Classifications

• • 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
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
  • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
  • A61K2039/515—Animal cells
  • A61K2039/5152—Tumor cells
• • 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
  • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
  • A61K2039/515—Animal cells
  • A61K2039/5156—Animal cells expressing foreign proteins
• • 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
  • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
  • A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
• • 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
  • C12N2760/18011—Paramyxoviridae
  • C12N2760/18111—Avulavirus, e.g. Newcastle disease virus
  • C12N2760/18133—Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory

Definitions

• the invention relates to the production of virus-modified tumor vaccines and their use in the immunotherapy of tumor metastases. 5
• oncolysates i.e. Tur cell lysates, mostly from tumor cell lines, are used to immunize the patient.
• Tur cell lysates mostly from tumor cell lines.
• 25 cell culture kept tumor cell lines are obtained, are not sufficiently immunogenic and therefore do not lead to a sufficient stimulation of the patient's immune system, so that the metastasis can be effectively prevented.
• the aim of the present invention was to produce improved tumor-specific vaccines with regard to immunogenicity and tumor specificity, which selectively increase the patient's immune system when the patient is actively immunized
• tumor-specific immune T-lymphocytes if they are present, occur only at a low frequency among the lymphocytes, since the antigenicity and immunogenicity of tumor antigens is generally poorly developed. In an animal model examined, for example, the frequency of such cells is only one in 15,000 splenic lymphocytes. In tumor-bearing animals, these tumor-specific T cells are generally not fully activated and require additional activation signals.
• the specific component is the autologous tumor cells, which are isolated from the operated tumor by mechanical and enzymatic methods.
• the non-specific component is a virus, in particular Newcastle Disease Virus (NDV), which contributes to the activation of an inflammatory reaction.
• NDV Newcastle Disease Virus
• the NDV is suitable for this because it is a good interferon activator and has been shown to activate tumor-specific T cells.
• the virus is also particularly well tolerated.
• the virus is incubated with irradiated tumor cells, which leads to adsorption of the virus on the tumor cells.
• the virus-modified tumor cells are inactivated by radiation so that they cannot grow out as tumors and then used as a vaccine.
• Immunization with this vaccine is said to selectively activate sensitized tumor-specific T cells in situ, and to use these cells, which circulate in the blood and in the lymph, for systemic therapy against micrometastases.
• the initial aim in tumor patients is to trigger a delayed-type skin reaction. This response, characteristic of cellular immune responses, indicates that a specific antigen has been recognized and has resulted in an inflammatory response at the vaccination site. This could be confirmed in experiments.
• the tumor-specific T cells should be concentrated due to the presence of the corresponding antigen and activated to form cytotoxic T lymphocytes with the help of the additional activation signals mediated by the virus.
• the activated tumor-specific T cells then get back into the circulation, ie into the blood and into the lymphatic system, they are able to migrate into the organs and can exercise their control function there by recognizing tumor cells with the same tumor antigen and removing them .
• the main advantage of the vaccines and their use for immunotherapy of metastases according to the present invention is that a combination of immunogens is used, with the result that on the one hand an autologous tumor antigen is optimally presented and on the other hand a second component for stimulating tumor-specific T -Lymphocytes are dosed optimally. This is done by simulating an immune response, such as occurs under physiological conditions when fighting a virus infection.
• the specific immunotherapy with the virus-modified tumor vaccines according to the present invention has the advantage that it is extremely low in side effects.
• the use of autologous intact tumor cells should guarantee that the optimal antigenicity and immunogenicity of the tumor material is preserved.
• the Newcastle Disease Virus (NDV) which is preferred as the non-specific viral component, has compared to other viruses, such as Influenza A
• Virus or vaccinia virus which are also used in immunizations with oncolysates, have the least neurotropic side effects.
• the NDV is a better interferon activator compared to the other viruses.
• the specific immunotherapy with virus-modified tumor vaccines according to the present invention could be experimentally tested on various models, namely the model system ESb of the mouse, the mouse bladder carcinoma of the C57 Bl mouse and the "3LL Lewis Lung” carcinoma system, and their effectiveness demonstrated.
• the first results of clinical studies are now available, which demonstrate the effectiveness of the vaccine according to the invention.
• lyophilized tumor material is used and an enzyme, namely neuraminidase (VCN), is used as adjuvant.
• VCN neuraminidase
• lyophilized tumor material has a lower immunogenicity than intact cells and, furthermore, the virus (NDV virus) used according to the invention is certainly a stronger adjuvant than the enzyme, since it has already been demonstrated that a A number of immunologically relevant gene products such as interferon alpha, beta and tumor necrosis factor alpha would be induced by the virus, while such activities could not be detected with the enzyme.
• DE-OS 29 18 927 shows a medicinal product for the treatment of carcinos and a process for the production thereof, the product containing carcinoma cells which have been weakened with a cytostatic agent to which the carcinoma cells are sensitive. No immunological adjuvant or immunostimulant is used at all, instead, living autologous tumor cells treated with cytostatics are used, which apparently have not yet been inactivated in any other way.
• cytostatics cytostatics-resistant tumor cells could grow out of the applied cell numbers and form tumors. It is not evident that immunological host reactions against the tumor are actually activated.
• the main advantage of this method of DE-OS 29 18 927 is likely to be that subsequently better tolerance for the
• the Newcastle Disease Virus is particularly suitable as a non-specific component of the vaccine, because in addition to the very good expression of viral antigens on the cell membrane, it is also an excellent interferon inducer.
• the virus is propagated in the egg and inactivated by radiation before the patient is inoculated.
• the NDV is particularly suitable for use in humans.
• NDV is a paramyxovirus (Myxovirus aviu multiforme) and the causative agent of atypical avian influenza.
• Myxovirus aviu multiforme paramyxovirus
• the virus is very little pathogenic for humans. After infection, only a few people develop unilateral conjunctivitis after one to four days, which usually resolves after three to five days, rarely after two to three weeks. Pre-auricular lymphadenitis may occur in 50% of patients. Occasionally there is a general feeling of illness with headache and temperature increase as with a flu infection, as well as tracheitis, pharyngitis and stomatitis.
• NDV Newcastle disease virus
• the effects of NDV on the immune system, as well as its ability to induce inflammatory signaling substances, in combination with specific tumor antigens, enable the production of a highly immunogenic vaccine, which initially triggers a strong direct immune response against the virus.
• lymphokines ultimately leads to an indirect activation of tumor-specific T-killer cells, for which the low antigenicity of the native tumor antigens would otherwise not have been sufficient.
• This cellular immune reaction against tumor-specific antigens can then be used therapeutically in order to prevent the growth of tumor cells or the growth of existing micrometastases after removal of the primary tumor.
• native NDV is incubated under sterile conditions for one hour with tumor cells inactivated by prior radiation. This results in tumor cells that carry the virus adsorbed on the surface.
• the adsorption of the NDV to the tumor cells can be monitored on samples of fixed cells by ELISA with anti-NDV antibody. The cells are then cryopreserved in liquid nitrogen until use.
• the NDV-modified are used for use as a vaccine
• the first vaccination is expedient 10 days postoperatively.
• the vaccination is repeated two to three times a week.
• the course of therapy is checked using various tests. This is followed by the patient's follow-up (combined with the tests) according to the general follow-up guidelines of clinical studies.
• the application takes place at least one week after the operation at intervals of one week, preferably at least three times.
• two or three or more injections with modified irradiated tumor cells and, for the test, the determination of the DTH reaction, a further injection with irradiated, unmodified tumor cells, preferably in a lower dose, are submitted in advance.
• autologous material is used for the induction period, i.e. the first two, three or four injections, i.e. material derived from the tumor that was taken from the patient himself.
• allogeneic material can also be used, that is, material that comes from corresponding tumors of third parties.
• NDV-modified tumor cells are used. They are cryopreserved in liquid nitrogen until use.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Mycology (AREA)
• Immunology (AREA)
• Microbiology (AREA)
• Epidemiology (AREA)
• Oncology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Micro-Organisms Or Cultivation Processes Thereof (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

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• 1988
  • 1988-03-01 DE DE3806565A patent/DE3806565A1/de active Granted
• 1989
  • 1989-02-27 EP EP19890103480 patent/EP0331102B1/de not_active Expired - Lifetime
  • 1989-02-27 AT AT89103480T patent/ATE90877T1/de active
  • 1989-02-27 JP JP1502563A patent/JPH02504034A/ja active Pending
  • 1989-02-27 KR KR1019890702004A patent/KR900700130A/ko not_active Withdrawn
  • 1989-02-27 DE DE8989103480T patent/DE58904760D1/de not_active Expired - Fee Related
  • 1989-02-27 US US07/449,851 patent/US5273745A/en not_active Expired - Fee Related
  • 1989-02-27 WO PCT/EP1989/000186 patent/WO1989007946A1/de not_active Ceased
  • 1989-02-27 ES ES89103480T patent/ES2042828T3/es not_active Expired - Lifetime
  • 1989-02-27 AU AU31889/89A patent/AU3188989A/en not_active Abandoned
  • 1989-10-31 DK DK541889A patent/DK541889A/da not_active Application Discontinuation

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