DE19960705A1 - Method and device for producing an autologous immunization vaccine against cancer (tumor vaccine) - Google Patents
Method and device for producing an autologous immunization vaccine against cancer (tumor vaccine)Info
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- DE19960705A1 DE19960705A1 DE19960705A DE19960705A DE19960705A1 DE 19960705 A1 DE19960705 A1 DE 19960705A1 DE 19960705 A DE19960705 A DE 19960705A DE 19960705 A DE19960705 A DE 19960705A DE 19960705 A1 DE19960705 A1 DE 19960705A1
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- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 1
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- VGVYRHYDNGFIGF-UHFFFAOYSA-N fumarin Chemical class OC=1OC2=CC=CC=C2C(=O)C=1C(CC(=O)C)C1=CC=CO1 VGVYRHYDNGFIGF-UHFFFAOYSA-N 0.000 description 1
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- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical compound [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 1
- 210000000633 nuclear envelope Anatomy 0.000 description 1
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- 239000003504 photosensitizing agent Substances 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical class N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- GPTFURBXHJWNHR-UHFFFAOYSA-N protopine acetate Natural products C1=C2C(=O)CC3=CC=C4OCOC4=C3CN(C)CCC2=CC2=C1OCO2 GPTFURBXHJWNHR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
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- Engineering & Computer Science (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Es soll ein Verfahren und eine Vorrichtung entwickelt werden, mittels derer es gelingt vitale, aus dem Körper des Menschen oder des Tieres gewonnene Tumorzellen derart zu modifizieren, dass sie, inaktiviert, jedoch das Immunsystem des Lebewesens stimulierend, im Rahmen einer einfachen oder Mehrfach- Impfung dem lebenden Organismus wieder zugeführt werden können.It is intended to be a method and an apparatus be developed by means of which it succeeds vital, from the human body or the tumor cells obtained from the animal modify that, inactivated, however Stimulating the immune system of the living being, as part of a single or multiple Vaccination the living organism again can be supplied.
Die extrakorporale Photopherese wird zur Immunmodulation bei Erkrankungen des Weißzellensystems (Autoimmunerkrankungen und cutaner T-Zell-Lymphom (CTCL)) mit Er folg eingesetzt. Bei der extrakorporalen Pho topherese handelt sich um eine Art der Pho totherapie, bei der durch das Zentrifugieren des dem Patienten entnommenen Blutes leu kozytenangereicherte Plasmafraktion entsteht, welche nach der Zugabe des photoaktiven Psoralens (Fumarinderivat) mit UVA-Licht (320-400 nm) bestrahlt, und anschließend dem Patientenkreislauf wieder zugeführt wird. Das Prinzip der Behandlung basiert darauf, dass sich das unter normalen Bedingungen inerte Psoralen nach Absorption von Photo nen an die Basen der Doppelstrang-DNA ko valent bindet und somit die DNA-Replikation verhindert, was zur Schädigung und Zerstö rung der Zellen (Apoptose) führt. Nach Zufüh rung dieser Zellen in den Blutkreislauf des Patienten sterben diese Zellen innerhalb von ca. zwei Wochen, was zu einer autologen Immunantwort des Organismus, die sich ge gen die Zellen dieser Art richtet, führt. Da bei Autoimmunerkrankungen bzw. bei dem CCTL vor allem die Zellen eines Klones überdurch schnittlich zahlreich im Blut auftreten, richtet sich die massive Immunantwort vor allem ge gen diese Zellen.Extracorporeal photopheresis becomes Immunomodulation in diseases of the White cell system (autoimmune diseases and cutaneous T-cell lymphoma (CTCL)) with Er followed. With the extracorporeal Pho topherese is a type of pho therapy, by centrifugation of the blood drawn from the patient leu the plasma fraction is enriched with cocytes, which after the addition of the photoactive Psoralens (fumarin derivative) with UVA light (320-400 nm) irradiated, and then is returned to the patient cycle. The principle of treatment is based on that this is under normal conditions inert psoralen after absorption of photo to the bases of the double-stranded DNA valent binds and thus DNA replication prevents what damage and destruction tion of the cells (apoptosis) leads. After feed tion of these cells in the bloodstream of the Patients die within these cells about two weeks, resulting in an autologous Immune response of the organism, the ge directed towards the cells of this type leads. There with Autoimmune diseases or at the CCTL above all the cells of a clone on average, numerous occur in the blood the massive immune response above all ge against these cells.
Ein entsprechendes Photophoresesystem wird beispielsweise unter dem Handelsnamen UVAR XTS System durch die Firma Therakos vertrieben.A corresponding photophoresis system is for example under the trade name UVAR XTS system by Therakos expelled.
Derartige Photophoresesysteme sind jedoch ausschließlich zur Behandlung von entarteten Leukozytenfraktionen geeignet. Such photophoresis systems are, however exclusively for the treatment of degenerate Leukocyte fractions suitable.
Es hat sich nun überraschenderweise gezeigt, dass bestimmte photoaktive Substanzen wie beispielsweise 5-ALA (Aminolävulinsäure), Hämatoporphyrinderivate (HpD, DHE), Ben zoporphyrinderivate (BpD), Photo-Chlorin (ATX-S10) oder auch Phtalocyaninderivate in der Lage sind, sich sowohl extra- wie auch intrazellulär an sensible Zellstrukturen, wie Zellmembran, Zellkernmembran, Mitochondri enmembran anzulagern und nach Bestrahlung mit geeigneten Lichtwellenlängen Spektralbe reich von 300 nm bis 3 µm selektiv die Zell strukturen, an denen sie sich vorzugsweise angelagert haben, nachhaltig zu schädigen, so dass nach einer durch die verabreichte Dosis vorher bestimmbaren Zeit eine Apopto se (Zelltod) eintritt.Surprisingly, it has now been shown that certain photoactive substances like for example 5-ALA (aminolevulinic acid), Hematoporphyrin derivatives (HpD, DHE), Ben zoporphyrin derivatives (bpD), photo-chlorine (ATX-S10) or phthalocyanine derivatives in are able to look both extra as well intracellular to sensitive cell structures, such as Cell membrane, nuclear membrane, mitochondrial attach to the membrane and after irradiation with suitable light wavelengths spectral selectively ranges from 300 nm to 3 µm structures that they prefer have sustained damage, so after one administered by the Dose predeterminable time an apopto se (cell death) occurs.
Es hat sich nun weiterhin überraschender weise gezeigt, dass in der präapoptotischen Phase derartige behandelte Zellen kein tumorgenes Potential mehr haben, anderer seits jedoch über Verabreichung einer erhöh ten Konzentration derartiger Zellen das Im munsystem des Organismus aktiviert wird und nunmehr derartige Zellen sowohl die prä apoptotischen - später apoptotischen - Zellen zerstört wie auch noch die weiterhin im Blut bzw. in Körperflüssigkeiten vorhandenen akti ven, morphogenetisch identischen Tumorzel len eliminiert.It has now continued to be more surprising shown wisely that in pre-apoptotic No such treated cells phase have more tumor potential, others on the other hand via administration of an increased th concentration of such cells the Im the organism 's immune system is activated and now such cells both the pre apoptotic - later apoptotic - cells still destroyed in the blood or existing in body fluids ven, morphogenetically identical tumor cell len eliminated.
In einem bevorzugten Ausführungsbeispiel werden den nach medizinischer Fragestellung in Betracht kommenden Körperflüssigkeiten (Blut, Lymphe, etc.) durch einen Zellsorter nach dem Stand der Technik Tumorzellen entnommen. Die angereicherte Suspension der Tumorzellen wird sodann mit einer vorher bestimmten Dosis eines bevorzugten photo chemischen Reaktanden, z. B. 5-Aminolävolin säure oder Photo-Chlorin, versetzt und mit einer Wellenlänge bestrahlt, die eine mög lichst hohe Apoptoserate erzielt. In einem be vorzugten Ausführungsbeispiel der 5- Aminolävolinsäure ist dies die Wellenlänge von ca. 510 bis 540 nm, die beispielsweise durch einen Argon-Ionen-Laser oder einem frequenzvervielfachten Neodym-YAG-Laser erzeugt werden kann.In a preferred embodiment be the medical question eligible body fluids (Blood, lymph, etc.) by a cell sorter according to the prior art tumor cells taken. The enriched suspension the tumor cells are then covered with a previously certain dose of a preferred photo chemical reactants, e.g. B. 5-aminolevin acid or photo-chlorine, added and with irradiated at a wavelength that is possible achieved the highest possible apoptosis rate. In a be preferred embodiment of the 5- Aminolevinic acid this is the wavelength from about 510 to 540 nm, for example by an argon ion laser or one frequency-multiplied neodymium YAG laser can be generated.
Die derartig bestrahlte Zellsuspension wird sodann dem erkrankten Organismus wieder zugeführt, um eine Autoimmunreaktion zu provozieren.The cell suspension irradiated in this way becomes then the diseased organism again fed to an autoimmune response provoke.
Erfindungsgemäß ist jedoch auch die Ent nahme einer Zell-Probe aus dem soliden Tu mor anstelle der Anwendung von körperflüs sigkeitsgängigen Einzelzellen.According to the invention, however, the Ent took a cell sample from the solid Tu mor instead of using body fluids viable single cells.
Neben dem bevorzugten Ausführungsbeispiel ist jedoch auch jede weitere photochemische Substanz, die selektiv in Tumorzellen ange reichert werden kann, mit nachfolgender Apoptose durch Bestrahlung im Spektralbe reich zwischen 300 nm und 3 µm erfindungs gemäß.In addition to the preferred embodiment is any other photochemical Substance that is selectively expressed in tumor cells can be enriched with subsequent Apoptosis by radiation in the spectral spectrum range between 300 nm and 3 µm fiction according to.
In Weiterführung des Erfindungsgedankens wird der Erfolg der photochemisch induzierten Apopthose durch die Bestimmung des aktiven Zellstoffwechsels überprüft. Erfindungsge mäß geschieht dies durch die quantitative Bestimmung des Koenzyms NADH mittels zeitaufgelöster Fluoreszenzmesstechnik. Nach erfolgter photochemischer Behandlung der Einzelzellen wird ja durch die intrazelluläre Schädigung, die anschließend zur Apoptose führt, der Zellmetabolismus derart geschädigt, dass durch eine quantitative Bestimmung des zeitlichen Umsätze von NADH durch Analyse des Zeitverlaufs der NADH-Konzentration er findungsgemäß zwischen der NADH- Konzentration in den Mitochondrien und im übrigen Zellraum unterschieden werden kann. Diese Konzentration ist im nativen Zustand in den Mitochondrien größer, wird aber hier durch die selektive Wirkung der photoaktiven Substanzen zeitlich schneller abfallen.In continuation of the inventive concept the success of the photochemically induced Apoptosis by determining the active Cell metabolism checked. Invention Ge according to this happens through the quantitative Determination of the coenzyme NADH using time-resolved fluorescence measurement technology. After photochemical treatment the single cell is made by the intracellular Damage that subsequently leads to apoptosis cell metabolism is so damaged, that by quantifying the temporal sales of NADH through analysis of the time course of the NADH concentration according to the invention between the NADH Concentration in the mitochondria and in remaining cell space can be distinguished. This concentration is in the native state the mitochondria, but gets bigger here through the selective effect of photoactive Substances fall off faster in time.
Erfindungsgemäß wird dieser Prozeß durch
folgendes mathematisches Modell beschrie
ben:
According to the invention, this process is described by the following mathematical model:
NADH(t) = A e-at + B e-bt + C.NADH (t) = A e -at + B e -bt + C.
Hierbei setzt sich der zeitliche Verlauf der NADH-Konzentration NADH(t) aus dem mito chondrialen Anteil A e-at, dem restlichen NADH-Anteil in der Zelle B e-bt und einem relativ kleinen, zeitunabhängigen Offset C zusammen. Die 5 Parameter A, a, B, b und C werden während der Applikation praktisch instantan mittels bekannter Methoden der numerischen Optimierung bestimmt. Mit die sen Parametern kann damit ebenfalls instan tan der zeitliche Verlauf der beiden NADH- Anteile separiert und bewertet werden.The time course of the NADH concentration NADH (t) is composed of the mito-chondrial component A e -at , the remaining NADH component in cell B e -bt and a relatively small, time-independent offset C. The 5 parameters A, a, B, b and C are determined almost instantaneously during application by means of known methods of numerical optimization. These parameters can also be used to separate and evaluate the time profile of the two NADH components.
In Abb. 1 sind auf x-Achse 2 die Zeit und auf der y-Achse 1 die Konzentration des NADH aufgetragen. Der zeitaufgelöste Verlauf der Gesamtkonzentration des NADH 3 setzt sich additiv aus zwei Anteilen zusammen, die sich hauptsächlich durch stark unterschiedli che Abklingzeiten unterscheiden. Dabei han delt es sich um den mitochondralen Anteil 4 und den Restanteil des NADH in der Zelle 5. Zum Zeitpunkt T6 ist der mitochondrale Anteil des NADH 4 bereits soweit abgefallen, dass die Zelle irreversibel geschädigt wurde. Dieser Prozess kann in der Gesamtkonzentration 3 nicht erkannt und damit auch nicht beurteilt werden. Wird allerdings der zeitliche Verlauf der NADH-Konzentration in der beschriebe nen Weise instantan nach seinen beiden Hauptkomponenten 4 und 5 aufgespalten, so kann aus der separaten Beurteilung dieser Komponenten eine Verfahrenskontrolle ab geleitet werden.In Fig. 1, the time is plotted on x-axis 2 and the concentration of NADH on y-axis 1 . The time-resolved course of the total concentration of the NADH 3 is additively composed of two parts, which differ mainly by greatly differing decay times. These are the mitochondral part 4 and the remaining part of the NADH in the cell 5 . By the time T6, the mitochondral portion of the NADH 4 had already dropped so far that the cell was irreversibly damaged. This process cannot be recognized in the total concentration 3 and therefore cannot be assessed. However, if the time course of the NADH concentration in the manner described is instantly split into its two main components 4 and 5 , a process control can be derived from the separate assessment of these components.
Abb. 2 verdeutlicht nochmals den erfin dungsgemäßen Prozess zur biotechnischen Herstellung einer Tumor-Vakzine. Die durch Entnahme aus Körperflüssigkeiten oder Ge webe gewonnene Zellsuspension 1 wird in einer Zellkultur 2 angezüchtet und dadurch vervielfacht. Anschließend werden die Zellen dieser Zellkultur in einem Reaktionsgefäß 4 mit einem Photosensibilisator 3 versetzt und daran anschließend in einem weiteren Reakti onsgefäß 6 einer erfindungsgemäßen Laser bestrahlung 5 zur Induzierung einer photody namischen Reaktion ausgesetzt. Anschlie ßend befindet sich die so vorbehandelte Zell suspension 7 in Apoptose. Zur Qualitätsiche rung wird in einem weiteren Reaktionsgefäß 8 der NADH-Nachweis wie in Abb. 1 er läutert durchgeführt. Anschließend werden durch einen Zellsorter nicht in Apoptose be findliche Zellen 9 aussortiert und durch eine sterile Rückführung 10 in den Behandlungsre aktor 4 zurückgeführt. Die nach dem Test im Reaktionsgefäß 8 in Apoptose befindlichen Zellen werden dann in einem Auffangbehälter 11 als Tumor-Vakzine gewonnen. Fig. 2 again illustrates the process according to the invention for the biotechnological production of a tumor vaccine. The cell suspension 1 obtained by removal from body fluids or tissue is grown in a cell culture 2 and thereby multiplied. The cells of this cell culture are then mixed with a photosensitizer 3 in a reaction vessel 4 and then exposed to a laser radiation 5 according to the invention in a further reaction vessel 6 for inducing a photodynamic reaction. The cell suspension 7 thus pretreated is then in apoptosis. For quality assurance tion in another reaction vessel 8 of the NADH-detection as shown in Fig. 1 will he explained performed. Subsequently, cells 9 that are not sensitive to apoptosis are sorted out by a cell sorter and returned to the treatment reactor 4 by a sterile return 10 . The cells in apoptosis in the reaction vessel 8 after the test are then obtained in a collecting container 11 as a tumor vaccine.
Claims (11)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19960705A DE19960705A1 (en) | 1999-12-16 | 1999-12-16 | Method and device for producing an autologous immunization vaccine against cancer (tumor vaccine) |
| PCT/DE2000/004608 WO2001043772A2 (en) | 1999-12-16 | 2000-12-18 | Method and device for producing an autologous immunization vaccine against cancerous diseases (tumour vaccine) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19960705A DE19960705A1 (en) | 1999-12-16 | 1999-12-16 | Method and device for producing an autologous immunization vaccine against cancer (tumor vaccine) |
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| DE19960705A1 true DE19960705A1 (en) | 2001-06-21 |
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| DE19960705A Withdrawn DE19960705A1 (en) | 1999-12-16 | 1999-12-16 | Method and device for producing an autologous immunization vaccine against cancer (tumor vaccine) |
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| WO (1) | WO2001043772A2 (en) |
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| JP4394334B2 (en) * | 2002-06-25 | 2010-01-06 | 浜松ホトニクス株式会社 | Photophysical chemical diagnosis and treatment for vascular disease |
| JP2006306743A (en) * | 2005-04-26 | 2006-11-09 | Hamamatsu Photonics Kk | Body fluid treating method |
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| HU220251B (en) * | 1992-09-21 | 2001-11-28 | Quadra Logic Technologies Inc. | In vivo transcutaneous activation of photosensitizers in blood |
| RU2118177C1 (en) * | 1993-08-02 | 1998-08-27 | Алексей Борисович Башкиров | Method of inducing immune response of body |
| US20020098469A1 (en) * | 1996-03-22 | 2002-07-25 | Morgan ,Lewis, Bockius Llp | Extracorporeal methods for enhancing antigen presentation and immune responsiveness |
| EP0896506A4 (en) * | 1996-03-22 | 2003-06-18 | Univ Yale | METHOD FOR INDUCING THE POSSIBILITY OF AN IMMUNE RESPONSE |
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1999
- 1999-12-16 DE DE19960705A patent/DE19960705A1/en not_active Withdrawn
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| Publication number | Publication date |
|---|---|
| WO2001043772A3 (en) | 2002-03-07 |
| WO2001043772A2 (en) | 2001-06-21 |
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