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WO1996007433A1 - Substance de therapie genique contre le cancer, composition medicale et methode therapeutique - Google Patents

Substance de therapie genique contre le cancer, composition medicale et methode therapeutique Download PDF

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Publication number
WO1996007433A1
WO1996007433A1 PCT/JP1995/001785 JP9501785W WO9607433A1 WO 1996007433 A1 WO1996007433 A1 WO 1996007433A1 JP 9501785 W JP9501785 W JP 9501785W WO 9607433 A1 WO9607433 A1 WO 9607433A1
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gene
cell
tumor
cancer
cells
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PCT/JP1995/001785
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English (en)
Japanese (ja)
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Hirofumi Hamada
Haruo Sugano
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Japanese Foundation For Cancer Research
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Publication of WO1996007433A1 publication Critical patent/WO1996007433A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4231—Cytokines
    • A61K40/4235—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/55—Lung
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention relates to a gene therapy agent and a pharmaceutical composition for cancer, and a treatment method.
  • the present invention relates to a gene therapy agent and a pharmaceutical composition for cancer, and a method for treating cancer. More specifically, the present invention relates to a gene therapy agent for cancer, comprising an effector cell into which a cytokin gene has been introduced and a tumor vaccine having a cytokine gene introduced into a tumor cell; a preparation comprising the effector cell A gene therapy method for cancer characterized by administering a preparation containing the tumor vaccine to a cancer patient; and a pharmaceutical composition comprising a combination of the effector cell and the tumor vaccine. Cytokines exhibit antitumor effects, but are roughly classified into the following three types according to their mechanism of action.
  • tumor necrosis factor (TNF) _a, ⁇ interferon (IFN) - ⁇ , ⁇ , ⁇ , interleukin (ID-1, etc.) directly inhibits growth or damages cancer cells in vitro in vitro
  • Interleukins (such as I-2, 4, 6, 7, 8, 9, 10, 11, 12) which have an antitumor effect indirectly through a mechanism of immune effectors in the living body , 3 IL-3, I-6, granulocyte macrophage colony stimulating factor (GM-CSF :), granulocyte colony stimulating factor (G-CSF), stem cell factor (SCF)
  • GM-CSF granulocyte macrophage colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • SCF stem cell factor
  • LAK cytotoxic T cells
  • TIL tumor-infiltrating lymphocytes
  • Retroviruses have been used to introduce cytokine genes into TILs, but the introduction efficiency is very poor. Is an obstacle.
  • the other is to introduce cytokine genes into tumor cells using a retrovirus vector or the like and use them as a tumor vaccine to induce tumor-specific immune cells in the host.
  • cytokine genes for example, Fearon et al. Transplanted a mouse colon cancer or malignant melanoma transfected with the 1L-2 gene into a syngeneic mouse and then spontaneously regressed after engraftment. The authors have reported that they acquire immune competence that is resistant to the disease (Fear on et al., Cell, 60, 397, 1990).
  • an object of the present invention is to provide a gene therapy agent for cancer that can exhibit higher antitumor activity and is also effective in suppressing cancer metastasis in order to solve the above-mentioned problems.
  • the present inventors have conducted intensive studies on the above-mentioned problems, and as a result, it was found that the combined use of a cytokine gene-introduced effector cell and a tumor vaccine in which a cytokine gene was introduced into a tumor cell resulted in efficient systemic immunity. Were found to enhance the antitumor effect and the metastasis suppressing effect, and completed the present invention.
  • the present invention provides an agent for cancer gene therapy comprising an effector cell into which a cytokine gene has been introduced and a tumor pectin having a cytokinin gene introduced into a tumor cell.
  • the present invention also relates to the simultaneous or sequential administration of a preparation containing a cytokine gene into which an effector cell has been introduced and a preparation containing a cytokine vaccine into which a cytokine gene has been introduced into a fistula cell to a cancer patient.
  • the present invention relates to a pharmaceutical composition used for gene therapy of cancer, wherein the composition is a combination of an effector cell into which a cytokine gene has been introduced and a tumor vaccine having a cytokine gene introduced into a tumor cell. And a pharmaceutically acceptable carrier
  • a pharmaceutical composition comprising:
  • gene therapy for cancer intends to treat cancer from both the antitumor effect and the metastasis inhibitory effect of cytokine genes.
  • the present invention will be described in detail.
  • the cytokine gene used in the present invention includes granulocyte macrophage colony stimulating factor (GM-CSF), interleukin (1-2, IL-3, IL_4, IL-6, IL-7, IL) -10, IL-12, IL-13, IL-15, interleukin-la (IL-1), interleukin receptor 1 antagonist (1 ⁇ 1RA), tumor necrosis factor (TNF) Lymphotoxin (LT) -15, granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), interferon (IFN) - ⁇ , macrophage migration inhibitory factor (MIF), leukemia inhibitory factor ( LIF), a gene encoding various cytokines such as T cell activation co-stimulator B7 (CD80) and B7-2 (CD86), kit 'ligand, oncostatin M, etc.
  • GM-CSF granulocyte macrophage colony stimulating factor
  • interleukin 1-2, IL-3,
  • the cytokine gene used in the present invention may be a cDNA isolated from cells using a known technique, or may be disclosed in the above-mentioned literature and the like. Although it may be chemically synthesized according to methods such as the polymerase chain reaction (PCR) based on information, humans may be used to minimize immune rejection and to increase the therapeutic effect. The origin is desirable.
  • PCR polymerase chain reaction
  • the effector cell refers to a cell population that is in charge of the final stage of destruction of a cancer cell and is directly involved in the destruction, and specifically, a tumor infiltrating lymphocyte (TIL), a lymphokine-activated killer cell ( LAK), cytotoxic T cells (CTL) and the like.
  • TIL tumor infiltrating lymphocyte
  • LAK lymphokine-activated killer cell
  • CTL cytotoxic T cells
  • the introduction of the cytokine gene into these effector cells can be performed very efficiently by using an adenovirus vector.
  • an adenovirus vector used here, any vector containing an insertion site for the cytokine gene and capable of expressing the cytokine in the introduced effector cell can be used.
  • Adexl derived from human type 5 adenovirus is preferably used.
  • tumor vaccine refers to the above-mentioned cytokine gene, which is isolated (cultured) by a retrovirus vector, introduced into tumor cells, and irradiated with X-rays. Production was stopped without inhibiting production. By administering this tumor pectin to the host, tumor-specific immune cells of the host can be induced.
  • the retroviral vector used here is not particularly limited as long as it contains an insertion site for a cytokine gene and can express cytokines in the introduced tumor cells.
  • the retrovirus vector inserted with the site force gene transfer was mixed with a plasmid having a neomycin resistance gene as a marker to select that the desired gene was introduced, and ⁇ 2, ⁇ - Am, CRIP, WCRE [Danos et al., PNAS, 85, 6460-6464 (1988)], etc., are introduced by a calcium coprecipitation method (cotransfection).
  • this is cultured in the presence of the drug G418, and by collecting cells that survive and form a colony, only cells into which the target gene has been introduced can be collected.
  • the culture supernatant of these cells was used to infect various types of fistula cells, such as N1H3T3 mouse fibroblasts and B16 mouse melanoma cells. It can be confirmed by hybridization.
  • the amount of cytokines secreted from infected cells can be measured by immunological assays such as ELISA.
  • the tumor cells into which the cytokine II gene has been introduced are usually irradiated with X-rays at a concentration of 0.0000 to 150,000 rad, and then used as a tumor vaccine.
  • the tumor cells here are melanoma cells or renal cancer cells, but other tumor cells, such as breast cancer cells, squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma, sarcoma, glioma, etc. Can be used.
  • the cytokine cytokine-introduced effector cells prepared as described above and the tumor vaccine can be used as they are, but they must be combined with a pharmaceutically acceptable carrier.
  • the composition can be administered as a pharmaceutical composition in the form of a solid such as tablets, powders, granules, and pills, or in the form of a solution, suspension, gel, or the like.
  • the carrier examples include excipients or diluents such as a filler, a bulking agent, a binder, a disintegrant, and a surfactant, which are commonly used for preparing a preparation according to a use form.
  • the administration forms of the gene therapy agent include the usual intravenous, intraarterial, subcutaneous, etc. systemic administration, local injection into the tumor lesion, or into the expected metastatic site corresponding to the cancer type. Local administration such as oral administration can be performed. Further, the administration of the gene therapy agent of the present invention may be in the form of administration in combination with catheter technology, gene transfer technology, surgical operation, or the like.
  • the cytokine hepatocyte guide effector one cell and the tumor pectin prepared as described above may be simultaneously administered, or the tumor vaccine may be administered after the effector one cell is first administered.
  • the tumor vaccine may be administered first and then sequentially, or the effector cells may be administered sequentially and subsequently.
  • the dosage of the gene therapy agent of the present invention varies depending on the age, sex, symptom, administration route, number of administrations, and dosage form. In general, in adults, about 0.1 to 100% by weight of cytokine gene per day is used. A range of 100 mg is appropriate.
  • FIG. 1 shows the construction of an expression cassette to be used for the introduction of the gene.
  • FIG. 2 shows the construction of a recombinant retrovirus vector used for introducing IL-2 or GM-CSF ⁇ gene.
  • FIG 3 shows the effector cell (TIL) derived from mouse melanoma (B16F10) transfected with the cytokine gene (I2) and the murine melanoma transfected with the cytokine gene (I2 + GM-CSF).
  • TIL effector cell
  • FIG. 4 shows mouse melanoma (B16F10) -derived effector cells (TIL) transfected with the cytokine gene (IFN-a) and mouse melanoma cells transfected with the cytokine gene (GM-CSF).
  • B16F10 shows the results of the cancer metastasis inhibitory effect of Pectin.
  • Fig. 5 shows the effector cells (TIL) derived from mouse colon cancer (Colon26) transfected with the site force gene (I-2 or IFN-a) and the site force gene (I-2). The results of mouse metastatic cancer (Colon 26) inhibitory effect on cancer metastasis by pectin are shown.
  • mice 1-2, mouse GM-CSF, and mouse IFN- ⁇ were obtained by RT-PCR (Reverse transcripi ton-pol ymera.se chain react ion) using mRNA of mouse spleen lymphocyte. Prepared.
  • T1L The preparation of T1L is described in Alexander, RB et al., J. Immunol., 145, 1615-1620 (199 0), Mat is, LA et al., Methods Enzymol., 150, 342-351 (1987), Livingst one, A. et al., Methods Enzymol., 150, 325-333 (1987) Was performed as follows. Fresh B16F10 (obtained from Whitehead Institute Dr.
  • CM complete culture medium
  • CM was heat-inactivated 103 ⁇ 4 fetal serum, 2 mM L-glutamine, 5 ⁇ 10 " 5 M 2-mercaptoethanol, 100 U / ml penicillin, 100 g / ml streptomycin, 0.5 ⁇ g / ml RPMI 1640 with addition of mlhotericin B, lOmM 3- (N-morpholino) propanesulfonic acid, and 70 U / ml recombinant human IL-2 (obtained from Shionogi & Co., Ltd.) TIL, etc. Volume of anti-CD-8-conjugated immunoadsorbent beads at 1 ⁇ 10 8 / ml and incubated for 2 hours at 4 ° C.
  • the method for preparing the recombinant adenovirus was carried out by a modification of Saito. I. et al., J. Viol., 54, 711-719 (1985). That is, an expression unit consisting of a cytomegalovirus enhancer, a chicken / S-actin promoter, a mouse 1L-2 cDNA sequence prepared in Reference Example 1, and a rabbit-1 yS-globin poly (A) signal sequence.
  • Saito. I. et al., J. Viol., 54, 711-719 (1985) That is, an expression unit consisting of a cytomegalovirus enhancer, a chicken / S-actin promoter, a mouse 1L-2 cDNA sequence prepared in Reference Example 1, and a rabbit-1 yS-globin poly (A) signal sequence.
  • the recombinant virus was subsequently propagated on 293 cells, and the virus solution was stored at -80 ° C.
  • Virus stock titers were determined by plaque assay on 293 cells.
  • the culture was removed from TIL cells seeded on a 12-well culture plate, and 150 ⁇ l of the virus stock was added to each mouse. After incubation at 37 ° C for 1 hour, a growth medium was added, and TIL cells were cultured for 2 to 3 days, to obtain mouse-transduced T1L cells (TIL / -2).
  • Retroviral vector MF G (Dranoff, G. et al., Proc. Natl. Acad. Sci. USA, 90, 3539-3543, 1993) Eagl / B amHI fragment containing two LTRs (Long Terminal Repeat) (5200bp :), Eagl / Xbal fragment (10OObp :), and Reference Examples
  • plasmid and pPGKneo [H. Takeshima et al., Nature, 369, 556-559 (1994;)] were co-precipitated with WCRIPCDanos et al., Proc. Natl. Acad. Sci. USA, 85 , 6460 (1988)] in a medium containing G-418 (GIBC0, lmg / ml).
  • the high titer recombinant retrovirus-producing clones of mouse 1 and mouse GM-CSF selected in (1) were cloned into B16F10 (Whitehead Institute Dr. Glenn Dranof), a highly transgenic strain of mouse melanoma B16 (ATCC CRL 6322). obtained from f).
  • the transfected cells were maintained in Dulbecco's Eagle's medium supplemented with 10% fetal serum and 2 mM glutamine, treated with trypsin / EDTA, and treated with 10,000 rad using a HITACHI MBR-1505R X-ray generator. X-rays were irradiated.
  • Irradiated cells were washed twice with HBSS (Hank's Balanced Salt Solution), resuspended in HBSS at a concentration of 5 xiO 6 cells / ml, and immunized with tumor vaccine (B16F10 / IL-2 + GM-CSF vaccine). Obtained.
  • HBSS Human's Balanced Salt Solution
  • the method for preparing the recombinant adenovirus was performed according to a modification of Saito. I. et al., J. Viol., 54, 711-719 (1985). That is, an expression unit consisting of a cytomegalovirus enhancer, a chicken yS-actin promoter, a mouse IFN-a cDNA sequence prepared in Reference Example 1, and a rabbit- ⁇ -globin poly (A) signal sequence [ Niwa, H. et a, J.
  • the recombinant virus containing the expression cassette was confirmed by digestion with an appropriate restriction enzyme.
  • the recombinant virus was subsequently grown on 293 cells and the virus solution was stored at -80 ° C.
  • the titer of the virus stock was determined by plaque assay on 293 cells.
  • the culture solution was removed from T1L cells seeded on a 12-well culture plate, and 150 ⁇ l of the virus stock was added to each well. After incubating at 37 ° C for 1 hour, a growth medium was added, and TIL cells were cultured for 2 to 3 days to obtain mouse 1FN-7 transgenic T1L cells (T1 / IFN-7).
  • the high titer recombinant retrovirus-producing clone of mouse GM-CSF selected in (1) was introduced into B16F10 (available from Whitehead Institute Dr. Glenn Dranoff), which is a highly metastatic strain of mouse melanoma B16 (ATCC CRL 6322).
  • the transfected cells were maintained in Dulbecco's Eagle's medium supplemented with 10X fetal serum and 2 mM glutamine, treated with tribsine / EDTA, and treated with X-ray of 10, OOOrad using a HITACHI MBR-1505R X-ray generator. The line was irradiated. Irradiated cells were washed twice with HBSS and resuspended in HBSS at a concentration of 5 xiO 6 cells / ml to obtain a tumor vaccine (B16F10 / GM-CSF vaccine).
  • TIL was prepared according to Alexander, RB et al., J. Immunol., 145, 1615-1620 (1990), Matis, A. et al., Methods Bnzymol., 150, 342-351 (1987), Livingst lo One, A. et al., Methods Enzymol., 150, 325-333 (1987) was modified as described below.
  • a 6-10 week old female BALB / C mouse purchased from Charles River Japan
  • CM complete culture medium
  • TIL TIL is attached is Perez toy spoon, washed 3 times with cold CM, suspended 1 xl0 7 b eads / ml in CM, were seeded in tissue culture plates in 24 Uweru, 37 ° C, 53 ⁇ 4C0 2 below Incubated. One day after culture: The beads separated from TIL were removed by pelleting. The isolated TILs were stimulated with 2 x 10 5 irradiated (10,000 rad) tumor cells per well and 1 x 10 6 irradiated (3, OOOrad) normal spleen cells per well. In vitro stimulation was repeated every 7 to 14 days. Sample was collected TIL when it is Konfuruen bets and resuspended 2 xi0 5 cell / ml in fresh CM.
  • Example 1 In the same manner as in Example 1 (2), the mouse I-2 cDNA prepared in Reference Example 1 was introduced into the TIL prepared in (1) above, and the mouse IL-2 gene-introduced TIL cells (TIL / I-2) I got
  • Example 3 The mouse IFN-7 CDNA prepared in Reference Example 1 was introduced into T1L prepared in (1) by the same method as in (2), and the mouse IFN-7 gene-transfected TIL cells (TIL / 1FN- ⁇ ) Got.
  • the IL-2 high titer recombinant retrovirus-producing clone selected in (1) was Introduced to colon 26 colon cancer.
  • the transfected cells were maintained in RPMI1640 medium supplemented with 10% fetal serum and 2 mM glutamine, and irradiated with 10,000 rad X-rays using a HITACHI MBR-1505R X-ray genera tor. Irradiated cells were washed twice with HBSS and resuspended in HBSS at a concentration of 5 x 10 6 cells / ml to obtain a tumor vaccine (Colon26 / IL-2 vaccine).
  • mice Six to ten week old female C57BL / 6 mice (purchased from Charles River Japan) were inoculated with 4 ⁇ 10 5 mouse melanoma B16F10 cells into the tail vein to induce lung metastasis. Two days later, TIL alone or TIL / IL-2 prepared in Example 1 was administered through 6 veins of 4 xlO [E / T ratio-10: E / T was a single cell (TIL / I 2 ) Number / tumor cell (B16F10) number]. At the same time, 5 ⁇ 10 5 B16F10 / IL-2 + GM-CSF vaccines prepared in Example 2 were subcutaneously administered.
  • INDUSTRIAL APPLICABILITY According to the present invention, it is possible to exhibit high antitumor activity on animals such as humans, mice, monkeys, dogs, cats, horses, pigs, etc.
  • Useful cancer gene therapy agents and pharmaceutical compositions, and therapeutic methods are provided.

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Abstract

Substance de thérapie génique contre le cancer, contenant des cellules effectrices renfermant des gènes de cytokine et des vaccins antitumoraux contenant des cellules tumorales renfermant des gènes de cytokine. Méthode de thérapie génique contre les cancers, consistant à administrer une préparation pharmaceutique renfermant les cellules effectrices et une préparation pharmaceutique renfermant les vaccins antitumoraux à un patient souffrant d'un cancer. Composition médicale contenant une combinaison de ces cellules effectrices et de ces vaccins antitumoraux. La substance, la composition et la méthode de traitement exercent de puissants effets antitumoraux, arrêtent les métastases cancereuses et se révèlent utiles pour le traitement du cancer micrométastatique.
PCT/JP1995/001785 1994-09-09 1995-09-08 Substance de therapie genique contre le cancer, composition medicale et methode therapeutique WO1996007433A1 (fr)

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JP21640994 1994-09-09
JP6/216409 1994-09-09
JP7/118382 1995-05-17
JP11838295A JP3822261B2 (ja) 1994-09-09 1995-05-17 癌の遺伝子治療剤

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WO1999029864A1 (fr) * 1997-12-09 1999-06-17 Virogenetics Corporation Vaccins de recombinaison exprimant l'interleukine 2 (il-2) feline, compositions et procedes d'utilisation
US6203787B1 (en) 1997-10-10 2001-03-20 The Regents Of The University Of California Treating tumors using implants comprising combinations of allogeneic cells
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
US7361332B2 (en) 1995-03-17 2008-04-22 The Regents Of The University Of California Treating tumors using implants comprising combinations of allogeneic cells
WO2018138682A1 (fr) 2017-01-26 2018-08-02 Immune Therapeutics Procédés et compositions utiles pour le traitement du cancer

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US6699468B1 (en) 1994-06-23 2004-03-02 Georgetown University Replication-competent herpes simplex virus mediates destruction of neoplastic cells
US6379674B1 (en) 1997-08-12 2002-04-30 Georgetown University Use of herpes vectors for tumor therapy

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WO1993019191A1 (fr) * 1992-03-16 1993-09-30 Centre National De La Recherche Scientifique Adenovirus recombinants defectifs exprimant des cytokines pour traitement antitumoral
WO1993021959A1 (fr) * 1992-05-01 1993-11-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Therapie antitumorale a 'effet spectateur'
JPH06157333A (ja) * 1992-11-13 1994-06-03 Ajinomoto Co Inc 抗腫瘍剤

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7361332B2 (en) 1995-03-17 2008-04-22 The Regents Of The University Of California Treating tumors using implants comprising combinations of allogeneic cells
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
US7264820B2 (en) 1996-07-25 2007-09-04 The Regents Of The University Of California Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokline
US7364726B2 (en) 1996-07-25 2008-04-29 The Regents Of The University Of California Pharmaceutical composition for cancer treatment containing cells that express a membrane cytokine
US6203787B1 (en) 1997-10-10 2001-03-20 The Regents Of The University Of California Treating tumors using implants comprising combinations of allogeneic cells
WO1999029864A1 (fr) * 1997-12-09 1999-06-17 Virogenetics Corporation Vaccins de recombinaison exprimant l'interleukine 2 (il-2) feline, compositions et procedes d'utilisation
WO2018138682A1 (fr) 2017-01-26 2018-08-02 Immune Therapeutics Procédés et compositions utiles pour le traitement du cancer

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