WO2012119646A1 - Method for reducing the risk of metastasis formation in cancerous diseases, and system for removing tumour cells from the blood circulation - Google Patents

Abstract

According to the invention, a method and a system are proposed with which the risk of metastasis formation in cancerous diseases can be reduced. In the method for reducing the risk of metastasis formation in cancerous diseases, tumour cells circulating in the blood of a human or animal patient are captured from the blood stream and made harmless, in particular removed and/or damaged and/or killed. The system according to the invention in which tumour cells circulating in the blood of a human or animal patient (P) are removed from the blood circulation involves: a means for forming a tumour cell retention area provided with an inlet for blood flowing in from the circulation of the patient (P) and with an outlet for blood flowing out and conveyed onwards in the circulation of the patient, said retention area being in a hollow space through which the patient's blood flows and which is integrated in the circulation of the patient (P), and a means for capturing circulating tumour cells and holding them back in the retention area.

Description

A method for reducing the risk of metastasis in cancers and system for removing tumor cells from the bloodstream

Technical area

The present invention relates to a method for reducing the risk of metastasis in cancers and a system for removing tumor cells, especially malignant tumor cells, from the bloodstream.

When the term "tumor" is used below for the sake of simplicity and comprehensibility, it also means all other cancers of all tissues, even if these do not form as a circumscribed solid tumor.

State of the art

It is known that in tumors primary tumors secrete cancer cells and the thus separated cancer cells get into the bloodstream and circulate about it in the diseased body. These cancer cells, which are typically present in the blood as foreign cells, e.g. as liver cells, when they originate from a primary tumor in the liver, as intestinal cells, when they originate from a primary tumor in the intestine, or as skin cells from a primary tumor of the skin, etc., are thus blood-foreign cells, ie cells that are usually not in the blood occurrence. In the blood typically occurring cells are erythrocytes, leukocytes and platelets.

The circulating tumor cells distributed in this way via the bloodstream in the body can now in turn settle in other tissue and lead there to the formation of secondary tumors, so-called metastases. This metastasis is a major cancer problem. In the vast majority of fatal cancer cases, the primary tumor is not causally responsible for the death of the patient, but these are the metastases.

The current treatment methods focus in particular on destroying the primary tumor in order to suppress the spread of circulating tumor cells and thus to reduce the risk of metastasis. Not infrequently, the primary tumor is thereby surgically sought to remove in a surgical procedure, with such an intervention always the risk of injury to the tumor tissue and possibly present in the tumor tissue and in the surrounding blood vessels with a corresponding release of tumor cells in the bloodstream and an associated increase in the risk of metastasis. The same risk can exist in any other procedure and every other measure of tumor development.

Studies in human cancer patients provide an estimate that in advanced cancer, the circulating in the blood tumor cells are still present in extremely low concentrations, the estimates are here about a circulating tumor cell among 10 ⁹ blood cells. Assuming an adult human of approximately 2.5 x 10 ¹³ blood cells, this results in an amount of approximately 2.5 x 10 ⁴ tumor cells circulating in a patient with advanced cancer. The probability of the formation of a metastasis depends considerably on the number of these circulating in the blood tumor cells.

Presentation of the invention

This is where the invention, which has set itself the task of specifying a method and a system with which the risk of metastasis in cancers can be reduced.

This object is achieved in terms of the method by such a method having the features specified in claim 1, advantageous developments of this method are further specified in the following claims 2 to 12. A solving the problem of the invention system is described in its general form in claim 13, advantageous developments of this system can be found in the dependent claims 14 to 25.

The essential idea of the invention is to reduce the risk of metastasis formation by capturing and rendering innocuous, in particular removed and / or killed and / or damaged circulating, blood-foreign tumor cells. In other words, this procedure requires, in other words, in particular detection and sorting out of blood-circulating tumor cells circulating in the bloodstream of the living patient. This patient may in particular be a human, but also basically an animal, in particular a mammal. The application of the invention to an animal, in particular mammal, is particularly advantageous for carrying out animal experiments accompanying the development of human medical procedures.

The core idea is to capture as many blood-borne tumor cells circulating in the blood as possible and render them harmless, since every single such tumor cell poses a certain risk of metastasis formation, which increases correspondingly as the number of tumor cells in the blood increases. Thus, in order to render harmless as many blood-circulating tumor cells circulating in the blood or the bloodstream of the blood circulating in the patient as possible, either a particularly high efficiency of the capture process must be achieved or it is necessary to achieve the largest possible cross-section. ie To treat as many of the blood circulating in the bloodstream as the method that there as many circulating tumor cells contained in the volume as possible captured and in particular removed and / or killed and / or damaged. Alternatively, an increase in the efficiency of the process can be achieved by a long-lasting treatment period. In any case, the other components of the blood should be damaged as little as possible by the treatment or otherwise be affected.

It is essential for the implementation of the method that the treatment of the blood of the patient, at least as far as it is returned to his bloodstream or continued in this bloodstream, takes place under sterile conditions.

The method can be used quite differently, even at different times. Thus, it is conceivable, for example, to use the method accompanying an operation for the removal of a primary tumor in order, if possible, to immediately capture and, in particular, to remove cells of the primary tumor which are released during the operation and enter the bloodstream, and so often after operations Increased risk of metastases can be selectively reduced or kept low. Likewise, however, the method may also be used generally therapeutically in a detected cancer, e.g. be performed by a doctor or a specialist ambulatory or inpatient once or repeatedly or be continuously performed on the patient by selecting appropriate treatment systems over a longer period of time. If circulating blood-borne tumor cells are reliably captured and removed and / or killed and / or damaged by the method according to the invention in the blood, the risk of metastasis formation remains significantly and permanently reduced, the statistical life expectancy of a patient thus liberated from the circulating tumor cells can even be reduced as clearly increased before existing primary tumor.

However, an existing primary tumor increases the likelihood that it will secrete tumor cells again and return to the bloodstream. Likewise, metastatic tumors (metastases) can also secrete tumor cells and enter the bloodstream. The method can thus also be used to reduce further metastases in already detectable metastases or if the primary tumor is unknown (so-called CUP syndrome, cancer of unknown primary).

The method can also be used in non-imaging (e.g., CT MRI, endoscopy, etc.) detectable tumors, but already present indirect evidence of the presence of a tumor, e.g. about increased tumor markers and already existing detection of circulating tumor cells. The method can also be used if the detection of circulating tumor cells is the only detection of tumor disease so far.

The duration of treatment may be limited or the procedure may be repeated indefinitely or continuously until a complete cure can be ensured or until termination of treatment is meaningful for other reasons.

A possible early use of the method or system, for example already at the time of diagnosis, increases the chance of a complete healing because it reduces the time window for the formation of metastases, for example, until a healing operation is attempted by removing a single primary tumor.

In principle, the method can be carried out extracorporeally with an extracorporeal capture arrangement which is connected to the blood circulation of the patient and through which at least part of the blood stream flows and in which the tumor cells are captured. Alternatively, it is also possible to provide an intracorporeal capture arrangement. Such may e.g. are introduced into a blood vessel of the bloodstream of the patient and held there or fixed so that it is traversed by the blood stream or flows around, wherein the tumor cells are trapped in the intracorporeal capture arrangement. Another and also within the scope of the invention possible and intended for implementation arrangement of the capture in intracorporeal way may consist in that a corresponding arrangement in the body of the patient but is implanted outside a blood vessel, the arrangement via an inlet and a drain with a or two blood vessels of the patient is connected to lead blood through the capture device. Optionally, such a capture assembly may then have a pump to assist in the circulation of blood or the transport of blood therethrough. For this purpose, the capture arrangement would then also have to be provided with a self-sufficient energy supply, as is already known, for example, from other implants such as insulin pumps, cardiac pacemakers, defibrillators or completely implantable artificial hearts. Another intracorporeal realization of the method according to the invention is to add trapping agents to the patient's blood that can circulate freely in the bloodstream of the patient, in his blood vessels, and trap tumor cells during the circulation. These can be achieved by means of a restraint arrangement, e.g. is activated, held back and collected only for capturing the capture agents. However, it is also possible for the freely circulating capture agents to be bioabsorbable and, if appropriate, to be biologically degraded or absorbed together with one or more captured tumor cells in the body of the patient.

Since tumor cells are accumulated over time in the intracorporeal capture assembly, and further because a capture device provided in the capture assembly or means for trapping and retaining the tumor cells may be lost over time, it may be necessary to remove the intracorporeal To remove input assembly from the body of the patient, in particular the blood vessel, and possibly replace it with a new such arrangement, if the treatment is to be continued. Equally, of course, a revision access to an intracorporeally arranged capture arrangement, which is not located within a blood vessel of the patient, be made in order there to make a corresponding exchange or possibly a complete removal. Similarly, it may be necessary to empty or refill an intracorporeally arranged capture arrangement from the outside or otherwise to renew the operating principle.

One way to capture tumor cells is to use antibodies that dock to the tumor cells and are captured in the capture assembly. The use of such antibodies in the blood is therefore effective and suitable for carrying out the method, since the tumor cells are blood-foreign cells. They come, as already mentioned, for example, from the intestine, the liver, the lung or the like. And have the corresponding cell properties of the respective tissue cells, so can be selectively or specifically coupled and thus held with the appropriate antibodies.

For carrying out the method with antibodies for trapping and retaining the tumor cells, it is advisable, indeed necessary, first of all to determine the type of tumor cells circulating in the blood, in order to select the appropriate and docking to the cells antibodies and used in the capture arrangement , These antibodies should not dock or at least only to a much lesser extent to the blood cells.

However, the determination of the tumor cells of a patient can be made not only from the tumor cells circulating in the blood, but also from other forms of the tumor, e.g. the primary tumor or metastases from which the tumor, tumor parts or cells are obtained by surgery, biopsy or other means.

The antibodies can be used in a variant of the method as described above, e.g. applied to and fixed on a surface where the blood flows past the capture assembly. If a tumor cell circulating with the blood enters the region of the antibodies, one or more of the antibodies can attach to the cell and thus bind it to the surface.

Examples of suitable antibodies are the anti-EpCAM antibody for tumor cells of epithelial origin, e.g. in breast, prostate, colon or lung carcinoma. For melanoma-derived tumor cells, bromarkers MART-1, GalNAc-T, PAX-3, MAGE-A3 and Mitf can be used.

For example, the following antigens are present on colorectal carcinomas: CD10, CD15s, CD24, CD29, CD44, CD44-v6, CD47, CD49f, CD55, CD59, CD66e, CD87, CD95, CD104, CD155, CD175s, CD227, CD244, CD26, CD261 , CD262, CD326, CD340, β-catenin, annexin II, CA125, claudin-4, FAP, galectin-3, galectin-4, MMP14, PIGR, CA19-9, TSP-1. Antibodies to these antigens can be used in an antibody-based practice of the invention.

These examples are intended to demonstrate that the number of antibodies currently available is unlimited and can be readily found and developed antibodies to suitable antigens that can be used in the invention.

The invention generally involves a procedure in which the best-effective antibodies are developed for each type of tissue, for each type of tumor and for each individual tumor of each individual patient, which then may also be adapted during the course of the disease.

Another way to trap tumor cells in the capture array is to use antibodies that are tightly bound to magnetic micro or nanobodies, e.g. with so-called magnetic beads, which are iron oxide particles which are coated or mixed with polymers and have sizes in the range of 100 to 2,500 nm as nanoparticles or 0.5 to 100 microns as so-called micro beads. Antibodies thus provided with magnetic material can now be used e.g. be kept in a magnetic field in a certain range, which defines the capture arrangement together with the antibodies. This is done in the usual way by applying a magnetic field, which acts repulsive or attractive to the magnetic particles, thus keeping the particles in one area. If the antibody held by the magnetic field in the bloodstream in a certain area now comes into contact with a tumor cell, it docks and is also retained by the force of the magnetic field in the region of the capture arrangement. Such a capture assembly formed by magnetic and magnetized antibodies by appropriate means can be used both intracorporeally, e.g. in a section of a patient's blood vessel by applying appropriate magnetic fields and introducing a dose of the magnetized antibodies in this section, as well as extracorporeally in a magnetic field equipped and magnetized antibody section of an external conduction system connected to the bloodstream the patient is connected and flows through the at least part of the circulating blood of the patient.

Alternatively, using antibodies associated with magnetic nanoparticles, it is also possible to freely introduce these particle constructs into the patient's bloodstream, e.g. via an infusion, and to circulate in the blood vessel system for one treatment period. To terminate the treatment, then e.g. a magnetic field is generated to capture the freely circulating particle constructs in a vessel section. There they can then, e.g. by means of a magnetic probe, which is attracted from outside into the blood vessel in which the particles are trapped and removed with the probe from the body. In principle, however, it would also be possible to absorb such nanoparticle-containing antibodies in the tissue if the tumor cells captured by the antibodies have previously been killed or at least damaged so far that they can no longer divide and thus form metastases; depending on the nature and strength of the binding of the tumor cells to the particles provided with the antibodies and the nature of the particle and its properties, this can even be done by this binding of the tumor cell to the antibody with particles. When choosing the dimensions of such combinations of nanoparticles and antibodies, care must be taken to ensure that they do not become too small, so that they can not penetrate into the tissue via the capillary and possibly cause damage there, at least for the purpose of capturing circulating tumor cells are no longer available, but on the other hand, they also do not become too large and possibly clog vessels (eg capillary) and thus cut off organs or other tissue areas of the blood supply behind partially or completely.

It is also possible to direct the antibodies associated with the magnetic particles into a specific blood vessel by one or more magnetic fields and to separate and capture the circulating tumor cells via this or from this blood vessel.

The feasibility of controlling magnetic particles in living things in magnetic fields has recently been demonstrated (Martel S .: Microrobotic navigable entities for Magnetic Resonance Targeting, Conf Proc IEEE Eng Med Biol Soc. 2010, 2010: 1942). 5, Samsel PA, Kisiswa L, Erichsen JT, Cross SD, Morgan JE: A novel method for the induction of experimental glaucoma using magnetic microspheres., Invest Ophthalmol Vis Sci., 2010, Oct 6. [Epub ahead of print]). The required strength of the magnetic fields must be made dependent on the design of the capture arrangement. Sizes in a range of up to 0.5 Tesla were in o.a. Sufficient investigations.

The analysis of the tumor cells for the best possible treatment - even in a non-based on the use of antibodies treatment - can be done either via the circulating tumor cells in the blood or even from material of tumors or metastases, the material during surgery, a sample collection ( Biopsy) or otherwise.

Since the properties of tumors and cancer cells can change in the course of the disease, a re-analysis of the circulating tumor cells or otherwise obtained tumor cells (see above) may be necessary in the course of the disease. The treatment can then be adapted to the altered properties of the tumor cells. If several types of tumor cells or tumors are active or likely to be of importance, the treatment may be directed against several different types of circulating tumor cells, including by several methods.

However, a filter, e.g. a simple mechanical filter can be used, which is dimensioned so that it restrains tumor cells, but allows the other, compared to the tumor cells smaller components of the blood to pass. The mechanical filter may for example consist of one or more membranes, consist of polymers or have a special molecular structure and arrangement. The filter may also be designed, along with an application of antibodies, to retain antibody-coated particles that are larger than blood cells and may be magnetic or non-magnetic but allow blood cells to pass through. This will trap tumor cells bound by antibodies on the particles in the filter.

Another alternative to designing the capture assembly is to use a selectively adhesive surface for the tumor cells to be captured. A selectively adhesive surface should be understood here as meaning that, irrespective of the principle of action, exerts a high binding force on the tumor cells, but does not bind other constituents of the blood or only with significantly less force per se. In turn, such a surface must be selected according to the respective species of tumor cells to be captured, wherein the choice of the surface material may play a role as well as its specific geometry, structure or coating. The aim is to form at least significantly higher adhesion to the tumor cells than to the regular constituents of the blood, which just should not adhere to the surface and should be retained, possibly at most to a much lesser extent.

Other ways to capture the circulating tumor cells are the use of flow cytometry. In this case, components of the blood, including the cells, are introduced in a fluid flow, wherein the cells pass through an observation point individually. At this observation point, the respective cell is illuminated with a special light source (laser) and the response signal is examined electronically. When the cells light up
Refraction and reflection effects, from which conclusions can be drawn about the size and granularity of the cell. Thus, conventional blood cells and circulating in the blood tumor cells can be distinguished. In this case, such smallest drops containing a tumor cell, for example, be charged by applying an electrical pulse at the time when this, the tumor cell containing drops detached, and the drops can be deflected by applying an electric field and discarded therefrom. The drops not loaded with a tumor cell then fall back into the bloodstream of the patient. This method is already known from analytical techniques and can be used at very high throughput speeds, making it suitable for use in the circulatory system of a living patient, extracorporeal.

Flow cytometry can also be used in combination with fluorescence labeling. In this case, tumor-specific antibodies coupled with fluorescent dye are added to the blood which flows in from the patient and thus contains circulating tumor cells. By binding the antibodies, the tumor cells are labeled with the fluorescent dye and can be detected and sorted out with the aid of laser light.

The trapping of the tumor cells can be accomplished by utilizing one or more of their properties which distinguish them from blood cells. These are, for example, physical properties such as size, weight, density, light transmittance, etc., physicochemical properties, e.g. Adhesion to certain surfaces or surface-applied materials and the like, biological properties such as antigens and the like, and other properties.

For example, in the selection of antibodies or surfaces of selectively adhesive property to the circulating tumor cells to make a quick selection of the appropriate medium or the appropriate antibodies, first a test agent with a plurality of differently formed retention means, e.g. different antibodies and / or different potentially selectively adhesive surfaces in the capture assembly or in a separate test capture unit to take, after a test run for a predetermined time, these test agents and to analyze which of the retaining means located thereon captures the highest amount of tumor cells has to then arrange such a retaining means in the capture arrangement and perform the actual treatment.

The cells for this assay can be obtained either from tumor cells circulating in the blood or from tumor tissue of the patient. The tumor cells can be decomposed by enzyme digestion in individual cells, washed and separated from dead cells. The thus prepared tumor cells may be e.g. applied to various surfaces in a first test agent and subsequently coated with a liquid, e.g. a buffer solution, to be rinsed.

In parallel, blood may also be applied to its surfaces in a second test agent of the same kind as the first test agent, and may then be applied to these surfaces with a liquid, e.g. Buffer solution to be rinsed. The blood cells retained in the second test agent in the first test agent retained in the first test agent are counted and evaluated separately. The surface on which many tumor cells but few blood cells are retained is qualified as suitable for the process or system and this surface or one of the surfaces is selected. The same or an analogous selection method can be used for the selection of the appropriate antibodies. For the selection of the antibodies is currently particularly a microchip-based method to mention, with up to hundreds of antibodies on a small support, similar to a slide anchored. Then tumor cells and blood cells are applied and the carrier is rinsed after a contact time. The subsequent evaluation determines which antibodies are suitable for specific docking of the tumor cells (and as little as possible in the blood cells). In a test, this method tests a very large number of antibodies for their effectiveness against the patient's specific tumor cells. The best-performing antibodies (or surfaces) are then used for the treatment.

In order to reliably rule out that the initially captured tumor cells can no longer pose a risk before they can be finally removed from the bloodstream, they can be killed or damaged after the capture from the bloodstream, e.g. by local irradiation of an extracorporeal capture device or by specific pharmaceutical agents, e.g. coupled with the antibodies and are effective when the antibodies dock on the tumor cell or drugs in a selectively adhesive surface, which develop their effects only after the attachment of the tumor cell or act only on attached cells. A killing or damaging of the tumor cells can also take place only after a possible removal from the bloodstream of the patient, if so desired.

When using the method according to the invention, an important goal is to send as possible no harmful tumor cells back into the circulation of the patient. The more complete and firm the capture and safe rendering harmless, especially removal that is tumor cells from the bloodstream in the capture array, the less necessary it can be to kill or damage the tumor cells in the blood.

The captured tumor cells may also be used for examination purposes after removal by the capture assembly. Thus, for example, the extent or number of tumor cells circulating in the blood may be more accurately detected than in currently practiced methods which assay for only a small amount, most often less than 10 ml, of blood for the presence of circulating tumor cells. Also, the captured tumor cells can be removed from the capture assembly and subsequently examined and diagnosed by known methods (e.g., staining and microscopy).

It is conceivable to preferentially capture the tumor cells from the patient's arterial bloodstream. This could prevent, e.g. From a capture arrangement unintentionally leaked or lost tumor cells can get directly into the bronchi or lung capillaries and form metastases there.

As arteries of access to the patient's vasculature, both arteries and veins may be selected for inflow and outflow to and from the capture arrangement, but the inflow and outflow accessway may be the same or different in vascularity. In principle, all currently known vascular access methods, e.g. also those used, for example, for dialysis (shunts, Sheldon and Demers catheters, etc.), as well as possible future developed such methods.

For carrying out the method, it is presently preferred that the patient be administered a blood clot blocking agent at least once before or during the removal of the tumor cells. Since in the method according to the invention exogenous materials are brought into contact with the blood, there is, as in all such cases, the risk of blood clotting and clot formation. This is advantageously dealt with in an appropriate manner by giving the patient e.g. a blood thinning agent is administered. Such agents for preventing clotting are well known, e.g. Heparins, platelet aggregation inhibitors, coumarins (e.g., Marcumar®) and other newer substances. Of course, it is also possible to form the surfaces of foreign substances to be introduced into the blood stream in such a way that blood coagulation is avoided, in any case stimulated to a much lesser extent. In this case, in particular biotechnologically produced coatings come into consideration.

Another aspect of the invention consists, as already mentioned, in a system for trapping and rendering harmless circulating tumor cells circulating in the blood of a human or animal patient out of the bloodstream. According to the invention, such a system comprises: a means for forming a blood cell retention region provided with an inlet for blood flowing out of the patient's circulation and an outlet for blood flowing away and continuing in the circulation of the patient in a blood flow through the patient's blood void integrated into the patient's circulation and means for capturing circulating tumor cells and retaining them in the retention area.

The system thus specifies one which can be integrated into or connected to the bloodstream of a patient, which is possible intracorporeally or extracorporeally. It has means for forming a retention area in which targeted tumor cells are trapped and retained there by the means also associated with the system for capturing circulating tumor cells and retaining them.

The means for forming the retention area do not have to be physical walls or the like. Here, other means come into consideration, in particular means for generating a magnetic field, which magnetic field can define the retention area, for example by means for capturing with corresponding magnetic sections of circulating tumor cells and retaining them in the retention area. Such materials provided with magnetic properties and associated with corresponding microparticles or nanoparticles can be, for example, antibodies which dock onto tumor cells to be captured and retain them.

The means for separating or catching the tumor cells can use all the physical, biological and chemical properties of the tumor cells, which distinguish them from the normal blood cells, or are different in the tumor cells differently pronounced.

A possible component of the system according to the invention may be a blood clot inhibiting agent. This may be in the form of a medicament which may be conveniently administered to the patient, but may also be administered as an addition to the bloodstream, e.g. be provided in the retention area or alternatively or additionally also in the form of appropriate coatings or equipment of the surfaces of introduced into the bloodstream and in contact with the blood foreign bodies.

The antibodies already mentioned in connection with the possibility of forming a retention region with magnetic fields may also be used in other ways than in conjunction with magnetic micro- or nanoparticles as part of the system, more specifically as means for trapping circulating tumor cells and retaining them in the retention region become. Thus, for example, it is conceivable to provide mechanical structures, such as surfaces against which the blood flows or past which it flows, with antibodies that are firmly attached to it, which attach to and hold the circulating tumor cells flowing past them. It is also conceivable, for example, to provide a grid which is arranged transversely to the blood stream and on the surface of which the antibodies are fixed so as to increase the cross-section. It is of course important to ensure that the blood stream can not be braked overly, u.a. to prevent the risk of blood clots and thus the risk of thrombosis or embolism.

Alternatively or in addition to the antibodies, at least one surface which is selectively adhesive to the tumor cells to be captured can be used. Surfaces of selected polymers come into consideration here, wherein the choice of the surface is to be adapted to the species of the tumor cells to be captured and captured. The blood cells should adhere to this surface as little as possible.

The system can be used as a means of trapping tumor cells, e.g. but also have filter openings which are smaller in cross-section than the tumor cells to be captured, but larger than the other components of the blood. The circulating, blood-foreign tumor cells are usually larger in size than the regular blood components, so that they can be isolated by filtration. Suitable filters are, for example, membrane filters, but also ultrafine tube filters, these being particularly well suited for an extracorporeal arrangement in a filter housing to be connected via the inlet and outlet and their respective cannulas to the blood circulation, in principle also an intracorporeal arrangement, however not in a blood vessel of the patient, but in an intracorporeal constructed branch is conceivable, in which case an implantation, eg under the skin or under the muscle, e.g. in the area of the pectoral muscle or in the abdomen, as is customary in cardiac pacemakers, defibrillators or fully implantable artificial hearts, is conceivable and practicable. In this case, a replacement or renewal of the capture arrangement from the outside by an intervention or without intervention by removing the used active principle and adding new principle of action is possible.

In general, the system according to the invention may also comprise, for other means for trapping and retaining the tumor cells for an extracorporeal assembly, a housing having an inflow opening and an outflow opening, a feed line connected to the inflow opening at a first end, a first cannula at a second end, and one at a first end connected to the discharge port, at a second end having a second cannula discharge. In use of the system, the two cannulas are each connected to one, possibly one and the same, blood vessel of the patient in order, advantageously with predefinable volumetric flow, to apply a specific quantity of blood via the housing and the means for capturing circulating tumor cells and retention to guide the same. This is done with advantage by resorting to a blood pump.

As an access route to the vascular system of the patient, any available access system can be selected, in addition to cannulas also tubes (catheters), vessel replicas (such as vascular prostheses) and endogenous vessels (veins or arteries as used in bypass surgery).

As means for trapping circulating tumor cells and retaining them in the retention area, however, it is also possible to use a means which can be brought into a blood vessel of the patient and at least temporarily can be used locally in the retention area and held firmly there. This can e.g. one or more bodies or micro-bodies which are coated with antibodies or provided with a surface which is selectively adhesive to the tumor cells and which can be anchored in the vessel for example with an expandable grid, similar to a stent; can. It is additionally advantageous for such a system if it additionally has a means for removing the means for capturing circulating tumor cells and retaining them from the blood vessel and from the patient's body. Since the therapy with an agent which is anchored directly in the blood vessel, is usually limited in time, such an agent will be exhausted in any case after a certain time in its effectiveness, it is important to remove this from the bloodstream. Otherwise, the retention of such a foreign body would constitute a continuing and increased risk to the patient, particularly the risk of blood clot formation and consequent embolism or thrombosis or an infarct caused by a blood clot (pulmonary embolism, arterial vascular occlusion).

The geometry, structure and coating of the surface, including the means to be introduced into the bloodstream, can be adapted individually to the circulating tumor cells to be treated (tissue, special tumor, individual tumor of a patient over time or simultaneously different properties). The retention area for the introduction of the capture arrangement can be freely selected in the vascular system and vary from measure to measure, but also remain the same.

The system may also include means for killing and / or damaging the tumor cells.

Finally, advantageously, the component of a system according to the invention can also be a test agent with differently designed means for trapping the tumor cells, which test agent can be introduced into the retention area as a whole. The advantage of such a test agent has already been set out above. It consists in that, before an actual treatment with such a test agent, the most effective means of trapping the tumor cells can be selected and the system can be equipped with an appropriate agent.

Brief description of the drawings

Further advantages and features of the invention will become apparent from the following description of embodiments with reference to the accompanying figures. Showing:

Figure 1 is a schematic representation of an apparatus for performing the method according to the invention extracorporeal.

Figure 2 is a schematic representation of a capture device with fixed to a support structure antibodies.

3 is a schematic representation of a capture device with antibodies bound to particles;

4 shows a schematic representation of a capture arrangement based on the principle of flow cytometry.

Fig. 5 shows the representation of a fiber filter coated with antibodies attached thereto or with specially selected surfaces, e.g. in the form of coatings, can be provided;

Fig. 6 is a schematic diagram of a device according to the invention with retained by a magnetic field, provided with magnetic microparticles antibodies in a capture arrangement;

Fig. 7 shows a modification of a capture arrangement with the principle of holding magnetic microparticle-coupled antibodies circulating in a retention area in the retention area in an extracorporeal device using a magnetic field;

8 shows in a schematic representation the mode of operation of the capture of tumor cells with antibodies coupled with magnetic microparticles, which are held intracorporally in a blood vessel by applying a magnetic field in a retention region and can be removed from this region with a magnetic probe;

Fig. 9 schematically shows an arrangement for treating the complete blood flow in a blood vessel without disconnecting lying behind a discharge point areas of the blood supply through the blood vessel and

10 shows schematically different mechanisms for retaining tumor cells on surfaces.

Way (s) for carrying out the invention

In the figures, different solution options are schematically and partially indicated as sketchy detail aspects with which the invention can be implemented. These are described below with reference to the figures, this description is by no means a conclusive list of all possible implementation variants, but rather for the skilled person readily other alternatives, partly determined by combinations of the possibilities shown here with each other.

FIG. 1 shows in a schematic structure a basic device for carrying out the method, this device containing an extracorporeal arrangement.

Shown in FIG. 1 on the right is schematically a patient P, who is symbolized here as a human patient. It should be noted here that the method can just as well be used in the treatment of animal patients, in particular mammals, just as the devices or systems described below can be used there.

At 1, access to a blood vessel is provided to the patient by means of a corresponding catheter. Blood is withdrawn there from the blood vessel and conveyed via a line 2 in the direction of a trapping arrangement 3 located in a housing. This is done by means of a blood pump 4. In the housing 3 encapsulated in the capture device 3 are trapped and retained in the blood to be shown in more detail later in the blood freely circulating tumor cells. The blood thus freed from the tumor cell leaves the capture arrangement 3 and flows back via a line 5 in the direction of the patient and returns via another access 6 back into its blood vessel system.

Via a supply line 7, an anticoagulant, ie a means for preventing blood clot formation, can be added via a metering arrangement, here a metering syringe 8, e.g. Heparin. This serves to prevent the formation of blood clots.

By means of pressure sensors 9 arranged variously in the system, the pressures in the extracorporeal system are controlled in accordance with the arterial and / or venous blood pressure of the patient P, and the blood pump 4 is addressed accordingly. In order to prevent air from entering the patient's bloodstream through the system, particularly when disconnecting the system from the patient's bloodstream, an air detector 10 is provided and a clamp 11 located downstream therefrom which is detected by the air detector 10 Air closes the line 5 and thus prevents this air is conveyed into the blood circulation of the patient P.

With such an extracorporeal arrangement, the method according to the invention for removing circulating tumor cells from the blood of the patient P can now be carried out. For this purpose, the patient P is connected to the system via the corresponding accesses 1, 6, so that part of the blood stream can be conveyed via the capture arrangement 3 and freed there from the circulating tumor cells in the blood circulation. This treatment is continued for a predeterminable time period, for example a period of one to several hours, e.g. Three hours, carried out to statistically at least a vast majority of circulating in the body of the patient P blood, preferably approximately all blood, passed over the capture assembly 3 and there have captured tumor cells from the blood when the treatment is completed. The treatment may also be prolonged, e.g. overnight or continuously e.g. in portable or intracorporeal systems.

It is also possible to connect an arrangement shown in FIG. 1 and such a system under an operation for removing a primary tumor to the patient in order to capture any tumor cells of the primary tumor which have been released during the operation directly in the capture arrangement 3. In such a case, it is advisable not to make accesses 1 and 6, as shown schematically in the example, on the arm of the patient, but to set the dissipative access 1 in a direction downstream in the circulation direction vessel, so as to best possible prevent tumor cells released during the operation from being able to spread widely before they can enter and be captured in the arrangement according to the invention.

In order to subject the blood outflow from the entire surgical or intervention area of the treatment according to the invention, it is advisable to administer the entire venous blood outflow from the tumor area and its surroundings to the treatment. This requires a diversion of the blood flow from a vein completely into a treatment unit according to the invention. With no further measures, blood will no longer flow in the branch of this vein leading to the heart, and there will almost inevitably be clots, a thrombosis. In order to be able to completely divert the bloodstream from a vein while at the same time flowing through the part of the vein leading to the heart, an arrangement as shown in FIG. 9 is considered. In this figure, a vein bounded by vein walls 41 is shown schematically. Through one access, two catheters or tubes 42 and 43 are placed in the vein, with the catheter 42 aligned to receive incoming tumor cell-displaced blood 44, the catheter 43 reintroduces purified blood 45 into the vein, from where it exits the bloodstream continues to flow through the normal path. Instead of the purified blood, the catheter 43 can also be supplied with rinsing fluid for keeping the vein open. By expandable balloons 46, 47, the catheters 42 and 43 can be sealed in the vein. The catheters 42 and 43 can now be connected to a system for removing tumor cells from the blood as already described above or to be described below.

Depending on the throughput of the capture assembly 3, the volume flow flowing through the system shown in Fig. 1, be adjusted. In principle, a high volume flow is advantageous for the efficiency of the therapy, since the blood of the patient can be freed of free-circulating tumor cells with high efficiency very quickly. However, at the same time, consideration must also be given to the stability of the patient's circulation P, which allows a discharge of the blood stream through the extracorporeal arrangement only to a limited volume flow, depending on the condition of the patient. In addition, as already mentioned, the flow rate through the trap assembly 3 is limited depending on the working principle thereof. If the volume flow rate is too high, depending on the type of construction, the capture efficiency can be reduced or the capture arrangement can fail or no longer capture with the desired effectiveness the free tumor cells present in the blood.

A first possibility, a capture arrangement, as e.g. is shown in Fig. 1, is shown schematically in Fig. 2. Here, it is shown how antibodies 13, which can dock on the freely circulating tumor cells 14 and can form a tumor cell 14-retaining compound, are fixedly arranged on two mutually opposite surfaces 12. The antibodies 13 are immobilized and fixed in a manner well known in the art to a corresponding material. If the blood now flows with its further components to be left in the bloodstream, in particular red blood cells 16 and white blood cells 17 through the arrangement in the direction of the arrow 18, the tumor cells 14 are captured by appropriate coupling of the antigens 15 with the antibodies 13 and with held on the surfaces 12 antibodies 13 in the capture arrangement, whereas the blood with the other components, in particular the red blood cells 16 and the white blood cells 17, this arrangement can pass freely, the capture arrangement so cleanly leaves the tumor cells 14, eg A corresponding, equipped with antibodies 13 capture device, as shown in Fig. 2, but (as will be described later) can also be used intracorporeal implant as an application.

Fig. 3 shows a highly schematic representation of another arrangement possibility, in which in a portion of a blood vessel 40, so intracorporeal, e.g. arranged by a net-like or lattice-like arrangement in the volume, there anchored or trapped in the net-like or lattice-like arrangement particles 53 are provided, which are passed by the blood flowing in the direction of the arrow 18. These particles are in this example coated with antibodies 13, which ensure that provided with appropriate antigens tumor cells 14 dock to the antibodies 13 and are captured and retained there. Alternatively, however, other principles of action can be used here, with which the tumor cells are bound to the surfaces of the particles 53, e.g. by means of selective adhesion due to a suitable choice of the material and / or the structure of the surface of the particles 53. The particles 53 are larger in size than the constituents of the blood and are thus in the with opening widths which are smaller than the dimensions of the particles 53, however greater than the dimensions of the blood components, provided net or grid structure captured or remain there. The blood with its components can pass through the mesh or lattice structure. Only the tumor cells 14 trapped and held on the particles 53 also remain suspended.

A further principle with which the free-circulating tumor cells can be eliminated in a capture arrangement, as indicated in FIG. 1 by 3 and shown schematically, is illustrated in FIG. 4. This works on the principle of flow cytometry. The principle of flow cytometry is known from the analysis. In a nozzle 19, entrained by a circulating fluid, which is illustrated by arrows 20, typically a flowing liquid, blood is separated dropwise, with drops of the blood leaving the nozzle 19 in rapid succession. These drops are transilluminated with a laser beam 21, wherein the laser generates different refractive or reflection patterns due to the properties of the enclosed cells, which are electronically detected and evaluated. If a tumor cell is detected in one of the drops, it is sorted out as follows, and as shown schematically on the right side of the figure. At the moment in which a drop 22 at the outlet 23 separates and falls in the direction of a collecting container, if in this drop previously by the transillumination with the laser, a tumor cell has been detected, an electric pulse, indicated by the arrow 24 given with which the drop is provided with an electrical charge. Subsequently, the drop falls through a region with electrically charged plates 25 and 26, wherein the charged drops are deflected due to the effect of the electric field between the plates 25 and 26, here in the form of positively charged drops are deflected to the left in the direction of here electrically negative loaded plate 25 (away from the electrically positively charged plate 26 here), and thus take a different fall path as the uncharged, no tumor cells contained drops. The deflected and sorted drops are collected, the continuous droplets not containing tumor cells are continued, in Fig. 1 in the direction of the line 5 and back to the patient P. It should be noted here that Fig. 1 in connection with that shown in FIG. 4, since, of course, in the principle illustrated in FIG. 4, the blood has to pass through the nozzle 19 in a vertical direction from top to bottom, since the principle of sorting also applies to the effect of gravity. To increase the efficiency and the throughput, any number of systems according to FIG. 4 can be connected in parallel.

FIG. 5 shows a further example of a capture arrangement, here in the form of a filter insert 27, which consists of woven or, as shown here, knitted fiber bundles 28. Here, these fiber bundles consist of individual, conjugate fibers 29, which in this embodiment consist of polypropylene strands 30 embedded in a bed 31 consisting of a composition of polysterene and polypropylene, here in the ratio 9: 1. In particular, these fibers are useful for establishing antibodies thereon so as to form a capture arrangement based on the above-described mode of action of coupling the tumor cells to antibodies. However, all other possible surface activity properties are also possible here, which distinguish circulating tumor cells from blood cells as strongly as possible, thus leading to a selective adhesion of the tumor cells. The filter may for example consist of one or more membranes, consist of polymers or have a special molecular structure and arrangement.

Another way of trapping and retaining the freely circulating tumor cells in the capture assembly 3 is shown schematically in FIG. Here, in the capture assembly 3, blood flow with micro or nanoparticles 32 that are magnetic, e.g. so-called micro-beads, coupled antibodies added, wherein these antibodies 13 are retained by means of a magnet 33 generated in the region of the trapping 3 magnetic field in the capture assembly 3.

If the blood supplied to tumor cells 14 via line 2, as illustrated in the enlarged view, now passes the capture arrangement 3 in its composition as shown on the left in the enlarged illustration in the direction of flow illustrated by arrows 56, the blood which has flowed through them onto the magnetic particles 32 in the direction of the arrow 57, so opposite to the flow direction 56 of the magnetic force acting in the area held, otherwise free-moving antibody 13 to the tumor cells 14, more specifically to their antigens 15, so now now due to the magnetic force and interaction between the magnetic particles 32 and the magnetic field 33 formed by the magnetic field with the antibodies 13 and the tumor cells 14 are retained in the catcher. The trapping arrangement then continues to flow only the blood with its other and desired constituents, namely the red blood cells 16 and the white blood cells 17, as shown in the enlarged detail of the situation in the line 5 in the figure above.

A modification of this principle with differently constructed geometry is shown in FIG. There, the magnetic particles 33 provided with the magnetic particles 32 are passed through an opening 34 in the main flow tube 35 in a side stream and pumped back via a pump 36 and again introduced into the main flow tube 35 via a formed by the magnets 33 transverse to the direction of movement of the magnetic field , According to the principle described above, the antibodies 13 connected to the magnetic particles 32 also dock to the corresponding antigens 15 of the tumor cells 14 so that the tumor cells 14 are also torn into the secondary flow through the opening 34 due to the action of the magnetic field. Arrow 48 here symbolizes the force acting on the magnetic particles 32 connected to the magnetic particles 32 due to the magnetic field. These antibodies 13 connected to magnetic particles 32 are bound in the magnetic field and kept circulated by the pump 36. In principle, it is possible to hold with the magnetic particles 32 connected to antibodies 13 and the captured tumor cells 14 via the pump 36 in a circulation in the main flow tube 35 and continually divert in the circuit through the opening 34 back into the sidestream. Thus, tumor cells 14 would accumulate at this point. However, in order to prevent the risk of accidental and unintentional loss of a still living tumor cell 14 in the direction of the effluent blood, a means for killing or damaging the tumor cells can additionally be provided in sideways flow in a region 54, e.g. by short-range radioactive irradiation 55.

The final removal of the antibodies and the tumor cell-occupied antibodies from the bloodstream and / or the treatment unit can be done by altering the principle of action, here for example by enhancing the principle of action and especially in extracorporeal location by thereby taking place here magnetic fixation on the wall of the cavity. But also the addition of another principle of action, e.g. of a mechanical filter with gaps, which restrains the larger particles with antibodies but allows blood cells to pass, would be possible for the eventual removal of the tumor cells from the blood circulation or from the treatment unit. The mechanical filter may for example consist of one or more membranes, consist of polymers or have a special molecular structure and arrangement.

As already shown, the connections to the blood vessel system can be made by vascular accesses that are rigid (cannulae, etc.) that are flexible (tubing, catheters, etc.) that are temporarily or permanently inserted, which are made of foreign bodies (eg Dacron prostheses as in arterial bypasses Others) or from the body's own material (veins, arteries, etc.) exist.

The above description of the principles of action has hitherto been made with particular reference to an extracorporeal device. However, it is also within the scope of the invention to perform a removal of free circulating tumor cells from the blood intracorporeally. In this case, artificial or natural conduit systems artificially constructed conduit systems are possible, which are implanted in a miniaturized manner similar to a large-scale extracorporeal arrangement and connected with blood vessels of the patient P for a longer-lasting treatment. Also, it is within the scope of the invention providable, may even be clearly preferred in certain applications, if a corresponding treatment is performed directly in a blood vessel, wherein the capture and a retention area are formed in the blood vessel itself. This procedure has the particular advantage that the entire cross-section of a blood stream flowing through such a blood vessel is detected by the treatment, and not just a small part, which is branched off into the artificial lines. When such a system is placed in a large blood vessel, e.g. The aorta, arranged, it is because of the per unit time large amount of blood flowing through here, a particularly high impact and efficiency.

However, care must be taken that appropriate bodies or structures are introduced into the blood stream for treatment, which do not slow down the blood flow too much or lead to an unacceptable pressure drop. Thus, it is also possible to prefer those systems which do not cover the entire vessel cross-section and thus not the entire blood stream. This may be necessary, in particular, if the treatment unit would lead, due to flow resistance, to a drop in blood pressure, and thus to reduced blood flow and / or reduced performance in the subsequent tissues (e.g., legs when used in the aorta). If the treatment unit is connected to only part of the bloodstream, the longer part of the treatment can again treat most of the blood.

FIG. 8 shows a principle in which, as an example, antibodies 13, which are in turn held with magnetic fields and are associated with magnetic particles 32, are used. These are retained in the position in the blood vessel 40 by appropriately configured magnetic fields, which are schematically indicated here by closed lines 37, which are intended to symbolize the current flowing through a solenoid generating the magnetic field. The force exerted by the magnetic field on the particles 32 and the antibodies 13 connected thereto is also here, as indicated by the arrow 57 and similar to the embodiment of FIG. 6, the flow direction (arrow 56) of the blood opposite. At the antibodies 13 thus held in position, they dock on tumor cells 14 transported with the blood and passing the blood vessel 40 at this point, more precisely on the antigens 15 formed on these tumor cells 14. The magnetic field causes the antibodies 13 to have magnetic particles attached thereto In order to complete the treatment, before the magnetic field can be switched off, the tumor cells 14 thus captured must be removed from the blood vessel 40. For this purpose, as indicated in the lower illustration of Fig. 8, inserted into the blood vessel 40, a probe 38, with a magnetic probe head 39. This magnetic probe head 39 may for example be a permanent magnet, but also an electromagnet, by a corresponding wiring with Power can be activated and deactivated. With this magnetic probe head 39, the magnetic particles 32 are attracted to the antibody 13 so that these antibodies 13 and also the trapped tumor cells 14 remain attached to the probe head 39 and withdrawn together with the probe from the blood vessel and out of the body of the patient can be removed. Now the magnetic field can be switched off and the treatment can be completed after removing the probe 38 and supplying the surgical wound.

Other methods and methods of trapping tumor cells extracorporeal or intercorporeal are conceivable, which are not shown in detail here. Thus, due to the size difference between the normal blood constituents, in particular red blood cells 16 and white blood cells 17 on the one hand and the significantly larger tumor cells 14 on the other hand always a simple physical filtration with e.g. a membrane filter is possible, which is conceivable especially in an extracorporeal arrangement or an implanted, but on artificial or natural material artificially reproduced lines to the blood circulation of the patient connected capture arrangement. Also, selectively adhesive surfaces, e.g. can be formed from special plastics or synthetic resins, are used, which are also conceivable in a use directly in a blood vessel of a patient. If such surfaces are to be used, they would need to be anchored to the patient's blood vessel, e.g. with a lattice-like mesh, which is similar to a stent supported on the vessel wall. In this case, however, a means for removing such an implant at the end of the treatment period would then also have to be provided for the complete system, this in turn u.a. Catheters, locks or probes can be.

In principle, it is also conceivable, in a capture arrangement as shown schematically in FIG. 1, to provide a physical means other than that already described for killing the tumor cells, and this also in other exemplary embodiments than that shown in FIG. 7 and explained therefor. Thus, e.g. also chemical or pharmaceutical means for killing the cells are used.

In FIG. 10, the different possibilities of binding and fixing tumor cells to a surface 12 are shown once again in schematic representations. Representation a) again symbolizes the determination by means of antibodies 13 which dock to the antigens 15 of the tumor cells 14 (see also FIG. 2). Representation b) symbolizes the formation of adhesion by means of large or long-chain molecules 49 applied to the surface, on which the tumor cells catch and adhere. Representation c) symbolizes the formation of corresponding adhesive layers with suitable, small molecules 50. The size specifications "large" and "small" with regard to the molecules is understood in relation to the dimension of the tumor cells 14. Large molecules 49 are at least the dimensions in their dimensions the tumor cells 14 correspondingly, small molecules 50, however, are well below the dimensions of the tumor cells 14. Representation d) symbolizes the formation of a coating with general adhesive properties against the tumor cells 14. Representation e) finally symbolizes a surface with a structure that eg forms geometric coupling regions 52 for the tumor cells 14 or through the structure binds tumor cells better than normal blood cells.

The essential idea and step of the invention is based on the idea of removing tumor cells in the sense of a true treatment from the blood of a patient as far as possible completely in order to prevent, delay or reduce the formation of metastases

Examination approaches have shown the additional possibility that the removal of tumor cells from the blood, the concentration of possibly present in the bone marrow tumor cells could also be reduced, since here to a certain extent a balance between deposited in the bone marrow, separated from primary tumors tumor cells and such seems to be recognizable in the blood circulating tumor cells.

In principle, the system according to the invention and its use, in addition to the use for therapeutic treatment, can also be used for a diagnosis. In particular, when there is sufficient data and experience with the binding of various types of tumors (e.g., lung cancer, colon cancer, breast cancer, melanoma, and the like) to certain individual or combination of antibodies and / or adhesive or other circulating tumor cell-binding surfaces, e.g. with a test agent comprising various restraining agents from the single or combination of restraining agents which have bound circulating tumor cells, not only determines the most suitable retention agent for the treatment, but also the nature of the tumor present in the patient, i. the diagnosis can be made. This may be particularly advantageous if the tumor's formations are inaccessible to surgery or sample collection (biopsy) or other measures, for example because a tumor is located in the lungs or other organ such that it is neither external nor internal (in this example via the airways) can be achieved. Tumor cells obtained by the method according to the invention can also be provided for further measures and uses.

LIST OF REFERENCE NUMBERS

1 access

2 line

3 trap assembly

4 blood pump

5 line

6 access

7 lead

8 Dosierspritze

9 pressure sensor

10 air detector

11 terminal

12 surface

13 antibody

14 tumor cell

15 antigen

16 red blood cells

17 white blood cells

18 arrow

19 nozzle

20 arrow

21 laser beam

22 drops

23 outlet

24 arrow

25 plate

26 plate

27 filter element

28 fiber bundles

29 fibers

30 polypropylene strand

31 bed

32 magnetic particles

33 magnet

34 opening

35 main flow tube

36 pump

37 line

38 probe

39 probe head

40 blood vessel

41 vein wall

42 catheter

43 catheter

44 blood loaded with tumor cells

45 purified blood

46 balloon

47 balloon

48 arrow

49 large molecules

50 small molecules

51 coating

52 coupling region

53 particles

54 area

55 radioactive irradiation

56 arrow

57 arrow

P patient

Claims (35)

A method of reducing the risk of metastasis in cancers, wherein in a human or animal patient from the bloodstream in the blood, blood-borne tumor cells are captured and rendered harmless, in particular removed and / or damaged and / or killed. A method according to claim 1, characterized in that an extracorporeal capture arrangement is provided and connected to the bloodstream of the patient so that it is traversed by the bloodstream, and that the tumor cells are trapped in the extracorporeal capture arrangement. A method according to claim 1, characterized in that an intracorporeal capture arrangement is provided and introduced into a blood vessel of the patient's bloodstream and held there so that it is flowed through by the bloodstream and the tumor cells are captured in the intracorporeal capture arrangement. A method according to claim 3, characterized in that after a predetermined residence time the intracorporeal capture assembly is removed from the blood vessel and optionally replaced by a new intracorporeal capture arrangement. A method according to claim 4, characterized in that when replacing the intrakorporalen capture a new intracorporal capture device is used with a relation to the previous intracorporal capture other working principle. Method according to one of claims 2 to 5, characterized in that for capturing the tumor cells to the tumor cells docking antibodies are used. A method according to claim 6, characterized in that the antibodies are fixedly connected to blood cells larger microbodies, and that in the capture arrangement, a filter system is created in which the blood cells larger microparticles with antibodies and possibly captured tumor cells are retained, which the blood cells but can flow through. A method according to claim 6, characterized in that the antibodies are held in the capture arrangement. A method according to claim 8, characterized in that the antibodies are firmly connected to magnetic microbodies and that in the capture arrangement, a magnetic field is applied which retains the antibodies therein. Method according to one of claims 2 to 5, characterized in that for trapping the tumor cells in the capture arrangement, a mechanical filter is used, which is dimensioned so that it retains tumor cells, but the other, compared to the tumor cells smaller components of the blood passes. Method according to one of Claims 2 to 5, characterized in that at least one surface which is selectively adhesive to the tumor cells to be captured is used to trap the tumor cells in the capture arrangement. Method according to one of claims 2 to 11, characterized in that in a first step, a first test agent with a plurality of differently formed retaining means is brought into contact with the circulating in the blood of the patient tumor cells to from the restraining means for the capture of the circulating tumor cells on to determine the most suitable retaining means, and that in a further step the catching arrangement is equipped with the most suitable retention means (s) for further treatment. Method according to one of claims 2 to 11, characterized in that in a first step, a first test agent with a plurality of differently formed retaining means is brought out of a tissue sample from the patient's tumor cells in contact to from the restraining means for the capture of the tumor cells on to determine the most suitable retaining means, and that in a further step the catching arrangement is equipped with the most suitable retention means (s) for further treatment. Method according to one of claims 12 or 13, characterized in that in the first step a second test means provided with the same different restraining means comprising the first test means is brought into contact with the blood of the patient and in the further step the catching arrangement for the further treatment with the retention agent (s), which at the same time had bound a high number of the tumor cells and at the same time captured a small amount of blood cells (s). Method according to one of the preceding claims, characterized in that the captured tumor cells are killed or damaged before or after removal from the bloodstream of the patient. Method according to one of the preceding claims, characterized in that the tumor cells are removed from the arterial blood stream of the patient. Method according to one of the preceding claims, characterized in that the patient at least once before or during the removal or after the removal of the tumor cells, a blood clot inhibiting agent is administered. System for removing blood-related tumor cells (14) circulating in the blood of a human or animal patient (P) from the bloodstream, comprising: a) means for forming a tumor cell (14) retaining region provided with an inlet for blood flowing out of the circulation of the patient (P) and an outlet for blood flowing away and continuing in the circulation of the patient in a blood flow through the patient; in the patient's circulation (P) integrated cavity, b) means for trapping circulating tumor cells (14) and retaining them in the retention area. A system according to claim 18, characterized in that it also contains a blood clot inhibiting agent. System according to one of claims 18 or 19, characterized by a retention area (3) to be formed outside the body of the patient. System according to one of claims 18 or 19, characterized by a retention area to be formed within the body of the patient. System according to one of Claims 18 to 21, characterized by means (33) for generating a magnetic field as a means for forming a retention region and by means of elements which can be coupled to the tumor cells (14) and at least in one section as means for capturing tumor cells (14). and retaining them in the retention area. A system according to claim 22, characterized by antibodies (13) firmly attached to magnetic micro or nanobodies (32) as means for trapping tumor cells (14) and retaining them in the retention area. A system according to any one of claims 18 to 21, characterized in that the means for trapping tumor cells (14) and retaining them in the retention area contains antibody (13). System according to one of claims 18 to 21, characterized in that the means for trapping tumor cells (14) and retaining them in the retention region at least one intended for contact with the blood, for the tumor cells to be trapped selectively adhesive surface (12). A system according to any one of claims 18 to 21, characterized in that the means for trapping tumor cells (14) and retaining them in the retention area comprises a filter (27) having openings smaller in cross-section than the tumor cells to be trapped but larger than the ones other components of the blood. A system according to any one of claims 18 to 21, characterized in that the means for trapping tumor cells (14) and retaining them in the retention area comprises a filter (27) having openings which are smaller in cross section than for trapping the particles provided for the tumor cells, but bigger than the other components of the blood. System according to one of claims 26 or 27, characterized in that the filter consists of one or more membranes, consists of polymers or has a special molecular structure and arrangement. A system according to any one of claims 18 to 28, characterized in that it comprises a housing having an inflow opening and an outflow opening, a first end connected to the inflow opening, a first access means at a second end for providing an access (1) to a blood vessel comprising a supply line (2) and a at a first end connected to the discharge port, at a second end a second Zuwegmittel for providing an access (6) to a blood vessel having discharge (5), wherein formed in the housing of the retaining portion and the means for trapping circulating tumor cells (14) and retaining them. A system according to any one of claims 18 to 28, characterized in that the means for trapping circulating tumor cells (14) and retaining them in the retention area comprises a means, which is at least temporarily fixed locally in the retention area and can be brought into a blood vessel (40) of the patient is. A system according to claim 30, characterized by means (38, 39) for removing the means for capturing circulating tumor cells (14) and retaining them from the blood vessel (40) and body of the patient. System according to one of claims 18 to 31, characterized in that it contains a means for killing and / or damaging the tumor cells (14). System according to one of claims 18 to 32, characterized by a test means with differently designed means for trapping the tumor cells (14), which test agent is collectively in the retention area can be introduced. A system for removing blood-related tumor cells (14) circulating in the blood of a human or animal patient (P) with a means for capturing circulating tumor cells (14) which contains means of micro- and / or nanoparticles (32, 53) which are freely insertable into the bloodstream of the patient (P) and comprise means for binding tumor cells (14), the means for capturing circulating tumor cells (14) being resorbable in the body of the patient. A system for suppressing metastasis by capturing circulating tumor cells (14) from the patient's bloodstream (P) and / or the vein draining blood from the tumor and its surroundings.