WO2023217109A1 - Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs - Google Patents
Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs Download PDFInfo
- Publication number
- WO2023217109A1 WO2023217109A1 PCT/CN2023/092911 CN2023092911W WO2023217109A1 WO 2023217109 A1 WO2023217109 A1 WO 2023217109A1 CN 2023092911 W CN2023092911 W CN 2023092911W WO 2023217109 A1 WO2023217109 A1 WO 2023217109A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- cells
- inhibitor
- stm2457
- tumor
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 52
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 title claims abstract description 17
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 title claims abstract description 17
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 title claims abstract description 17
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 title claims abstract description 17
- 229940122555 RNA methylase inhibitor Drugs 0.000 title abstract description 3
- OBERVORNENYOLE-UHFFFAOYSA-N STM2457 Chemical compound C1(CCCCC1)CNCC=1C=CC=2N(C=1)C=C(N=2)CNC(=O)C=1N=C2N(C(C=1)=O)C=CC=C2 OBERVORNENYOLE-UHFFFAOYSA-N 0.000 claims abstract description 60
- 229940125531 STM-2457 Drugs 0.000 claims abstract description 58
- 101100065749 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) eutC gene Proteins 0.000 claims abstract description 58
- 201000001441 melanoma Diseases 0.000 claims abstract description 26
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 17
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 17
- 239000002955 immunomodulating agent Substances 0.000 claims abstract description 13
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 51
- 210000004027 cell Anatomy 0.000 claims description 47
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 32
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 16
- 230000000259 anti-tumor effect Effects 0.000 claims description 14
- 239000012270 PD-1 inhibitor Substances 0.000 claims description 13
- 239000012668 PD-1-inhibitor Substances 0.000 claims description 13
- 229940121655 pd-1 inhibitor Drugs 0.000 claims description 13
- 239000000427 antigen Substances 0.000 claims description 9
- 108091007433 antigens Proteins 0.000 claims description 9
- 102000036639 antigens Human genes 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 8
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 claims description 8
- 210000002865 immune cell Anatomy 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 150000003384 small molecules Chemical class 0.000 claims description 5
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 239000012275 CTLA-4 inhibitor Substances 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 4
- 206010014733 Endometrial cancer Diseases 0.000 claims description 4
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 239000012271 PD-L1 inhibitor Substances 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 4
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 4
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 4
- 206010057644 Testis cancer Diseases 0.000 claims description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 206010047741 Vulval cancer Diseases 0.000 claims description 4
- 208000004354 Vulvar Neoplasms Diseases 0.000 claims description 4
- 208000008383 Wilms tumor Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 239000012634 fragment Substances 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
- 208000022013 kidney Wilms tumor Diseases 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 210000002540 macrophage Anatomy 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 210000001616 monocyte Anatomy 0.000 claims description 4
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 4
- 201000008026 nephroblastoma Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 229940121656 pd-l1 inhibitor Drugs 0.000 claims description 4
- 229920001184 polypeptide Polymers 0.000 claims description 4
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 210000003289 regulatory T cell Anatomy 0.000 claims description 4
- 201000003120 testicular cancer Diseases 0.000 claims description 4
- 201000002510 thyroid cancer Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 201000005102 vulva cancer Diseases 0.000 claims description 4
- 230000008685 targeting Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 2
- 201000003733 ovarian melanoma Diseases 0.000 claims 2
- 206010038038 rectal cancer Diseases 0.000 claims 2
- 201000001275 rectum cancer Diseases 0.000 claims 2
- 238000004806 packaging method and process Methods 0.000 claims 1
- 238000002648 combination therapy Methods 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 238000009509 drug development Methods 0.000 abstract description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- 238000000034 method Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 210000004700 fetal blood Anatomy 0.000 description 7
- 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 6
- 229940079131 Methylase inhibitor Drugs 0.000 description 6
- 238000000684 flow cytometry Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 210000005087 mononuclear cell Anatomy 0.000 description 6
- 210000000952 spleen Anatomy 0.000 description 6
- 229920000858 Cyclodextrin Polymers 0.000 description 5
- 239000001116 FEMA 4028 Substances 0.000 description 5
- 229960004853 betadex Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 4
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 102000008096 B7-H1 Antigen Human genes 0.000 description 3
- 108010074708 B7-H1 Antigen Proteins 0.000 description 3
- -1 MCF7 Chemical compound 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010041067 Small cell lung cancer Diseases 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000005909 tumor killing Effects 0.000 description 3
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 208000001382 Experimental Melanoma Diseases 0.000 description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000002224 dissection Methods 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 102000049320 CD36 Human genes 0.000 description 1
- 108010045374 CD36 Antigens Proteins 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100035716 Glycophorin-A Human genes 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 description 1
- 101001074244 Homo sapiens Glycophorin-A Proteins 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101000967135 Homo sapiens N6-adenosine-methyltransferase catalytic subunit Proteins 0.000 description 1
- 101001013582 Homo sapiens N6-adenosine-methyltransferase non-catalytic subunit Proteins 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000744745 Homo sapiens YTH domain-containing family protein 2 Proteins 0.000 description 1
- 101000976373 Homo sapiens YTH domain-containing protein 1 Proteins 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 102100025305 Integrin alpha-2 Human genes 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- VQAYFKKCNSOZKM-IOSLPCCCSA-N N(6)-methyladenosine Chemical compound C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VQAYFKKCNSOZKM-IOSLPCCCSA-N 0.000 description 1
- 102100040619 N6-adenosine-methyltransferase catalytic subunit Human genes 0.000 description 1
- 102100031578 N6-adenosine-methyltransferase non-catalytic subunit Human genes 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 230000026279 RNA modification Effects 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102100039644 YTH domain-containing family protein 2 Human genes 0.000 description 1
- 102100023905 YTH domain-containing protein 1 Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001745 anti-biotin effect Effects 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000012174 single-cell RNA sequencing Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
- 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
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This disclosure belongs to the field of biomedicine and relates to the combined treatment of tumors with an m6A RNA methylase inhibitor and an immune checkpoint inhibitor.
- m6A N6 methyladenosine
- mRNA eukaryotic messenger RNA
- m6A modified proteins include METTL3, METTL14, YTHDC1, YTHDF2, etc.
- m6A modification plays a key role in regulating RNA processing, splicing, nucleation, translation and stability, which is critical for the development of various human diseases such as cancer.
- m6A modifications are abnormal in various types of cancer and are associated with patient prognosis. Abnormalities in m6A modification are closely related to the occurrence, development and drug resistance of malignant tumors. As oncogenic factors, m6A-modified proteins promote tumor progression by upregulating oncogenes or downregulating tumor suppressor genes.
- PD-1 Programmed cell death protein 1 plays an important role in suppressing immune responses and promoting self-tolerance, including regulating the activity of T cells, activating antigen-specific T cell apoptosis programs and inhibiting the apoptosis of conventional T cells .
- PD-L1 is a transmembrane protein that is considered a common inhibitory factor of the immune response. It can combine with PD-1 to reduce the proliferation of PD-1-positive cells, inhibit their cytokine secretion, and induce cell apoptosis.
- PD-L1 also plays an important role in the progression of various malignant tumors. It inhibits the immune system's recognition and killing of tumor cells and promotes tumor immune escape. Blocking the PD-1/PD-L1 interaction through monoclonal antibodies has had a huge impact on cancer treatment.
- Melanoma is a malignant tumor that originates from melanocytes. As an aggressive skin cancer, the incidence of melanoma is increasing worldwide. Many studies have explored the relationship between tumor cells and the tumor microenvironment. However, more than half of melanoma patients do not respond to immune checkpoint inhibitor treatment, which is closely related to the immunosuppressive microenvironment in which tumor cells live. By combining with other drugs, it is important to increase the level of tumor-infiltrating CD8+T cells and the CD8/Treg ratio in the tumor microenvironment, turn immune "cold" tumors into "hot” tumors, and improve the effectiveness of tumor immunotherapy. clinical significance.
- the present disclosure provides a composition comprising: an anti-tumor immunotherapeutic agent and STM2457 or a derivative thereof.
- the anti-tumor immunotherapeutic agent includes immune cells or one or more immune checkpoint inhibitors.
- the immune cells are selected from T cells, macrophages and/or monocytes or T cells containing artificial T cell receptors.
- the T cells are selected from one or more of natural killer (NK) cells, cytotoxic T lymphocytes (CTL), and regulatory T cells.
- NK natural killer
- CTL cytotoxic T lymphocytes
- the T cells are selected from T lymphocytes.
- the T cells are selected from umbilical cord blood-derived T lymphocytes.
- the immune checkpoint inhibitor includes a polypeptide, a monoclonal antibody, or a chemically synthesized small molecule inhibitor.
- the immune checkpoint inhibitor includes a PD-L1 inhibitor, a PD-1 inhibitor, and/or a CTLA-4 inhibitor.
- the PD-1 inhibitor is an antibody or antigen-binding fragment thereof.
- the PD-1 inhibitor is a PD-1 antibody.
- the anti-tumor immunotherapeutic agent includes an antibody or antibody fragment that targets a tumor-specific antigen.
- the structural formula of STM2457 is as shown in formula (I):
- the composition further includes a pharmaceutically acceptable carrier, excipient, or stabilizer.
- the composition is an anti-tumor composition.
- the tumors include lung cancer (including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer), gastrointestinal cancer, pancreatic cancer, glioblastoma, glioma, cervical cancer, Ovarian cancer, liver cancer, hepatoma, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, myeloma, multiple myeloma, salivary gland cancer, kidney cancer, renal cell carcinoma, nephroblastoma, Basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, or human mononuclear leukemia cells.
- lung cancer including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer
- gastrointestinal cancer pancreatic cancer
- glioblastoma glioma
- cervical cancer Ovarian cancer
- liver cancer hepatoma
- bladder cancer breast cancer
- colon cancer colorectal cancer
- the inventors have found that PD-1 inhibitors (or PD-1 blockers) or T cells combined with STM2457 have very significant effects in the treatment of melanoma and ovarian cancer, and the effect of the combination group is far better than Single drug group.
- the combination even produces synergistic therapeutic effects that exceed the expectations of those skilled in the art.
- Combining anti-CTLA-4 and anti-PD-1 therapies offers the potential for superior efficacy, which may be attributed to each agent acting in a complementary or even synergistic manner. But combination therapy may lead to greater toxicity.
- drug-related grade 3-4 adverse events occurred in 54% to 55% of patients and in 24% to 27% of patients with concurrent blockade compared with 24% to 27% alone. The incidence was 24% to 27% with ipilimumab and 15% to 16% with nivolumab alone. Therefore, this disclosure finds new anti-tumor drug combination therapy, which is of great significance for drug development and clinical treatment of melanoma.
- the present disclosure provides a kit comprising a first container, a second container and a package insert; the first container contains an anti-tumor immunotherapeutic agent, the second container contains STM2457 or its A derivative of a drug, and the package insert contains instructions for using the drug to treat cancer in an individual.
- the anti-tumor immunotherapeutic agent includes immune cells or one or more immune checkpoint inhibitors.
- the immune cells are selected from T cells, macrophages and/or monocytes or T cells containing artificial T cell receptors.
- the T cells are selected from one or more of natural killer (NK) cells, cytotoxic T lymphocytes (CTL), and regulatory T cells.
- NK natural killer
- CTL cytotoxic T lymphocytes
- the T cells are selected from T lymphocytes.
- the T cells are selected from umbilical cord blood-derived T lymphocytes.
- the immune checkpoint inhibitors include polypeptides, monoclonal antibodies, or chemically synthesized small molecule inhibitors.
- the immune checkpoint inhibitor includes a PD-L1 inhibitor, a PD-1 inhibitor, and/or a CTLA-4 inhibitor.
- the PD-1 inhibitor is an antibody or antigen-binding fragment thereof.
- the PD-1 inhibitor is a PD-1 antibody.
- the anti-tumor immunotherapeutic agent includes an antibody or antibody fragment targeting a tumor-specific antigen.
- the structural formula of STM2457 is as shown in formula (I):
- the present disclosure provides the use of any of the compositions in the preparation of a medicament for the treatment of cancer.
- the cancer includes lung cancer (including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer), gastrointestinal cancer, pancreatic cancer, glioblastoma, glioma, cervical cancer, Ovarian cancer, liver cancer, hepatoma, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, myeloma, multiple myeloma, salivary gland cancer, kidney cancer, renal cell carcinoma, nephroblastoma, Basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, or human mononuclear leukemia cells.
- lung cancer including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer
- gastrointestinal cancer pancreatic cancer
- glioblastoma glioma
- cervical cancer Ovarian cancer
- liver cancer hepatoma
- bladder cancer breast cancer
- colon cancer colorectal cancer
- the present disclosure provides a composition as described above for treating cancer.
- the present disclosure provides a method of treating cancer, comprising administering to a patient or subject any of the compositions described above.
- the present disclosure provides the use of STM2457 or a derivative thereof in the preparation of a medicament for the treatment of melanoma or ovarian cancer.
- the structural formula of STM2457 is as shown in formula (I):
- the present disclosure provides a method of treating melanoma or ovarian cancer, comprising administering STM2457 or a derivative thereof to a patient or subject.
- the present disclosure provides STM2457 or derivatives thereof for the treatment of melanoma or ovarian cancer.
- Figure 1 shows the volume and mass measurements of mouse tumors in the four groups of regimens, showing that the combination of STM2457 and PD-1 antibodies can effectively inhibit the growth of melanoma in mice.
- Figure 1A Among the four-group regimens, the STM2457 and PD-1 antibody groups significantly reduced tumor weight compared to the NC control group.
- Figure 1B Among the four groups of regimens, the STM2457 and PD-1 antibody groups significantly reduced tumor volume compared with the NC control group.
- Figure 2 shows the results of single-cell CD45 flow cytometry analysis of mouse tumors in the four groups of regimens.
- STM2457 and PD-1 antibodies can effectively improve the tumor microenvironment, that is, increase the proportion of hematopoietic lineage cells in B16F0 tumors.
- FIG. 3 Analysis of tumor single cell sequencing data. The results show that the combined use of STM2457 and PD-1 antibodies can effectively promote the mitosis of T cell populations and the expression of genes related to the maintenance of stem cell populations in B16F0 tumors.
- Figure 4 is a flow chart for the combined administration of STM2457 and PD-1 antibodies.
- Figure 5 shows the combination of STM2457 and T cells in the treatment of ovarian cancer.
- Figure 5A Fluorescence photography of A1847 cells (marked with red fluorescence), T cells, and STM2457 treatment.
- Figure 5B Tumor cell death rate (%) calculated based on the number of A1847 cells detected by flow cytometry, STM2457 group vs NC+T group ***P ⁇ 0.001.
- Figure 6 shows the comparison of the inhibitory effects of m6A methylase inhibitor STM2457 alone on different tumor cells.
- Figure 7 shows the combination of STM2457 and T cells to treat B16 melanoma. It is the tumor cell death rate (%) calculated based on the number of B16 cells detected by flow cytometry, STM2457 group vs NC+T group ***P ⁇ 0.001.
- the ⁇ -cyclodextrin solution used in the following examples was purchased from Aladdin-e Company (https://www.aladdin-e.com/), and the product number is H108813.
- the PD-1 antibody used was purchased from BioXcell (https://bxcell.com) with the product number BE0146.
- the PBS buffer used was purchased from HyClone Company, product number SH30028.02.
- compositions eg, media
- methods include the recited elements but do not exclude other elements.
- Consisting essentially of is meant to exclude other elements that are of any importance in combination for the stated purpose.
- a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed disclosure.
- Consisting of means trace elements and substantial method steps excluding other components. Embodiments defined by each of these transitional terms are within the scope of this disclosure.
- the components of a "composition” may be present in a mixed form or may be packaged separately.
- the separately packaged components may also contain their respective adjuvants.
- the adjuvant refers to a means in medicine that can assist the efficacy of a drug.
- the separately packaged components may be administered simultaneously or in any sequential order, wherein the patient is first treated with one drug and then the other drug.
- the patient refers to a mammalian subject, especially a human.
- Tumor immunotherapy is a treatment method that controls and eliminates tumors by restarting and maintaining the tumor-immune cycle and restoring the body's normal anti-tumor immune response.
- Tuor immunotherapy agents refer to drugs used for "tumor immunotherapy", including monoclonal antibody immune checkpoint inhibitors, therapeutic antibodies, cancer vaccines, cell therapy and small molecule inhibitors, etc.
- step (2) Dissolve the STM2457 drug in the ⁇ -cyclodextrin solution described in step (1), shake and mix thoroughly at 42 degrees Celsius to form a homogeneous STM2457- ⁇ -cyclodextrin solution.
- the final concentration of STM2457 is 6.25mg/mL.
- the PD-1 antibody was diluted to 2.5mg/mL using PBS buffer.
- Mouse melanoma B16F0 (or “B16") was inoculated into 6-8 week old C57BL/6J mice, and each mouse was inoculated with 2*10 ⁇ 5 cells. After the tumor mass can be touched, start injecting different drug combinations (a total of four groups, namely: NC, STM2457, PD-1 antibody, STM2457+PD-1 antibody), and regularly detect changes in the mouse's weight and tumor volume. Variety. The results showed that the STM2457+PD-1 antibody group had the most significant effect in inhibiting tumor growth (Figure 1).
- NC group (or NC+NC):
- the STM injection dose is 50mg/kg, approximately 1.25mg/mouse, once a day; the PD-1 antibody injection dose is 250ug/mouse, twice a week.
- a 2-week dosing period started from the time when mice were subcutaneously inoculated with B16F0 tumors and had obvious touch sensation (about 5-7 days later).
- the flow chart is shown in Figure 4.
- human ovarian cancer cell A1847 was treated with 1 ⁇ M m6A methylase inhibitor STM2457 and then co-incubated with cord blood-derived T cells.
- the specific steps are: seed 1,000 A1847 cells in a 96-well plate, treat and culture them at a concentration of 1uM STM2457 for 3 days, then add umbilical cord blood-derived T cells in different combinations (the number of T cells added is based on the ratio of A1847 to T cells). 1:1), a total of four groups (respectively: NC; STM2457; NC+T; STM2457+T). After incubation for 24 hours, the cells were collected. The number of A1847 cells was detected by flow cytometry, and the killing of tumor cells was calculated.
- the steps of the method for isolating T cells derived from umbilical cord blood include:
- Umbilical cord blood is separated from mononuclear cells by density gradient centrifugation. The specific steps are: (1) dilute the umbilical cord blood 2 times with PBS and centrifuge it in a clean sterile collection tube at 25°C and 750g for 30 minutes; (2) transfer the white middle layer of MNC into a new 50mL centrifuge tube; (3) Add 30mL PBS to each tube, centrifuge at 350g for 10min at 4°C; (4) Discard the supernatant, add 5mL of red blood cell lysis solution, incubate at 25°C for 10min, fill with PBS to dilute the red blood cells for lysis solution, centrifuge at 300g for 10 minutes at 4°C; (5) Resuspend the cell pellet in 25 mL of PBS, centrifuge at 300g for 10 minutes at 4°C, and repeat once; (6) Resuspend the cells in PBS, count, and the cells obtained are mononuclear cells.
- biotin-conjugated antibodies (CD14, CD15, CD16, CD19, CD34, CD36, CD56, CD123, CD235a) to the resuspended mononuclear cells and incubate for 5 minutes, followed by incubation with anti-biotin magnetic beads for 10 minutes.
- the magnetically labeled cells are removed through a magnetic column to isolate high-purity T lymphocytes.
- 5 ⁇ M m6A methylase inhibitor STM2457 was used to treat mouse melanoma cells B16; human breast cancer cells MDA-MB-231 and MCF7; human monocytic leukemia cells Thp1; mouse lung cancer cells LLC; and human Melanoma cells A375; human lung cancer cells H1299, H23, H460, and H522 were processed.
- THP-1 and MDA-MB-231 cells are sensitive to STM2457, MCF7, LLC, and H460 have about 20% inhibitory effect, and the other cancer cells are not very sensitive.
- murine melanoma B16 cells were treated with 1 ⁇ M m6A methylase inhibitor STM2457 and then co-incubated with mouse spleen-derived T cells.
- the specific steps are: seed 1,000 B16 cells in a 96-well plate, treat and culture them at a concentration of 1 ⁇ M STM2457 for 3 days, then add mouse spleen-derived T cells in different combinations (the number of T cells added is based on the number of B16 and T cells). Ratio 1:2), a total of four groups (respectively: NC; STM2457; NC+T; STM2457+T). After incubation for 24 hours, the cells were collected. The number of B16 cells was detected by flow cytometry, and the killing of tumor cells was calculated.
- the steps of the method for isolating T cells derived from mouse spleen include:
- Mononuclear cells were isolated from the spleen obtained by dissection of mice. The specific procedures are as follows: (1) Soak the spleen of the dissected mouse in PBS, use a 1mL syringe to back-grind the spleen to 1mL, and filter with a filter.
- Centrifuge the filtrate collection tube at 750g for 5 minutes at 25°C; (2) Discard the supernatant, add 5mL of red blood cell lysate, incubate at 25°C for 10 minutes, fill with PBS diluted red blood cell lysate, and centrifuge at 300g for 10 minutes at 4°C; (5) Resuspend with 25mL of PBS Suspend the cells to pellet, centrifuge at 300g for 10 minutes at 4°C, and repeat once; (6) Resuspend the cells in PBS and count. The cells obtained are mononuclear cells.
- biotin-conjugated antibodies CD11b, CD11c, CD19, CD45R (B220), CD49b (DX5), CD105, MHC class II and Ter-119) to the resuspended mononuclear cells and incubate for 5 minutes, followed by anti- The biotin magnetic beads are incubated for 10 minutes, and the magnetically labeled cells are removed through the magnetic column to isolate high-purity T lymphocytes.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Cell Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Virology (AREA)
- Zoology (AREA)
- Developmental Biology & Embryology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne une combinaison d'un inhibiteur d'ARN méthylase m6A et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs. La polythérapie comprenant la combinaison d'un agent immunothérapeutique tumoral et de STM2457 ou d'un dérivé de celui-ci est utilisée pour traiter des tumeurs comprenant des mélanomes et un cancer de l'ovaire. La nouvelle polythérapie de médicaments antitumoraux présente une grande importance dans le développement de médicaments et le traitement clinique de mélanomes ou de cancer de l'ovaire.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210524211 | 2022-05-13 | ||
CN202210524211.X | 2022-05-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023217109A1 true WO2023217109A1 (fr) | 2023-11-16 |
Family
ID=88663339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2023/092911 WO2023217109A1 (fr) | 2022-05-13 | 2023-05-09 | Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN117045801A (fr) |
WO (1) | WO2023217109A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN118021819A (zh) * | 2024-04-15 | 2024-05-14 | 中国医学科学院基础医学研究所 | Xpo1抑制剂和mettl3抑制剂联合在制备治疗胃癌的药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020207550A1 (fr) * | 2019-04-07 | 2020-10-15 | Chemestmed Ltd. | Méthode d'inhibition du cancer par des inhibiteurs de l'alkbh5, la déméthylase ciblant les m6a de l'arn |
WO2021076617A1 (fr) * | 2019-10-14 | 2021-04-22 | The Regents Of The University Of California | Composés anticancéreux à large spectre |
CN113905787A (zh) * | 2019-04-05 | 2022-01-07 | 斯托姆治疗有限公司 | Mettl3抑制化合物 |
-
2023
- 2023-05-09 WO PCT/CN2023/092911 patent/WO2023217109A1/fr unknown
- 2023-05-09 CN CN202310516010.XA patent/CN117045801A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113905787A (zh) * | 2019-04-05 | 2022-01-07 | 斯托姆治疗有限公司 | Mettl3抑制化合物 |
WO2020207550A1 (fr) * | 2019-04-07 | 2020-10-15 | Chemestmed Ltd. | Méthode d'inhibition du cancer par des inhibiteurs de l'alkbh5, la déméthylase ciblant les m6a de l'arn |
WO2021076617A1 (fr) * | 2019-10-14 | 2021-04-22 | The Regents Of The University Of California | Composés anticancéreux à large spectre |
Non-Patent Citations (1)
Title |
---|
YANG SEUNGWON, WEI JIANGBO, CUI YAN-HONG, PARK GAYOUNG, SHAH PALAK, DENG YU, APLIN ANDREW E., LU ZHIKE, HWANG SEUNGMIN, HE CHUAN, : "m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade", NATURE COMMUNICATIONS, vol. 10, no. 1, 25 June 2019 (2019-06-25), XP093107141, DOI: 10.1038/s41467-019-10669-0 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN118021819A (zh) * | 2024-04-15 | 2024-05-14 | 中国医学科学院基础医学研究所 | Xpo1抑制剂和mettl3抑制剂联合在制备治疗胃癌的药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN117045801A (zh) | 2023-11-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Tavazoie et al. | LXR/ApoE activation restricts innate immune suppression in cancer | |
Chesi et al. | IAP antagonists induce anti-tumor immunity in multiple myeloma | |
Hanna et al. | Inhibition of Hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer | |
Shevtsov et al. | Ex vivo Hsp70-activated NK cells in combination with PD-1 inhibition significantly increase overall survival in preclinical models of glioblastoma and lung cancer | |
Ozao-Choy et al. | The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies | |
Ray et al. | A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma | |
Zhu et al. | Stroma-derived fibrinogen-like protein 2 activates cancer-associated fibroblasts to promote tumor growth in lung cancer | |
Alvarez et al. | Intratumoral co-injection of the poly I: C-derivative BO-112 and a STING agonist synergize to achieve local and distant anti-tumor efficacy | |
Fu et al. | Combination foretinib and anti-PD-1 antibody immunotherapy for colorectal carcinoma | |
Lieberman et al. | Immunotherapy for brain tumors: understanding early successes and limitations | |
Panagi et al. | Immunotherapy in soft tissue and bone sarcoma: unraveling the barriers to effectiveness | |
Guo et al. | Advances and challenges in immunotherapy of small cell lung cancer | |
WO2021239817A1 (fr) | Combinaisons thérapeutiques comprenant des agonistes de la ferroptose pour le traitement de troubles évolutifs | |
WO2023217109A1 (fr) | Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs | |
Zhao et al. | TIGIT blockade enhances tumor response to radiotherapy via a CD103+ dendritic cell-dependent mechanism | |
Xiao et al. | Impaired function of dendritic cells within the tumor microenvironment | |
Aquino et al. | Effect of the combined treatment with 5-fluorouracil, gamma-interferon or folinic acid on carcinoembryonic antigen expression in colon cancer cells. | |
Nakazawa et al. | Establishment of an efficient ex vivo expansion strategy for human natural killer cells stimulated by defined cytokine cocktail and antibodies against natural killer cell activating receptors | |
Wang et al. | TIGIT immune checkpoint blockade enhances immunity of human peripheral blood NK cells against castration-resistant prostate cancer | |
Mao et al. | Immunogenic hypofractionated radiotherapy sensitising head and neck squamous cell carcinoma to anti-PD-L1 therapy in MDSC-dependent manner | |
Gojkovic et al. | Oxygen-mediated suppression of CD8+ T cell proliferation by macrophages: role of pharmacological inhibitors of HIF degradation | |
Wang et al. | Gemcitabine-facilitated modulation of the tumor microenvironment and PD-1/PD-L1 blockade generate a synergistic antitumor effect in a murine hepatocellular carcinoma model | |
Rohila et al. | Targeting macrophage Syk enhances responses to immune checkpoint blockade and radiotherapy in high-risk neuroblastoma | |
Gao et al. | Targeting sphingosine 1-phosphate receptor 3 inhibits T-cell exhaustion and regulates recruitment of proinflammatory macrophages to improve antitumor efficacy of CAR-T cells against solid tumor | |
Qin et al. | Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: Challenges and opportunities |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23802879 Country of ref document: EP Kind code of ref document: A1 |