WO1998016246A9 - Immunotherapie amelioree par cytokine pour tumeurs cerebrales - Google Patents
Immunotherapie amelioree par cytokine pour tumeurs cerebralesInfo
- Publication number
- WO1998016246A9 WO1998016246A9 PCT/US1997/018455 US9718455W WO9816246A9 WO 1998016246 A9 WO1998016246 A9 WO 1998016246A9 US 9718455 W US9718455 W US 9718455W WO 9816246 A9 WO9816246 A9 WO 9816246A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cytokine
- tumor
- cells
- csf
- days
- Prior art date
Links
- 208000003174 Brain Neoplasms Diseases 0.000 title claims abstract description 12
- 238000009169 immunotherapy Methods 0.000 title description 20
- 210000004027 cells Anatomy 0.000 claims abstract description 119
- 108010002350 Interleukin-2 Proteins 0.000 claims abstract description 114
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 96
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims abstract description 55
- 210000004881 tumor cells Anatomy 0.000 claims abstract description 37
- 239000000427 antigen Substances 0.000 claims abstract description 21
- 102000038129 antigens Human genes 0.000 claims abstract description 21
- 108091007172 antigens Proteins 0.000 claims abstract description 21
- 108090000978 Interleukin-4 Proteins 0.000 claims abstract description 18
- 102000000588 Interleukin-2 Human genes 0.000 claims description 113
- 102100006400 CSF2 Human genes 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 54
- 102000004127 Cytokines Human genes 0.000 claims description 39
- 108090000695 Cytokines Proteins 0.000 claims description 39
- 230000003248 secreting Effects 0.000 claims description 19
- 238000009472 formulation Methods 0.000 claims description 18
- 102000004388 Interleukin-4 Human genes 0.000 claims description 17
- 229940028885 Interleukin-4 Drugs 0.000 claims description 17
- 239000011159 matrix material Substances 0.000 claims description 9
- 230000002459 sustained Effects 0.000 claims description 9
- 239000011859 microparticle Substances 0.000 claims description 7
- 230000012010 growth Effects 0.000 claims description 6
- 230000004614 tumor growth Effects 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 4
- 102000015696 Interleukins Human genes 0.000 claims 1
- 108010063738 Interleukins Proteins 0.000 claims 1
- 239000004005 microsphere Substances 0.000 abstract description 27
- 201000011510 cancer Diseases 0.000 abstract description 23
- 238000002560 therapeutic procedure Methods 0.000 abstract description 17
- 239000003981 vehicle Substances 0.000 abstract description 7
- 238000007910 systemic administration Methods 0.000 abstract description 6
- 239000003937 drug carrier Substances 0.000 abstract description 4
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 60
- 238000007917 intracranial administration Methods 0.000 description 58
- 230000004083 survival Effects 0.000 description 58
- 206010025650 Malignant melanoma Diseases 0.000 description 48
- 201000001441 melanoma Diseases 0.000 description 48
- 239000007924 injection Substances 0.000 description 31
- 210000004556 Brain Anatomy 0.000 description 30
- 239000007943 implant Substances 0.000 description 30
- 238000002255 vaccination Methods 0.000 description 22
- 229920000642 polymer Polymers 0.000 description 21
- 230000000259 anti-tumor Effects 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000002347 injection Methods 0.000 description 16
- 239000002609 media Substances 0.000 description 16
- 239000002246 antineoplastic agent Substances 0.000 description 15
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 14
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- 230000028993 immune response Effects 0.000 description 12
- 229960005486 vaccines Drugs 0.000 description 12
- 210000001744 T-Lymphocytes Anatomy 0.000 description 11
- 230000004044 response Effects 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 238000002512 chemotherapy Methods 0.000 description 9
- 229940079593 drugs Drugs 0.000 description 9
- 210000003169 Central Nervous System Anatomy 0.000 description 8
- 230000002708 enhancing Effects 0.000 description 8
- 230000007787 long-term memory Effects 0.000 description 8
- 102000004965 antibodies Human genes 0.000 description 7
- 108090001123 antibodies Proteins 0.000 description 7
- 239000004621 biodegradable polymer Substances 0.000 description 7
- 229920002988 biodegradable polymer Polymers 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000001802 infusion Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 231100000419 toxicity Toxicity 0.000 description 7
- 230000001988 toxicity Effects 0.000 description 7
- 229960004562 Carboplatin Drugs 0.000 description 6
- OLESAACUTLOWQZ-UHFFFAOYSA-L Carboplatin Chemical compound O=C1O[Pt]([N]([H])([H])[H])([N]([H])([H])[H])OC(=O)C11CCC1 OLESAACUTLOWQZ-UHFFFAOYSA-L 0.000 description 6
- 102100018758 IL3 Human genes 0.000 description 6
- 229940100601 Interleukin-6 Drugs 0.000 description 6
- 102000004889 Interleukin-6 Human genes 0.000 description 6
- 108090001005 Interleukin-6 Proteins 0.000 description 6
- 210000004185 Liver Anatomy 0.000 description 6
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Nitrumon Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 6
- 238000006065 biodegradation reaction Methods 0.000 description 6
- 238000002648 combination therapy Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000002633 protecting Effects 0.000 description 6
- 239000007929 subcutaneous injection Substances 0.000 description 6
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 5
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 5
- 101700086956 IFNG Proteins 0.000 description 5
- 102100016020 IFNG Human genes 0.000 description 5
- 108010002386 Interleukin-3 Proteins 0.000 description 5
- 229940076264 Interleukin-3 Drugs 0.000 description 5
- 229940100994 Interleukin-7 Drugs 0.000 description 5
- 102000000704 Interleukin-7 Human genes 0.000 description 5
- 108010002586 Interleukin-7 Proteins 0.000 description 5
- 206010027476 Metastasis Diseases 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 239000000945 filler Substances 0.000 description 5
- 230000002163 immunogen Effects 0.000 description 5
- 210000002864 mononuclear phagocyte Anatomy 0.000 description 5
- 230000003389 potentiating Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005563 spheronization Methods 0.000 description 5
- 238000010254 subcutaneous injection Methods 0.000 description 5
- 210000003719 B-Lymphocytes Anatomy 0.000 description 4
- 210000001218 Blood-Brain Barrier Anatomy 0.000 description 4
- 210000001266 CD8-Positive T-Lymphocytes Anatomy 0.000 description 4
- 210000001175 Cerebrospinal Fluid Anatomy 0.000 description 4
- 210000000822 Killer Cells, Natural Anatomy 0.000 description 4
- 206010061289 Metastatic neoplasm Diseases 0.000 description 4
- CXMXRPHRNRROMY-UHFFFAOYSA-N Sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 230000001413 cellular Effects 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 230000002962 histologic Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000001394 metastastic Effects 0.000 description 4
- 230000002035 prolonged Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 229920001059 synthetic polymer Polymers 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 206010018338 Glioma Diseases 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 210000001152 Parietal Lobe Anatomy 0.000 description 3
- 229920002732 Polyanhydride Polymers 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000001472 cytotoxic Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000004059 degradation Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 230000003628 erosive Effects 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 230000003362 replicative Effects 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 206010048962 Brain oedema Diseases 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N Camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 210000002889 Endothelial Cells Anatomy 0.000 description 2
- 210000000987 Immune System Anatomy 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 210000004698 Lymphocytes Anatomy 0.000 description 2
- 210000000138 Mast Cells Anatomy 0.000 description 2
- 206010059282 Metastases to central nervous system Diseases 0.000 description 2
- 229950008885 Polyglycolic acid Drugs 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 210000002966 Serum Anatomy 0.000 description 2
- 210000000278 Spinal Cord Anatomy 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229920000249 biocompatible polymer Polymers 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 230000001461 cytolytic Effects 0.000 description 2
- 230000000593 degrading Effects 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 229940044627 gamma-interferon Drugs 0.000 description 2
- 230000002440 hepatic Effects 0.000 description 2
- 238000010231 histologic analysis Methods 0.000 description 2
- 230000001024 immunotherapeutic Effects 0.000 description 2
- 230000001976 improved Effects 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 230000002757 inflammatory Effects 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 230000001665 lethal Effects 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 230000000414 obstructive Effects 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- 230000001936 parietal Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920000747 poly(lactic acid) polymer Polymers 0.000 description 2
- 229920002627 poly(phosphazenes) Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001681 protective Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000001177 retroviral Effects 0.000 description 2
- 238000009781 safety test method Methods 0.000 description 2
- 238000000807 solvent casting Methods 0.000 description 2
- 230000004936 stimulating Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000002522 swelling Effects 0.000 description 2
- 231100000041 toxicology testing Toxicity 0.000 description 2
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- UYKWDAPDQOLFRV-UHFFFAOYSA-N 2-methyloxirane;molecular iodine;oxirane Chemical compound II.C1CO1.CC1CO1 UYKWDAPDQOLFRV-UHFFFAOYSA-N 0.000 description 1
- LCSKNASZPVZHEG-UHFFFAOYSA-N 3,6-dimethyl-1,4-dioxane-2,5-dione;1,4-dioxane-2,5-dione Chemical group O=C1COC(=O)CO1.CC1OC(=O)C(C)OC1=O LCSKNASZPVZHEG-UHFFFAOYSA-N 0.000 description 1
- WVKOPZMDOFGFAK-UHFFFAOYSA-N 4-hydroperoxycyclophosphamide Chemical compound OOC1=NP(O)(N(CCCl)CCCl)OCC1 WVKOPZMDOFGFAK-UHFFFAOYSA-N 0.000 description 1
- GDFUWFOCYZZGQU-UHFFFAOYSA-N 4-propoxybenzoic acid Chemical compound CCCOC1=CC=C(C(O)=O)C=C1 GDFUWFOCYZZGQU-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 1
- 102100001249 ALB Human genes 0.000 description 1
- 101710027066 ALB Proteins 0.000 description 1
- 208000009956 Adenocarcinoma Diseases 0.000 description 1
- 229940009456 Adriamycin Drugs 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 210000000612 Antigen-Presenting Cells Anatomy 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 208000006673 Asthma Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 210000003651 Basophils Anatomy 0.000 description 1
- 210000001185 Bone Marrow Anatomy 0.000 description 1
- 210000000481 Breast Anatomy 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010007541 Cardiac disease Diseases 0.000 description 1
- 208000008761 Central Nervous System Neoplasms Diseases 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N Cesium Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 210000000349 Chromosomes Anatomy 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920002676 Complementary DNA Polymers 0.000 description 1
- 229960001681 Croscarmellose Sodium Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229960000913 Crospovidone Drugs 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- 210000000188 Diaphragm Anatomy 0.000 description 1
- 229960004679 Doxorubicin Drugs 0.000 description 1
- 210000003238 Esophagus Anatomy 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 231100000776 Exotoxin Toxicity 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 210000001652 Frontal Lobe Anatomy 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229940014259 Gelatin Drugs 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- WZUVPPKBWHMQCE-VYIIXAMBSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2C[C@@]2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-VYIIXAMBSA-N 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 108020001267 IL3 Proteins 0.000 description 1
- 102000018358 Immunoglobulins Human genes 0.000 description 1
- 108060003951 Immunoglobulins Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N Intaxel Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940117681 Interleukin-12 Drugs 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000010787 Interleukin-4 Receptors Human genes 0.000 description 1
- 108010038486 Interleukin-4 Receptors Proteins 0.000 description 1
- 229940096397 Interleukin-8 Drugs 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- XKTZWUACRZHVAN-VADRZIEHSA-N Interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 1
- 238000010824 Kaplan-Meier survival analysis Methods 0.000 description 1
- 229960004184 Ketamine Hydrochloride Drugs 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- 210000003810 Killer Cells, Lymphokine-Activated Anatomy 0.000 description 1
- 210000001865 Kupffer Cells Anatomy 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 208000006552 Lewis Lung Carcinoma Diseases 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 229920002521 Macromolecule Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 210000000274 Microglia Anatomy 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- 229960001592 Paclitaxel Drugs 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 229940049954 Penicillin Drugs 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920001273 Polyhydroxy acid Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229940068965 Polysorbates Drugs 0.000 description 1
- 229940045057 Prepodyne Drugs 0.000 description 1
- 210000000664 Rectum Anatomy 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 229960005322 Streptomycin Drugs 0.000 description 1
- 210000002330 Subarachnoid Space Anatomy 0.000 description 1
- 210000003283 T-Lymphocytes, Helper-Inducer Anatomy 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N Xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 Xylazine Drugs 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 229940093612 Zein Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001772 anti-angiogenic Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 230000000840 anti-viral Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000003190 augmentative Effects 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 230000001580 bacterial Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229960000626 benzylpenicillin Drugs 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004271 bone marrow stromal cells Anatomy 0.000 description 1
- 201000005216 brain cancer Diseases 0.000 description 1
- 210000003008 brain-resident macrophage Anatomy 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 230000000973 chemotherapeutic Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 210000004748 cultured cells Anatomy 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000002354 daily Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 230000000534 elicitor Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002095 exotoxin Substances 0.000 description 1
- 238000002710 external beam radiation therapy Methods 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 230000001605 fetal Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 201000008808 fibrosarcoma Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 102000037240 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- 230000003394 haemopoietic Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000010238 heart disease Diseases 0.000 description 1
- 230000002008 hemorrhagic Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- VCMGMSHEPQENPE-UHFFFAOYSA-N ketamine hydrochloride Chemical compound [Cl-].C=1C=CC=C(Cl)C=1C1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000004882 non-tumor cells Anatomy 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 229940005943 ophthalmologic Antivirals Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 230000000284 resting Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- MAKUBRYLFHZREJ-JWBQXVCJSA-M sodium;(2S,3S,4R,5R,6R)-3-[(2S,3R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylate Chemical compound [Na+].CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@H](O)[C@H]1O MAKUBRYLFHZREJ-JWBQXVCJSA-M 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003356 suture material Substances 0.000 description 1
- 230000001360 synchronised Effects 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 229930003347 taxol Natural products 0.000 description 1
- 229940026754 topical Antivirals Drugs 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- 102000035402 transmembrane proteins Human genes 0.000 description 1
- 108091005683 transmembrane proteins Proteins 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
Definitions
- systemic chemotherapy has had minor success in the treatment of cancer of the colon- rectum, esophagus, liver, pancreas, and kidney.
- a major problem with systemic chemotherapy for the treatment of these types of cancer is that the systemic doses required to achieve control of tumor growth frequently result in unacceptable systemic toxicity.
- Efforts to improve delivery of chemotherapeutic agents to the tumor site have resulted in advances in organ- directed chemotherapy, as by continuous systemic infusion, for example.
- continuous infusions of anticancer drugs generally have not shown a clear benefit over pulse or short-term infusions.
- Implantable elastomer access ports with self-sealing silicone diaphragms have also been tried for continuous infusion, but extravasation remains a problem.
- Portable infusion pumps are now available as delivery devices and are being evaluated for efficacy.
- Controlled release biocompatible polymers have been used successfully for local drug delivery and have been utilized for contraception, insulin therapy, glaucoma treatment, asthma therapy, prevention of dental related disorders, and certain types of cancer chemotherapy.
- Laser, R. , and Wise, D. , eds, Medical Applications of Controlled Release, Vol. I and II, Boca Raton, CRC Press (1986) ).
- the design and development of effective anti-tumor agents for treatment of patients with malignant neoplasms of the central nervous system have been influenced by two major factors: 1) the blood-brain barrier provides an anatomic obstruction, limiting access of drugs to these tumors; and 2) the drugs given at high systemic levels are generally cytotoxic.
- Efforts to improve drug delivery to the tumor bed in the brain have included transient osmotic disruption of the blood brain barrier, cerebrospinal fluid perfusion, and direct infusion into a brain tumor using catheters. Each technique has had significant limitations. Disruption of the blood brain barrier increased the uptake of hydrophilic substances into normal brain, but did not significantly increase substance transfer into the tumor.
- the examples demonstrate that systemic administration (vaccination) with GM-CSF transduced tumor cells or microencapsulated GM-CSF protects against growth of intracranial melanoma.
- the examples also demonstrate that local intracranial delivery of IL-2 transduced tumor cells or microencapsulated IL-2 generates immediate anti-tumor responses within the central nervous system as well as long term memory capable of generating potent anti-tumor responses against multiple subsequent tumor challenges, including challenges outside the central nervous system.
- the examples further demonstrate that combination immunotherapy using systemic vaccination with GM-CSF transductants and local intracranial administration of IL-2 transductants produces an anti-tumor effect that is significantly enhanced as compared to treatment with either treatment alone.
- a therapy for treatment of tumors has been developed which relies on the combination of an initial systemic "priming" of the immune system, most preferably through the combination of administration of a cytokine such as GM-CSF and tumor antigen such as replication incompetent tumor cells along with local release at the tumor site (or site of resection following tumor removal) of a cytokine such as IL-2 which enhances the immune response against the tumor cells.
- Local release can be obtained using any of several means, but a preferred method is using microparticles to release cytokine over a period of at least days or transduced cells, most preferably replication incompetent tumor cells which are transduced with the gene encoding the cytokine to be released. The latter is shown to release for at least five days after implantation. Microparticles can be designed to release for between hours and weeks or even months, as required.
- GM-CSF Granulocyte-macrophage colony stimulating factor
- GM-CSF Granulocyte-macrophage colony stimulating factor
- GM-CSF has been shown to prime systemic immune responses via stimulation of bone marrow derived antigen presenting cells. See Inaba, K.
- Interleukin-2 is produced by CD4+ T cells, and in lesser quantities by CD8+ T cells.
- Secreted IL-2 is a 14 to 17 kD glycoprotein encoded by a single gene on chromosome 4 in humans.
- IL- 2 acts on the same cells that produce it, i.e., it functions as an autocrine growth factor.
- IL-2 also acts on other T lymphocytes, including both CD4 + and CD8+ cells.
- IL-2 induces a local inflammatory response leading to activation of both helper and cytotoxic subsets of T cells.
- IL-2 also stimulates the growth of natural killer cells and enhances their cytolytic function.
- Tumor necrosis factor was originally identified as a mediator of tumor necrosis present in the serum of animals exposed to bacterial lipopolysaccharide (LPS) such as endotoxin.
- LPS lipopolysaccharide
- the major endogenous source of TNF is the LPS-activated mononuclear phagocyte, although antigen-stimulated T cells, activated natural killer cells, and activated mast cells can also secrete this protein.
- TNF is initially synthesized as a nonglycosylated transmembrane protein of approximately 25 kD. TNF has potent anti-tumor effects in vitro, although clinical trials of TNF in advanced cancer patients have been discontinued due to toxicity.
- TNF- ⁇ has a diverse range of biological properties including inducing expression of a number of cytokines such as interleukin-6, interleukin-8, GM-CSF, and granulocye-colony stimulating factor, as well as causing hemorrhagic necrosis in established tumors. TNF has been reported to generate tumor suppression after tumor cell-targeted TNF- ⁇ gene transfer. Blankenstein, T. , et al., J. Exp. Med. , 173:1047-52 (1991). iv. Interleukin-4.
- Interleukin-4 is a helper T cell- derived cytokine of approximately 20 kD which stimulates the proliferation of mouse B cells in the presence of anti-Ig antibody (an analog of antigen) and causes enlargement of resting B cells as well as increased expression of class II MHC molecules.
- the principal endogenous source of IL-4 is from CD4+ T lymphocytes. Activated mast cells and basophils, as well as some CD8+ T cells, are also capable of producing IL-4.
- Gamma interferon is a homodimeric glycoprotein containing approximately 21 to 24 kD subunits. IFN- ⁇ is produced by some CD4+ helper T cells and nearly all CD8+ T cells. Transcription is directly initiated as a consequence of antigen activation and is enhanced by IL-2 and interleukin-12. IFN- ⁇ is also produced by natural killer cells.
- IFN- ⁇ acts as a potent activator of mononuclear phagocytes, acts directly on T and B lymphocytes to promote their differentiation and acts to stimulate the cytolytic activity of natural killer cells.
- IFN- ⁇ transduced non-immunogenic sarcoma has been reported to elicit CD8+ T cells against wild type tumor cells. Restifo, N. , et al., J. Exp. Med. , 175: 1423-28 (1992). vi. Interleukin-3.
- Interleukin-3 also known as multilineage colony-stimulating factor, is a 20 to 26 kD product of CD4+ T cells that acts on the most immature marrow progenitors and promotes the expansion of cells that differentiate into all known mature cell types. IL-3 has been reported to enhance development of tumor reactive cytotoxic T cells by a CD4-dependent mechanism. Pulaski, B. A. , et al., Cancer Res. , 53:2112-57 (1993). vii. Interleukin-6.
- Interleukin-7 is a cytokine secreted by marrow stromal cells that acts on hematopoietic progenitors committed to the B lymphocyte lineage. IL-7 has been reported to induce CD42+ T cell dependent tumor rejection. Hock, H. , et al., J. Exp. Med. , 174: 1291-99 (1991). ix. Granulocyte-colony stimulating factor. Granulocyte- colony stimulating factor (G-CSF) is made by the same cells that make GM- CSF. The secreted polypeptide is approximately 19 kD. G-CSF gene transfer has been reported to suppress tumorgenicity of murine adenocarcinoma.
- cytokines are known in the art to have an anti-tumor effect and can be used in the pharmaceutical compositions described herein. Moreover, since cytokines are known to have an effect on other cytokines, one can admimster the cytokine which elicits one of the cytokines described above, or directly administer one of the cytokines which is elicited. Additional cytokines are known to those skilled in the art and are described in Abbas, et al., "Cytokines", chapter 12, pp. 239-61, Cellular and Molecular Immunology. 2nd Ed., W.B.
- dexamefhasone a synthetic corticosteroid used systemically to control cerebral edema
- Other compounds which can be included are preservatives, antioxidants, and fillers, coatings or bulking agents which may also be utilized to alter polymeric release rates.
- Cytokine Formulations The cytokines can be administered in a pharmaceutically acceptable carrier such as saline, phosphate buffered saline, cells transduced with a gene encoding the cytokine, microparticles, or other conventional vehicles, i.
- the cytokines can be encapsulated into a biocompatible polymeric matrix, most preferably biodegradable, for use in the treatment of solid tumors.
- the cytokine is preferably released by diffusion and/or degradation over a therapeutically effective time, usually eight hours to five years, preferably one week to one year.
- microencapsulated includes incorporated onto or into or on microspheres, microparticles, or microcapsules.
- Microcapsules is used interchangeably with microspheres and microparticles, although it is understood that those skilled in the art of encapsulation will recognize the differences in formulation methods, release characteristics, and composition between these various modalities.
- the microspheres can be directly implanted or delivered in a physiologically compatible solution such as saline.
- Buffers, acids and bases are used to adjust the pH of the composition.
- Agents to increase the diffusion distance of agents released from the implanted polymer can also be included.
- Surfactants may be necessary in implant formulations to enhance wettability of poorly soluble or hydrophobic materials.
- Surfactants such as polysorbates or sodium lauryl sulfate are, if necessary, used in low concentrations, generally less than 5%.
- Controlled release devices are typically prepared in one of several ways.
- the polymer can be melted, mixed with the substance to be delivered, and then solidified by cooling.
- Such melt fabrication processes require polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive.
- the device can be prepared by solvent casting, where the polymer is dissolved in a solvent, and the substance to be delivered dissolved or dispersed in the polymer solution. The solvent is then evaporated, leaving the substance in the polymeric matrix. Solvent casting requires that the polymer be soluble in organic solvents and that the agents to be encapsulated be soluble or dispersible in the solvent. Similar devices can be made by phase separation or emulsification or even spray drying techniques. In still other methods, a powder of the polymer is mixed with the cytokine and then compressed to form an implant.
- TNF gene transfer is described in Blankenstein, T., et al., J. Exp. Med., 73:1047-52 (1991).
- IL-6 transfection into lung carcinoma tumor cells is described in Progador, A, et al., Cancer Res. , 52:3679-87 (1992).
- ⁇ lFN cDNA transduced into non-immunogenic sarcoma is described in Restifo, N., I. Exp. Med. , 175: 1423-28 (1992).
- G-CSF gene transfer is described in Colombo, M., et al., Cancer Res., 52:4853-57 (1991).
- Suitable pharmaceutical vehicles are known to those skilled in the art.
- Inducers can also be used to produce cells which secrete cytokines.
- Inducers may be used alone in some cases or in combination with transforming agents, and include tumor necrosis factor (TNF), endotoxin, and other agents known to those skilled in the art.
- TNF tumor necrosis factor
- the cultured cells are exposed to an amount effective to activate the cells, as determined by cytokine expression, immunoglobulin secretion, and/or other indicators such as proliferation or alteration of cell surface properties or markers.
- cells are initially exposed to a small amount to "prime" the cells, then to a subsequent dose to elicit greater activation of the cells.
- Cells can be admimstered in medium or washed and administered in saline. Alternatively, cells can be encapsulated in a polymeric matrix and administered. II. Administration to Patients
- Animals were then placed in a stereotactic frame and cells were delivered by a 26 gauge needle to a depth of 3 mm over a period of 3 minutes.
- the total volume of injected cells was 10 ⁇ l.
- the needle was removed, the site irrigated with sterile 0.9% NaCl solution, and the skin was sutured closed with 4.0 vicryl.
- mice Development of an intracranial B16-F10 melanoma model in C57BL/6 mice.
- animals were divided into five groups of at least eight animals and received stereotactic intracranial injections of either 10 2 , 10 3 , 10 4 , or 10 5 wild type B16-F10 melanoma cells into the left parietal region by the method described above.
- Control animals received similar intracranial injections of 0.9% NaCl solution. Animals were assessed daily for survival.
- brains were removed at the time of death and fixed in 10% formalin for at least 5 days, sectioned, embedded in paraffin, and stained with hematoxylin and eosin.
- This study demonstrates that a significant anti-tumor immune response is generated using a systemic vaccination with GM-CSF microspheres. This response is comparable to that generated by GM-CSF transduced tumor cells and represents a practical method for delivering GM-CSF in treatments employing GM-CSF immunotherapy.
- IL-2 transduced cells were found to be highly effective in treating intracranial tumor when they were delivered directly to the brain.
- Initial studies showed that the IL-2 effect was dose-dependent.
- the results are shown in Figure 3.
- Doses of 0.08 ng per day of IL-2 (10 3 IL-2 producing cells) showed no enhanced survival compared, to controls, whereas a dose of 0.8 ng per day (10 4 IL-2 producing cells) showed a trend toward prolonged survival that did not reach statistical significance.
- a dose of 8.0 ng per day (10 5 IL-2 producing cells) a significant prolongation in survival was seen.
- B16-F10 melanoma cells were used for systemic delivery of GM-CSF or intracranial delivery of IL-2. Forty-nine C57B16 mice were vaccinated in the flank with either GM-CSF producing B16-F10 cells or medium followed by intracranial delivery of IL-2 or medium 2 weeks later. Every animal received an intracranial co-injection of wild-type melanoma at a dose uniformly fatal to untreated animals. Initial survivors and a new control group were rechallenged with a second intracranial dose of wild-type B16-F10 melanoma 134 days after their first challenge.
Abstract
La présente invention concerne une thérapie permettant de traiter des patients atteints de cancer en combinant l'administration par voie générale d'une cytokine et d'un véhicule pharmaceutiquement acceptable avec l'administration locale d'une cytokine et d'un véhicule pharmaceutiquement acceptable. Dans le mode de réalisation préféré, les tumeurs cérébrales sont traitées au moyen d'une cytokine telle que le GM-CSF administré par voie générale, de préférence en combinaison avec un antigène tumoral tel que des cellules tumorales incapables de se répliquer, et d'une cytokine telle que l'IL-2 ou l'IL-4 administrée localement, de préférence dans un véhicule assurant sa libération lente tel que des cellules transduites, et de préférence des cellules tumorales incapables de se répliquer, ou incorporée dans des véhicules microparticulaires tels que des microsphères polymères.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU48182/97A AU4818297A (en) | 1996-10-16 | 1997-10-15 | Cytokine enhanced immunotherapy for brain tumors |
EP97910921A EP0930892A1 (fr) | 1996-10-16 | 1997-10-15 | Immunotherapie amelioree par cytokine pour tumeurs cerebrales |
JP10518504A JP2001502331A (ja) | 1996-10-16 | 1997-10-15 | 脳腫瘍に対するサイトカインで増強した免疫療法 |
CA002267977A CA2267977A1 (fr) | 1996-10-16 | 1997-10-15 | Immunotherapie amelioree par cytokine pour tumeurs cerebrales |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US73159796A | 1996-10-16 | 1996-10-16 | |
US08/731,597 | 1996-10-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1998016246A1 WO1998016246A1 (fr) | 1998-04-23 |
WO1998016246A9 true WO1998016246A9 (fr) | 1998-08-13 |
Family
ID=24940192
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/018455 WO1998016246A1 (fr) | 1996-10-16 | 1997-10-15 | Immunotherapie amelioree par cytokine pour tumeurs cerebrales |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0930892A1 (fr) |
JP (1) | JP2001502331A (fr) |
AU (1) | AU4818297A (fr) |
CA (1) | CA2267977A1 (fr) |
WO (1) | WO1998016246A1 (fr) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995016464A1 (fr) * | 1993-12-14 | 1995-06-22 | Johns Hopkins University School Of Medicine | Liberation controlee de substances pharmaceutiquement actives pour l'immunotherapie |
US6277368B1 (en) | 1996-07-25 | 2001-08-21 | The Regents Of The University Of California | Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokine |
ATE412418T1 (de) * | 1998-04-02 | 2008-11-15 | Univ California | Zusammensetzungen zur erhöhung der zahl antigen präsentierender zellen und der antitumoralen antwort in menschlichen patienten |
US20020110538A1 (en) * | 1999-12-28 | 2002-08-15 | Health Research, Inc. | Methods and products for tumor immunotherapy using cytokines |
CA2412845C (fr) * | 2000-06-29 | 2014-07-22 | Lexigen Pharmaceuticals Corp. | Renforcement des reponses immunitaires dont la mediation est assuree par une proteine de fusion anticorp-cytokine via le traitement combine a base d'agents ameliorant la fixation des immunocytokines |
US6911204B2 (en) | 2000-08-11 | 2005-06-28 | Favrille, Inc. | Method and composition for altering a B cell mediated pathology |
DE60331725D1 (de) * | 2002-03-25 | 2010-04-29 | Technologie Biolactis Inc | Therapeutische mittel als antikrebs impfstoffadjuvantien und deren therapeutische verfahren |
EP1374893A1 (fr) | 2002-06-17 | 2004-01-02 | NovImmune S.A. | Vaccination au moyen de cellules immuno-isolées produisant un immunomodulateur |
US7695723B2 (en) * | 2002-12-31 | 2010-04-13 | Sygnis Bioscience Gmbh & Co. Kg | Methods of treating neurological conditions with hematopoietic growth factors |
CN108289942A (zh) | 2015-09-25 | 2018-07-17 | 迈斯免疫公司 | 用生产免疫调节剂的免疫-分离的细胞接种疫苗 |
EP3806888B1 (fr) | 2018-06-12 | 2024-01-31 | Obsidian Therapeutics, Inc. | Constructions régulatrices dérivées de pde5 et procédés d'utilisation en immunothérapie |
WO2020123716A1 (fr) | 2018-12-11 | 2020-06-18 | Obsidian Therapeutics, Inc. | Il12 liée à la membrane, compositions et procédés de régulation accordable |
CN113966397A (zh) | 2019-03-08 | 2022-01-21 | 黑曜石疗法公司 | 人碳酸酐酶2组合物和用于可调调节的方法 |
US20220267398A1 (en) | 2019-06-12 | 2022-08-25 | Obsidian Therapeutics, Inc. | Ca2 compositions and methods for tunable regulation |
CN114450308A (zh) | 2019-06-12 | 2022-05-06 | 黑曜石疗法公司 | 用于调节性调控的ca2组合物和方法 |
US20230092895A1 (en) | 2019-08-30 | 2023-03-23 | Obsidian Therapeutics, Inc. | Tandem cd19 car-based compositions and methods for immunotherapy |
US11058725B2 (en) | 2019-09-10 | 2021-07-13 | Obsidian Therapeutics, Inc. | CA2 compositions and methods for tunable regulation |
-
1997
- 1997-10-15 AU AU48182/97A patent/AU4818297A/en not_active Abandoned
- 1997-10-15 CA CA002267977A patent/CA2267977A1/fr not_active Abandoned
- 1997-10-15 EP EP97910921A patent/EP0930892A1/fr not_active Ceased
- 1997-10-15 JP JP10518504A patent/JP2001502331A/ja active Pending
- 1997-10-15 WO PCT/US1997/018455 patent/WO1998016246A1/fr not_active Application Discontinuation
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Hanes et al. | Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors | |
Riley et al. | Delivery technologies for cancer immunotherapy | |
CA2194555C (fr) | Implantation de cellules tumorales destinee au traitement du cancer | |
WO1998016246A9 (fr) | Immunotherapie amelioree par cytokine pour tumeurs cerebrales | |
Yang et al. | Biomaterial scaffold-based local drug delivery systems for cancer immunotherapy | |
EP0930892A1 (fr) | Immunotherapie amelioree par cytokine pour tumeurs cerebrales | |
Egilmez et al. | In situ tumor vaccination with interleukin-12-encapsulated biodegradable microspheres: induction of tumor regression and potent antitumor immunity | |
US5861159A (en) | Controlled release of pharmaceutically active substances for immunotherapy | |
US6156305A (en) | Implanted tumor cells for the prevention and treatment of cancer | |
US4832686A (en) | Method for administering interleukin-2 | |
Xie et al. | Immunoengineering with biomaterials for enhanced cancer immunotherapy | |
JPH10505587A (ja) | 固形腫瘍を処置するための化学療法薬剤の制御された局所送達 | |
US9814682B2 (en) | Vaccination with immuno-isolated cells producing an immunomodulator | |
Gu et al. | Sustained release of bioactive therapeutic proteins from a biodegradable elastomeric device | |
CA2258608A1 (fr) | Administration de gm-csf pour le traitement des tumeurs cerebrales et la prevention de leur recurrence | |
WO2010123971A2 (fr) | Hydrogels pour administration combinatoire de biomolécules modulant l'immunité | |
Wang et al. | Construction of single-injection vaccine using new time-controlled release system | |
Egilmez et al. | Controlled-release particulate cytokine adjuvants for cancer therapy | |
US20040005302A1 (en) | Encapsulated cells to elicit immune responses | |
EP1143934B1 (fr) | Immunisation genetique avec administration conjointe d'acide nucleique et de cytokines | |
Amsden | Review of osmotic pressure driven release of proteins from monolithic devices | |
Stokes Jr | Immunomodulatory biomaterials for cancer immunotherapy | |
TW442294B (en) | Device and process for manufacturing a device for implanting tumor cells for the prevention and treatment of cancer | |
Zhang et al. | Macrophage membrane-coated Eucommia ulmoides polysaccharides-loaded PLGA nanoparticles as an effective antigen-targeted delivery system | |
JP2001199879A (ja) | 薬物放出製剤 |