WO1990011765A1 - Preparation antitumorale obtenue apres traitement d'un oncolysat - Google Patents

Preparation antitumorale obtenue apres traitement d'un oncolysat Download PDF

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Publication number
WO1990011765A1
WO1990011765A1 PCT/US1990/000787 US9000787W WO9011765A1 WO 1990011765 A1 WO1990011765 A1 WO 1990011765A1 US 9000787 W US9000787 W US 9000787W WO 9011765 A1 WO9011765 A1 WO 9011765A1
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Prior art keywords
antitumor
cells
factor
viral
preparation
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PCT/US1990/000787
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English (en)
Inventor
Eva Lotzova
Jim Klostergaard
Ralph S. Freedman
James M. Bowen
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Board Of Regents, The University Of Texas System
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Publication of WO1990011765A1 publication Critical patent/WO1990011765A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K35/13—Tumour cells, irrespective of tissue of origin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16133—Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory

Definitions

  • the present invention relates to novel antitumor preparations, including processes for their preparation and use.
  • the invention concerns antitumor preparations obtained from viral oncolysate treated individuals bearing ascites-producing ovarian tumors.
  • Virus augmentation is a biologic response modifier approach to antitumor therapy by which the immunogenicity of tumor cell extracts is enhanced by infecting the tumor cells with a selected virus such as influenza virus, vesicular stomatitis virus (VSV), Newcastle disease virus (NCDV) and vaccinia (1-5).
  • a selected virus such as influenza virus, vesicular stomatitis virus (VSV), Newcastle disease virus (NCDV) and vaccinia (1-5).
  • the virus-augmentation effect was first demonstrated in animals.
  • researchers compared the reactions of animals protection from transplanted tumors by prior immunization with viral oncolysates to those of animals receiving non- viral modified tumor cell extract, virus alone, or an admixture of virus and extract.
  • Intensified delayed-type hypersensitivity reactions were observed in animals injected with viral oncolysates .
  • Some animals with established tumors survived unexpectedly longer when injected with viral oncolysates (2,4)
  • Humans receiving allogeneic extracts of cultured tumor cells similar to their own tumors also showed intensified delayed-type hypersensitivity reactions (1) and potentiation of natural immunity (22).
  • Newcastle disease virus oncolysate (7) the treatment of vulvar carcinoma (8) squamous carcinoma (9) and others (10-15).
  • Various novel oncolysate preparations have been described in patent disclosures for use in the treatment of cancer.
  • Wallack (16) describes a viral oncolysate vaccine for stimulating the immune mechanism of mammals to species-specific tumors. The vaccine was prepared by infecting monolayers of tumor cells with live vaccinia virus, incubating for three to five days and collecting the lysate in the form of a supernatant
  • the vaccine prepared in this manner was employed to treat species-specific tumors, apparently through stimulating the immune mechanism of the tumor burdened animal.
  • the invention concerns generally a soluble, complement-dependent antitumor factor which is derived from ascites fluids of viral oncolysate-treated ovarian cancer
  • the antitumor factor itself is characterized as having the molecular weight of approximately 90-120 kilodaltons when subjected to exclusion chromatography, such as chromatography on a gel exclusion matrix.
  • the invention concerns a process for preparing an antitumor preparation which comprises treating an individual bearing an ascites-producing ovarian tumor with a viral oncolysate to stimulate the appearance of a soluble, antitumor factor into the ascites fluid of the treated individual. This is followed by collecting the ascites fluid, and fractionating it in a manner to provide a preparation enriched for the antitumor factor.
  • fractionating is meant to refer broadly to any procedure wherein a biologically active portion or fraction of the ascites containing the antitumor factor is obtained. Therefore, fractionating includes concentrating, dialyzing, molecular weight fractionation, chromatography and the like.
  • influenza virus viral oncolysate in that influenza virus, preferably a type A influenza virus, is employed to infect cell lines used in a preparation of the oncolysate.
  • influenza virus preferably a type A influenza virus
  • a particularly useful type A influenza virus is provided by strain PR8/34, such as described by
  • ovarian tumor cells for viral infection.
  • the ovarian tumor cells employed typically an ovarian tumor cell line such as OV-2774 and CaOV3, are characterized in that upon infection with the influenza virus, the infected cells will not be lysed prior to extract preparation.
  • the cell line will be allogeneic.
  • autologous tumor or established cell line may be used.
  • the selected ovarian tumor or cell line will be characterized by phenotypic cell surface features and chromosomal analysis. In particular, one can identify suitable allogeneic ovarian tumor cells for use in connection with the present invention by their
  • MDAH 2774 and CaOV3 Two ovarian carcinoma cell lines, designated MDAH 2774 and CaOV3, have been found by the inventors to work well in connection with the practice of the present invention.
  • the MDAH 2774 cell line has been described in some detail in previous publications (18, 19).
  • the CaOV3 cell line has been characterized in various publications (6).
  • the CaOV3 cell line has been deposited in the ATCC, and accorded serial number ATCC HTB75.
  • the surface membranes of the selected allogeneic cultured ovarian tumor cells through the use of the influenza virus, without lysing the cells.
  • Surface membrane modification is achieved by infecting the selected ovarian carcinoma cells with the virus until virus modification of the membrane occurs, usually on the order of approximately 20 hours.
  • the cells are then washed and an extract prepared.
  • the virus-infected ovarian tumor cell extract is then administered, preferably intraperitoneally, to an individual bearing an ascitic ovarian tumor in order to elicit the appearance of the soluble antitumor factor into the ascites fluid.
  • the ascites fluid bearing the antitumor factor is then
  • the ascites fluid is fractionated by means of dialysis.
  • Dialysis serves to remove small molecules from the preparation in order to purify the preparation, and render it more acceptable pharmacologically.
  • dialysis is employed to remove molecules such as low molecular weight hormones and polypeptide growth factors.
  • a preferred dialysis membrane is one having relatively large pore sizes, allowing the passage of molecules of on the order of 8 or even 12-14 kilodaltons in size. Such large pore dialysis membranes are employed in order to assist in removing relatively large molecular weight contaminations.
  • the size of the antitumor factor has been estimated to be on the order of 90 to 120 kilodaltons, a large pore dialysis membrane will have little or no effect in removing the antitumor factor from the ascites fluid preparation upon dialysis.
  • the invention is directed to a process which includes dialyzing the ascite fluid, or a biologically active fraction thereof, to provide a preparation enriched for the antitumor factor.
  • the antitumor factor of the present invention has been characterized as having a molecular weight of on the order of about 90 to about 120 kilodaltons, when the ascites fluid is subjected to exclusion chromatography, and fractions therefrom are assayed for antitumor activity.
  • exclusion chromatography will not generally give a precise measurement of size.
  • the size range of 90 to 120 kilodaltons refers only to the apparent molecular weight obtained for this factor when ascites fluid is subjected to exclusion chromatography in the manner detailed herein. Therefore, other molecular sizing techniques may reflect an apparent molecular weight for the factor which is different than that observed upon exclusion chromatography as detailed herein. In any event, molecular exclusion chromatography can be employed to fractionate the antitumor "activated" ascites fluid and thereby provide the antitumor factor of the present invention in a more highly purified form.
  • preparation will include subjecting the ascites fluid, or a fraction thereof, to exclusion chromatography to provide a fraction enriched for the antitumor factor.
  • the ascites fluid-derived material can be sterilized through the use of sterilization filters such as nitrocellulose membranes and the like.
  • the invention is concerned with the use of one of the foregoing antitumor treatment of ovarian cancer. It has generally been found that the antitumor factor is highly active against several types of ovarian cell lines.
  • the antitumor preparation of the present invention has not shown activity against nonovarian derived cells, such as the leukemia cell lines K-562 or the murine tumor YAC-1. Accordingly, the antitumor factor of the invention can be classified in particular as an anti ovarian tumor factor. However, since limited panel of tumors has been analyzed, this antitumor factor might not be limited to ovarian tumors.
  • Figure 1 illustrates the cytotoxic effect of the soluble antitumor factor against ovarian carcinoma cell line OV-2774, induced by intraperitoneal administration of viral oncolysates.
  • Viral oncolysates were administered to patients with ovarian carcinoma in two injections, three weeks apart and ascitic fluids were drawn before or 24 hours after each injection.
  • the cytotoxic effect of the soluble antitumor factor was assayed at 40 percent concentration in a three hour Cr-release assay.
  • Figure 2 illustrates a dose-response curve of the cytotoxic activity of the soluble antitumor factor against the ovarian carcinoma cell line OV-2774. Ascitic fluids collected from peritoneum of patients with ovarian
  • carcinoma treated with viral oncolysates were tested for cytotoxic effect against OV-2774 in a three hour 51 Cr- release assay.
  • the fluids were collected three weeks after a single injection of oncolysates.
  • the figure shows the results (mean plus/minus s.d.) of the effect of ascitic fluids from three different patients.
  • the present invention is based on the surprising discovery that the ascitic fluids of patients with ovarian carcinoma who have been treated with viral oncolysates exhibit the appearance of a soluble antitumor factor highly cytotoxic for human ovarian tumor cells in vitro.
  • This soluble antitumor factor in studies to date, have displayed a certain degree of selectivity. Its cytotoxic activity has been exhibited most profoundly in connection with the treatment of ovarian tumors. While ovarian tumor cell lines have been found to be sensitive to the antitumor factor, non-ovarian cell lines have generally not been found to be sensitive. This selectivity may be related to the antigenic profile of viral oncolysates used for patients' treatment.
  • compositions containing the antitumor factor of the present invention are achieved in the following manner:
  • the MDAH 2774 cell line was developed from ascites borne cells obtained from a 40 year old female (0 Rh+ blood group) bearing an ovarian tumor. Tissue diagnosis indicated a mixed mucinous and serous adenocarcinoma of the ovary. The tumor was untreated. Ascites fluid collected from the patient was allowed to sediment in a vacuum collecting bottle. The sedimented cells were collected, resuspended and plated. The cells were cultured in L-15medium+10% Fetal Bovine Serum (FBS) and a split ratio of about 1:40, weekly, was employed. The cells were characterized on passage 132 (18). The following represents various results obtained in characterizing MDAH 2774 cells: 1. Cytogenetics
  • TEM Transmission Electron Microscopy
  • nucleoli fenestrated nucleoli, granular endoplasmic reticulum, numerous mitochondria and annular lamellae.
  • the cell culture was obtained by the inventors at about passage 132 and has been cultured in L-15 (Gibco #320-1415AJ) and 10% FBS (Hazelton #12-10378).
  • the cells were grown as thick, multilayered colonies, with an epithelial-like morphology.
  • the cells exhibited a lack of contact inhibition, numerous mitotic figures, irregular hyperchromatic nuclei, high nuclear cytoplasmic ratios and multiple nucleoli.
  • the CaOV 3 cell line is an ovarian carcinoma cell line which was derived and characterized as described in reference 6,20.
  • the cell line MDAH 2774 was heterozygous for EsD, and CaOV3 was homozygous type 1 for that locus, which indicates that the origins of the lines were independent of each other. Genotypes at certain other loci may be informative for identifying these cell lines in the future: MDAH 2774 was heterozygous (2,2) for PGP and had the less common form (type 1) for GLO1; CaOV3 had the less common forms, 2 and 1, for ME2 and GLO1, respectively.
  • Type A influenza virus PR8/34, was used to infect the ovarian carcinoma cells.
  • the virus was egg adapted and originally obtained from Flow Laboratories, Rockville passages in leukosis-free embryonated hens' eggs.
  • PBS phosphate-buffered saline
  • the washed cell pellets were then resuspended in an equal volume of 1 mM MgCl 2 and DNAse.
  • a preferred source for DNAse has been Sigma Chemical Company Type II-S D4513 (endotoxin-free and chromatographically purified).
  • the resulting suspension was sonicated for 3 minutes in a Raytheon cup sonicator with an output of 310 KHz.
  • Sonications were carried out in small plastic tubes packed in ice in the sonicator cup.
  • Ultraviolet irradiation to reduce viral infection of the sonicates was carried out as follows: A homogenate layer of less than 4 mm in a sterile 50 mm Petri dish was irradiated in a hood with a shortwave UV lamp, set to deliver 40 erg sec -1 M 2 . The irradiated lysates were then pooled and adjusted to a uniform protein concentration. Each was placed in labeled precapped serum vials and stored at -70°C. Lysates of the virus infected cell line MDAH 2774 have been designated OVO1.
  • the CaOV3 cell line is infected, and oncolysate prepared, in essentially the same manner as the foregoing MDAH 2774 description.
  • oncolysates are administered intra- peritoneally (i.p.) to patients in aliquots containing protein contents ranging from about 1.5 to about 9.0 mg, with about 9 mg being preferred.
  • Such aliquots are typically administered i.p. by a schedule such as bimonthly or monthly, with monthly administration being found optimal in many cases. However, this schedule can be varied, depending on the patient or response.
  • Most preferably, about 9 mg of the oncolysate is administered by a schedule such as monthly or bi-monthly. It has been found that mixtures of oncolysates obtained from different cell sources may be particularly useful in eliciting the appearance of the antitumor factor. The advantage of the mixture of ovarian cell lines is to broaden the immunogenicity of the preparation. Of course, other reasons for the improved performance of oncolysate mixtures may exist.
  • epithelia ovarian cancer patients are selected on the basis of ascites production and failure to respond to conventional therapy. Ascites production is determined both through physical examination of the patient and by cytology. The particular type of ascites producing ovarian tumor has not been found to be important in obtaining a highly active antitumor preparation.
  • Lysates of the two virus-infected ovarian carcinoma cell lines, MDAH 2774 and CaOV3, prepared as above were designated OVO1 and OVO2, respectively.
  • An aliquot of each extract was adjusted to a protein content of 4.5 mg and suspended in 5 ml N saline for i.p. injections.
  • OVO1 and OVO2 aliquots were mixed and suspended in 10 ml nonpyrogenic saline for i.p. injection, usually through a No. 15-gauge angiocatheter.
  • Each i.p. dose was
  • i.p. injections were administered simultaneously with initial i.p. injections in patients who had presented with pleural effusions and ascites, and at later dates to 2 patients who developed pleural effusions while undergoing i.p. OVO injections.
  • preferred dosage and schedule involved the i.p. administration of 9 mg of a 1:1 mixture of OVO1 and OVO2, at bi- monthly to monthly intervals, administered over several minutes.
  • ANTITUMOR FACTOR PREPARATION Following oncolysate treatment, the antitumor factor- bearing ascites fluid is removed from the patient by paracenthesis (removal of fluid from abdomen). It has generally been found that 2 injections of oncolysate are needed in order to obtain a high titer of antitumor
  • the ascites fluid is centrifuged at 1500 rpm to remove particulate matter, cells, and cellular debris and either tested for its effect on tumor cells in cytotoxicity assay or stored at -20° C and tested later.
  • a preferred dialysis treatment employs a large pore membrane, such as one having a pore size allowing the passage of molecules on the order of 8 to 14 kilodaltons. This facilitates the removal of contaminating low molecular weight material.
  • a preferred membrane for dialysis is one such as Spectra/Por, obtained from Spectrum Medical Industries, Inc., Los Angeles, CA.
  • the ascites fluid will typically be subjected to further fractionation, for example, on the basis of molecular weight or size.
  • a preferred technique employs gel exclusion chromatography of the ascites fluid on a gel exclusion matrix such as Ultrogel AcA44 (IBF Biotechnics, France). Ultrogel AcA44 is an acrylamide cross-linked agarose matrix with an effective range of 10,000-130,000 daltons, which has been found to work particularly well in the practice of the invention.
  • the antitumor activity of the ascites preparation containing the antitumor factor can be monitored during fractionation by a variety of techniques, such as through the use of in vitro cytotoxicity assays employing ovarian carcinoma cell lines, or using cell lines developed from the patient to be subsequently treated.
  • a preferred assay for screening the antitumor activity is the 51 Cr-release assay. This assay measures the release of radioactive chromium by dead tumor "target" cells in vitro, upon incubation with agents which lyse these cells.
  • Aqueous solutions should be suitably buffered if necessary and the liquid diluent first
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intra- peritoneal administration.
  • sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • novel factor of the invention may be
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • the dosage of course, will be
  • FIG. 1 is demonstrated the cytotoxic effect of the soluble antitumor factor elicited in the ascites fluids of three separate individuals.
  • the cytotoxic activity of the soluble factor was measured in an in vitro 51 Cr-release assay using the ovarian carcinoma OV-2774 as a target.
  • Three separate patients were treated with the viral oncolysate injection in the manner
  • Ascitic fluid obtained from these patients at various intervals was tested for its ability to lyse the target ovarian carcinoma cells (see Ref. 21). Therefore, the data is representative of the kinetics of appearance of the antitumor factor in the ascitic preparations.
  • Figure 2 represents a dose response curve of the cytotoxic activity of the soluble antitumor factor against the OV-2774 cell line, again in a three hour 51 Cr-release assay.
  • Ascitic fluids were collected from the peritoneum of patients with ovarian carcinoma who had been treated with viral oncolysates prepared in the manner detailed above in section II. The fluids were collected three weeks after a single injection of viral oncolysate. Shown in the figure are the results of the effect of ascitic fluids obtained from three different patients and tested at various volume percent concentrations (mean plus/minus s.d.).
  • the antitumor factor exhibited a fair degree of specificity for ovarian carcinoma tumor targets.
  • a high degree of antitumor activity was exerted against both the OV-2774 and OV-F1 tumor targets. No activity was observed against the CML tumor target.

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Abstract

On expose l'emploi d'oncolysats viraux dans la préparation d'un facteur antitumoral soluble et dépendant du complément, ayant une activité antitumorale particulière à l'encontre des carcinomes ovariens. Les oncolysats viraux employés dans la préparation du facteur antitumoral objet de la présente invention sont obtenus par l'utilisation d'un virus PR8/34 de la grippe de souche A, qui est employé pour modifier in vitro les membranes de cellules de carcinomes ovariens sans soumettre ces cellules à une lyse virale. Le facteur antitumoral est préparé par administration d'une quantité efficace d'oncolysat viral à une patiente présentant un carcinome ovarien avec production d'ascites. Après traitement, la présence du facteur antitumoral est mise en évidence dans les ascites de la patiente. Les fluides ascitiques contenant le facteur antitumoral sont recueillis et le facteur antitumoral est obtenu à partir de ces fluides. On présente également des lignées cellulaires de carcinomes ovariens particulièrement utiles pour la préparation d'oncolysats, du MDAH 2774 et des lignées cellulaires CaOV3.
PCT/US1990/000787 1989-04-11 1990-02-12 Preparation antitumorale obtenue apres traitement d'un oncolysat WO1990011765A1 (fr)

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US33604589A 1989-04-11 1989-04-11
US336,045 1989-04-11
US34714089A 1989-05-02 1989-05-02
US347,140 1989-05-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6110461A (en) * 1997-08-13 2000-08-29 Oncolytics Biotech Inc. Reovirus for the treatment of neoplasia
US6136307A (en) * 1997-08-13 2000-10-24 Oncolytics Biotech Inc. Reovirus for the treatment of cellular proliferative disorders
US6565831B1 (en) 1999-02-24 2003-05-20 Oncolytics Biotech Inc. Methods for preventing reovirus recognition for the treatment of cellular proliferative disorders
EP2661278A4 (fr) * 2011-01-04 2015-10-07 Sillajen Biotherapeutics Inc Génération d'anticorps contre des antigènes tumoraux et génération de cytotoxicité dépendante du complément spécifique d'une tumeur par l'administration du virus oncolytique de la vaccine

Citations (1)

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FR2353641A1 (fr) * 1976-06-01 1977-12-30 Wistar Inst Vaccin anti-tumoral et son procede de preparation

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Title
Biological Abstracts, Vol. 85, No. 12, 1988, Biological Abstracts, Inc., R.S. FREEDMAN et al.: "Viral Oncolysates in Patients with Advanced Ovarian Cancer", see page 74 *Abstract 123974, & Gynecol. Oncol. 29(3), 337-347, 1988* *
Cancer Immunol Immunotherapy, Vol. 17, 1987, Springer-Verlag, R.S. FREEDMAN et al.: "Virus-Augmented Delayed Hypersensitivity Skin Tests in Gynecological Malignancies", pages 142-146 *
Lymphokine Research, Vol. 8, No. 2, 1989, Mary Ann Liebert, Inc., Publishers, R.S. FREEDMAN et al.: "Lymphokine Activity in Malignant Effusions after Intracavitary Viral Oncolysate", pages 115-122 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7014847B2 (en) 1997-08-13 2006-03-21 Oncolytics Biotech Inc. Methods for preventing reovirus recognition for the treatment of cellular proliferative disorders
US7708987B2 (en) 1997-08-13 2010-05-04 Oncolytics Biotech Inc. Methods for preventing reovirus recognition for the treatment of cellular proliferative disorders
US7300650B2 (en) 1997-08-13 2007-11-27 Oncolytics Biotech Inc. Reovirus for the treatment of neoplasia
US6110461A (en) * 1997-08-13 2000-08-29 Oncolytics Biotech Inc. Reovirus for the treatment of neoplasia
US6455038B1 (en) 1997-08-13 2002-09-24 Oncolytics Biotech Inc. Reovirus for the treatment of cellular proliferative disorders
US6136307A (en) * 1997-08-13 2000-10-24 Oncolytics Biotech Inc. Reovirus for the treatment of cellular proliferative disorders
US6576234B2 (en) 1997-08-13 2003-06-10 Oncolytics Biotech Inc. Reovirus for the treatment of neoplasia
US7476382B2 (en) 1997-08-13 2009-01-13 Oncolytics Biotech Inc. Reovirus for the treatment of neoplasia
US7452723B2 (en) 1997-08-13 2008-11-18 Oncolytics Biotech Inc. Methods for preventing reovirus recognition for the treatment of cellular proliferative disorders
US6261555B1 (en) 1997-08-13 2001-07-17 Oncolytics Biotech, Inc. Reovirus for the treatment of neoplasia
US6344195B1 (en) 1997-08-13 2002-02-05 Oncolytics Biotech, Inc. Reovirus for the treatment of neoplasia
US6811775B2 (en) 1999-02-24 2004-11-02 Oncolytics Biotech Inc. Reovirus for the treatment of cellular proliferative disorders
US6565831B1 (en) 1999-02-24 2003-05-20 Oncolytics Biotech Inc. Methods for preventing reovirus recognition for the treatment of cellular proliferative disorders
US8066985B2 (en) 1999-02-24 2011-11-29 Oncolytics Biotech Inc. Reovirus for the treatment of cellular proliferative disorders
US8071087B2 (en) 1999-02-24 2011-12-06 Oncolytics Biotech Inc. Reovirus for the treatment of cellular proliferative disorders
US8709443B2 (en) 1999-02-24 2014-04-29 Oncolytics Biotech Inc. Reovirus for the treatment of cellular proliferative disorders
US7374752B2 (en) 1999-02-24 2008-05-20 Oncolytics Biotech Inc. Reovirus for the treatment of cellular proliferative disorders
EP2661278A4 (fr) * 2011-01-04 2015-10-07 Sillajen Biotherapeutics Inc Génération d'anticorps contre des antigènes tumoraux et génération de cytotoxicité dépendante du complément spécifique d'une tumeur par l'administration du virus oncolytique de la vaccine

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