WO1997026910A2 - Tumour vaccine for immunotherapy of malignant tumours - Google Patents

Tumour vaccine for immunotherapy of malignant tumours Download PDF

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Publication number
WO1997026910A2
WO1997026910A2 PCT/DE1997/000172 DE9700172W WO9726910A2 WO 1997026910 A2 WO1997026910 A2 WO 1997026910A2 DE 9700172 W DE9700172 W DE 9700172W WO 9726910 A2 WO9726910 A2 WO 9726910A2
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Prior art keywords
tumor
vaccine according
heat shock
shock protein
protein
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PCT/DE1997/000172
Other languages
German (de)
French (fr)
Other versions
WO1997026910A3 (en
Inventor
Jürgen MILLECK
Werner Reichardt
Rainer Benndorf
Windfried Liebrich
Peter Schlag
Original Assignee
Max-Delbrück-Centrum für Molekulare Medizin
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Priority claimed from DE19602985A external-priority patent/DE19602985A1/en
Priority claimed from DE19604380A external-priority patent/DE19604380A1/en
Application filed by Max-Delbrück-Centrum für Molekulare Medizin filed Critical Max-Delbrück-Centrum für Molekulare Medizin
Publication of WO1997026910A2 publication Critical patent/WO1997026910A2/en
Publication of WO1997026910A3 publication Critical patent/WO1997026910A3/en

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    • 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
    • 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
    • A61K39/001169—Tumor associated carbohydrates
    • A61K39/00117—Mucins, e.g. MUC-1
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55588—Adjuvants of undefined constitution
    • A61K2039/55594—Adjuvants of undefined constitution from bacteria
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6043—Heat shock proteins

Definitions

  • the invention relates to the production of a vaccine from genetically modified tumor cells or from biochemically isolated tumor-associated antigens or synthetically produced antigenic substructures for the immunotherapy of malignant tumors. Areas of application of the invention are medicine and the pharmaceutical industry.
  • the basic therapy for solid malignant tumors is the surgical or radiotherapy removal of the primary tumor.
  • chemotherapy is carried out or biological therapy is attempted.
  • the generation of an immune response directed against cancer cells which leads to the destruction of the cancer cells, but which does not disturb the healthy tissue, is the optimal method for combating tumor metastases.
  • the fact that it is possible in principle to generate an immune response directed against cancer cells is demonstrated by the results of vaccination experiments with animal experimental tumors and also with some human tumors.
  • tumor cell vaccines In order to elicit an effective immunological defense reaction against malignant tumors, it is essential to artificially increase the immunogenicity of those tumor cells or tumor-associated antigens with which one wants to vaccinate.
  • this can be done by externally modifying the tumor cells chemically, enzymatically or by adding apathogenic viruses or weakened tubercle bacteria (BCG) or by genetic engineering by transmission e.g. a cytokingens changed (Specific Immunotherapy of Can cer with Vaccines, eds. Bystryn et al., Ann NY Acad Sei 690 (1993); Pardoll, Curr Opin Immunol 4, 619-623 (1992)).
  • BCG tubercle bacteria
  • Subcellular, soluble tumor-associated antigens e.g. Proteins or peptides with corresponding immunodominant epitopes from melanoma cells (van der Bruggen et al., Science 254, 1643-1647 (1991), adenocarcinomas (Taylor-Papadimitriou et al., Ann NY Acad Sei 690, 69-79 (1993) ) or other tumors (Slingluff et al., Curr Opin Immunol 6, 733-740 (1994)) must be bound to an immunogenic carrier molecule in order to increase their weak immunogenicity or to make them immunogenic at all.
  • an immunogenic carrier molecule in order to increase their weak immunogenicity or to make them immunogenic at all.
  • Peptides without Carrier molecules generally only act as haptens, ie, although they react with a corresponding peptide-specific antibody, but cannot themselves elicit an immune response, certain serum proteins or bacterial toxoids are used as the carrier molecule.
  • the conjugate of peptide and carrier molecule is used Usually an adjuvant is added, which further strengthens the immune response.
  • the immune response is recognizable from the formation of antigen-specific antibodies and / or T lymphocytes.
  • T-lymphocyte-mediated immunity As results from animal experiments and in vitro tests with human tumor cells show, the generation of a therapeutic effective immune response against cancer cells primarily to T-lymphocyte-mediated immunity and less to the formation of antibodies (Hellström and Hellström, Ann NY Acad Sei 690, 24-33 (1993)).
  • the aim of the present invention was therefore to provide a tumor vaccine which makes it possible to use both tumor cells and tumor-associated antigens or antigenic structures for an effective defense reaction against native tumor cells.
  • the object of the invention was to effectively increase the immunogenicity of tumor cells, tumor-associated antigens or antigenic substructures used as vaccines by genetic modification of the tumor cells or by bio-chemical modification of tumor-associated antigens or antigenic substructures, and in particular by To stimulate T-lymphocyte mediated immunity.
  • tumor cells which, according to the invention, additionally contain the gene of an exogenous heat shock protein or by binding tumor-associated antigens or antigenic substructures to an exogenous heat shock protein.
  • the tumor vaccine according to the invention contains tumor cells which contain the gene of an exogenous heat shock protein or tumor-associated antigens or antigenic substructures which are bound to an exogenous heat shock protein.
  • a microbial heat shock protein or its gene is preferably used.
  • the gene of heat shock proteins or heat shock proteins from Mycobacteria, Escherichia coli and from Chlamydia trachomatis are particularly preferred, in particular it is the heat shock proteins HSP65 and HSP70 from Mycobacteria, HSP70 from Escherichia coli (DnaK) and HSP60 and HSP70 from Chlamydia tris.
  • Autologous tumor cells which are isolated from surgically removed tumor tissue using mechanical or enzymatic methods are suitable for producing the tumor vaccine.
  • Tumor cell lines derived from allogeneic tumors of the same histology can also be used, an example of which are cells from a colon carcinoma line, such as e.g. the lines LS174T or LOVO.
  • the vaccine is administered postoperatively, before application the tumor cells are devitalized by radioactive radiation.
  • the gene of an exogenous heat shock protein and its expression the tumor cells are permanently alienated and thus more immunogenic.
  • the gene of the heat shock protein is e.g. inserted into the vector pcDNA3 (Invitrogen Corp.).
  • tumor vaccines can be produced for the treatment of patients with carcinoma, sarcoma, malignant melanoma, leukemia or malignant lymphoma.
  • biochemically isolated tumor-associated antigens and synthetically produced antigens are also b
  • a tumor-associated antigen is, for example, the carcinoembryonic antigen.
  • Synthetically produced mucin peptides, in particular monomers and oligomers of the mucin peptides MUC1 and MUC2, are used as synthetically produced antigenic partial structures.
  • the tumor vaccine is produced by conventional methods under sterile cauldrons, in which the heat shock protein is chemically bound to the tumor-associated antigens or antigenic substructures.
  • a novel strategy is being pursued with the tumor vaccine according to the invention.
  • the genetic engineering modification of tumor cells with the gene of a heat shock protein or by binding to an exogenous heat shock protein surprisingly effectively increases the immunogenicity of tumor cells and of tumor-associated antigens or antigenic substructures, i.e. This makes it possible for the first time to use tumor-associated antigens or antigenic substructures in a targeted manner and thereby stimulate the immunity mediated by T lymphocytes.
  • the tumor vaccines according to the invention are used for the treatment of patients with carcinoma, sarcoma or malignant melanoma and are preferably administered postoperatively.

Abstract

The invention concerns a tumour vaccine in which the immunogenicity of tumour cells, tumour associated antigens or antigen partial structures are reinforced through genetic modification or through chemical bonding to an exogenous thermal shock protein. The use of microbial thermal shock proteins or their genes is preferred which are derived from mycobacteria, Escherichia coli or from Chlamydia trachomatis.

Description

Tumorimpfstoff für die Immuntherapie von malignen Tumoren Tumor vaccine for the immunotherapy of malignant tumors
Beschreibungdescription
Die Erfindung betrifft die Herstellung eines Impfstoffes aus gentechnisch modifizierten Tumorzellen beziehungswei¬ se aus biochemisch isolierten tumorassoziierten Antigenen oder synthetisch hergestellten antigenen Teilstrukturen für die Immuntherapie von malignen Tumoren. Anwendungsge- biete der Erfindung sind die Medizin und die pharmazeuti¬ sche Industrie.The invention relates to the production of a vaccine from genetically modified tumor cells or from biochemically isolated tumor-associated antigens or synthetically produced antigenic substructures for the immunotherapy of malignant tumors. Areas of application of the invention are medicine and the pharmaceutical industry.
Die grundlegende Therapie solider maligner Tumoren ist die chirurgische oder strahlentherapeutische Entfernung des Primärtumors. Bei systemischen Formen der Krebser¬ krankung oder chirurgisch nicht erreichbaren Tumormeta¬ stasen führt man eine Chemotherapie durch oder versucht eine biologische Therapie. Theoretisch gesehen ist die Erzeugung einer gegen Krebszellen gerichteten Immunant- wort, die zur Zerstörung der Krebszellen führt, das ge¬ sunde Gewebe aber nicht behelligt, die optimale Methode, um Tumormetastasen zu bekämpfen. Daß es prinzipiell mög¬ lich ist, eine gegen Krebszellen gerichtete Immunantwort zu erzeugen, wird durch Ergebnisse von Impfversuchen mit tierexperimentellen Tumoren sowie auch mit einigen Tumo¬ ren des Menschen belegt.The basic therapy for solid malignant tumors is the surgical or radiotherapy removal of the primary tumor. In the case of systemic forms of cancer or tumor metastases which cannot be reached with surgery, chemotherapy is carried out or biological therapy is attempted. In theory, the generation of an immune response directed against cancer cells, which leads to the destruction of the cancer cells, but which does not disturb the healthy tissue, is the optimal method for combating tumor metastases. The fact that it is possible in principle to generate an immune response directed against cancer cells is demonstrated by the results of vaccination experiments with animal experimental tumors and also with some human tumors.
Es sind jedoch noch Hemmnisse zu überwinden, ehe diese Form der aktiven spezifischen Immunisierung zur Therapie von Krebserkrankungen eine breitere klinische Anwendung finden kann. Eines der größten Hemmnisse ist die geringe Immunogenität spontan entstandener Tumoren. Unstrittig ist, daß die meisten Tumoren, auch diejenigen des Men¬ schen, tumorassoziierte Antigene besitzen, durch die sie sich vom gesunden Gewebe unterscheiden. Da Tumoren jedoch körpereigenes Gewebe darstellen, registriert das Immunsy¬ stem lediglich die Existenz tumorassoziierter Antigene auf den malignen Zellen, ist aber von sich aus nicht in der Lage, eine wirksame Abwehrreaktion gegen die nativen Tumorzellen zustandezubringen.However, there are still obstacles to be overcome before this form of active specific immunization for cancer therapy can be used more widely. One of the biggest obstacles is the low immunogenicity of spontaneously occurring tumors. It is indisputable that most tumors, including those of humans, have tumor-associated antigens which distinguish them from healthy tissue. However, since tumors represent the body's own tissue, the immune system only registers the existence of tumor-associated antigens on the malignant cells, but is not inherently in itself able to bring about an effective defense reaction against the native tumor cells.
Um eine wirksame immunologische Abwehrreaktion gegen ma- ligne Tumoren hervorzurufen, ist es unerläßlich, die Im- munogenität derjenigen Tumorzellen oder tumorassoziierten Antigene mit denen man eine Impfung vornehmen will, künstlich zu verstärken. Bei Tumorzellimpfstoffen kann dieses dadurch geschehen, daß man die Tumorzellen che- misch, enzymatiεch oder durch Hinzufügen apathogener Vi¬ ren bzw. abgeschwächter Tuberkelbakterien (BCG) äußerlich modifiziert oder gentechnisch durch Übertragung z.B. ei¬ nes Zytokingens verändert (Specific Immunotherapy of Can¬ cer with Vaccines, eds. Bystryn et al. , Ann NY Acad Sei 690 (1993); Pardoll, Curr Opin Immunol 4, 619-623 (1992)). Subzelluläre, lösliche tumorassoziierte Antige¬ ne, z.B. Proteine oder Peptide mit entsprechenden im¬ mundominanten Epitopen aus Melanomzellen (van der Bruggen et al., Science 254, 1643-1647 (1991), Adenokarzinomen (Taylor-Papadimitriou et al., Ann NY Acad Sei 690, 69-79 (1993)) oder anderen Tumoren (Slingluff et al., Curr Opin Immunol 6, 733-740 (1994)) müssen an ein immunogenes Trä¬ germolekül gebunden werden, um ihre schwache Immunogeni- tät zu verstärken bzw. sie überhaupt immunogen zu machen. Peptide ohne Trägermolekül wirken in der Regel lediglich als Hapten, d.h. sie reagieren zwar mit einem entspre¬ chenden peptidspezifischen Antikörper, können aber selbst keine Immunantwort hervorrufen. Als Trägermolekül werden bestimmte Serumproteine oder bakterielle Toxoide verwen- det. Vor der Impfung wird dem Konjugat aus Peptid und Trägermolekül üblicherweise ein Adjuvans zugefügt, wo¬ durch die Immunantwort nochmals verstärkt wird.In order to elicit an effective immunological defense reaction against malignant tumors, it is essential to artificially increase the immunogenicity of those tumor cells or tumor-associated antigens with which one wants to vaccinate. In the case of tumor cell vaccines, this can be done by externally modifying the tumor cells chemically, enzymatically or by adding apathogenic viruses or weakened tubercle bacteria (BCG) or by genetic engineering by transmission e.g. a cytokingens changed (Specific Immunotherapy of Can cer with Vaccines, eds. Bystryn et al., Ann NY Acad Sei 690 (1993); Pardoll, Curr Opin Immunol 4, 619-623 (1992)). Subcellular, soluble tumor-associated antigens, e.g. Proteins or peptides with corresponding immunodominant epitopes from melanoma cells (van der Bruggen et al., Science 254, 1643-1647 (1991), adenocarcinomas (Taylor-Papadimitriou et al., Ann NY Acad Sei 690, 69-79 (1993) ) or other tumors (Slingluff et al., Curr Opin Immunol 6, 733-740 (1994)) must be bound to an immunogenic carrier molecule in order to increase their weak immunogenicity or to make them immunogenic at all. Peptides without Carrier molecules generally only act as haptens, ie, although they react with a corresponding peptide-specific antibody, but cannot themselves elicit an immune response, certain serum proteins or bacterial toxoids are used as the carrier molecule. Before the vaccination, the conjugate of peptide and carrier molecule is used Usually an adjuvant is added, which further strengthens the immune response.
Prinzipiell wird die Immunantwort erkennbar an Hand der Bildung antigenspezifischer Antikörper und/oder T- Lymphozyten. Wie Ergebnisse von tierexperimentellen Un¬ tersuchungen und in-vitro-Tests mit humanen Tumorzellen zeigen, kommt es bei der Erzeugung einer therapeutisch wirksamen Immunantwort gegen Krebszellen in erster Linie auf eine durch T-Lymphozyten vermittelte Immunität an und weniger auf die Bildung von Antikörpern (Hellström and Hellström, Ann NY Acad Sei 690, 24-33 (1993)). Allerdings existieren bisher keine klaren Vorstellungen darüber, wie man bei einer Impfung von Tumorpatienten mit tumorassozi¬ ierten Antigenen oder kurzkettigen Peptiden verfahren muß, um vor allem die Bildung tumorantigenspezifischer T- Lymphozyten hervorzurufen (Time of Truth for Cancer Vac- eines, J Natl Cancer Inst 86, 330-331 (1994)).In principle, the immune response is recognizable from the formation of antigen-specific antibodies and / or T lymphocytes. As results from animal experiments and in vitro tests with human tumor cells show, the generation of a therapeutic effective immune response against cancer cells primarily to T-lymphocyte-mediated immunity and less to the formation of antibodies (Hellström and Hellström, Ann NY Acad Sei 690, 24-33 (1993)). To date, however, there are no clear ideas about how to proceed when vaccinating tumor patients with tumor-associated antigens or short-chain peptides, in particular to cause the formation of tumor antigen-specific T-lymphocytes (Time of Truth for Cancer Vac- an, J Natl Cancer Inst 86: 330-331 (1994)).
Das Ziel der vorliegenden Erfindung war es deshalb, einen Tumorimpfstoff bereitzustellen, der es gestattet, sowohl Tumorzellen als auch tumorassoziierte Antigene oder anti- gene TeilStrukturen für eine wirksame Abwehrreaktion ge¬ gen native Tumorzellen einzusetzen. Die Aufgabe der Er¬ findung bestand dabei darin, die Immunogenität von als Impfstoff verwendeten Tumorzellen, tumorassoziierten An¬ tigenen oder antigenen Teilstrukturen durch gentechnische Modifizierung der Tumorzellen beziehungsweise durch bio¬ chemische Modifizierung von tumorassoziierten Antigenen oder antigenen Teilstrukturen wirksam zu verstärken und dabei insbesondere die durch T-Lymphozyten vermittelte Immunität zu stimulieren.The aim of the present invention was therefore to provide a tumor vaccine which makes it possible to use both tumor cells and tumor-associated antigens or antigenic structures for an effective defense reaction against native tumor cells. The object of the invention was to effectively increase the immunogenicity of tumor cells, tumor-associated antigens or antigenic substructures used as vaccines by genetic modification of the tumor cells or by bio-chemical modification of tumor-associated antigens or antigenic substructures, and in particular by To stimulate T-lymphocyte mediated immunity.
Überraschend konnte diese Aufgabe durch gentechnische Mo¬ difizierung von TumorZellen, die erfindungsgemäß zusätz¬ lich das Gen eines exogenen Hitzeschockproteins enthalten oder durch Bindung von tumorassoziierten Antigenen oder antigenen Teilstrukturen an ein exogenes Hitzeschockpro¬ tein gelöst werden.Surprisingly, this task could be solved by genetic modification of tumor cells which, according to the invention, additionally contain the gene of an exogenous heat shock protein or by binding tumor-associated antigens or antigenic substructures to an exogenous heat shock protein.
Der erfindungsgemäße Tumorimpfstoff enthält Tumorzellen, die das Gen eines exogenen Hitzeschockproteins enthalten beziehungsweise tumorassoziierte Antigene oder antigene TeilStrukturen, die an ein exogenes Hitzeschockprotein gebunden sind. Bevorzugt wird ein mikrobielles Hitzeschockprotein bezie¬ hungsweise sein Gen verwendet. Besonders bevorzugt sind das Gen von Hitzeschockproteinen beziehungsweise Hitze¬ schockproteine aus Mycobakterien, Escherichia coli und aus Chlamydia trachomatis, insbesondere sind es die Hit¬ zeschockproteine HSP65 und HSP70 aus Mycobakterien, HSP70 aus Escherichia coli (DnaK) sowie HSP60 und HSP70 aus Chlamydia trachomatis.The tumor vaccine according to the invention contains tumor cells which contain the gene of an exogenous heat shock protein or tumor-associated antigens or antigenic substructures which are bound to an exogenous heat shock protein. A microbial heat shock protein or its gene is preferably used. The gene of heat shock proteins or heat shock proteins from Mycobacteria, Escherichia coli and from Chlamydia trachomatis are particularly preferred, in particular it is the heat shock proteins HSP65 and HSP70 from Mycobacteria, HSP70 from Escherichia coli (DnaK) and HSP60 and HSP70 from Chlamydia tris.
Zur Herstellung des Tumorimpfstoffes eignen sich autologe Tumorzellen, die mit Hilfe mechanischer oder enzymati- scher Methoden aus chirurgisch entferntem Tumorgewebe isoliert werden. Tumorzellinien, die von allogenen Tumo¬ ren gleicher Histologie stammen, können ebenfalls verwen- det werden, ein Beispiel dafür sind Zellen einer Colon- karzinomlinie, wie z.B. die Linien LS174T oder LOVO. Der Impfstoff wird postoperativ verabfolgt, vor der Applika¬ tion werden die Tumorzellen durch radioaktive Bestrahlung devitalisiert. Infolge der Bereitstellung dieses erfindungsgemäßen Tumo- rimpfεtoffes durch Einschleusen des Gens eines exogenen Hitzeschockproteins und dessen Expression werden die Tu¬ morzellen nachhaltig verfremdet und damit stärker immuno- gen. Das Gen des Hitzeschockproteins wird z.B. in den Vektor pcDNA3 (Invitrogen Corp.) insertiert. Die Ein¬ schleusung und Expression des Gens eines Hitzeschockpro¬ teins erfolgt nach an sich bekannten Methoden, wie z.B. durch Transfektion mit dem liposomalen Reagenz DOTAP (Boehringer Mannheim GmbH) nach Feigner et al. Proc Natl Acad Sei USA 84 (1987), 7413-7417, Li et al. Biochemica, 30-31 (1995).Autologous tumor cells which are isolated from surgically removed tumor tissue using mechanical or enzymatic methods are suitable for producing the tumor vaccine. Tumor cell lines derived from allogeneic tumors of the same histology can also be used, an example of which are cells from a colon carcinoma line, such as e.g. the lines LS174T or LOVO. The vaccine is administered postoperatively, before application the tumor cells are devitalized by radioactive radiation. As a result of the provision of this tumor vaccine according to the invention by introducing the gene of an exogenous heat shock protein and its expression, the tumor cells are permanently alienated and thus more immunogenic. The gene of the heat shock protein is e.g. inserted into the vector pcDNA3 (Invitrogen Corp.). The introduction and expression of the gene of a heat shock protein takes place according to methods known per se, such as e.g. by transfection with the liposomal reagent DOTAP (Boehringer Mannheim GmbH) according to Feigner et al. Proc Natl Acad Sei USA 84 (1987), 7413-7417, Li et al. Biochemica, 30-31 (1995).
Danach können Tumorimpfstoffe für die Behandlung von Pa¬ tienten mit Karzinom, Sarkom, malignem Melanom, Leukämie oder malignem Lymphom hergestellt werden.Thereafter, tumor vaccines can be produced for the treatment of patients with carcinoma, sarcoma, malignant melanoma, leukemia or malignant lymphoma.
Gemäß der Erfindung werden auch biochemisch isolierte tu¬ morassoziierte Antigene und synthetisch hergestellte an- bAccording to the invention, biochemically isolated tumor-associated antigens and synthetically produced antigens are also b
tigene Teilstrukturen verwendet. Ein tumorassoziiertes Antigen ist beispielsweise das Carcinoembryonale Antigen. Als synthetisch hergestellte antigene Teil≤trukturen wer¬ den gemäß der Erfindung synthetisch hergestellte Mucin- peptide, insbesondere Monomere und Oligomere der Mucin- peptide MUC1 und MUC2 eingesetzt.tigen substructures used. A tumor-associated antigen is, for example, the carcinoembryonic antigen. Synthetically produced mucin peptides, in particular monomers and oligomers of the mucin peptides MUC1 and MUC2, are used as synthetically produced antigenic partial structures.
Der Tumorimpfstoff wird nach an sich üblichen Methoden unter sterilen Kautelen hergestellt, in dem das Hitze- schockprotein chemisch an die tumoraεsoziierten Antigene oder antigenen Teilstrukturen gebunden wird.The tumor vaccine is produced by conventional methods under sterile cauldrons, in which the heat shock protein is chemically bound to the tumor-associated antigens or antigenic substructures.
Mit dem erfindungsgemäßen Tumorimpfstoff wird eine neuar¬ tige Strategie verfolgt. Durch die gentechnische Modifi- zierung von Tumorzellen mit dem Gen eines Hitzeschockpro¬ teins beziehungseise durch die Bindung an ein exogenes Hitzeschockprotein wird überraschend die Immunogenität von Tumorzellen und von tumorassoziierten Antigenen oder antigenen Teilstrukturen wirksam verstärkt, d.h. es wird dadurch erstmalig möglich, auch tumorassoziierte Antigene oder antigene TeilStrukturen gezielt einzusetzen und da¬ durch die durch T-Lymphozyten vermittelte Immunität zu stimulieren.A novel strategy is being pursued with the tumor vaccine according to the invention. The genetic engineering modification of tumor cells with the gene of a heat shock protein or by binding to an exogenous heat shock protein surprisingly effectively increases the immunogenicity of tumor cells and of tumor-associated antigens or antigenic substructures, i.e. This makes it possible for the first time to use tumor-associated antigens or antigenic substructures in a targeted manner and thereby stimulate the immunity mediated by T lymphocytes.
Die erfindungsgemäßen Tumorimpfstoffe werden für die Be¬ handlung von Patienten mit Karzinom, Sarkom oder malignem Melanom verwendet und vorzugsweise postoperativ verab¬ folgt. The tumor vaccines according to the invention are used for the treatment of patients with carcinoma, sarcoma or malignant melanoma and are preferably administered postoperatively.

Claims

Patentansprüche claims
1. Tumorimpfstoff für die Immuntherapie von Tumoren ent¬ haltend Tumorzellen, tumorassoziierte Antigene oder antigene TeilStrukturen, wobei die Tumorzellen das Gen eines exogenen Hitzschockproteins enthalten, und die tumorassoziierten Antigene oder antigenen Teil¬ strukturen an ein exogenes Hitzeschockprotein gebun¬ den sind.1. Tumor vaccine for the immunotherapy of tumors containing tumor cells, tumor-associated antigens or antigenic structures, the tumor cells containing the gene of an exogenous heat shock protein, and the tumor-associated antigens or antigenic structures being bound to an exogenous heat shock protein.
2. Tumorimpfstoff nach Anspruch 1, dadurch gekennzeichnet, daß als Tumorzellen devitalisierte autologe oder allogene Tumorzellen eingesetzt werden.2. Tumor vaccine according to claim 1, characterized in that devitalized autologous or allogeneic tumor cells are used as tumor cells.
3. Tumorimpfstoff nach Anspruch 1, dadurch gekennzeichnet, daß die tumorassoziierten Antigene oder antigenen Teil¬ strukturen biochemisch isoliert oder synthetisch her- gestellt werden.3. Tumor vaccine according to claim 1, characterized in that the tumor-associated antigens or antigenic substructures are biochemically isolated or synthetically produced.
4. Tumorimpfstoff nach einem der Ansprüche 1 oder 3, dadurch gekennzeichnet, daß als tumorassoziierte Antigene oder antigene Teil- Strukturen synthetisch hergestellte Mucinpeptide ver¬ wendet werden.4. Tumor vaccine according to one of claims 1 or 3, characterized in that synthetically produced mucin peptides are used as tumor-associated antigens or antigenic substructures.
5. Tumorimpfstoff nach Anspruch 4, dadurch gekennzeichnet, daß synthetisch hergestellte Monomere oder Oligomere der Mucinpeptide MUC1 und MUC2 verwendet werden.5. Tumor vaccine according to claim 4, characterized in that synthetically produced monomers or oligomers of the mucin peptides MUC1 and MUC2 are used.
6. Tumorimpfstoff nach einem der Ansprüche 1 oder 3, dadurch gekennzeichnet, daß als tumorassoziiertes Antigen oder antigene Teil¬ strukturen Carcinoembryonales Antigen oder antigene Teilstrukturen des Carcinoembryonalen Antigens ver¬ wendet werden. 6. Tumor vaccine according to one of claims 1 or 3, characterized in that Carcinoembryonic antigen or antigenic substructures of the Carcinoembryonic antigen are used as tumor-associated antigen or antigenic substructures.
7. Tumorimpfstoff nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß das exogene Hitzeschockprotein ein mikrobielles Hit- zeschockprotein ist.7. Tumor vaccine according to one of claims 1 to 6, characterized in that the exogenous heat shock protein is a microbial hit shock protein.
8. Tumorimpfstoff nach Anspruch 7, dadurch gekennzeichnet, daß das Hitzeschockprotein das Protein HSP65 aus Mycobak- terien ist.8. Tumor vaccine according to claim 7, characterized in that the heat shock protein is the HSP65 protein from Mycobacteria.
9. Tumorimpfstoff nach Anspruch 7, dadurch gekennzeichnet, daß das Hitzeschockprotein das Protein HSP70 aus Mycobak- terien ist.9. tumor vaccine according to claim 7, characterized in that the heat shock protein is the protein HSP70 from Mycobacteria.
10. Tumorimpfstoff nach Anspruch 7, dadurch gekennzeichnet, daß das Hitzeschockprotein das Protein HSP70 aus Escheri- chia coli (DnaK) ist.10. Tumor vaccine according to claim 7, characterized in that the heat shock protein is the HSP70 protein from Escherichia coli (DnaK).
11. Tumorimpfstoff nach Anspruch 7, dadurch gekennzeichnet, daß das Hitzeschockprotein das Protein HSP60 aus Chlamy- dia trachomatis ist.11. Tumor vaccine according to claim 7, characterized in that the heat shock protein is the HSP60 protein from Chlamy dia trachomatis.
12. Tumorimpfstoff nach Anspruch 7, dadurch gekennzeichnet, daß das Hitzeschockprotein das Protein HSP70 aus Chlamy- dia trachomatis ist.12. Tumor vaccine according to claim 7, characterized in that the heat shock protein is the HSP70 protein from Chlamy dia trachomatis.
13. Verwendung eines Tumorimpfstoffes nach einem der An¬ sprüche 1 bis 12 zur Behandlung von Patienten mit Karzinom, Sarkom, malignem Melanom, Leukämie oder ma- lignem Lymphom. 13. Use of a tumor vaccine according to one of claims 1 to 12 for the treatment of patients with carcinoma, sarcoma, malignant melanoma, leukemia or malignant lymphoma.
14. Verfahren zur Herstellung eines Tumorimpfstoffes nach einem der Ansprüche 1,2 und 7 bis 12, dadurch gekennzeichnet, daß man in Tumorzellen die cDNA des Gens eines Hitze- sehoekproteins einschleust und dort zur Expression bringt.14. A method for producing a tumor vaccine according to any one of claims 1, 2 and 7 to 12, characterized in that the cDNA of the gene of a heat-sensitive protein is introduced into tumor cells and brought to expression there.
15. Verfahren zur Herstellung eines Tumorimpfstoffs für die Immuntherapie nach den Ansprüchen 1 und 3 bis 12, dadurch gekennzeichnet, daß das Hitzschockprotein an die tumorassoziierten Anti¬ gene oder antigenen Teilstrukturen gebunden wird. 15. A method for producing a tumor vaccine for immunotherapy according to claims 1 and 3 to 12, characterized in that the heat shock protein is bound to the tumor-associated anti-genes or antigenic substructures.
PCT/DE1997/000172 1996-01-27 1997-01-27 Tumour vaccine for immunotherapy of malignant tumours WO1997026910A2 (en)

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