CN113368246A - 一种增效的抗肿瘤药物 - Google Patents
一种增效的抗肿瘤药物 Download PDFInfo
- Publication number
- CN113368246A CN113368246A CN202110515987.0A CN202110515987A CN113368246A CN 113368246 A CN113368246 A CN 113368246A CN 202110515987 A CN202110515987 A CN 202110515987A CN 113368246 A CN113368246 A CN 113368246A
- Authority
- CN
- China
- Prior art keywords
- tumor
- inhibitor
- composition
- cancer
- glioma
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 title abstract description 5
- 230000002195 synergetic effect Effects 0.000 title abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 74
- 241000711975 Vesicular stomatitis virus Species 0.000 claims abstract description 57
- 239000003814 drug Substances 0.000 claims abstract description 38
- 239000012828 PI3K inhibitor Substances 0.000 claims abstract description 34
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 claims abstract description 34
- 239000012270 PD-1 inhibitor Substances 0.000 claims abstract description 25
- 239000012668 PD-1-inhibitor Substances 0.000 claims abstract description 25
- 229940121655 pd-1 inhibitor Drugs 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 30
- XOZLHJMDLKDZAL-UHFFFAOYSA-N 5-[6-(3-methoxyoxetan-3-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl]pyrimidin-2-amine Chemical compound S1C2=C(N3CCOCC3)N=C(C=3C=NC(N)=NC=3)N=C2C(C)=C1C1(OC)COC1 XOZLHJMDLKDZAL-UHFFFAOYSA-N 0.000 claims description 26
- 206010018338 Glioma Diseases 0.000 claims description 26
- 208000032612 Glial tumor Diseases 0.000 claims description 23
- 230000000259 anti-tumor effect Effects 0.000 claims description 9
- 230000035772 mutation Effects 0.000 claims description 9
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 claims description 6
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 claims description 6
- 230000037430 deletion Effects 0.000 claims description 5
- 238000012217 deletion Methods 0.000 claims description 5
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-N1-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4-pyridinyl]-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 claims description 4
- XTKLTGBKIDQGQL-UHFFFAOYSA-N 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-morpholin-4-ylbenzimidazole-4-carboxylic acid Chemical compound CC1=NC2=C(C(O)=O)C=C(N3CCOCC3)C=C2N1CC1=CC=CC(C(F)(F)F)=C1C XTKLTGBKIDQGQL-UHFFFAOYSA-N 0.000 claims description 4
- ADGGYDAFIHSYFI-UHFFFAOYSA-N 5-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=NC(N2CCOCC2)=NC(N2CCOCC2)=N1 ADGGYDAFIHSYFI-UHFFFAOYSA-N 0.000 claims description 4
- 206010003571 Astrocytoma Diseases 0.000 claims description 4
- 229950010482 alpelisib Drugs 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- -1 copulisib Chemical compound 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- CGBJSGAELGCMKE-UHFFFAOYSA-N omipalisib Chemical compound COC1=NC=C(C=2C=C3C(C=4C=NN=CC=4)=CC=NC3=CC=2)C=C1NS(=O)(=O)C1=CC=C(F)C=C1F CGBJSGAELGCMKE-UHFFFAOYSA-N 0.000 claims description 4
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002018 overexpression Effects 0.000 claims description 3
- 239000000816 peptidomimetic Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 claims description 2
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 201000010133 Oligodendroglioma Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 102000007079 Peptide Fragments Human genes 0.000 claims description 2
- 108010033276 Peptide Fragments Proteins 0.000 claims description 2
- 102100037596 Platelet-derived growth factor subunit A Human genes 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 206010002224 anaplastic astrocytoma Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 239000008176 lyophilized powder Substances 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 230000009401 metastasis Effects 0.000 claims description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 108010017843 platelet-derived growth factor A Proteins 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 102100023990 60S ribosomal protein L17 Human genes 0.000 claims 1
- 208000013938 anaplastic oligoastrocytoma Diseases 0.000 claims 1
- 229940102223 injectable solution Drugs 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 27
- 239000000890 drug combination Substances 0.000 abstract description 8
- 238000009169 immunotherapy Methods 0.000 abstract description 8
- 230000001225 therapeutic effect Effects 0.000 abstract description 8
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 abstract description 3
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 abstract description 3
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 abstract description 3
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 abstract description 3
- 230000004043 responsiveness Effects 0.000 abstract description 2
- 230000001348 anti-glioma Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 47
- 241000699670 Mus sp. Species 0.000 description 44
- 230000004083 survival effect Effects 0.000 description 30
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 29
- 150000001875 compounds Chemical class 0.000 description 23
- 241000699666 Mus <mouse, genus> Species 0.000 description 21
- 244000309459 oncolytic virus Species 0.000 description 18
- 241000700605 Viruses Species 0.000 description 13
- 230000012010 growth Effects 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 10
- 230000008901 benefit Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 101100120176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) FKS1 gene Proteins 0.000 description 7
- 238000011081 inoculation Methods 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 230000004614 tumor growth Effects 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- 208000005623 Carcinogenesis Diseases 0.000 description 6
- 239000006285 cell suspension Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 229940002612 prodrug Drugs 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 108091007960 PI3Ks Proteins 0.000 description 5
- 230000036952 cancer formation Effects 0.000 description 5
- 231100000504 carcinogenesis Toxicity 0.000 description 5
- 238000012258 culturing Methods 0.000 description 5
- 230000006054 immunological memory Effects 0.000 description 5
- 238000007917 intracranial administration Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- 102000038030 PI3Ks Human genes 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 238000011503 in vivo imaging Methods 0.000 description 4
- 229960002725 isoflurane Drugs 0.000 description 4
- 230000000174 oncolytic effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 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
- 108091027967 Small hairpin RNA Proteins 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000004055 small Interfering RNA Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HBZBAMXERPYTFS-SECBINFHSA-N (4S)-2-(6,7-dihydro-5H-pyrrolo[3,2-f][1,3]benzothiazol-2-yl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)[C@H]1CSC(=N1)c1nc2cc3CCNc3cc2s1 HBZBAMXERPYTFS-SECBINFHSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000001024 immunotherapeutic effect Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000024121 nodulation Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 1
- 101000595741 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Proteins 0.000 description 1
- 101000595746 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Proteins 0.000 description 1
- 101000595751 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Proteins 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229940124780 PI3K delta inhibitor Drugs 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 1
- 102100036061 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Human genes 0.000 description 1
- 102100036056 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 241001068263 Replication competent viruses Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 229950002550 copanlisib Drugs 0.000 description 1
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000010460 detection of virus Effects 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
- 230000029087 digestion Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 201000004058 mixed glioma Diseases 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229950004941 pictilisib Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000000316 virotherapy Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K35/766—Rhabdovirus, e.g. vesicular stomatitis virus
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明属于生物医药领域,涉及一种增效的抗肿瘤药物。尤其涉及包含水疱性口炎病毒,PI3K抑制剂和PD‑1抑制剂的组合物在制备抗胶质瘤药物中的应用。本公开首次发现,水疱性口炎病毒,PI3K抑制剂和PD‑1抑制剂的三药组合极大地提高免疫治疗的反应性,以及提高免疫检查点抑制剂作为抗肿瘤药物时的治疗有效性。这对于治疗免疫治疗抵抗的肿瘤具有极其重要的意义。
Description
技术领域
本发明属于生物医药领域,涉及一种增效的抗胶质瘤药物。
背景技术
溶瘤病毒(oncolytic virus)是一类选择性的感染并杀伤肿瘤细胞,而不损伤正常细胞的可复制病毒。溶瘤病毒疗法(oncolytic virotherapy)是一种创新的肿瘤靶向治疗策略,它利用天然的或经基因工程改造的病毒选择性的感染肿瘤细胞,并在肿瘤细胞中复制,达到靶向性溶解、杀伤肿瘤细胞的作用,但是对正常细胞没有损伤。
肿瘤免疫治疗极大革新了肿瘤的治疗现状和发展方向。但是目前,临床上免疫治疗单用时,包括免疫检查点抑制剂治疗和T细胞介导的免疫疗法患者的反应率较低,仅有很少部分的患者能获得治疗益处。如何提高肿瘤免疫治疗反应率是重要的临床需求和科学问题。多个研究指出恶性胶质瘤肿瘤是一群免疫治疗抵抗肿瘤,因此如何降低恶性胶质瘤肿瘤的免疫治疗抵抗和如何提高其免疫治疗反应率的是本领域十分关注的问题。
发明内容
一方面,本公开提供了一种组合物,包含:水疱性口炎病毒,PI3K抑制剂,和PD-1抑制剂。
“PI3K抑制剂”是指能够抑制磷酸肌醇-3-激酶的任何一种同种型(例如PIK3CA、PIK3CB、PIK3CD和PIK3CG基因的基因产物)的任何化合物或物质。PI3K抑制剂包括PI3K-α、PI3K-β和PI3K-δ抑制剂。在一些实施方案中,“PI3K抑制剂”可以是抑制PI3K通路中任意一个靶点的形成,或抑制靶点活性,或降解靶点的物质或工具,包括化学的或生物的物质或工具等。
所述PI3K抑制剂或PD-1抑制剂,包括截至目前所公开的PI3K抑制剂或PD-1抑制剂。可能地,未来可能会有一些其他被研究出具有类似的抑制PI3K或PD-1作用的PI3K抑制剂或PD-1抑制剂,这些PI3K抑制剂和PD-1抑制剂与水疱性口炎病毒的联用也是在本发明的范围之内。本领域技术人员可以对所述的抑制化合物或者基因工具进行修饰、替换、改变等,作为可选的方式,这些情况也属于本发明的保护范围。
一方面,本公开提供了一种药品套装,包含:水疱性口炎病毒,PI3K抑制剂,和PD-1抑制剂。
所述药品套装包含独立包装的水疱性口炎病毒,独立包装的PI3K抑制剂和独立包装的PD-1抑制剂。
药品套装区别于组合物的地方在于,PI3K抑制剂、PD-1抑制剂不同于水疱性口炎病毒的剂型,而是独立包装(例如:药丸、或胶囊、或药片或安剖瓶中,含有PI3K抑制剂、PD-1抑制剂;另外的药丸、或胶囊、或药片或安剖瓶中,含有水疱性口炎病毒)。在一些实施例中,水疱性口炎病毒,PI3K抑制剂,和PD-1抑制剂,也可含一种或多种佐剂。所述的佐剂是指在药物组成中,可辅助药物疗效的成分。药品套装也可以包含独立包装的PI3K抑制剂、PD-1抑制剂,以及独立包装的水疱性口炎病毒。药物套装中水疱性口炎病毒,PI3K抑制剂和PD-1抑制剂的施用,可以是同时施用或者是以任意的前后顺序施用,例如在水疱性口炎病毒之前施用PI3K抑制剂、或PD-1抑制剂,或者在水疱性口炎病毒之后施用PI3K抑制剂、或PD-1抑制剂,或者三者同时施用。在各种实施例中,患者可以是哺乳动物。
在一些实施方案中,本公开还提供了所述的组合物或所述的药品套装在制备抗肿瘤的药物中的应用。
“抗肿瘤”的药物能够例如通过以下方式来负面影响受试者体内的肿瘤/癌细胞:促进对肿瘤/癌细胞的杀伤、诱导肿瘤/癌细胞的凋亡、降低肿瘤/癌细胞的生长速率、降低发病率或转移数量、减小肿瘤大小、抑制肿瘤生长、减少对肿瘤/癌细胞的血液供应、促进针对肿瘤/癌细胞的免疫应答、预防或抑制肿瘤/癌细胞的进展,或延长患有肿瘤/癌细胞的受试者的寿命。
在一些实施方案中,本公开还提供了所述的组合物或所述的药品套装在制备用于预防和/或治疗肿瘤转移或复发的药物中的应用。
在一些实施方案中,“治疗”指代获得有益或希望的结果的方法,所述有益或希望的结果包括但不限于治疗益处。治疗益处包括但不限于根除、抑制、减少或改善所治疗的潜在障碍。另外,治疗益处是通过根除抑制、减少或改善与潜在的障碍相关的一种或多种生理症状实现的,从而在患者中观察到改善,但是患者仍然可能患有潜在障碍。
在一些实施方案中,“预防”用于本文中以指代获得有益或希望的结果的方法,所述有益或希望的结果包括但不限于预防方面的益处。为了获得预防方面益处,可以向处于患上特定疾病的风险的患者或向报告具有疾病的一种或多种生理症状的患者施用药物组合物,即使尚未诊断出该疾病。
本公开所说的水疱性口炎病毒可以尤其地指目前已有的水疱性口炎病毒,但也不排除一些自然变异或者进行了突变、修饰、序列增加、减少等的水疱性口炎病毒。这些变异、突变、修饰、序列增加或减少的病毒有可能具有类似的作用、或甚至是稍微降低、或者增强的作用等等。这些情况同在本发明的保护范围之内。
在一些实施方案中,所述水疱性口炎病毒选自野生的或经过工程化改造后的水疱性口炎病毒。
在一些实施方案中,所述水疱性口炎病毒选自VSVΔ51。
在一些实施方案中,所述PI3K抑制剂选自化合物。
在一些实施方案中,所述化合物选自包括但不限于以下化合物或其具有PI3K抑制剂作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体:Pictilisib(GDC-0941)、GNE-317、copanlisib、BYL-719、GSK2126458、PQR309或GSK2636771。化合物的获取方式可选但不限于:自己化学分离或合成或者从商业途径购买。
在一些实施方案中,所述化合物选自Pictilisib(GDC-0941)(式1)、GNE-317(式2)、copanlisib(式3)、BYL-719(式4)、GSK2126458(式5)、PQR309(式6)或GSK2636771(式7)或其各自药学上可接受的形式中的至少一种。
式1:Pictilisib
式2:GNE-317
式3:copanlisib
式4:BYL-719
式5:GSK2126458
式6:PQR309
式7:GSK2636771
在一些实施方案中,所述PI3K抑制剂选自GNE-317或其药学上可接受的形式。
在一些实施方案中,所述的化合物的“药学上可接受的形式”包括但不限于,化合物的药学上可接受的盐、水合物、溶剂化物、异构体、前药及同位素标记的衍生物。
在一些实施方案中,药学上可接受的形式是药学上可接受的盐。如本文所使用,术语“药学上可接受的盐”是指在合理医学判断的范围内适合用于与对象的组织接触而无过度的毒性、刺激性、过敏反应等,且与合理的效益/风险比相符的那些盐。药学上可接受的盐在本领域是熟知的。例如,Berge等人在J.Pharmaceutical Sciences(1977)66:1–19中详细描述了药学上可接受的盐。所述的化合物的药学上可接受的盐包括衍生自适合的无机和有机酸和碱的盐。
在一些实施方案中,药学上可接受的形式为溶剂化物(例如,水合物)。术语“溶剂化物”是指还包括化学计量的或非化学计量的量的通过非共价分子间力结合的溶剂的化合物。溶剂化物可以是所公开的化合物或其药学上可接受的盐。当溶剂为水时,溶剂化物为“水合物”。药学上可接受的溶剂和水合物是例如可以包括1个至约100个、或1个至约10个、或1个至约2个、约3个或约4个溶剂或水分子的复合物。应理解的是,如本文所使用的术语“化合物”包括化合物和化合物的溶剂化物,以及其混合物。
在一些实施方案中,药学上可接受的形式为异构体。“异构体”是具有相同分子式的不同的化合物。“立体异构体”是仅原子的空间排列方式不同的异构体。如本文所使用,术语“异构体”包括任何以及所有几何异构体和立体异构体。例如,“异构体”包括几何双键顺式和反式异构体,也称为E–和Z–异构体;R–和S–对映异构体;非对映异构体、(d)–异构体和(l)–异构体、其外消旋混合物;及其落入本公开范围内的其他混合物。
在一些实施方案中,药学上可接受的形式为前药。如本文所使用,术语“前药”是指在体内转化得到所公开的化合物或化合物的药学上可接受的形式的化合物。前药在向对象施用时可以是非活性的,但是在体内例如通过水解(例如,在血液中水解)转化为活性化合物。在某些情况下,前药具有比母体化合物改善的物理和/或递送性质。前药通常被设计成提高与母体化合物相关的基于药学和/或药物动力学的性质。
在一些实施方案中,药学上可接受的形式为互变异构体。如本文所使用,术语“互变异构体”是一种类型的异构体,其包括由氢原子的至少一种形式迁移及化合价的至少一种变化(例如,单键到双键、三键到双键或三键到单键,反之亦然)产生的两种或多种可相互转化的化合物。
在一些实施方案中,所述PD-1抑制选自PD-1抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种。例如,结合至PD-1任意部位的任意功能结构域的抗体、抗体功能性片段、肽类、或拟肽。其中,所述的抗体可能是单克隆抗体,多克隆抗体,多价抗体,多特异性抗体(例如:双特异性抗体),纳米抗体,和/或连接在PD-1上的抗体片段。该抗体可以是嵌合抗体、人源化抗体、CDR移植抗体或人型抗体。抗体片段可以是,例如,Fab,Fab’,F(ab’)2,Fv,Fd,单链Fv(scFv),具二硫键的FV(sdFv),或VL、VH结构域。抗体可能是一个共轭的形式,例如,结合一个标签、一个可检测标记,或一种细胞毒性剂。抗体可能是同型IgG(例如:IgG1、IgG2、IgG3、IgG4)、IgA、IgM、IgE或IgD。
在一些实施方案中,所述PD-1抑制剂选自单克隆抗体;在一些实施方案中,所述PD-1抑制剂选自抗原表位为RMP1-14的单克隆抗体。
在一些实施方案中,所述肿瘤为实体瘤或血液瘤;在一些实施方案中,所述的实体瘤为结直肠癌、胰腺癌、肝癌、膀胱癌、乳腺癌、宫颈癌、前列腺癌、胶质瘤、黑素瘤、鼻咽癌、肺癌或胃癌;在一些实施方案中,所述的肿瘤选自胶质瘤。
在一些实施方案中,所述胶质瘤选自PTEN突变或缺失、P53突变或缺失、IDH1突变、RB突变、PDGFA过表达或EGFR过表达的胶质瘤中的至少一种。
在一些实施方案中,所述胶质瘤选自胶质母细胞瘤、星形胶质瘤、少突胶质胶质瘤、间变性星形细胞瘤或混合型胶质瘤中的至少一种。
在一些实施方案中,所述的组合物/药品套装还包含药学上可接受的载体或药学上可接受的赋形剂。
“药学上可接受的载体”或“药学上可接受的赋形剂”包括任何及所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。针对药物活性物质使用这样的介质和试剂在本领域中是熟知的。除非任何常规的介质或试剂与活性成分不相容,考虑其在本文公开的治疗组合物中的使用。补充的活性成分也可以加入到药物组合物中。
在一些实施方案中,所述的组合物/药品套装的剂型选自冻干粉剂、注射剂、片剂、胶囊或贴剂。
本公开首次发现,水疱性口炎病毒,PI3K抑制剂,和PD-1抑制剂的三药组合极大地提高免疫治疗的反应性,以提高免疫检查点抑制剂作为抗肿瘤药物时的治疗有效性。这对于胶质瘤这类免疫治疗抵抗肿瘤具有极其重要的意义。
在一个示范性的实施例中,在肿瘤的动物实验模型中,GNE317作为PI3K抑制剂和VSVΔ51病毒,可以极大提高PD-1抗体治疗的反应率和有效性,可以使得肿瘤生长停滞,甚至在部分小鼠中引起肿瘤消退和形成持久的抗肿瘤免疫记忆功能,且未见明显的药物组合毒性。
在一个示范性的实施例中,双药组(包括VSVΔ51和PD-1抗体双药组、GNE317和PD-1抗体双药组),仅能延缓肿瘤的生长速度,无法使得荷瘤小鼠的肿瘤消退,而获得存活。水疱性口炎病毒,PI3K抑制剂和PD-1抑制剂的三药组合则可以达到,1+1+1>3的效果,使得大部分小鼠的肿瘤消退,并使得荷瘤小鼠获得长期的生存获益。
附图说明
图1为实施例1的不同处理组的方式及不同组的小鼠生存情况统计;
图2为实施例2中不同处理组的活体成像分析和定量分析;
图3为实施例3中不同小鼠的生存情况统计;
图4为实施例4中的体重变化曲线及重要脏器的H&E染色情况示意图;
图5为实施例5中,A,动物实验模式图,对裸鼠左右对侧分别接种不同胶质瘤细胞,左侧接种PTEN完整的GSC1细胞(GSC1-shNC);右侧接种PTEN敲低的GSC1细胞(GSC1-shPTEN)。肿瘤成瘤后,通过尾静脉注射溶瘤病毒VSVΔ51,检测两侧瘤内的病毒复制。B,GSC1-shPTEN移植瘤中的病毒复制量显著高于GSC1-shNC移植瘤。C,皮下肿瘤的生长曲线。每个3天对皮下的肿瘤的体积测量,并绘制肿瘤生长曲线。溶瘤病毒VSVΔ51可以显著抑制GSC1-shPTEN移植瘤的生长速度,而对GSC1-shNC移植瘤影响较小。
具体实施方式
以下通过具体的实施例进一步说明本申请的技术方案,具体实施例不代表对本申请保护范围的限制。其他人根据本申请理念所做出的一些非本质的修改和调整仍属于本申请的保护范围。
实施例1 PI3K抑制剂GNE317、VSVΔ51溶瘤病毒和PD-1抗体组合显著延长小鼠胶质瘤荷瘤小鼠生存期
材料:
带荧光素酶标记的小鼠胶质瘤细胞GL261-luc,VSVΔ51溶瘤病毒,PI3K抑制剂GNE317,体内级抗小鼠PD-1单克隆抗体(抗原表位为RMP1-14),免疫健全的C57品系小鼠,小动物活体成像仪器。
方法:
a)细胞的培养:小鼠胶质瘤细胞GL261-luc生长在含有10%FBS、100μU/ml的青霉素及0.1mg/ml链霉素的DMEM完全培养基中;所有细胞株均置于5%二氧化碳,37℃恒温密闭式孵箱(相对湿度95%)内培养传代,大约2-3天传代一次,取对数生长期的细胞用于小鼠成瘤实验。
b)小鼠胶质瘤模型构建:将上述培养的GL261消化为单细胞悬液,通过小动物立体定位仪系统,将105的GL261细胞注射到小鼠的右侧半脑,大约一周后通过小动物活体成像仪系统观察成瘤情况。实验采用随机、单盲设计,将成瘤后小鼠随机分为9组,每组8只小鼠。
分组情况:对照组,VSVΔ51溶瘤病毒单药组,PI3K抑制剂GNE317单药组,PD-1抗体单药组,VSVΔ51和GNE317双药组,VSVΔ51和PD-1抗体双药组,GNE317和PD-1抗体双药组,以及GNE317、VSVΔ51和PD-1抗体三药组。
药物剂量:GNE-317 20mg/kg,灌胃给药;PD-1抗体10mg/kg,腹腔注射给药;VSVΔ513*107PFU,尾静脉注射;
c)观察小鼠生存情况,并绘制生存曲线,评估治疗效果:对上述小鼠进行给药治疗,每日跟踪观察小鼠死亡情况,最后汇总数据绘制小鼠的生存曲线。
结果:
如图1所示,每组设置8只小鼠,给予药物处理后,根据小鼠的生存情况的观察和记录,对照组小鼠在接种肿瘤后,会在30天内全部死亡,中位生存期为20.5天,60天时存活比率为0只(存活)/8只(总数);VSVΔ51溶瘤病毒单药组为28.5天,60天时存活比率为0只(存活)/8只(总数),即小鼠全部死亡;PI3K抑制剂GNE317单药组为22.5天,60天时存活比率为0只(存活)/8只(总数),即小鼠全部死亡;PD-1抗体单药组为23天,60天时存活比率为0只(存活)/8只(总数),即小鼠全部死亡;VSVΔ51和GNE317双药组为35.5天,60天时存活比率为0只(存活)/8只(总数);VSVΔ51和PD-1抗体双药组为30.5天,60天时存活比率为1只(存活)/8只(总数);GNE317和PD-1抗体双药组为27天,60天时存活比率为0只(存活)/8只(总数);GNE317、VSVΔ51和PD-1抗体三药组,60天时存活比率为5只(存活)/8只(总数)。
单用药物组或双药组均无法诱导半数以上的小鼠获得长期的存活,仅有GNE317、VSVΔ51和PD-1抗体三药组可以使得部分小鼠获得长时程的生存获益。
实施例2 PI3K抑制剂GNE317、VSVΔ51溶瘤病毒和PD-1抗体组合显著抑制胶质瘤的生长
材料:
荧光素酶底物(在肿瘤细胞的荧光素酶催化下发生荧光,用于追踪颅内肿瘤生长);小动物活体成像系统;异氟烷气体麻醉剂。
方法:
a)注射荧光素酶底物:对实施例1中的小鼠,使用小动物活体成像系统观察小鼠颅内肿瘤的生长。由于颅内肿瘤为稳定表达荧光素酶的GL261细胞形成的,其在荧光素底物的作用下会发出生物荧光,荧光强弱则代表肿瘤的相对大小。荧光素酶底物的浓度配置为1.5mg/ml,对小鼠按照10μl/g的剂量进行腹腔注射。
b)异氟烷气体麻醉:将待观察小鼠放入仪器自带的麻醉箱中,封闭箱门,释放异氟烷气体,大约3分钟的吸入后,小鼠进入麻醉状态。
c)小动物活体成像观察:将上述麻醉好的小鼠,放入小动物活体成像装置,小鼠口鼻对准异氟烷气体管道,在荧光记录过程中保持麻醉状态,之后通过软件记录颅内肿瘤的荧光强度,并进行定量分析。
结果:
分别在接种小鼠第8天、第13天和第17天的时候分别对小鼠进行了荧光定量分析。如图2所示,对照组小鼠在接种肿瘤后,根据小动物活体成像仪器的分析和定量显示,对照组的小鼠肿瘤随着时间推移,呈现荧光强度不断增强,提示在没有药物干预的情况,GL261细胞形成的肿瘤会不断恶性增殖、扩大。而单用PD-1抗体组,无法明显抑制GL261细胞形成的肿瘤的生长;双药组,(包括VSVΔ51和PD-1抗体双药组、GNE317和PD-1抗体双药组)仅能延缓肿瘤的生长速度,并无法使得肿瘤生长停滞或者使得肿瘤消退。相比之下,GNE317、VSVΔ51和PD-1抗体三药组可以显著抑制肿瘤生长,使得肿瘤生长停滞,并引起部分肿瘤的消退。
实施例3 PI3K抑制剂GNE317、VSVΔ51溶瘤病毒和PD-1抗体组合引起部分小鼠的肿瘤消退,并形成抗肿瘤免疫记忆
材料:
GL261细胞,实施例2中的三药组合治疗下的存活小鼠(给药后80天仍然存活),年龄匹配的未经过任何处理的对照小鼠。
方法:
a)细胞的培养:小鼠胶质瘤细胞GL261-luc生长在含有10%FBS、100μU/ml的青霉素及0.1mg/ml链霉素的DMEM完全培养基中;所有细胞株均置于5%二氧化碳,37℃恒温密闭式孵箱(相对湿度95%)内培养传代,大约2-3天穿戴一次,取对数生长期的细胞用于小鼠成瘤实验。
b)肿瘤重接种,观察抗肿瘤免疫记忆形成情况:对上述培养的GL261细胞,消化为单细胞悬液后,通过小动物立体定位仪器,以5倍的剂量,即5*105个GL261细胞,重新接种到三药治疗后的存活小鼠的脑内,并对年龄匹配的未经过任何处理的对照小鼠接种同样剂量的GL261细胞。
c)观察小鼠生存情况,并绘制生存曲线,评估治疗效果:对上述小鼠进行肿瘤重接种后,每日跟踪观察小鼠死亡情况,最后汇总数据绘制小鼠的生存曲线。
结果:
如图3所示,年龄匹配的对照小鼠,在接种肿瘤后,全部在20天内死亡;而三药治疗后存活的5只小鼠,在重接种5倍剂量的GL261肿瘤细胞后,在没有任何药物的干预下,仅有一只小鼠出现死亡,大部分小鼠可以仍可以继续存活。
以上结果表明,三药治疗后的小鼠获得了持久的抗肿瘤免疫记忆功能,即使肿瘤重新复发,被唤醒的肿瘤免疫记忆可以将复发肿瘤清除。
实施例4 PI3K抑制剂GNE317、VSVΔ51溶瘤病毒和PD-1抗体组合对在本小鼠实验中未见明显药物毒性
材料:
小动物体重器;苏木精-伊红染料;组织切片机。
方法:
1)小鼠体重观察,接种肿瘤后,每间隔2天对小鼠的体重进行一次检测和记录,并绘制体重变化曲线。
2)苏木精-伊红(H&E)染色:麻醉处死小鼠,分离肿瘤组织,制成石蜡切片;脱蜡,脱蜡二甲苯Ⅰ、Ⅱ各10分钟;覆水,100%、90%、80%、70%酒精各5分钟,冲洗5分钟;苏木精染色5分钟;5%乙酸分化1分钟;伊红染色1分钟;脱水:70%、80%、90%、100%酒精各10秒,二甲苯1分钟,可以在通风橱自然晾干再封片,约5分钟左右;滴上中性树胶,封片。
结果:
如图4所示,从小鼠的体重曲线变化观察中,与对照组相比,PI3K抑制剂GNE317、VSVΔ51溶瘤病毒和PD-1抗体的三药组合并未显著影响小鼠的体重。通过重要脏器病理检测,包括心、肝、脾、肺、肾,苏木精-伊红(H&E)染色的结果显示未见明显的病理学异常和变化。
以上的结果证明,使用GNE317(20mg/kg,灌胃给药)、VSVΔ51病毒(3*107PFU,尾静脉注射)和PD-1抗体(10mg/kg,腹腔注射)的三药组合,在该药物浓度和注射方式下,在小鼠模型总未见明显的药物组合毒性。
实施例5胶质瘤中的PTEN缺陷促进溶瘤病毒复制及其溶瘤效应
材料:
短发夹RNA(shRNA)稳定敲低PTEN的人胶质瘤GSC1细胞(GSC1-shPTEN),对照细胞GSC1-shNC,VSVΔ51溶瘤病毒和免疫缺失的裸鼠。靶向PTEN的shRNA序列如下:CCGGTGCAGCAATTCACTGTAAACTCGAGTTTACAGTGAATTGCTGCATTTTTG。
方法:
a)细胞的培养:分别培养人胶质瘤细胞GSC1-shPTEN和GSC1-shNC,生长在含有20ng/mlb FGF、20ng/ml EGF、B27、100μU/ml的青霉素及0.1mg/ml链霉素的DMEM/F12培养基中;细胞株均置于5%二氧化碳,37℃恒温密闭式孵箱(相对湿度95%)内培养传代,大约2-3天传代一次,取对数生长期的细胞用于小鼠成瘤实验。
b)小鼠胶质瘤模型构建及病毒注射:将上述培养的人胶质瘤细胞GSC1-shPTEN和GSC1-shNC消化为单细胞悬液,注射到裸鼠的对侧斜腹侧皮下,接种5*106细胞,左侧接种PTEN完整的GSC1细胞(GSC1-shNC);右侧接种PTEN敲低的GSC1细胞(GSC1-shPTEN)。大约5天后成瘤后,尾静脉给与3*107PFU的VSVΔ51溶瘤病毒或PBS处理。
c)TCID50检测病毒滴度和复制情况
将上述GSC1-shPTEN移植瘤和GSC1-shNC的移植瘤,分别研磨破碎细胞后,释放组织内的VSVΔ51病毒颗粒,通过离心、过滤得到移植瘤的病毒提取液,用于后续的TCID50检测病毒滴度。
培养BHK-21细胞,取对数生长期细胞,接种到96孔板中,每孔加入细胞悬液100μl,使细胞量达到2~3×105个/ml。将VSV病毒液作连续10倍的稀释,从10-1-10-10。将稀释好的病毒接种到96孔微量培养板中,每一稀释度接种一纵排共8孔,每孔接种20μl。设正常细胞对照,正常细胞对照作两纵排(20μl生长液+100μl细胞悬液)。逐日观察并记录结果,观察5-7天。结果的计算,按Karber法如下表1。
表1
病毒液稀释度 | 出现CPE的孔数 | 出现CPE孔的比率 |
10<sup>-1</sup> | 8 | 8/8=1 |
10<sup>-2</sup> | 8 | 8/8=1 |
10<sup>-3</sup> | 7 | 7/8=0.875 |
10<sup>-4</sup> | 3 | 3/8=0.375 |
10<sup>-5</sup> | 1 | 1/8=0.125 |
10<sup>-6</sup> | 0 | 0/8=0 |
lgTCID50=L-d(s-0.5)
L:最高稀释度的对数(本例为-1)
D:稀释度对数之间的差(本例为-1)
S:阳性孔比率总和
lgTCID50=-1-1×(3.375-0.5)
=-3.875
TCID50=10-3.875/0.1ml
含义:将该病毒稀释103.875接种100μl可使50%的细胞发生病变。
病毒滴度为:103.875TCID50/0.1ml=7.5×104TCID50/ml
d)检测移植瘤的生长曲线和评估溶瘤病毒的抗肿瘤效应:对皮下肿瘤每三天使用游标卡尺进行长、宽的测量,肿瘤体积通过长*宽*宽/2的计算公式得到。通过连续的肿瘤体积测量,绘制出肿瘤生长曲线,统计肿瘤生长差异。
结果:
如图5所示,对裸鼠左右对侧分别接种不同胶质瘤细胞,左侧接种PTEN完整的GSC1细胞(GSC1-shNC);右侧接种PTEN敲低的GSC1细胞(GSC1-shPTEN)。肿瘤成瘤后,通过尾静脉注射溶瘤病毒VSVΔ51,检测两侧瘤内的病毒复制。发现GSC1-shPTEN移植瘤中的病毒量显著高于GSC1-shNC移植瘤(图5B);皮下肿瘤的生长曲线的绘制(图5C),提示溶瘤病毒VSVΔ51可以更显著抑制GSC1-shPTEN移植瘤的生长速度。这些结果提示PTEN缺失促进了溶瘤病毒在肿瘤中的复制和抗肿瘤效应。
鉴于可以应用所公开的发明的原理的许多可能的实施例,应当认识到,所示的实施例仅是本申请的优选示例,而不应视为限制本申请的范围。相反,本申请的范围由所附权利要求书限定。因此,我们要求保护所有落入这些权利要求的范围和精神内的发明。
Claims (9)
1.一种组合物,其特征在于,包含:
水疱性口炎病毒,
PI3K抑制剂,和
PD-1抑制剂。
2.如权利要求1所述的组合物在制备抗肿瘤的药物中的应用。
3.如权利要求1所述的组合物在制备用于预防和/或治疗肿瘤转移或复发的药物中的应用。
4.如权利要求1-3任一所述的组合物/应用,其特征在于,所述水疱性口炎病毒选自野生型或经过工程化改造后的水疱性口炎病毒;
优选地,所述水疱性口炎病毒选自VSVΔ51。
5.如权利要求1-3任一所述的组合物/应用,其特征在于,所述PI3K抑制剂选自Pictilisib(GDC-0941)、GNE-317、copanlisib、BYL-719、GSK2126458、PQR309或GSK2636771,或其各自药学上可接受的形式中的至少一种;
优选地,所述PI3K抑制剂选自GNE-317或其药学上可接受的形式。
6.如权利要求1-3任一所述的组合物/应用,其特征在于,所述PD-1抑制剂选自PD-1抗体、抗体功能性片段、肽类和拟肽类中的一种或几种;
优选地,所述PD-1抑制剂选自抗体;
优选地,所述PD-1抑制剂选自单克隆抗体;
优选地,所述PD-1抑制剂选自抗原表位为RMP1-14的单克隆抗体。
7.如权利要求2-3任一所述的应用,其特征在于,所述肿瘤为实体瘤或血液瘤;
优选地,所述的实体瘤为结直肠癌、胰腺癌、肝癌、膀胱癌、乳腺癌、宫颈癌、前列腺癌、胶质瘤、黑素瘤、鼻咽癌、肺癌或胃癌;
优选地,所述的肿瘤选自胶质瘤;
优选地,所述胶质瘤选自PTEN突变或缺失、P53突变或缺失、IDH1突变、RB突变、PDGFA过表达或EGFR过表达的胶质瘤中的至少一种;
或者优选地,所述胶质瘤选自胶质母细胞瘤、星形胶质瘤、少突胶质胶质瘤、间变性星形细胞瘤或混合型胶质瘤中的至少一种。
8.根据权利要求1所述的组合物,其特征在于,还包含药学上可接受的载体或药学上可接受的赋形剂。
9.据权利要求1或2所述的组合物,其特征在于,所述的组合物的剂型选自冻干粉剂、注射剂、片剂、胶囊或贴剂。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110515987.0A CN113368246B (zh) | 2021-05-12 | 2021-05-12 | 一种增效的抗肿瘤药物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110515987.0A CN113368246B (zh) | 2021-05-12 | 2021-05-12 | 一种增效的抗肿瘤药物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113368246A true CN113368246A (zh) | 2021-09-10 |
CN113368246B CN113368246B (zh) | 2023-05-26 |
Family
ID=77572581
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110515987.0A Active CN113368246B (zh) | 2021-05-12 | 2021-05-12 | 一种增效的抗肿瘤药物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113368246B (zh) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030086942A1 (en) * | 2001-03-30 | 2003-05-08 | Petersen Jeannine M. | Inhibition of nucleocytoplasmic transport by vesicular stomatitis virus M protein-like polypeptides |
CA2663034A1 (en) * | 2006-09-15 | 2009-02-05 | Ottawa Health Research Institute | Oncolytic rhabdovirus |
WO2018033126A1 (en) * | 2016-08-18 | 2018-02-22 | Guangzhou Virotech Pharmaceutical Co., Ltd. | Use of vcp inhibitor and oncolytic virus in the preparation of an anti-tumor drug |
CN109069561A (zh) * | 2016-01-11 | 2018-12-21 | 图恩斯通有限合伙公司 | 溶瘤病毒和检查点抑制剂组合疗法 |
CN109219450A (zh) * | 2016-01-11 | 2019-01-15 | 玛丽女王伦敦大学 | 在癌症治疗中用于递送病毒的PI3K P-δ110抑制剂 |
CN111373032A (zh) * | 2017-11-24 | 2020-07-03 | 渥太华医院研究所 | 用于增强干扰素敏感性病毒的生产、生长、扩散或溶瘤和免疫治疗功效的组合物和方法 |
CN111494432A (zh) * | 2019-01-31 | 2020-08-07 | 惠君生物医药科技(杭州)有限公司 | 一种用于治疗肿瘤或癌症的药物组合物及其应用 |
CN112020510A (zh) * | 2018-03-19 | 2020-12-01 | 茂体外尔公司 | 包含用于治疗癌症的肿瘤抑制基因疗法和cd122/cd132激动剂的方法及组合物 |
-
2021
- 2021-05-12 CN CN202110515987.0A patent/CN113368246B/zh active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030086942A1 (en) * | 2001-03-30 | 2003-05-08 | Petersen Jeannine M. | Inhibition of nucleocytoplasmic transport by vesicular stomatitis virus M protein-like polypeptides |
CA2663034A1 (en) * | 2006-09-15 | 2009-02-05 | Ottawa Health Research Institute | Oncolytic rhabdovirus |
CN109069561A (zh) * | 2016-01-11 | 2018-12-21 | 图恩斯通有限合伙公司 | 溶瘤病毒和检查点抑制剂组合疗法 |
CN109219450A (zh) * | 2016-01-11 | 2019-01-15 | 玛丽女王伦敦大学 | 在癌症治疗中用于递送病毒的PI3K P-δ110抑制剂 |
WO2018033126A1 (en) * | 2016-08-18 | 2018-02-22 | Guangzhou Virotech Pharmaceutical Co., Ltd. | Use of vcp inhibitor and oncolytic virus in the preparation of an anti-tumor drug |
CN111373032A (zh) * | 2017-11-24 | 2020-07-03 | 渥太华医院研究所 | 用于增强干扰素敏感性病毒的生产、生长、扩散或溶瘤和免疫治疗功效的组合物和方法 |
CN112020510A (zh) * | 2018-03-19 | 2020-12-01 | 茂体外尔公司 | 包含用于治疗癌症的肿瘤抑制基因疗法和cd122/cd132激动剂的方法及组合物 |
CN111494432A (zh) * | 2019-01-31 | 2020-08-07 | 惠君生物医药科技(杭州)有限公司 | 一种用于治疗肿瘤或癌症的药物组合物及其应用 |
Non-Patent Citations (9)
Title |
---|
JUNFEI ZHAO 等: "1、Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma", 《 NATURE MEDICINE》 * |
LUKE RUSSELL 等: "2、PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance", 《NATURE COMMUNICATIONS 》 * |
LUKXMI BALATHASAN 等: "Activating Peripheral Innate Immunity Enables Safe and Effective Oncolytic Virotherapy in the Brain", 《 MOLECULAR THERAPY ONCOLYTICS》 * |
RYUICHI KANAI 等: "3、A Novel Oncolytic Herpes Simplex Virus that Synergizes with Phosphoinositide 3-kinase/Akt Pathway Inhibitors to Target Glioblastoma Stem Cells", 《 CLIN CANCER RES》 * |
张保惠等: "基于水疱性口炎病毒(VSV)的溶瘤病毒研究进展", 《中国生物工程杂志》 * |
田海龙等.: "4、溶瘤病毒联合新型小分子抑制剂治疗胶质瘤的实验研究", 《 中华神经医学杂志》 * |
董雅璐;张军;: "表达IL-15的溶瘤病毒在胃癌中的抗肿瘤活性研究", 医学研究杂志 * |
齐兵;方心葵;吴祥甫;孙涛;: "基质蛋白第51位氨基酸缺失的水泡性口炎病毒疫苗载体的研究", 上海农业学报 * |
齐兵等: "基质蛋白第51位氨基酸缺失的水泡性口炎病毒疫苗载体的研究", 《上海农业学报》 * |
Also Published As
Publication number | Publication date |
---|---|
CN113368246B (zh) | 2023-05-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Nagathihalli et al. | Signal transducer and activator of transcription 3, mediated remodeling of the tumor microenvironment results in enhanced tumor drug delivery in a mouse model of pancreatic cancer | |
JP6956159B2 (ja) | 腫瘍溶解性アデノウイルスによる脳癌の処置方法 | |
Igarashi et al. | Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: decoy, trap and kill chemotherapy moves toward the clinic | |
Pérez-Sayáns et al. | Multidrug resistance in oral squamous cell carcinoma: the role of vacuolar ATPases | |
De Ridder et al. | Hypoxic tumor cell radiosensitization through nitric oxide | |
TWI707695B (zh) | Iap抑制劑和溶瘤病毒在製備抗腫瘤藥物中的應用 | |
CN110022867A (zh) | 高迁移率族蛋白box i突变体 | |
US20190328666A1 (en) | Cyclodextrin compositions encapsulating a selective atp inhibitor and uses thereof | |
WO2021182573A1 (ja) | 癌の治療及び/又は予防のための医薬品 | |
Ady et al. | Oncolytic gene therapy with recombinant vaccinia strain GLV-2b372 efficiently kills hepatocellular carcinoma | |
Faranoush et al. | Evaluation of the in vitro and in vivo effect of liposomal doxorubicin along with oncolytic Newcastle disease virus on 4T1 cell line: Animal preclinical research | |
TWI486172B (zh) | 鼻咽癌治療的醫藥 | |
CN106974908A (zh) | 含有hdac抑制剂和ire1抑制剂的药物组合物及用途 | |
Miller et al. | Semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia | |
CN113368246B (zh) | 一种增效的抗肿瘤药物 | |
CN106389437A (zh) | 低剂量西地那非作为抗肿瘤药物的应用 | |
Li et al. | Oncolytic virus Ad-TD-nsIL-12 inhibits glioma growth and reprograms the tumor immune microenvironment | |
CN109793727A (zh) | 一种有效抗恶性肿瘤的药物组合物及其应用 | |
Tang et al. | Effects of hyperbaric oxygen therapy on tumor growth in murine model of PC-3 prostate cancer cell line | |
CN105521482B (zh) | 联合应用HNF1α、HNF4α、FOXA3诱导分化治疗肝细胞癌 | |
US20230172882A1 (en) | Method For Treating Pancreatic Cancer | |
CN106727603A (zh) | 去甲泽拉木醛在制备治疗胰腺癌的药物中的应用 | |
CN105251023A (zh) | AXL/c-Met抑制剂在制备逆转肾癌舒尼替尼耐药的药物中的应用 | |
CN107073009A (zh) | 含有NecroX作为有效成分的用于预防或治疗粘膜炎的组合物 | |
CN110038006A (zh) | 表没食子儿茶素没食子酸酯联合酪氨酸激酶抑制剂在制备癌症治疗药物中的应用 |
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 | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20240407 Address after: No. 66, Gongchang Road, Xinhu Street, Guangming District, Shenzhen, Guangdong 518000 Patentee after: Shenzhen, Zhongshan University Country or region after: China Patentee after: SUN YAT-SEN University Address before: 510275 No. 135 West Xingang Road, Guangzhou, Guangdong, Haizhuqu District Patentee before: SUN YAT-SEN University Country or region before: China |