(ii)向受试者施用表达相同肿瘤抗原的溶瘤病毒。
在其他实施方案中,所述组合疗法包括(i)在存在载有肿瘤抗原肽的APC、IL21、IL15和雷帕霉素的条件下离体培养来自患有肿瘤的受试者的TILS,在培养物中扩增所述细胞并将它们重新引入受试者,以及(ii)向受试者施用表达相同肿瘤抗原的溶瘤病毒。
在其他实施方案中,所述组合疗法包括(i)在存在载有肿瘤抗原肽的APC和IL21的条件下离体培养来自受试者的PBMC,在培养物中扩增所述细胞并将它们重新引入受试者中,以及(ii)向受试者施用表达相同肿瘤抗原的溶瘤病毒。
在其他实施方案中,所述组合疗法包括(i)在存在载有肿瘤抗原肽的APC、IL21、IL15和雷帕霉素的条件下离体培养来自受试者的PBMC,在培养物中扩增所述细胞并将它们重新引入受试者体内,以及(ii)向受试者施用表达相同肿瘤抗原的溶瘤病毒。
在相关实施方案中,在离体培养之前,用对所述肿瘤抗原特异的重组TCR或CAR转导PBMC。
在一些实施方案中,在转移肿瘤抗原特异性CD8+ T细胞约8至72小时后,将表达所述肿瘤抗原的溶瘤病毒施用于哺乳动物。在优选的实施方案中,在转移肿瘤抗原特异性CD8+ T细胞约12至48小时后、约20至28小时后、或约24小时后,将表达所述肿瘤抗原的溶瘤病毒施用至受试者。
表达肿瘤抗原的任何具有复制能力的溶瘤病毒都可根据本文所述的组合疗法施用。 在一些优选的实施方案中,复制型溶瘤病毒是弹状病毒,例如VSV或Maraba弹状病毒,其优选包含一种或多种遗传修饰以增加病毒对癌细胞的选择性。
复制型溶瘤病毒疫苗可以通过一种或多种途径给药。在一些实施方案中,复制型溶瘤病毒是弹状病毒,并通过静脉内途径给予哺乳动物。在其他实施方案中,复制型溶瘤病毒是痘苗病毒(vaccinia virus),并且通过静脉内(IV)、肌肉内(IM)、腹膜内(IP)或肿瘤内(IT)途径给予哺乳动物。如本领域技术人员所理解的,复制型溶瘤病毒(例如弹状病毒或痘苗病毒)将在合适的载体(例如盐水或其他药学上合适的缓冲液)中施用。
附图简述
通过以下对下面列出的各个附图的描述更深入地示出了本发明的实施方案。
图1:用IL15、IL21和雷帕霉素离体培养的P14或24H9R CD8+ T细胞的中枢记忆表型(CD44 +和CD62L +)的获得。A图显示在开始后的所示天数时来自P14小鼠(上图)或24H9R小鼠(下图)的CD8+ T细胞、CD62L+ T细胞上CD44的表达增加。B图显示了在离体培养过程中观察到的逐渐增加的细胞数量。
图2:在离体培养期间需要组合使用IL15、IL21和雷帕霉素以产生在组合疗法中具有最佳抗肿瘤效果的Tcm细胞。图中显示了用所示的IL15、IL21和雷帕霉素的组合体外培养7天后P14 CD8T细胞的倍数扩增(A)以及CD62L(B)和CD44(C)表达水平。在感染后的每个指定日(dpi)使用卡尺测量肿瘤体积并表示为mm3,0 dpi表示溶瘤病毒注射的当天。图中显示了在输注用指定的IL15、IL21和雷帕霉素组合培养的P14细胞后用VSV-gp33处理的小鼠的肿瘤体积结果(D-G)。感染后第5、12和21天的应答表示为在用gp3333-41肽刺激时外周循环中产生干扰素γ(IFNγ)的CD8+ T细胞的%(H)。图中显示肿瘤大小低于1000 mm3(即肿瘤终点的截止值)的图D-G中的小鼠的百分比(I)。
图3:24H9R Tcm ACT+ OV-hDCT组合疗法诱导强烈的抗原特异性T细胞应答和B16F10肿瘤的消退。在感染后的每个指定日(dpi)使用卡尺测量肿瘤体积并表示为mm3,0dpi表示溶瘤病毒注射的当天(A)。感染后第5、12和21天的应答表示为在用DCT180-188肽刺激时外周循环中产生干扰素γ(IFNγ)的CD8+ T细胞的%(H)。
图4:DUC18 Tcm ACT+ OV-Erk9M组合疗法诱导强烈的抗原特异性T细胞应答和CMS5肿瘤的消退。在感染后的每个指定日(dpi)使用卡尺测量肿瘤体积并表示为mm3,0 dpi表示溶瘤病毒注射的当天(A)。感染后第5、12和21天的应答表示为在用Erk9M136-144肽刺激时外周循环中产生干扰素γ(IFNγ)的CD8+ T细胞的%(H)。 在激发后的每个指定日,使用卡尺测量先前使用Tcm+ OV-Erk9M疗法治愈并用CMS5细胞再次激发的小鼠的肿瘤体积并表示为mm3(C)。
图5:P14Tcm ACT+ OV-gp33组合疗法诱导强烈的抗原特异性T细胞应答和B16-gp33肿瘤的消退。在感染后的每个指定日(dpi)使用卡尺测量肿瘤体积并表示为mm3,0 dpi表示溶瘤病毒注射的当天。图中显示了VacV-gp33、VSV-gp33和MRB-gp33注射的结果(A)。感染后第5、12和21天的应答表示为在用gp3333-41肽刺激时外周循环中产生干扰素γ(IFNγ)的CD8+ T细胞的%(B)。
图6:当通过IV、IT、IP和IM注射途径施用病毒时P14Tcm ACT+ OV加强的肿瘤消退功效。在感染后的每个指定日(dpi)使用卡尺测量肿瘤体积并表示为mm3,0 dpi表示溶瘤病毒注射的当天。
图7:当通过IV、IT、IP和IM注射给药时,由P14Tcm ACT+ OV诱导的抗原特异性CD8+T细胞应答的水平。图中显示了感染后5天和12天时的应答,表示为在用gp3333-41肽刺激时外周循环中产生干扰素γ(IFNγ)的CD8+ T细胞的%。
图8:虽然显示出与P14 Tcm ACT+ VSV-gp33治疗相似的肿瘤消退动力学和峰值T细胞应答水平,但P14 Tcm ACT+ VacV-gp33组合疗法不诱导自身免疫性糖尿病。 在感染后的每个指定日(dpi)使用卡尺测量肿瘤体积并表示为mm3,0 dpi表示溶瘤病毒注射的当天(A)。感染后第5、12和21天的应答表示为在用gp33肽刺激时外周循环中产生干扰素γ(IFNγ)的CD8+ T细胞的%(B)。在感染后的每个指定日(dpi)用血糖仪监测血糖水平并表示为mmol/L,其中0 dpi代表溶瘤病毒注射当天(C)。
图9:在P14Tcm+ VSV-gp33处理的RIPgp小鼠中诱导了胰腺β细胞破坏,但未在P14Tcm+ VacV-gp33处理的RIPgp小鼠中诱导(虽然有免疫细胞浸润的证据)。 图中显示了在1和5 dpi时获取的用苏木精和曙红染色的胰腺组织切片(A)或胰岛素免疫组织化学(B)。
图10:用IL21、IL15和雷帕霉素扩增程序化T细胞产生高水平的pp65特异性CD8+ T细胞而不需细胞分选。来自相同来源的PBMC的等分人T细胞通过Yee方法培养两周,包括与树突细胞、IL21、IL7和IL2共培养(A和B),或与树突细胞、 IL21、IL15和雷帕霉素共培养(C)。在这样的富集/程序化两周后,每个共培养物中的细胞使用pp65四聚体染色分选并用抗CD3/CD28Ab和IL2扩增(A),或直接用抗CD3/CD28Ab和IL2扩增而不进行预先分选(B和C)。在扩增1周和2周后,测定每种培养物中所需pp65特异性CD8+ T细胞的总体水平。
图11:淋巴细胞耗竭对于建立有效的ACT+ OV应答不是必需的。野生型Balb/c小鼠中的建立的CMS5肿瘤可以通过DUC18转基因T细胞+ Maraba-Erk9M治愈,而不需要消除宿主淋巴细胞(A)。然而,缺乏任何内源性淋巴细胞的Balb/c-NRG小鼠未能完全清除肿瘤,其仅经历初始阶段的部分肿瘤清除并复发(B)。
图12:环磷酰胺淋巴细胞耗竭对Tcm ACT+ OV治疗的抗肿瘤作用是有害的。图中显示了P14Tcm+ VacV-gp33对已建立的B16-gp33肿瘤的组合治疗,其进行了或没有进行以低剂量(50mg/kg)和高剂量(150mg/kg)环磷酰胺预先消除宿主淋巴细胞(A)。在感染后的每个指定日(dpi)使用卡尺测量肿瘤体积并表示为mm3,0 dpi表示溶瘤病毒注射的当天。感染后第5、12和21天的应答表示为在用gp33肽刺激时外周循环中产生干扰素γ(IFNγ)的CD8+ T细胞的%(B)。
定义
除非另有说明,否则本节和其他节中描述的定义和实施方案旨在应用于根据本领域技术人员理解所适合的本文所述的所有实施方案和本申请的所有方面。
在理解本申请的范围时,如本文所使用的术语“包括”及其派生词是开放式术语,其指定所述的特征、元素、成分、组、整体和/或步骤,但不排除存在其他未说明的特征、元素、成分、组、整体和/或步骤。前述内容也适用于具有类似含义的词语,例如术语“包含”、“具有”及其衍生词。这里使用的术语“由......组成”及其衍生词是封闭的术语,其指定所述的特征、元素、成分、组、整体和/或步骤的存在,但排除其他未说明的特征、元素、成分、组、整体和/或步骤的存在。如本文所用,术语“基本上由......组成”旨在指定所述特征、元素、成分、组、整体和/或步骤的存在以及不会实质上影响基本和新颖特征的那些特征、元素、成分、组、整体和/或步骤。
应理解的是,“组合疗法”是指顺次向对象施用根据本文所述的ACT方法产生的肿瘤抗原特异性中枢记忆T细胞群和表达相同肿瘤抗原的复制性溶瘤病毒。根据本文所述的ACT方法所产生的记忆T细胞群和表达相同肿瘤抗原的溶瘤病毒在允许治疗剂显示协作作用(例如协同作用)的时间间隔内施用。在优选的实施方案中,记忆T细胞群和溶瘤病毒彼此相隔在约1小时至约72小时内(例如在约1、2、3、6、12、24、48或72小时内)、约1天至约4周内(例如在约1、2或3或4周内)、在约1周至约3周内或其间的任何范围内给药。在相关实施方案中,记忆T细胞群和溶瘤病毒彼此相隔在4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天内给药。
本文使用的诸如“基本上”、“大约”和“约”的程度术语表示所修饰的术语的合理偏差量,使得结果不会显著改变。 这些程度术语应被解释为包括修饰术语的至少±5%偏差(如果该偏差不会否定其修饰词的含义)。
如在本申请中所使用的,除非内容另有明确说明,否则单数形式“一(a)”、“一(an)”和“该(the)”包括复数指代。 例如,包括“一T细胞”的实施方案应理解为一种物质或两种或多种另外的物质。
在包含“另外的”或“第二”组分(例如另外的或第二种细胞因子)的实施方案中,如本文所用的第二组分在化学上不同于其他组分或第一组分。 第三”组份与其他组分、第一组分和第二组分不同,并且进一步列举的或“附加”的组分也同样不同。
如本文所用的术语“和/或”意指所列出的项目单独或组合地存在或使用。实际上,该术语意味着使用或存在所列项目中的“至少一个”或“一个或多个”。
详细描述
T细胞
在一些实施方案中,本文所述的组合疗法利用根据本文所述方法产生的肿瘤抗原特异性中枢记忆T细胞的过继转移。因此,令人惊讶地发现,在存在APC、肿瘤抗原和包含IL21、IL15和雷帕霉素的组合物或基本上由IL21、IL15和雷帕霉素组成的组合物的情况下培养T细胞(例如初始T细胞)产生了肿瘤抗原特异性T细胞群,与单独的IL21、IL15或雷帕霉素相比,其实质上富集了表现中枢记忆表型的T细胞,并且其可以离体扩增并引入患者,然后向患者施用表达相同抗原的溶瘤病毒以协同治疗癌症,而不需要昂贵的细胞分选技术,也不需要在引入T细胞之前对患者施用淋巴细胞耗竭方案,并且不需要向患者施用IL2。在一些实施方案中,IL21和IL15以约1ng/ml至约20 ng/ml,优选约10 ng/ml的浓度存在。在相关的实施方案中,雷帕霉素以约10 ng/ml至约30 ng/ml,优选约20 ng/ml的浓度存在。
例如,APC可以是自体树突细胞,其可以通过用GM-CSF(例如约800 U/ml)和IL-4(例如约500 U/ml)培养粘附的PBMC约5天以将它们分化为树突状细胞来获得。可以通过在第5天添加TNFα(例如约10 ng/ml)、IL-1b(例如约2 ng/ml)、IL-6(例如约1000 U/ml)、PGE-2(例如约1000 ng/ml)、IL-4(例如约500 U/ml)和GM-CSF(例如约800 U/ml)并培养2天以上来刺激所得的树突细胞。 在第7天,可以用40μg/ ml的肽肿瘤抗原脉冲树突细胞约2小时并照射,以用作根据本文所述的方法的负载肿瘤抗原肽的APC。
在一些实施方案中,在存在APC、肿瘤抗原和IL21、IL15和雷帕霉素的情况下培养初始T细胞产生肿瘤抗原特异性T细胞群,其至少50%、至少60%、至少70% 、至少80%或更多显示中枢记忆表型。在一个实施方案中,根据本文描述的ACT方法获得的中枢记忆T细胞显示CD44+ CD62L+ CD127 +表型。
本文所述的ACT方法所使用的T细胞可以从血液、淋巴组织(例如脾)或肿瘤(例如肿瘤浸润淋巴细胞)获得。在一些实施方案中,本文所述的ACT方法所使用的T细胞由PBMC产生,所述PBMC具有与待治疗的癌症的受试者的组织相容的表型。在相关的实施方案中,PBMC是患有待治疗的癌症的受试者自体的。
在一个优选的实施方案中,通过在存在IL21、IL15和雷帕霉素、由癌症表达的肿瘤抗原和抗原呈递细胞的条件下培养来自该人癌症受试者的PBMC(例如,培养1至4周,优选约3周),从而获得用于本发明组合的过继细胞转移的CD8 +人T细胞群,用抗CD3抗体和抗CD28抗体和IL2扩增该CD8 +人T细胞群,并将细胞重新引入患者体内,随后( 例如,在间隔24小时后)施用复制型溶瘤病毒(例如溶瘤弹状病毒),该复制型溶瘤病毒被工程化以表达编码相同肿瘤抗原的转基因。
在相关实施方案中,通过将对人受试者中癌症表达的肿瘤抗原特异性的重组TCR或CAR转导至从该受试者获得的PBMC中,并在存在IL21、IL15、雷帕霉素、抗原呈递细胞和肿瘤抗原的条件下培养该遗传修饰的细胞(例如培养约一至四周,优选约三周),从而获得用于本发明组合的过继细胞转移的CD8 +人T细胞群,用抗CD3抗体和抗CD28抗体和IL2扩增该CD8 +人T细胞群,并将细胞重新引入患者体内,随后( 例如,在间隔24小时后)施用复制型溶瘤病毒(例如溶瘤弹状病毒),该复制型溶瘤病毒被工程化以表达编码相同肿瘤抗原的转基因。
在另一个实施方案中,通过在存在IL21、IL15、雷帕霉素、由癌症表达的肿瘤抗原和抗原呈递细胞的条件下培养从该人癌症对象获得的肿瘤浸润性淋巴细胞(例如培养约一至四周,优选约三周),获得用于本发明组合的过继细胞转移的CD8 +人T细胞群,用抗CD3抗体和抗CD28抗体和IL2扩增该CD8 +人T细胞群,并将细胞重新引入患者体内,随后( 例如,在间隔24小时后)施用复制型溶瘤病毒(例如溶瘤弹状病毒),该复制型溶瘤病毒被工程化以表达编码相同肿瘤抗原的转基因。
在相关实施方案中,通过将对人受试者中癌症表达的肿瘤抗原特异性的重组TCR或CAR转导至从该受试者获得的肿瘤浸润性淋巴细胞中,并在存在IL21、IL15、雷帕霉素、抗原呈递细胞和肿瘤抗原的条件下培养该遗传修饰的细胞(例如培养约一至四周,优选约三周),从而获得用于本发明组合的过继细胞转移的CD8 +人T细胞群,用抗CD3抗体和抗CD28抗体和IL2扩增该CD8 +人T细胞群,并将细胞重新引入患者体内,随后( 例如,在间隔24小时后)施用复制型溶瘤病毒(例如溶瘤弹状病毒),该复制型溶瘤病毒被工程化以表达编码相同肿瘤抗原的转基因。
溶瘤病毒
所述组合的表达肿瘤抗原的具有复制能力的溶瘤病毒包括任何天然存在的(例如来自“野外来源”)或修饰的具有复制能力的溶瘤病毒。除了表达肿瘤抗原之外,该溶瘤病毒例如还可被修饰以增加病毒对癌细胞的选择性。
根据本发明的复制型溶瘤病毒包括但不限于作为下述病毒科成员的溶瘤病毒:肌尾噬菌体科(myoviridae)、长尾噬菌体科(siphoviridae)、短尾噬菌体科(podpviridae)、复层噬菌体科(teciviridae)、覆盖噬菌体科(corticoviridae)、芽生噬菌体科(plasmaviridae)、脂毛噬菌体科(lipothrixviridae)、微小纺锤形噬菌体科(fuselloviridae)、痘病毒科(poxyiridae)、虹彩病毒科(iridoviridae)、藻类DNA病毒科(phycodnaviridae)、杆状病毒科(baculoviridae)、疱疹病毒科(herpesviridae)、腺病毒科(adnoviridae)、乳多空病毒科(papovaviridae)、多分体DNA病毒科(polydnaviridae)、丝状噬菌体科(inoviridae)、微小噬菌体科(microviridae)、双生病毒科(geminiviridae)、圆环病毒科(circoviridae)、细小病毒科(parvoviridae)、嗜肝DNA病毒科(hepadnaviridae)、逆转录病毒科(retroviridae)、囊状噬菌体科(cyctoviridae)、呼肠孤病毒科(reoviridae)、双RNA病毒科(birnaviridae)、副粘液病毒科(paramyxoviridae)、弹状病毒科(rhabdoviridae)、丝状病毒科(filoviridae)、正粘液病毒科(orthomyxoviridae)、布尼安病毒科(bunyaviridae)、沙粒病毒科(arenaviridae)、光滑噬菌体科(leviviridae)、小RNA病毒科(picornaviridae)、伴生病毒科(sequiviridae)、豇豆花叶病毒科(comoviridae)、马铃薯Y病毒科(potyviridae)、杯状病毒科(caliciviridae)、星状病毒科(astroviridae)、野田病毒科(nodaviridae)、四病毒科(tetraviridae)、番茄丛矮病毒科(tombusviridae)、冠状病毒科(coronaviridae)、黄病毒科(glaviviridae)、披膜病毒科(togaviridae)和杆状RNA病毒科(barnaviridae)。
用于本发明实践的具有复制型溶瘤病毒的具体实例包括腺病毒、逆转录病毒、呼肠孤病毒、弹状病毒、新城疫病毒(NDV)、多瘤病毒、痘苗病毒(VacV)、单纯疱疹病毒、小核糖核酸病毒、柯萨奇病毒和细小病毒。
在一些优选的实施方案中,根据所述组合的表达肿瘤抗原的复制型溶瘤病毒是溶瘤弹状病毒。
原型弹状病毒是狂犬病病毒和水疱性口炎病毒(VSV),它们是该病毒科中研究最多的病毒。 弹状病毒是一类具有非分段( - )义RNA基因组的子弹形病毒。弹状病毒科包括但不限于:Arajas病毒, Chandipura病毒 (AF128868/gi:4583436, AJ810083/gi:57833891, AY871800/gi:62861470, AY871799/gi:62861468, AY871798/gi:62861466,AY871797/gi:62861464, AY871796/gi:62861462, AY871795/gi:62861460, AY871794/gi:62861459, AY871793/gi:62861457, AY871792/gi:62861455, AY871791/gi:62861453), Cocal病毒 (AF045556/gi:2865658), Isfahan病毒 (AJ810084/gi:57834038), Maraba病毒 (美国专利No. 8,481,023, SEQ ID ON: 1-6, 通过引用并入本文; HQ660076.1), Carajas病毒(美国专利No. 8,481,023, SEQ ID NO:7-12, 通过引用并入本文, AY335185/gi:33578037), Piry病毒 (D26175/gi:442480, Z15093/gi:61405), Alagoas水疱性口炎病毒,BeAn 157575病毒, Boteke病毒, Calchaqui病毒, 美洲鳗病毒 (Eel virus American), Gray Lodge病毒, Jurona病毒, Klamath病毒,Kwatta病毒, La Joya病毒, Malpais Spring病毒, Mount Elgon蝙蝠病毒 (DQ457103/gi:91984805), Perinet病毒 (AY854652/gi:71842381), Tupaia病毒 (NC_007020/ gi:66508427), Bahia Grande病毒 (美国专利No. 8,481,023, SEQ ID NO:13-18, 通过引用并入本文, KM205018.1), Muir Springs病毒 (KM204990.1), Reed Ranch病毒, HartPark病毒, Flanders病毒 (AF523199/gi:25140635, AF523197/gi:25140634, AF523196/gi:25140633, AF523195/gi:25140632, AF523194/gi:25140631, AH012179/gi:25140630), Kamese病毒, Mosqueiro病毒, Mossuril病毒, Barur病毒, Fukuoka 病毒(AY854651/gi:71842379), Kern Canyon病毒, Nkolbisson病毒, Le Dantec病毒(AY854650/gi:71842377), Keuraliba病毒, Connecticut病毒,新Minto病毒(New Mintovirus), Sawgrass病毒, Chaco病毒, Sena Madureira病毒, Timbo病毒, Almpiwar病毒(AY854645/gi:71842367), Aruac病毒, Bangoran病毒, Bimbo病毒, Bivens Arm病毒,蓝蟹病毒(Blue crab virus),Charleville病毒, Coastal Plains病毒, DakArK 7292病毒, Entamoeba病毒, Garba病毒, Gossas病毒, Humpty Doo病毒(AY854643/gi:71842363), Joinjakaka病毒, Kannamangalam病毒, Kolongo病毒 (DQ457100/gi:91984799 核蛋白 (N) mRNA, 部分cds); Koolpinyah 病毒, Kotonkon病毒 (DQ457099/gi:91984797, AY854638/gi:71842354); Landjia病毒, Manitoba病毒, Marco病毒,Nasoule病毒, Navarro病毒, Ngaingan病毒(AY854649/gi:71842375), Oak-Vale病毒(AY854670/gi:71842417), Obodhiang病毒 (DQ457098/gi|91984795), Oita病毒(AB116386/gi:46020027), Ouango病毒, Parry Creek病毒 (AY854647/gi:71842371),Rio Grande鲷病毒(Rio Grande cichlid virus), Sandjimba病毒 (DQ457102/gi|91984803), Sigma病毒 (AH004209/gi:1680545, AH004208/gi:1680544, AH004206/gi:1680542), Sripur病毒, Sweetwater Branch病毒, Tibrogargan病毒 (AY854646/gi:71842369), Xiburema病毒, Yata病毒, 罗德岛(Rhode Island), Adelaide River病毒(U10363/gi:600151, AF234998/gi:10443747, AF234534/gi:9971785, AY854635/gi:71842348), Berrimah病毒 (AY854636/gi:71842350]), Kimberley病毒 (AY854637/gi:71842352), 或牛流行热病毒 (Bovine ephemeral fever virus) (NC_002526/gi:10086561)。 这些弹状病毒或其变体的任何一个都可被改造以表达肿瘤抗原,从而用于本发明的组合。
在一些优选的实施方案中,所述组合中表达肿瘤抗原的溶瘤弹状病毒是野生型或重组水泡病毒,例如野生型或重组VSV、金迪普拉(Chandipura)、Maraba或Carajas(包括它们的变体)。在其他实施方案中,溶瘤弹状病毒是野生型或重组非水疱病毒,例如MuirSprings、Farmington或Bahia grande病毒(包括它们的变体)。
在一个特别优选的实施方案中,该组合中表达肿瘤抗原的溶瘤病毒是野生型Maraba菌株弹状病毒或其变体,其任选地经遗传修饰以例如提高肿瘤选择性。例如,该Maraba病毒可以是如在美国专利9,045,729号(通过引用将其全部内容合并至此)第2栏第24-42行所描述的在G蛋白的氨基酸242处和/或在M蛋白的氨基酸123处具有取代的Maraba病毒。 在一个特别优选的实施方案中,该Maraba病毒是在Brun et al., Mol. Ther., 18(8):1440-1449 (2010)中所述的Maraba MG1。Maraba MG1是一种遗传修饰Maraba菌株弹状病毒,其含有G蛋白突变(Q242R)和M蛋白突变(L123W),使得该病毒在癌细胞中具有高毒性,而在正常细胞中毒力减弱。
在另一个优选的实施方案中,所述组合中的表达肿瘤抗原的溶瘤弹状病毒是VSV毒株或其任选经遗传修饰以例如提高肿瘤选择性的变体。在特别优选的实施方案中,该VSV包含M蛋白51位的甲硫氨酸缺失,如在Stojdl et al., Cancer Cell., 4(4):263-75(2003)中所述,通过引用将其全部内容合并至此。
根据本文所述的方法,在ACT治疗后,通过全身给药向受试者施用所述组合的表达肿瘤抗原的复制型溶瘤弹状病毒,优选通过血管内(静脉内和/或动脉内)给药,包括注射、输注等,给药剂量为以下一种或多种:10、100、103、104、105、106、107、108、109、1010、1011、1012、1013、1014或更多个病毒颗粒(vp)或噬斑形成单位(pfu)。 在优选的实施方案中,根据本文所述的方法,表达肿瘤抗原的溶瘤弹状病毒在ACT治疗后血管内施用于受试者,给药剂量为以下一种或多种:105-1014 pfu、106-1012 pfu、108-1014 pfu或108-1012 pfu。
在一些优选的实施方案中,该组合的表达肿瘤抗原的复制型溶瘤病毒是溶瘤痘苗病毒。
在优选的实施方案中,该组合的表达肿瘤抗原的复制型溶瘤痘苗病毒是Copenhagen菌株、Western Reserve菌株、Lister菌株或Wyeth菌株。Western Reserve牛痘株的基因组已经测序(登录号AY243312)。
可以将表达肿瘤抗原的复制型溶瘤痘苗病毒工程化成缺失一种或多种功能基因,以增加病毒的癌症选择性。在一些优选的实施方案中,将溶瘤痘苗病毒改造成缺乏胸苷激酶(TK)活性。另一方面,可以将溶瘤痘苗病毒改造成缺乏痘苗病毒生长因子(VGF)。另一方面,可以将溶瘤痘苗病毒改造成缺乏VFG和TK活性。在其他方面,可以将溶瘤痘苗病毒改造成缺少一种或多种参与逃避宿主干扰素(IFN)应答的基因,例如E3L、K3L、B18R或B8R。在一些优选的实施方案中,复制型溶瘤痘苗病毒是Western Reserve菌株、Copenhagen菌株、Lister菌株或Wyeth菌株并且缺乏功能性TK基因。在其他实施方案中,溶瘤痘苗病毒是缺乏功能性B18R和/或B8R基因的Western Reserve菌株、Copenhagen菌株、Lister菌株或Wyeth菌株。
根据本文所述的方法,在ACT治疗后,该组合的表达肿瘤抗原的复制型溶瘤痘苗病毒可局部或全身给予受试者,例如通过瘤内、腹膜内、静脉内、动脉内、肌肉内、皮内、颅内、皮下或鼻内给药,给药剂量为以下一种或多种:1 x 105 噬斑形成单位(pfu)、5 x 105 pfu、至少1 x 106 pfu、5 x 106 或约5 x 106 pfu、1 x 107、至少1 x 107 pfu、1 x 108 或约1 x108 pfu、至少1 x 108 pfu、约或至少5 x 108 pfu、1 x 109 或至少1 x 109 pfu、5 x 109或至少5 x 109 pfu、1 x 1010 pfu 或至少1 x 1010 pfu、5 x 1010或至少5 x 1010 pfu、1 x1011或至少1 x1011、1 x 1012 或至少1 x 1012、1 x 1013 或至少1 x 1013 pfu。例如,病毒给药剂量可为约107-1013 pfu、约108-1013 pfu、约109-1012 pfu、约108-1012 pfu、或约109 and1010 pfu。
本发明预期,单剂量的表达肿瘤抗原的溶瘤病毒是指在0.1、0.5、1、2、5、10、15、20或24小时期间(包括其间的所有值)给予受试者或肿瘤的量。该剂量可以在整个时间段内分摊或通过单独注射进行。通常,将多个剂量施用于大体相同的目标区域,例如在肿瘤附近,或在静脉内施用的情况下,在受试者的血流或淋巴系统中的特定进入点。在某些方面,病毒剂量通过含针注射装置递送,该装置在单个针中提供多个端口,或将多个针头(prones)连接至注射器,或其组合。可以在一个治疗期内施用单剂量或多剂量的溶瘤病毒,一个治疗期可包括1、2、3、4、5、6、7、8、9、10、11、12或更多个周。例如,溶瘤病毒可以每隔一天、每周、每隔一周、每隔三周施用一次,持续1、2、3、4、5、6或更多个月。
如本领域技术人员所理解的,表达肿瘤抗原的溶瘤病毒通常作为药物组合物的一部分与药学上可接受的载体(例如盐水或其他合适的缓冲液)一起施用。 如本文所用,“载体”包括任何和所有溶剂、分散介质、赋形剂、包衣、稀释剂、抗菌剂和抗真菌剂、等渗和吸收延迟剂、缓冲剂、载体溶液、悬浮液、胶体等。这些介质和药剂用于药物活性物质的用途是本领域熟知的。 除非任何常规介质或试剂与活性成分不相容,否则考虑其在治疗组合物中的用途。补充的活性成分也可以加入组合物中。
肿瘤抗原
该组合的溶瘤病毒表达由本文所述的ACT方法产生的T细胞所靶向的相同抗原。可由溶瘤病毒表达的合适抗原包括但不限于癌胚抗原(例如甲胎蛋白(ALF)和癌胚抗原(CEA))、表面糖蛋白(例如CA 125)、癌基因(例如Her2)、黑素瘤相关抗原(例如多巴色素互变异构酶( DCT)、GP100和MART-1)、肿瘤-睾丸抗原(如MAGE蛋白和NY-ESO-1)、病毒癌基因如HPV E6和E7,以及在通常限于胚胎或胚外组织的肿瘤中异位表达的蛋白(例如PLAC1)或肿瘤相关抗原的变体。
肿瘤相关抗原的“变体”是指这样的蛋白质:(a)包括至少一种来自肿瘤相关抗原蛋白的肿瘤相关抗原表位,并且(b)与肿瘤相关抗原蛋白至少70%、优选至少80%、 更优选至少90%或至少95%相同。Van der Bruggen P, Stroobant V, Vigneron N, Van denEynde B在"Database of T cell-defined human tumor antigens: the 2013 update."Cancer Immun 2013 13:15中提供了总结公认的抗原表位的数据库,可在www.cancerimmunity.org/peptide在线获取。
在一些实施方案中,所述溶瘤病毒表达MAGEA3、人乳头瘤病毒E6/E7融合蛋白、前列腺蛋白的人六跨膜上皮抗原或肿瘤睾丸抗原1。
在其他实施方案中,本发明提供鉴定肿瘤抗原的方法,包括在包含IL21、IL15和雷帕霉素或基本上由IL21、IL15和雷帕霉素组成的组合物以及抗原呈递细胞(如树突细胞)存在下将PBMC与受试者分离的肿瘤材料共培养;从培养物中分离出T细胞群;从该T细胞群克隆单个T细胞;以及表征T细胞克隆的抗原特异性。在一些实施方案中,所述肿瘤材料包含总RNA、裂解的肿瘤细胞或凋亡小体。本文所述的ACT方法可用于产生对通过该方法鉴定的抗原特异的中枢记忆T细胞群,并与经过工程改造以表达相同抗原的溶瘤病毒组合以提供协同的癌症治疗。
癌症
可根据本文所述的组合治疗的癌症包括但不限于白血病、急性淋巴细胞白血病、急性髓细胞白血病、成髓细胞早幼粒细胞、髓单核细胞红细胞白血病、慢性白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、套细胞淋巴瘤、原发性中枢神经系统淋巴瘤、Burkitt淋巴瘤和边缘区B细胞淋巴瘤、真性红细胞增多症淋巴瘤、霍奇金病、非霍奇金病、多发性骨髓瘤、Waldenstrom巨球蛋白血症、重链疾病、实体瘤、肉瘤和癌、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨原性肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮细胞瘤、滑膜瘤、间皮瘤、Ewing氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠肉瘤、结肠直肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、Wilm氏瘤、宫颈癌、子宫癌、睾丸瘤、肺癌、小细胞肺癌、非小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、血管瘤、神经母细胞瘤、视网膜母细胞瘤、鼻咽癌、食管癌、基底细胞癌、胆道癌、膀胱癌、骨癌、脑和中枢神经系统(CNS)癌、宫颈癌、绒毛膜癌、结直肠癌、结缔组织癌、消化系统癌症、子宫内膜癌、食道癌、眼癌、头颈癌、胃癌、上皮内瘤、肾癌、喉癌、肝癌、 肺癌(包括小细胞肺癌、鳞状非小细胞肺癌和非鳞状非小细胞肺癌)、黑素瘤(包括转移性黑素瘤)、神经母细胞瘤、口腔癌(例如唇、舌、口和咽)、卵巢癌、胰腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸系统癌、肉瘤、皮肤癌、胃癌、睾丸癌、甲状腺癌、子宫癌和泌尿系统癌症。在一些优选的实施方案中,待治疗的癌症选自非小细胞肺癌(NSCLC)、乳腺癌(例如激素难治性转移性乳腺癌)、头颈癌(例如头颈部鳞状细胞癌)、转移性结肠直肠癌、激素敏感或激素难治性前列腺癌、结肠直肠癌、卵巢癌、肝细胞癌、肾细胞癌、软组织肉瘤和小细胞肺癌。
在一个方面,所述组合治疗的受试者是患有癌症的人,所述癌症难以用一种或多种化学治疗剂治疗和/或难以用一种或多种抗体治疗。
实施例
以下实施例说明了本发明的范围。该实施例的具体要素仅用于描述目的,并不意图限制本发明的范围。本领域技术人员可以开发出等同的方法并使用类似材料,而仍属于本发明范围内。
实验方法和程序
细胞系
将所有细胞保持在37℃和含5%CO2的潮湿气氛中。将B16F10和B16gp33细胞(其为B16F10细胞工程化以表达对应于LCMV gp33表位的小基因)保持在含有10%FBS、2mM L-谷氨酰胺、5ml丙酮酸钠、5ml非必需氨基酸、5ml维生素溶液、55μM 2-巯基乙醇、100 U/mL青霉素和100 ng/mL链霉素的MEM/F11中。用800μg/ ml G418维持gp33小基因的表达。所有细胞培养试剂来自Invitrogen(Invitrogen, Grand Island, NY)。将CMS5细胞维持在含有10%FBS、2mM L-谷氨酰胺、100U/mL青霉素和100ng/mL链霉素的DMEM中。
动物
C57BL/6和BALB/c小鼠购自Charles River Laboratory(Wilmington,MA)并饲养在无特定病原体的设施中。DUC18小鼠由Lyse Norian(University of Iowa, Iowa)赠送,它是经工程化改造的转基因小鼠,其表达对同源CMS5纤维肉瘤排斥抗原突变Erk9M(136-144)特异性的T细胞受体。24H9R小鼠由Arthur Hurwitz博士(NIH,Frederick,MD)赠送,它是一种携带TCR转基因的转基因小鼠品系,该转基因识别DCT/TRP-2180–188的H-2Kb限制性表位。P14小鼠购自Taconic Breeding Laboratories(Germantown,NY),它是携带用于gp33肽的TCR的转基因小鼠品系(B6.Cg-Tcra tm1Mom Tg(TcrLCMV)327Sdz)。B6.Cg -Tg(Ins2-GP)34-20Olds转基因小鼠(称为RIPgp小鼠)由Pamela Ohashi(UHN Research, Toronto,Canada)赠送,并在McMaster University的中心动物设施中繁殖。NRG小鼠(Cg-Rag1 tm1Mom Il2rg tm1Wjl /SzJ)购自The Jackson Laboratory(Farmington,Connecticut)。所有动物研究均符合加拿大动物保护协会指南,并获得McMaster University动物研究伦理委员会的批准。
皮肤瘤动物模型
用2x105 B16-gp33或B16F10细胞或106 CMS5细胞皮内刺激6至8周龄的BALB/c、C57BL/6或RIPgp小鼠。在肿瘤植入后5至7天(当肿瘤直径达到约5mm时)施用ACT和随后的OV疫苗接种。每天监测肿瘤生长并且每隔一天用卡尺测量。肿瘤体积计算为宽x长x深。肿瘤终点定义为至少二个维度> 10mm或一个维度> 20mm。需要时,使用Contour next glucometer(Ascensia Diabetes)监测血糖水平。显示> 14 mmol/L血糖的动物被认为是患糖尿病。
病毒
VSV-gp33载体 [22]和VacV-gp33 [23]载体分别是重组水泡性口炎病毒和重组痘苗病毒,其表达淋巴细胞脉络丛脑膜炎病毒糖蛋白(分别是LCMV-gp33-41和LCMV-gp61-80)的显性CD8+和CD4+ T细胞表位)。MRB-GP是假型化的重组Maraba病毒,其天然糖蛋白经基因工程被LCMV的糖蛋白取代。VSV-hDCT和MRB-hDCT分别是重组水泡性口炎病毒和重组Maraba病毒,其表达全长人多巴色素互变异构酶(DCT)[24]。VacV-hDCT是重组胸苷激酶和痘苗生长因子双缺失痘苗病毒,其被工程化以表达hDCT。Ad-hDCT是基于编码全长人黑素瘤抗原DCT的人血清型5的复制缺陷型腺病毒(E1/E3缺失)[24]。VSV-Erk9M和MRB-Erk9M分别是重组水泡性口炎病毒和重组Maraba病毒,其表达CMS5细胞系中表达的ERK突变形式的显性CD8+ T细胞表位。如文献所述,修饰VSV-gp33和VSV-hDCT以通过缺失基质蛋白的51位的甲硫氨酸残基来消除其抑制I型IFN应答的能力[25]。如文献所述,MRB-hDCT和MRB-Erk9M也通过突变基质中的残基和糖蛋白中的残基来消除其抑制I型IFN应答的能力[26]。
肽
LCMV-GP的H-2Db限制性肽(gp33-41; KAVYNFATM (SEQ ID NO. 1))、DCT的H-2Kb限制性肽(DCT180–188 SVYDFFVWL (SEQ ID NO. 2))、以及突变ERK的H-2Kd限制性肽(Erk9M136–144; QYIHSANVL (SEQ ID NO. 3))均购自Biomer Technology (Pleasanton,California)。肽溶解于蒸馏水中并存储于-20°C。
离体Tcm培养以及ACT+疫苗接种方案
通过常规方法从TCR转基因小鼠中分离脾细胞。在补充有10%胎牛血清(FBS)、2mML-谷氨酰胺、55μM 2-巯基乙醇、100 U/mL青霉素、100 ng/mL链霉素、10 ng/mL IL21、10ng/mL IL15、20 ng/mL雷帕霉素和0.1μg/ mL同源抗原肽的RPMI培养基中以3百万/ mL的密度接种脾细胞(含有大量APC)。初始接种后4天,使用初始培养基和不含肽的补充物将培养物体积扩增5倍。3天后收获细胞,洗涤并悬浮于PBS中用于注射。给小鼠静脉注射(IV)在200μLPBS中的106 Tcm细胞,24小时后,静脉注射在200 μLPBS中(除非另有说明)的2×108 pfu的VSV-gp33、VSV-DCT和MRB-DCT;1×108 pfu的VacV-gp33和VacV-DCT;5×108 pfu VSV-erk9m 和MRB-erk9m。当指定时,在输注Tcm细胞前3天通过IP注射20mg/kg环磷酰胺(CPX)进行淋巴细胞耗竭处理。
Tcm表面标志物的流式染色
收获离体培养的细胞,沉淀并用Fc阻断剂处理。然后,对细胞染色以显示CD8、CD44、CD62L和CD127的表面表达。使用具有FACSDiva软件的LSRFortessa(BD Biosciences,Mississauga, ON, Canada)获得数据,并用FlowJo软件(Tree Star, Ashland, OR)分析。
抗原特异性T细胞应答的检测
从眶周窦血液样品中获得外周血单核细胞。用ACK裂解缓冲液裂解红细胞。用gp33肽(1μg/ mL)在37℃刺激单核细胞5小时,并在孵育的最后4小时期间加入布雷菲德菌素A(Golgi Plug,1μg/ mL; BD Biosciences)。用Fc阻断剂处理细胞并染色以显示CD8的表达。随后将细胞固定、透化(Cytofix/Cytoperm, BD Biosciences)并染色细胞内干扰素γ。使用具有FACSDiva软件的LSRFortessa(BD Biosciences)获取数据,并用FlowJo软件(TreeStar, Ashland, OR)分析。
组织病理学和免疫组化染色
将组织在10%福尔马林中固定24小时,然后在70%乙醇中脱水。将固定的组织包埋在石蜡中并以5μm切片。切片用苏木精和曙红染色或通过免疫组织化学(IHC)探测胰岛素表达。对于IHC,切片在室温下用3%过氧化氢处理15分钟,并用在含有0.2%Triton X-100的PBS中的5%BSA和2%山羊血清封闭45分钟,随后用抗生物素蛋白/生物素封闭试剂盒(Vector labs)处理。将载玻片在4℃下与兔抗小鼠胰岛素抗体(abcam; ab181547)一起温育过夜,然后与生物素化的抗兔抗体(Vector labs)一起温育。使用Vectastain ABC试剂盒(Vector labs)和ImmPACT AMEC Red过氧化物酶底物试剂盒(Vector labs)连续处理载玻片,然后用Harris苏木精复染并用Permount(Fisher)固定。
实施例1
TAA特异性CD8T细胞的离体培养诱导中枢记忆表型
离体T细胞培养物通常利用通过共同γ链(IL2Rγ或CD132)进行信号传导的细胞因子。常见的γ链家族细胞因子包括但不限于IL2、IL15和IL21 [27]。CD132主要在淋巴细胞上表达,通过该受体的信号传导驱动CD8+ T细胞和其他淋巴细胞亚型的增殖和成熟[27]。已知IL2诱导CD8T细胞的快速增殖和效应分化[28-30],而IL15和IL21驱动较慢的稳态增殖并使CD8+ T细胞偏向中枢记忆分化状态[30-32]。因此,我们在离体培养系统中使用了IL15和IL21补充剂。此外,我们还使用雷帕霉素,一种常用的mTOR抑制剂。研究显示,mTOR途径的调节在病毒疫苗系统中支持T细胞的存活并诱导记忆T细胞分化[33,34]。雷帕霉素短期体内处理可增加记忆T细胞分化,并增强疫苗诱导的T细胞的抗肿瘤功效[35]。因此,在我们的T细胞培养方案中IL15、IL21和雷帕霉素的组合使得T细胞能够扩增并获得中枢记忆表型和功能。
为了建立Tcm培养物,从P14或24H9R小鼠中提取脾细胞,并在0.1μg/ mL gp33或DCT肽、20ng/mL雷帕霉素和IL15和IL21各10ng/mL的存在下培养7天。在开始后3天,用不含肽但补充有20ng/mL雷帕霉素和IL15和IL21各10ng/mL的标准T细胞培养基(含有L谷氨酰胺、抗生素和β-巯基乙醇的RPMI培养基)将培养体积扩大5倍。在培养之前,P14 CD8 T细胞(图1A,第0天)是CD44阴性,但CD62L阳性,这是典型的初始T细胞表型。在离体培养7天后收获(图1A,第7天),细胞仍然显示出具有高水平表达的CD44和CD62L的中枢记忆表型。除了获得Tcm表型外,培养的细胞显示出强劲的增殖,基于从细胞计数计算的总细胞产量, P14和24H9R培养物在7天内扩增约20倍(图1B)。肿瘤抗原刺激联合IL-15驱动了T细胞增殖; IL-21和雷帕霉素在T细胞的增殖中诱导中枢记忆分化和控制,使得它们不会成为效应T细胞。
实施例2
IL21、IL15和雷帕霉素的特定组合是引导分化在组合治疗中具有最佳抗肿瘤作用的抗原特异性中枢记忆CD8+ T细胞所必需的。
雷帕霉素、IL15和IL21的特定组合是在本文所述的组合疗法中具有最佳的抗肿瘤作用的抗原特异性中枢记忆CD8+ T细胞的离体培养、扩增和分化所必需的。这些组分中的每一种和所有组分对于产生这样的Tcm细胞都是必需的,并且在缺乏一种或多种这些组分的情况下产生的细胞在体内输注和OV疫苗接种后具有次优的T细胞扩增和/或降低的抗肿瘤作用。
培养方案中需要IL15来驱动CD8+ T细胞扩增和中枢记忆分化。与在完整组合(图2A中的IL15/IL21/Rapa)中生长的细胞相比,在不存在IL15的情况下培养的细胞显示出离体培养物的增殖受损和细胞产量降低(图2A中的IL21/Rapa)。此外,以这种方式培养的细胞显示出改变的表型,其偏向于初始表型(图2C中降低的CD44水平)而不是中枢记忆表型(如图2B和C中完整组合中生长的细胞所示)。输注和VSV -gp33刺激后,在不存在IL15的情况下生长的细胞产生略微降低的抗原特异性CD8T细胞应答强度(图2H),并且不能完全消退肿瘤或延长存活期(图2E和I)。
IL21在将培养的细胞编程成具有最佳抗原特异性细胞溶解功能的优质中枢记忆表型中起着不可或缺的作用。在不存在IL21(IL15/Rapa)的情况下培养的细胞具有CD62L(图2B)和CD44(图2C)的正常表达水平,并具有与用完整组合培养的细胞相当的离体增殖率。在用VSV-gp33输注和刺激后,在不存在IL21的情况下生长的细胞产生了与用完整组合培养的细胞相当的体内应答强度。无论如何,与在完整组合中生长的细胞相比,用在不存在IL21的条件下生长的细胞处理的小鼠的肿瘤消退(图2F)和存活率(图2I)较差。
雷帕霉素对抗原特异性CD8+ T细胞的增殖发挥抑制作用,其不干扰Tcm表型的获得。相反,雷帕霉素在本文所述的培养方案中的作用是在OV刺激后增强细胞质量(细胞溶解功能和抗肿瘤作用)。在不存在雷帕霉素的情况下产生的细胞,与在完整组合中生长的细胞相比,显示出相等同的离体增殖率(图2A中的IL15/Il21组),但中枢记忆T细胞标记蛋白CD62L和CD44(分别为图2A和B)的表达改变。这些细胞中CD62L表达的降低表明它们没有获得真正的中枢记忆分化状态。实际上,在不存在雷帕霉素的情况下生长的细胞在OV刺激后5天显示出增强的体内增殖(图2H)。这是短暂的,并且到感染后12和21天,抗原特异性CD8T细胞的水平下降至与在完整组合中生长的细胞相当的水平。总之,这些结果表明在不存在雷帕霉素的情况下生长的细胞呈现效应记忆表型(30),并且在VSV-gp33刺激后对体内递送的死亡信号更敏感。最后,这些细胞具有削弱的抗肿瘤功效,无法完全消退肿瘤(图2G),导致存活率降低(图2I)。
实施例3
离体培养的记忆T细胞的转移需要OV疫苗加强以获得抗肿瘤活性
中枢记忆CD8 T细胞驻留在淋巴结中并且在通过其同源肽呈递刺激之前保持无活性。在抗原特异性刺激后,Tcm细胞快速分裂并分化成效应细胞,以产生强大的全身细胞溶解响应。离体培养产生的Tcm细胞的抗原特异性细胞溶解功能通过过继转移到携带表达被转移细胞靶向的抗原的肿瘤的小鼠中,然后用表达相同抗原的溶瘤病毒疫苗活化来测试。我们测试了三种TCR转基因小鼠品系(24H9R、DUC18和P14小鼠),它们靶向在常用肿瘤细胞系模型上表达的抗原,代表真正的自身抗原、新生抗原和病毒抗原(分别是B16F10细胞中的DCT、DUC18细胞中的Erk9M和B16-gp33细胞)。将培养的Tcm细胞过继转移到携带表达T细胞的抗原靶标的肿瘤的小鼠中。单独转移Tcm细胞不能诱导显著的全身性抗原特异性应答,并且不显示任何抗肿瘤作用(图3、4和5中的Tcm组)。这是Tcm细胞的预期特征,因为它们被隔离到淋巴器官,在淋巴器官中肽的水平最低。由于抗原呈递是激活Tcm细胞和发生效应细胞应答的先决条件,因此我们将Tcm ACT与表达同源肽的溶瘤病毒疫苗载体组合。我们选择使用水泡性口炎病毒、Maraba病毒和痘苗病毒载体,因为它们是溶瘤病毒,并且过去曾被用作疫苗载体。这些病毒具有强烈的溶瘤活性,这意味着它们优先感染和裂解癌细胞,因此它们可以协同增强CD8介导的肿瘤破坏。将转基因盒包含在这些与转移的T细胞的肽特异性相关的病毒载体中而产生溶瘤疫苗,并允许将肽递送至淋巴结并激活先前施用的Tcm ACT细胞。当与VSV、MRB(图3A、4A和5A)和VacV疫苗接种(图3A和5A)组合时,Tcm ACT诱导快速和完全的肿瘤消退。对于VSV和Maraba,在感染后5天,用该组合疗法诱导的CD8T细胞应答最显著,具有约10-30%IFNγ+ CD8T细胞的平均峰值应答(图3B、4B和5B),而对于VacV,显著应答出现在感染后第12天(图3B和5B)。将溶瘤疫苗与ACT组合是必需的,因为单独的VSV-gp33和VacV-gp33疫苗均不能在gp33模型中诱导完全肿瘤消退(图5A),尽管诱导了针对gp33肽的显著反应(图5B)。实验观察到了肿瘤生长延迟,但最终肿瘤克服了由溶瘤疫苗施加的免疫攻击和生长抑制。这可能是因为肿瘤生长超过了正在发展的抗肿瘤免疫反应。或者,肿瘤的免疫抑制作用可能使单独由溶瘤疫苗诱导的gp33特异性细胞功能失调。这些数据表明将Tcm ACT和溶瘤疫苗疗法相结合诱导了完全的免疫介导的肿瘤消退,而其中任何一个单项治疗都不能实现。
使用非溶瘤腺病毒疫苗载体(图3中的Ad-hDCT)与Tcm ACT组合不能控制肿瘤生长(图3A),尽管其诱导了转移的Tcm细胞显著的扩增和活化,其在感染后12天的峰值响应为约10%IFNγ+ CD8T细胞(图3B)。这表明溶瘤病毒疫苗载体(例如VSV、MRB和VacV)非常适合ACT Tcm的活化,并且在该组合疗法中是完全肿瘤响应所必需的。
组合治疗的抗肿瘤特性不仅能够完全消退肿瘤,而且还能持续至少60天并抑制随后的抗原匹配的肿瘤细胞的移植和生长。皮内注射CMS5肿瘤细胞再次激发60天前用DUC18Tcm和VSV-Erk9M的组合处理治疗且治愈CMS5肿瘤的BALB/c小鼠。在初始对照小鼠中观察到快速肿瘤生长,但在先前治愈的小鼠中不存在(图4C),表明组合疗法诱导的响应持续存在并抑制任何表达靶抗原的新肿瘤细胞的生长。
实施例4
OV介导的P14 Tcm活化的注射途径依赖性
理想地,溶瘤疫苗载体通过直接病毒感染同时引起肿瘤减灭并刺激TAA特异性细胞溶解性T细胞。因此,在设计溶瘤疫苗免疫疗法时,病毒注射途径是一个重要的考虑因素,因为疫苗必须有效地传播到肿瘤和淋巴器官以实现这两个目标。此外,在设计组合疗法时,必须考虑病毒的安全性、病毒的天然嗜性及其注射后复制和传播的能力。因此,我们测试了当通过不同途径给予溶瘤疫苗时我们的组合疗法消除肿瘤的能力。C57BL/6小鼠在皮内植入1x105个B16-gp33细胞后7天,注射1x106个P14 Tcm细胞,24小时后,静脉内(IV)、腹膜内(IP)、肿瘤内(IT)或肌内(IM)注射2x108 pfu VSV-gp33或7.5x107 pfu VacV-gp33。监测肿瘤体积并表示为mm3(图5)。仅当IV给药时,弹状病毒载体(VSVgp33)诱导有效的肿瘤消退,而当通过其他途径给药时仅显示部分肿瘤消退(图6,左栏图)。测定通过所有注射途径的gp33特异性效应T细胞应答的诱导,并且如在肿瘤消退中观察到的,仅在IV注射途径中导致P14 Tcm+ VSV-gp33处理的小鼠中的显著响应(图7A)。相反,基于溶瘤疫苗接种的牛痘疫苗显示出更大的灵活性。无论痘苗疫苗通过哪种途径给药,在P14 Tcm+ VacV-gp33组合治疗的情况下,观察到了肿瘤的完全消退且没有复发(图6,右栏图)并且诱导了显著的gp33特异性CD8T细胞应答(图7B)。因此,我们的组合治疗中的VSV施用在IV施用时产生有效的肿瘤根除响应,而VacV施用是灵活的并且IV、IT、IP和IM给药都导致有效的治疗结果。
实施例5
OV介导的P14 Tcm ACT活化导致肿瘤消退,而对正常组织没有共同的抗原特异性自身免疫损伤
癌细胞发生突变,导致宿主产生失调的细胞。因此,癌细胞的许多抗原靶标(TAA)是自身抗原,其也可以在正常细胞上表达。仔细选择TAA靶标可以最大限度地减少由癌症免疫疗法诱导的对正常组织的抗原特异性附带损伤,但在其他基于ACT的疗法中观察到不可预见的肽交叉反应性和正常组织破坏[36,37]。因此,评估了与组合疗法诱导的完全肿瘤消退并排的正常组织的抗原特异性破坏。
携带B16-gp33肿瘤的RIPgp小鼠被用于确定由P14Tcm ACT和OV组合疗法诱导的抗原特异性自身免疫。RIPgp小鼠是一种转基因品系,其在胰腺β细胞中选择性地表达含有gp33肽的LCMV糖蛋白。因此,这些小鼠中针对gp33的细胞溶解性免疫应答可导致肿瘤和胰腺β细胞破坏,分别导致肿瘤消退和糖尿病。RIP-gp小鼠在皮内植入1×105个B16-gp33细胞后7天,注射1×106个P14 Tcm细胞,然后在24小时后静脉内注射2×108 pfu VSV-gp33或7.5×107 pfu VacV-gp33。监测用任一种病毒处理后的肿瘤消退。对于两种病毒处理,肿瘤体积在感染后5天达到峰值,均为约100 mm3,之后稳定下降(图8A)。VSV-gp33诱导肿瘤消退的速度略快于VacV-gp33,但最终P14 Tcm+ VacV-gp33处理的肿瘤完全消退并且没有复发,而P14 Tcm+ VSV-gp33处理的肿瘤未能在复发前完全消退(图8A)。
使用血糖仪监测经处理的小鼠的血糖水平以检测糖尿病诱导。对于这些实验,糖尿病被定义为血糖高于14 mmol/L(在图8C中以虚线示出)。在VSV-gp33处理的小鼠中,在感染后第5天诱导糖尿病(图8C),其与该疗法诱导的峰值免疫应答相关。在用VSV-gp33处理后第5天取自小鼠的苏木精和伊红染色的胰腺组织中观察到胰岛结构的破坏(图9A)。在相同组织上进行胰岛素蛋白的免疫组织化学探测显示胰岛中胰岛素阳性细胞数量的急剧减少(图9B),表明在这些小鼠中产生胰岛素的β细胞已被破坏。由于gp33肽在RIP-gp小鼠的β细胞中特异性表达,因此当与VSV组合时,似乎P14 Tcm ACT诱导正常组织的抗原特异性损伤。相反,用P14Tcm+ VacVgp33组合疗法治疗的小鼠在治疗后的任何时间点都没有患上糖尿病(图8C),尽管显示出相当的gp33特异性T细胞峰值应答(图8B)。来自这些小鼠的胰腺组织显示在感染后第5天胰岛扩大(图8A),这是由于胰岛素阴性细胞(图9B)显著浸润到胰岛中。在胰岛中仍然观察到大量胰岛素阳性细胞,因此看起来这些浸润性细胞没有表现出有效的β细胞gp33特异性细胞溶解活性(如果有的话)。VacV-gp33和VSV-gp33都诱导了相当的gp33特异性峰值应答,因此溶瘤疫苗之间的自身免疫损伤的差异不能归因于诱导的应答强度,而归因于被刺激的T细胞的质量。因此,P14 Tcm ACT与任一种测试的溶瘤疫苗的组合都能够诱导肿瘤消退,但VSV-gp33诱导正常组织的附带抗原特异性损伤,而在同一系统中VacV-gp33不诱导这种损伤。
实施例6
用抗原呈递细胞、IL21、IL15和雷帕霉素编程人T细胞选择性地富集抗原特异性Tcm细胞
在存在抗原脉冲的自体树突细胞、IL21、IL17和IL2的情况下,人抗原特异性CD8T细胞可以富集并“编程”(引导分化)为中枢记忆表型[21]。在最初的编程之后是细胞分选步骤以纯化群体以获得所需类型的T细胞(通常通过四聚体染色),然后通过在存在抗CD3/CD28抗体和IL2的情况下培养T细胞来扩增(称为REP的快速扩增方案)该纯化的群体。虽然这种方法可以产生非常高水平的所需T细胞,但是它耗时且需要昂贵的设备。相反,通过在存在抗原、IL21、IL15和雷帕霉素的情况下将淋巴细胞与树突细胞共培养以进行编程/富集,选择性地富集原始T细胞群中存在的Tcm细胞,而不需要在随后的扩增(REP)之前进行细胞分选。
为了证明这一点,按照美国专利申请公开2015/0023938中描述的方法(第一周30ng/mL IL-21,然后第二周加入10 ng/mL IL-2和5 ng/mL IL-7)或本文所述的IL21、IL15、雷帕霉素方法,将来自相同来源的等分的人PBMC与用pp65(人巨细胞病毒(HCMV)衍生的免疫显性肽)脉冲的树突细胞(DC)共培养,以富集和 编程pp65特异性CD8+ T细胞。 简言之,CD25耗尽的PMBC与负载肽的辐射的DC以及IL21、IL15和雷帕霉素共培养两周,并与仅IL21、IL15和雷帕霉素共培养一周(没有肽负载的DC)(定义为I期:富集和编程) ,然后用IL2和CD3/CD28抗体扩增两周(定义为II期:快速扩增或REP),无需中间分选步骤。如果在REP之前用细胞分选器分选富集的程序化细胞,那么美国专利申请公开2015/0023938中描述的富集/编程方法可以在扩增1周后产生具有> 99%抗原特异性T细胞的T细胞群,扩增2周后,数值降至约95%(图10A)。相同方法如果没有进行细胞分选,那么在扩增1周后产生具有约22%抗原特异性T细胞的T细胞群,扩增2周后降至<12%(图10B)。相反,本文所述的利用IL21、IL15和雷帕霉素的方法在扩增1周后产生具有约66%抗原特异性T细胞的T细胞群,在扩增2周后上升至> 82%(图10C)。因此,IL21、IL15、雷帕霉素编程/富集步骤不仅产生高度富集了中枢记忆T细胞的T细胞群,而且这些细胞能够更好地耐受长时间暴露于REP中抗CD3/CD28 Ab和IL2的应激。
这些结果一起表明,可以为ACT制备治疗有效量的人Tcm细胞,而不需要时间和费用进行细胞分选。 此外,结果表明,当用IL21、IL15和雷帕霉素对细胞进行编程和富集时,抗-CD3/CD28Ab介导的扩增所固有的在较低效力和较高数量的T细胞之间的平衡向更高效力的Tcm细胞倾斜。
实施例7
使用ACT+ OV组合疗法根除肿瘤不需要事先淋巴细胞耗竭
使用BALB/c(野生型)和BALB/c NRG小鼠测试先前淋巴细胞耗竭对ACT+ OV组合疗法根除肿瘤的能力的影响,其中BALB/c-NRG小鼠完全缺乏任何内源性淋巴细胞,因为具有Rag1KO (Cg-Rag1 tm1Mom ) 和IL2RγcKO (Il2rg tm1Wjl )敲除突变。向BALB/c和BALB/c-NRG小鼠注射CMS5细胞,使肿瘤发展6天。然后如所示给小鼠注射DUC18 Tcm ACT细胞,一天后注射所示的重组Maraba病毒构建体,然后监测受试小鼠的肿瘤体积5至6周。
如所预期的,未处理的BALB/c小鼠以及仅接受ACT或仅接受OV处理的BALB/c小鼠未显示出肿瘤控制且肿瘤体积迅速增长(图11A,分别为Tcm和MRB-Erk9m)。此外,包含DUC18Tcm ACT和用重组Maraba-GFP构建体进行OV处理的组合疗法也未能影响这些小鼠中的肿瘤生长(图11A,Tcm+ MRB-GFP)。相反,包含DUC18 Tcm ACT和用重组Maraba-Erk9M进行OV治疗的组合治疗完全根除肿瘤,表明表达特异性抗原的Tcm和OV载体都是完全肿瘤根除所必需的。
令人惊讶的是,BALB/c-NRG小鼠的表现略有不同。在该情况下,DUC18 Tcm ACT和OV Maraba-Erk9M治疗的相同组合仅产生短暂的肿瘤消退,并且在2-3周后肿瘤复发(图11B)。不受理论束缚,这可能表明内源性T细胞需要与转移的(ACT)T细胞合作以实现完全肿瘤根除,或通过涉及靶向其他肿瘤抗原的内源性T细胞的表位扩散介导抗原丢失的变体的排斥。
还测试了化学诱导的淋巴细胞耗竭预处理对Tcm+ ACT C57BL/6小鼠的后果。携带B14-gp33肿瘤的小鼠用P14Tcm+ VacV-gp33处理,预先进行或不进行CPX处理诱导淋巴细胞耗竭。在没有CPX预处理的情况下,用P14Tcm+ VacV-gp33处理的小鼠显示完全肿瘤消退(图12A),并且在感染后12天达到~12%IFNγ+ CD8T细胞峰值应答。相反,用低剂量(50mg/kg)和高剂量(150mg/kg)CPX预处理的小鼠不能完全消退肿瘤,最终肿瘤复发(图12A)。在CPX处理的小鼠中缺乏肿瘤控制与gp33特异性CD8T细胞应答的量级无关,因为与未用药物治疗的小鼠相比,这些小鼠产生相当的或更大幅度的应答(图12B)。因此,化学淋巴细胞耗竭不会增强组合治疗诱导的抗肿瘤作用。实际上,CPX治疗似乎对由Tcm ACT+ OV组合疗法诱导的抗原特异性CD8+ T细胞应答的抗肿瘤活性具有不利影响。
这些结果不仅证明本文所述的ACT+ OV治疗的组合可以绕过淋巴细胞耗竭或淋巴清除预处理,而且淋巴细胞耗竭/淋巴清除可能对治疗的总体功效有害。
通过上述实施例显示了本发明的不同实施方案。 本领域技术人员可以开发出上述方法的替代方案,这些方法在本发明和所定义的权利要求的范围内。
所有出版物、专利和专利申请均通过引用整体并入本文,其程度如同每个单独的出版物、专利或专利申请被具体和单独地指出通过引用整体并入。在本申请中的术语在通过引用并入本文的文件中被不同地定义的情况下,本文提供的定义用作该术语的定义。
参考文献
1. Minniti G, Sanctis V, Muni R, Filippone F, Bozzao A, Valeriani M,et al. Radiotherapy plus concomitant and adjuvant temozolomide forglioblastoma in elderly patients. J. Neurooncol. 2008 88:97–103.
2. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age.Nature 2011 480:480–9.
3. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME,White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumorexpress high levels of PD-1 and are functionally impaired. Blood. 2009 114:1537–44.
4. Rabinovich GA, Gabrilovich D, Sotomayor EM. ImmunosuppressiveStrategies that are Mediated by Tumor Cells. Annu. Rev. Immunol. 2007 25:267–96.
5. Kim R, Emi M, Tanabe K, Arihiro K. Tumor-driven evolution ofimmunosuppressive networks during malignant progression. Cancer Res. 2006 66:5527–36.
6. Mahoney KM, Freeman GJ, McDermott DF. The Next Immune-CheckpointInhibitors: PD-1/PD-L1 Blockade in Melanoma. Clin. Ther. 2015 37:764-82.
7. Leach DR, Krummel MF, Allison JP. Enhancement of antitumorimmunity by CTLA-4 blockade. Science. 1996 271:1734–6.
8. Camacho LH. CTLA-4 blockade with ipilimumab: biology, safety,efficacy, and future considerations. Cancer Med. 2015 4:661–72.
9. Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P,et al. Localized oncolytic virotherapy overcomes systemic tumor resistance toimmune checkpoint blockade immunotherapy. Sci. Transl. Med. 2014 6:226–32.
10. Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer ARL, Bajor DL,et al. Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 andCTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. CancerImmunol. Res. 2015 3:399–411.
11. Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy forcancer: harnessing the T cell response. Nat. Rev. Immunol. 2012. 12:269–81.
12. Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, VoglDT, Lacey SF, et al. NY-ESO-1-specific TCR-engineered T cells mediatesustained antigen-specific antitumor effects in myeloma. Nat. Med. 2015 21:1–20.
13. Nakazawa Y, Huye LE, Salsman VS, Leen AM, Ahmed N, Rollins L, etal. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol. Ther. 2011 19:2133–43.
14. Stevanović S, Draper LM, Langhan MM, Campbell TE, Kwong ML,Wunderlich JR, et al. Complete regression of metastatic cervical cancer aftertreatment with human papillomavirus-targeted tumor-infiltrating T cells. J.Clin. Oncol. 2015 33:1543–50.
15. Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, CardonesAR, Finkelstein SE, et al. Central memory self/tumor-reactive CD8+ T cellsconfer superior antitumor immunity compared with effector memory T cells.Proc. Natl. Acad. Sci. U. S. A. 2005 102:9571–6.
16. Topalian SL, Muul LM, Solomon D, Rosenberg SA. Expansion of humantumor infiltrating lymphocytes for use in immunotherapy trials. J. Immunol.Methods 1987 102:127–41.
17. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, etal. Adoptive cell therapy for patients with metastatic melanoma: Evaluationof intensive myeloablative chemoradiation preparative regimens. J. Clin.Oncol. 2008;26:5233–9.
18. Ram R, Storb R, Sandmaier BM, Maloney DG, Woolfrey A, FlowersMED, et al. Non-myeloablative conditioning with allogeneic hematopoietic celltransplantation for the treatment of high-risk acute lymphoblastic leukemia.Haematologica. 2011 96:1113–20.
19. Topalian SL, Solomon D, Avis FP, Chang AE, Freerksen DL, LinehanWM, et al. Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study. J ClinOncol 1988 6:839–53.
20. Chapuis AG, Thompson JA, Margolin KA, Rodmyre R, Lai IP, Dowdy K,et al. Transferred melanoma-specific CD8+ T cells persist, mediate tumorregression, and acquire central memory phenotype. Proc. Natl. Acad. Sci. 2012109:4592–7.
21. Pollack SM, Jones RL, Farrar E a, Lai IP, Lee SM, Cao J, et al.Tetramer guided, cell sorter assisted production of clinical grade autologousNY-ESO-1 specific CD8(+) T cells. J. Immunother. Cancer 2014 2:36.
22. Zhang L, Bridle BW, Chen L, Pol J, Spaner D, Boudreau JE, et al.Delivery of viral-vectored vaccines by B cells represents a novel strategy toaccelerate CD8(+) T-cell recall responses. Blood. 2013 121:2432–9.
23. Oldstone MB, Tishon A, Eddleston M, de la Torre JC, McKee T,Whitton JL. Vaccination to prevent persistent viral infection. J. Virol. 199367:4372–8.
24. Pol JG, Zhang L, Bridle BW, Stephenson KB, Rességuier J, HansonS, et al. Maraba virus as a potent oncolytic vaccine vector. Mol. Ther. 201422:420–9.
25. Boudreau JE, Bridle BW, Stephenson KB, Jenkins KM, Brunellière J,Bramson JL, et al. Recombinant vesicular stomatitis virus transduction ofdendritic cells enhances their ability to prime innate and adaptive antitumorimmunity. Mol. Ther. 2009 17:1465–72.
26. Brun J, McManus D, Lefebvre C, Hu K, Falls T, Atkins H, et al.Identification of genetically modified Maraba virus as an oncolyticrhabdovirus. Mol. Ther. 2010 18:1440–9.
27. Rochman Y, Spolski R, Leonard WJ. New insights into theregulation of T cells by gamma(c) family cytokines. Nat. Rev. Immunol. 20099:480–90.
28. Crawley AM, Katz T, Parato K, Angel JB. IL-2 receptor gamma chaincytokines differentially regulate human CD8+CD127+ and CD8+CD127- T celldivision and susceptibility to apoptosis. Int. Immunol. 2009 21:29–42.
29. Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA.Generation of tumor-infiltrating lymphocyte cultures for use in adoptivetransfer therapy for melanoma patients. J. Immunother. 2003 26:332–42.
30. Hinrichs CS, Spolski R, Paulos CM, Gattinoni L, Kerstann KW,Palmer DC, et al. IL-2 and IL-21 confer opposing differentiation programs toCD8+ T cells for adoptive immunotherapy. Blood 2008 111:5326–33.
31. Schluns KS, Lefrançois L. Cytokine control of memory T-celldevelopment and survival. Nat. Rev. Immunol. 2003 3:269–79.
32. Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS,et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion andfunction. J. Exp. Med. 2005 201:139–48.
33. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller S a, BachmannMF, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009460:108–12.
34. Rao RR, Li Q, Odunsi K, Shrikant PA. The mTOR Kinase DeterminesEffector versus Memory CD8+ T Cell Fate by Regulating the Expression ofTranscription Factors T-bet and Eomesodermin. Immunity. 2010 32:67–78.
35. Li Q, Rao R, Vazzana J, Goedegebuure P, Odunsi K, Gillanders W,et al. Regulating mammalian target of rapamycin to tune vaccination-inducedCD8(+) T cell responses for tumor immunity. J. Immunol. 2012 188:3080–7.
36. Cameron BJ, Gerry AB, Dukes J, Harper J V, Kannan V, Bianchi FC,et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci. Transl. Med.2013 5:197ra103.
37. Chinnasamy N, Wargo J a, Yu Z, Rao M, Frankel TL, Riley JP, etal. A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizesmultiple epitopes of the MAGE-A antigen superfamily in several types ofcancer. J. Immunol. 2011 186:685–96.
SEQUENCE LISTING
<110> 麦克马斯特大学
<120> 过继细胞转移与溶瘤病毒组合疗法
<130> PAT 104106W-90
<150> US 62/354,506
<151> 2016-06-24
<160> 3
<170> PatentIn version 3.5
<210> 1
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 淋巴细胞脉络丛脑膜炎病毒gp33表位LCMV-gp33-41
<400> 1
Lys Ala Val Tyr Asn Phe Ala Thr Met
1 5
<210> 2
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 多巴色素互变异构酶 (DCT)表位DCT180-188
<400> 2
Ser Val Tyr Asp Phe Phe Val Trp Leu
1 5
<210> 3
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CMS5纤维肉瘤排斥抗原突变ERK2 (MAPK1)表位
Erk9M136-144
<400> 3
Gln Tyr Ile His Ser Ala Asn Val Leu
1 5
Claims (36)
1.用于治疗有此需要的受试者的癌症的药物组合,其包括(i)向受试者施用的包含CD8+T细胞群的过继细胞治疗剂(ACT),其中至少50%的CD8+T细胞显示中枢记忆表型并且对所述癌症表达的肿瘤抗原具有特异性,以及(ii)随后向受试者施用的表达所述肿瘤抗原的复制型溶瘤病毒(OV)疫苗;
其中所述CD8+T细胞群是通过以下方法制备的:
在包含IL21、IL15和雷帕霉素并且不包含IL2的组合物中离体共培养CD25耗竭的外周血单核细胞(PBMC)和抗原呈递细胞(APC)两周,其中APC包含负载肿瘤抗原肽的经辐照的树突状细胞;以及
在不存在肿瘤抗原和APC的情况下,在包含IL21、IL15和雷帕霉素的组合物中离体培养所述PBMC一周。
2.根据权利要求1所述的药物组合,其中至少60%或至少70%CD8+T细胞显示中枢记忆表型并且对所述癌症表达的肿瘤抗原具有特异性。
3.根据权利要求1所述的药物组合,其中所述复制型溶瘤病毒(OV)是溶瘤弹状病毒或痘苗病毒。
4.根据权利要求1所述的药物组合,其中制备所述CD8+T细胞群的方法还包括包含抗CD3抗体和抗CD28抗体和IL2的快速扩增方案(REP)。
5.根据权利要求4所述的药物组合,其中所述PBMC为自体PBMC。
6.根据权利要求1所述的药物组合,其中IL21和IL15以1ng/ml至20ng/ml的浓度存在,并且雷帕霉素以10ng/ml至30ng/ml的浓度存在。
7.根据权利要求6所述的药物组合,其中IL21和IL15以10ng/ml的浓度存在。
8.根据权利要求6所述的药物组合,其中雷帕霉素以20ng/ml的浓度存在。
9.根据权利要求1所述的药物组合,其中在离体培养后不进行T细胞纯化步骤。
10.根据权利要求9所述的药物组合,其中在培养物中的所述CD8+T细胞在包含抗CD3抗体和抗CD28抗体和IL2的组合物中离体扩增。
11.根据权利要求9所述的药物组合,其中所述CD8+T细胞在培养物中离体扩增一周至四周。
12.根据权利要求9所述的药物组合,其中所述T细胞纯化步骤是细胞分选。
13.根据权利要求1所述的药物组合,其中所述复制型溶瘤病毒是弹状病毒。
14.根据权利要求13所述的药物组合,其中所述弹状病毒是水泡病毒。
15.根据权利要求13所述的药物组合,其中所述弹状病毒是重组或野生型Maraba病毒,或重组或野生型VSV。
16.根据权利要求15所述的药物组合,其中Maraba病毒是Maraba MG1。
17.根据权利要求15所述的药物组合,其中VSV病毒是VSVdelta51。
18.根据权利要求1所述的药物组合,其中所述复制型溶瘤病毒是野生型或重组痘苗病毒。
19.根据权利要求18所述的药物组合,其中所述痘苗病毒是Wyeth株、Western Reserve株或Copenhagen株。
20.根据权利要求19所述的药物组合,其中所述Wyeth株、Western Reserve株或Copenhagen株具有胸苷激酶缺失和/或痘苗病毒生长因子基因缺失。
21.根据权利要求1所述的药物组合,其中所述肿瘤抗原选自甲胎蛋白(AFP)、癌胚抗原(CEA)、CA125、Her2、多巴色素互变异构酶(DCT)、GP100、Melan-A/MART-1、MAGE蛋白、BAGE蛋白、GAGE蛋白、NY-ESO1、WT-1、存活蛋白、酪氨酸酶、SSX2、细胞周期蛋白-A1、KIF20A、MUC5AC、Meloe、Lengsin、激肽释放酶4、IGF2B3、磷脂酰肌醇蛋白聚糖3、HPV E6和HPV E7。
22.根据权利要求1所述的药物组合,其中所述癌症选自黑素瘤、淋巴瘤、脑癌、乳腺癌、肝癌、肺癌、肾癌、胰腺癌、食道癌、胃癌、结肠癌、结肠直肠癌、膀胱癌、前列腺癌和白血病。
23.根据权利要求22所述的药物组合,其中所述脑癌是神经胶质瘤。
24.根据权利要求1至23中任一项所述的药物组合,其中所述癌症是实体瘤。
25.根据权利要求1至23中任一项所述的药物组合,其中所述癌症是转移癌。
26.根据权利要求1至23中任一项所述的药物组合,其中所述肿瘤抗原是肿瘤特异性抗原。
27.根据权利要求1至23中任一项所述的药物组合,其中所述肿瘤抗原是自身抗原。
28.根据权利要求1至23中任一项所述的药物组合,其中所述CD8+T细胞群对于所述受试者是自体同源的。
29.根据权利要求1至23中任一项所述的药物组合,其中所述受试者是人。
30.根据权利要求1所述的药物组合,其中所述负载肿瘤抗原肽的经辐照的树突状细胞通过以下方法获得:(i)用GM-CSF和IL-4培养来自受试者的贴壁PBMC以获得自体树突细胞;(ii)用所述肿瘤抗原肽脉冲所述树突状细胞;和(iii)辐照负载肿瘤抗原肽的树突状细胞。
31.根据权利要求30所述的药物组合,其中用GM-CSF和IL-4培养来自受试者的贴壁PBMC以获得自体树突细胞,随后用TNFα、IL-1b、IL-6、PGE-2、IL-4和GM-CSF刺激所述树突状细胞。
32.一种制备具有中枢记忆表型的肿瘤抗原特异性人CD8+T细胞群的方法,包括(i)在包含IL15、IL21和雷帕霉素并且不包含IL2的组合物中离体共培养从人获得的CD25耗竭的外周血单核细胞(PBMC)和抗原呈递细胞(APC)两周,其中APC包含负载肿瘤抗原肽的经辐照的树突状细胞;
(ii)在不存在肿瘤抗原和APC的情况下,在包含IL15、IL21和雷帕霉素的组合物中离体培养所述PBMC一周以获得具有中枢记忆表型的肿瘤抗原特异性人CD8+T细胞群;
(iii)扩增获得的CD8+T细胞。
33.根据权利要求32所述的方法,其中在含有抗CD3抗体和抗CD28抗体以及IL2的培养基中扩增获得的CD8+T细胞。
34.根据权利要求32所述的方法,其中所述方法不包括在步骤(ii)和(iii)之间的T细胞纯化步骤。
35.根据权利要求34所述的方法,其中所述T细胞纯化步骤是细胞分选。
36.根据权利要求32所述的方法,其中所述PBMC获自患有癌症的人。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311501171.8A CN117731763A (zh) | 2016-06-24 | 2017-06-23 | 过继细胞转移与溶瘤病毒组合疗法 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662354506P | 2016-06-24 | 2016-06-24 | |
US62/354,506 | 2016-06-24 | ||
PCT/CA2017/050772 WO2017219150A1 (en) | 2016-06-24 | 2017-06-23 | Adoptive cell transfer and oncolytic virus combination therapy |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311501171.8A Division CN117731763A (zh) | 2016-06-24 | 2017-06-23 | 过继细胞转移与溶瘤病毒组合疗法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109310746A CN109310746A (zh) | 2019-02-05 |
CN109310746B true CN109310746B (zh) | 2023-12-05 |
Family
ID=60783592
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780038919.1A Active CN109310746B (zh) | 2016-06-24 | 2017-06-23 | 过继细胞转移与溶瘤病毒组合疗法 |
CN202311501171.8A Pending CN117731763A (zh) | 2016-06-24 | 2017-06-23 | 过继细胞转移与溶瘤病毒组合疗法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311501171.8A Pending CN117731763A (zh) | 2016-06-24 | 2017-06-23 | 过继细胞转移与溶瘤病毒组合疗法 |
Country Status (8)
Country | Link |
---|---|
US (3) | US11045496B2 (zh) |
EP (2) | EP3474888B1 (zh) |
JP (1) | JP2019524667A (zh) |
KR (1) | KR20190033066A (zh) |
CN (2) | CN109310746B (zh) |
CA (1) | CA3028813A1 (zh) |
SG (2) | SG10201913600RA (zh) |
WO (1) | WO2017219150A1 (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111836887A (zh) * | 2018-01-08 | 2020-10-27 | 艾欧凡斯生物治疗公司 | 产生富含肿瘤抗原特异性t细胞的til产品的方法 |
US11713446B2 (en) | 2018-01-08 | 2023-08-01 | Iovance Biotherapeutics, Inc. | Processes for generating TIL products enriched for tumor antigen-specific T-cells |
CN110305198B (zh) * | 2018-03-27 | 2021-01-29 | 睿丰康生物医药科技(浙江)有限公司 | 一种溶瘤棒状病毒减毒株及其在肿瘤治疗中的应用 |
EP3773626A4 (en) * | 2018-03-28 | 2022-01-05 | Board of Regents, The University of Texas System | USING HISTONE MODIFIERS TO REPROGRAM LYMPHOCYTES AND EFFECTORS |
CA3132054A1 (en) * | 2018-04-09 | 2019-10-17 | Children's Hospital Of Eastern Ontario Research Institute Inc. | A heterologous combination prime:boost therapy and methods of treatment |
WO2020096927A1 (en) * | 2018-11-05 | 2020-05-14 | Iovance Biotherapeutics, Inc. | Expansion of tils utilizing akt pathway inhibitors |
CN111494414A (zh) * | 2019-01-31 | 2020-08-07 | 惠君生物医药科技(杭州)有限公司 | 一种用于癌症的联合免疫治疗的药物组合及其应用 |
GB201909144D0 (en) * | 2019-06-25 | 2019-08-07 | Autolus Ltd | Culture medium |
JP2022554217A (ja) * | 2019-10-23 | 2022-12-28 | ザ・カウンシル・オヴ・ザ・クイーンズランド・インスティテュート・オヴ・メディカル・リサーチ | 養子免疫療法 |
WO2023049860A1 (en) * | 2021-09-24 | 2023-03-30 | Oregon Health & Science University | Immune cells with reduced androgen receptor (ar) level, and methods of their use to enhance anti-cancer therapy |
WO2023088437A1 (zh) * | 2021-11-19 | 2023-05-25 | 南开大学 | 重组武装溶瘤病毒组合物及其在til过继治疗中的用途 |
WO2023130040A2 (en) * | 2021-12-31 | 2023-07-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | T cell therapy with vaccination as a combination immunotherapy against cancer |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101273122A (zh) * | 2005-08-08 | 2008-09-24 | 塔博尔山圣拉弗尔基金中心 | 普通γ链细胞因子在记忆T淋巴细胞的显影、分离和遗传修饰中的应用 |
CN102448487A (zh) * | 2009-03-16 | 2012-05-09 | 麦克马斯特大学 | 疫苗接种方法 |
CN103930130A (zh) * | 2011-09-08 | 2014-07-16 | 耶达研究及发展有限公司 | 抗第三方中央型记忆t细胞、其产生方法以及其在移植和疾病治疗中的应用 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008521406A (ja) | 2004-11-24 | 2008-06-26 | フレッド ハッチンソン キャンサー リサーチ センター | 養子免疫療法のためのil−21の使用法および腫瘍抗原の同定法 |
CN105769931B (zh) | 2006-09-15 | 2021-04-27 | 渥太华医院研究机构 | 溶瘤弹状病毒 |
AU2010329551B2 (en) | 2009-12-10 | 2016-02-11 | Turnstone Limited Partnership | Oncolytic rhabdovirus |
AR100657A1 (es) | 2014-06-05 | 2016-10-26 | Pontifica Univ Católica De Chile | Método para producir células dendríticas tolerogénicas autólogas (toldcs) con antígenos específicos y su uso en la preparación de un medicamento útil para el tratamiento de lupus eritematoso sistémico (les) |
EP3347473A4 (en) * | 2015-09-09 | 2019-04-10 | Tvax Biomedical I, LLC | METHODS FOR COMBINING ADOPTIVE TRANSFER THERAPY OF T-CELLS WITH ONCOLYTIC VIRUS ADHERENCE THERAPY |
-
2017
- 2017-06-23 SG SG10201913600RA patent/SG10201913600RA/en unknown
- 2017-06-23 JP JP2018567182A patent/JP2019524667A/ja active Pending
- 2017-06-23 CA CA3028813A patent/CA3028813A1/en active Pending
- 2017-06-23 US US16/312,897 patent/US11045496B2/en active Active
- 2017-06-23 KR KR1020197002322A patent/KR20190033066A/ko unknown
- 2017-06-23 SG SG11201811408PA patent/SG11201811408PA/en unknown
- 2017-06-23 EP EP17814390.5A patent/EP3474888B1/en active Active
- 2017-06-23 CN CN201780038919.1A patent/CN109310746B/zh active Active
- 2017-06-23 WO PCT/CA2017/050772 patent/WO2017219150A1/en unknown
- 2017-06-23 CN CN202311501171.8A patent/CN117731763A/zh active Pending
- 2017-06-23 EP EP22208589.6A patent/EP4197551A3/en active Pending
-
2021
- 2021-05-20 US US17/325,557 patent/US20210338732A1/en not_active Abandoned
-
2023
- 2023-11-01 US US18/499,857 patent/US20240058383A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101273122A (zh) * | 2005-08-08 | 2008-09-24 | 塔博尔山圣拉弗尔基金中心 | 普通γ链细胞因子在记忆T淋巴细胞的显影、分离和遗传修饰中的应用 |
CN102448487A (zh) * | 2009-03-16 | 2012-05-09 | 麦克马斯特大学 | 疫苗接种方法 |
CN103930130A (zh) * | 2011-09-08 | 2014-07-16 | 耶达研究及发展有限公司 | 抗第三方中央型记忆t细胞、其产生方法以及其在移植和疾病治疗中的应用 |
Non-Patent Citations (5)
Title |
---|
Adoptive cell transfer as personalized immunotherapy for human cancer;Rosenberg SA等;《Science》;20150430;第48卷(第6230期);全文 * |
An HSV-2 based oncolytic virus can function as an attractant to guide migration of adoptively transferred T cells to tumor sites;Fu X等;《Oncotarget》;20150120;第6卷(第2期);全文 * |
Ex vivo expansion protocol for human tumor specific T cells for adoptive T cell therapy;Anne-MarieRasmussen等;《Journal of immunological methods》;20100415;第355卷(第1-2期);第 53 页左栏最后1-2段,第 54 页第 2.3 节,第 55 页第 3.2 节 * |
Privileged Antigen Presentation in Splenic B Cell Follicles Maximizes T Cell Responses in Prime-Boost Vaccination;Bridle BW等;《J Immunol》;20160101;第196卷(第11期);第4588页左栏最后1段至右栏第1段,第4589页右栏最后1段至第4591页右栏第1段 * |
Sorting through subsets: Which T cell populations mediate highly effective adoptive immunotherapy?;Klebanoff CA等;《J Immunother》;20121130;第35卷(第9期);第7页最后1-2段至第8页第1-2段 * |
Also Published As
Publication number | Publication date |
---|---|
JP2019524667A (ja) | 2019-09-05 |
SG10201913600RA (en) | 2020-02-27 |
EP4197551A2 (en) | 2023-06-21 |
SG11201811408PA (en) | 2019-01-30 |
US11045496B2 (en) | 2021-06-29 |
CA3028813A1 (en) | 2017-12-28 |
CN117731763A (zh) | 2024-03-22 |
EP3474888B1 (en) | 2022-11-23 |
KR20190033066A (ko) | 2019-03-28 |
US20240058383A1 (en) | 2024-02-22 |
CN109310746A (zh) | 2019-02-05 |
US20190321400A1 (en) | 2019-10-24 |
US20210338732A1 (en) | 2021-11-04 |
EP4197551A3 (en) | 2023-10-25 |
EP3474888A1 (en) | 2019-05-01 |
WO2017219150A1 (en) | 2017-12-28 |
EP3474888A4 (en) | 2020-03-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109310746B (zh) | 过继细胞转移与溶瘤病毒组合疗法 | |
WO2019184459A1 (zh) | 溶瘤病毒疫苗和过继性免疫细胞联合疗法 | |
JP2018188475A (ja) | カスパーゼポリペプチドを使用して部分的なアポトーシスを誘導するための方法 | |
US9238064B2 (en) | Allogeneic cancer cell-based immunotherapy | |
JPWO2010030002A1 (ja) | 外来性gitrリガンド発現細胞 | |
JP2022547154A (ja) | 調節可能な制御のためのca2-il15融合タンパク質 | |
US11965177B2 (en) | Method of manufacturing dual specific T-cells for use in cancer immunotherapy | |
KR20210013013A (ko) | 종양 치료 방법 및 조성물 | |
CN110404061B (zh) | 改进的t细胞治疗方法 | |
AU2015233542B2 (en) | A medicament for use in a method of inducing or extending a cellular cytotoxic immune response | |
CN111094553A (zh) | 用于癌症治疗的改良同种异体树突状细胞 | |
CN111320677A (zh) | 溶瘤病毒疫苗和过继性免疫细胞联合疗法 | |
JP2008523067A (ja) | 癌ワクチンアジュバントとしてのαサイモシンペプチド | |
Mierzejewska et al. | The Beneficial Effect of IL‐12 and IL‐18 Transduced Dendritic Cells Stimulated with Tumor Antigens on Generation of an Antitumor Response in a Mouse Colon Carcinoma Model | |
WO2023088437A1 (zh) | 重组武装溶瘤病毒组合物及其在til过继治疗中的用途 | |
RU2739073C2 (ru) | Новые медицинские агенты и их применение | |
WO2023276395A1 (ja) | キメラサイトカイン受容体 | |
CN111494414A (zh) | 一种用于癌症的联合免疫治疗的药物组合及其应用 | |
Yorty et al. | Rapid accumulation of adoptively transferred CD8+ T cells at the tumor site is associated with long-term control of SV40 T antigen-induced tumors | |
Serafini et al. | The immune system in head and neck squamous cell carcinoma: Interactions and therapeutic opportunities | |
JP2023554319A (ja) | がんを治療するための方法及び材料 | |
KR20240102997A (ko) | 암 치료를 위한 방법 및 물질 | |
JP2024540276A (ja) | がんを治療するための方法及び材料 | |
Xia | Cancer Immunogene Therapy Using Viral Vectors Encoding Cytokines and Chimeric Antigen Receptors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TG01 | Patent term adjustment |