EP3562551A1

EP3562551A1 - Device for the treatment of malignant diseases by using tumor-destructive mechanical pulses (tmi)

Info

Publication number: EP3562551A1
Application number: EP16831817.8A
Authority: EP
Inventors: Axel Erich Theuer; Irmengard Theuer
Original assignee: Richard Wolf GmbH
Current assignee: THEUER, AXEL ERICH; THEUER, IRMENGARD
Priority date: 2016-02-09
Filing date: 2016-12-28
Publication date: 2019-11-06
Also published as: US11752365B2; WO2017137134A1; US20200038694A1

Abstract

Disclosed are a device and a method for the treatment of malignant diseases, which is individual to a patient, by using selectively acting tumor-destructive mechanical pulses (TMI). In this case, tumor-destructive pulse shapes are determined using physical cell properties, which are individual to each patient, and the device is controlled in such a manner that lethal pulse fields are applied in the tumor area.

Description

TREATMENT DEVICE FOR MALIGNER DISEASES THROUGH TUMOR SECTOR MECHANICAL IMPULSE (TMI)

The invention relates to a device for the treatment of malignant diseases using tumor-destructive mechanical impulses (TMI) and defines the operation and control of this device. Apparatus for the treatment of diseased cells in living bodies by means of sonic and / or ultrasonic waves have been known for several decades. Thus, DE 44 14 239 A1 describes a device in which a sound source for the selective destruction of cells pathological appearance, such as tumor cells, for the generation of sound and / or ultrasound waves with a typical cell type, these cells destructive resonant frequency spectrum is designed.

WO 2009/156156 A1 discloses an arrangement for destroying tumor cells, in which an ultrasound generator for generating a thermally active, high-frequency oscillation comprises a plurality of low-frequency ultrasound generators, each generating a different frequency, and a controller connected to a radiofrequency oscillator. Ultrasonic generator is connected so that the tumor cells with a high-frequency, the tumor cells thermally acting vibration and a low-frequency oscillation can be acted upon, in addition to a biopsy device is provided with multiple individual images for tissue samples.

WO 2010/020406 A1 discloses a device for destroying tumor cells or pathogens in the blood circulation, in which at least one ultrasonic frequency generator and a device for forming an extracorporeal blood circulation are provided, wherein the device comprises at least one heat exchanger, a blood pump and a treatment container to receive Includes blood, wherein the treatment tank is arranged downstream of the heat exchanger, forms a treatment space and is connected to at least one ultrasonic oscillating head. The ultrasonic oscillating head is coupled to the ultrasonic frequency generator, so that a low-frequency ultrasonic vibration can be introduced in the treatment space.

From WO 2010/049 176 A1 a medical device for the treatment of tumor tissue is known, which comprises a surgical instrument insertable into a body with a housing, in which a vibration element is arranged, which is operable to generate an ultrasonic vibration. The vibration element is associated with a transmission region which at least partially comprises a wall of the housing, which is arranged in use facing the tumor tissue to be treated. The transmission range is adapted, in use, to transfer the ultrasonic vibration into the tumor tissue to be treated. The transmission area cooperates with at least one tempering device.

From WO 2001/37735 A1 a device for the vibration-induced, selective treatment of malignant diseases by means of mechanical vibrations and / or sound waves is known in which by means of a targeted selection those cells can be taken, which are to be treated with the aid of the device , For this purpose, a microsurgical device is provided which has a vibration generator. It is an object of the invention to provide a TMI device for the treatment of malignant diseases by means of mechanical impulses or to define the operation and control of the device, compared to the known from the prior art devices or methods, a further improvement of the Treatment is achieved and extendable to other forms of therapy. This object is solved by the features of claims 1 and 17, respectively. Further advantageous embodiments of the invention are each the subject of the dependent claims. These can be combined in a technologically meaningful way. The description additionally characterizes and specifies the invention.

A device according to the invention (TMI device) for the treatment of malignant diseases using tumor-destructive mechanical impulses uses a cell biologically optimized, optimally destructive and tumor-selective patient-specific pulse shape and / or pulse sequences resulting from the mechanical, visco-elastic properties of the tumor cells and the intertumoral or tumor-surrounding extracellular matrix (ECM) results or is or is adapted to it. A method according to the invention for operating and controlling the TMI device comprises determining an optimal pulse shape and / or pulse sequence and / or further operating parameters before use of the device in a cell experiment on cells removed from a patient or by means of a tissue assay or from a database for cell experiments and tissue tests, whereby measurements, in particular AFM (Atomic Force Microscopy) measurements, physical properties of the extracted cells are determined and integrated into FEM (Finite Element) simulation models. The device can be designed to apply a cell biologically optimized, optimally destructive and tumor-selective pressure pulse train.

Furthermore, a cell biologically optimized, optimally destructive and tumor-selective delay time can be set or adjustable between the pulses. It can be provided that the device is designed to dilute tumor-activated fibroblasts by expanding a target volume impinged by the pulses into healthy tissue. The device may comprise at least one pressure sounding head and at least one control unit for controlling the pressure sounding head for generating the tumor-destructive mechanical impulses or pulse trains.

It can furthermore have at least one positioning mechanism for positioning the pressure-sounding head relative to a target volume impinged by the pulses, preferably in accordance with the control unit.

It can be provided that the pressure sounding head can be positioned or positioned and modulated or modulated in terms of its pulse output in such a way that tumor-destructive shearing forces arise in the target volume.

It can also be provided that at least two pressure sounding heads or oppositely polarized piezo elements are provided in phased array technology for the generation of the tumor-selective pulse shapes and pulse sequences, preferably with corresponding positioning mechanisms.

In addition, it can be provided that, in particular for the treatment of mammary carcinoma or brain metastases, at least three or more pressure sounding heads are provided with corresponding positioning mechanisms, wherein preferably the pressure sound heads are positioned or positionable and modulated or modulated with regard to their pulse output in such a way Tumor area tumor-destructive shear forces arise.

The positioning mechanisms may be controlled or controllable in such a way that a preferably punctiform focus area is first directed to a tumor edge and scans it, the pulse edges being deflected due to the high frequency of the tumor. Preferably tumor-protective TAF (tumor-dense fibroblasts) at the tumor edge preferably high frequency fractions of about 1 MHz to 10 MHz.

The positioning mechanisms can also be controlled in such a way that a preferably punctiform focus area is directed at the target volume and scans it, pulse edges having patient-specific low-frequency components, preferably at about 0.1 MHz-3 MHz.

The device may be configured to heat a target volume to about 39 ° C to 41 ° C, preferably about 40 ° C, by suitable pulses or pulse trains to further enhance its effectiveness.

The device may comprise at least one ballistic and / or at least one electrohydraulic or piezoelectric shock wave generator or corresponding treatment applicators, in particular for generating positive shock wave pulses.

The at least one ballistic shock wave generator can be provided for generating second shock wave pulses with specific, tumor-destructive properties.

The device may comprise at least two shock wave generators and a control unit, wherein the shock wave generators are successively controlled or controlled by the control unit such that the respective pressure maxima of the shock wave pulses follow one another at a time interval which is smaller than the pulse duration of the shock wave pulses.

In addition, the device can be equipped with at least one diagnostic unit for continuously monitoring a treatment success, in particular for monitoring an ultrasound echo image (frequency spectrum) of a tumor area, a number of circulating tumor cells in the blood and / or immune parameters. A development of the method provides that the operating parameters are determined individually for each patient with the aid of physical properties of cells removed from a patient and on the basis of MRI / CT data of the patient.

Another development of the method provides that lethal pulse forms and pulse sequences are determined with the aid of individual patient numerical simulation models and experimentally validated.

Yet another development of the method provides that the operation of the TML treatment via a central treatment center (CTC) and decentralized treatment facilities (TF) takes place. The TMI device can also be targeted to tumor-involved lymph nodes, which thus can be treated individually and need not be excised.

The TMI device can be used simultaneously with the use of immunomodulators.

In a preferred embodiment, the TMI device comprises treatment applicators or pressure sound heads, which serve for the application of mechanical impulses or shock waves. The treatment applicators preferably also have a possibly centrally arranged diagnostic unit. Between the treatment pulses thus ultrasonic noise waves can be evaluated and short pulses in the low intensity range for excitation and evaluation of the pulse echo (spectral analysis) are sent. The TMI device may further comprise one or more pulse generators. Depending on the intended use, ultrasound generators or shock wave generators are used, in which the me- chanical impulses are generated ballistically, piezoelectrically, electromechanically or electro-hydraulically. In the case of multiple shock wave or pulse generators, it may be useful if different shock wave generators, such as a ballistic and an electro-hydraulically operating shock wave generator, are present.

Piezoelectric pulse generators are designed to be planar or focused according to the type of tumor and the position of the tumor area. In this case, tumor-destructive pulse fields can take place with the aid of a series of capacitive discharges or with the aid of tumor-specific pulsed sinusoidal oscillations in the high intensity range (60.0 - 200.0 MPa).

It is advantageous if the components of the treatment applicators include, in addition to focused electromagnetic or piezoelectric pulse generators, low frequency (20-30 kHz) planar pulse generators, a diagnostic unit, positioning mechanisms, and a transmission medium.

The focused pulse generators may preferably generate continuous or pulsed high-intensity sinusoidal oscillations, which apply pressure pulse impulses in the focus area through the division of the sine wave, or low-intensity pulsed sinusoidal oscillations, which induce resonance phenomena in the tumor area. It is advantageous to vary the power of the TMl pulse generators to apply sequentially positioned surge pressure pulses and continuous sinusoidal vibrations.

To initiate the generated pulse fields, a coupling surface is preferably present, which can be applied, for example, to a body region of a patient to be treated. The coupling surface may be, for example, a cavity of the treatment applicator filled with transfer fluid. In the case of a ballistic shock wave generator, there is a baffle plate, preferably made of metal, onto which a projectile is fired, wherein the the shot direction of the projectile side facing away from the baffle plate forms the coupling surface (however, there may be more intermediate elements).

As a further component or as a further component, the device in a preferred embodiment comprises a control unit, which is signal-connected to the at least one pulse generator. If a control unit is referred to here in simplified terms, this is to be understood as a unit which is suitable for controlling and / or regulating. The control unit can be designed so that the pulse generators generate pulses with a pulse frequency of 0.5 Hz to 600 Hz, a maximum pressure with an absolute value of 0.01 MPa to 300 MPa and a rise time of 2 ns to 4000 ns without the invention would be limited to these values.

With such a TMI device, it is possible to selectively destroy tumor cells, in particular therapy-resistant tumor cells, such as those resistant to vemurafenib, a protein kinase inhibitor, ie without or at most with slight damage to healthy tissue or cells by necrosis and / or initiation of apoptotic processes. It is particularly crucial for the tumor-destructive action that the pulse frequency and the pulse sequence according to the invention are adapted to the respective type of tumor and thus in tumorous tissue in particular the effect can be generated that one of the shock wave generated by the TMI device stretched cell or cell organelles a subsequent shock wave is / are applied before the cell or the Zellorganellen has returned to its original state / are. Healthy body cells are mechanically more stable in comparison to tumor cells and are thereby deformed only in a harmless manner, while tumor cells are permanently damaged or destroyed. The mechanical impulses generated by the TMI device can be both positive and negative or inverted impulse waves, where a pulse train of shock waves can have both types of pressure waves. With several, modulated shockwaves or pressure waves For example, particularly high and destructive shear forces on tumor cells and tumor cell organelles can be produced.

In the context of the invention, selective, tumor-destroying pulse forms and pulse trains are determined from tumor-specific viscoelastic properties of malignant cells and the intertumoral or tumor-surrounding extracellular matrix (ECM), preferably outside the body after appropriate sampling. Tumor cells have concise, tumor-specific mechanical properties. Particularly relevant are the viscoelastic properties of malignant protein structures. The rigidity of cells is determined primarily by the cytoskeleton and the size and consistency of the cell organelles. The cytoskeleton consists of a variety of different protein structures and determines the overall rigidity of the cell. Especially actin filaments, microtubules, microfilaments and interfilaments characterize the overall cellular stiffness and determine the mechanical properties and dynamic behavior of cellular structures. A special role is played by actin filaments and microtubules. Actin filaments determine the dynamic deformation behavior of the cells. They support the cell membranes. In most of the malignant cells, especially on the inside of the cortical bone, filaments of filaments are almost absent, less concentrated, and can not fulfill their physiological protective protective function of malignant cell membranes.

Our own calculations and validating cell experiments, tissue experiments and animal experiments have led to the finding that specific, selectively acting tumor-destroying impulses have the ability to tumor cells and

Selectively destroy necrotic tumor tissue and also have a tumor-destroying effect on therapy-resistant cells (for example, vermurafenib). Healthy cells survive the pulse train without damage. The physical properties (stiffness, viscosity, density, size and kinematic hardening) of a patient's tumor cells are different from the physical properties of a second patient. you speaks in this context of patient-individual physical properties of the tumor cells.

In the propagation of the pulse fields generated by the TMI device through the tumor area, there are deformations of the cells and the cell organelles. If the value of the membrane expansions (especially in the tangential direction) exceeds a lethal value, a necrotic failure occurs. The cell membrane ruptures and malignant protein structures flow into the surrounding ECM. Malignant cell fragments, malignant protein structures and, in particular, mitochondrial fragments are released. This can lead to a tumor-specific maturation of dendritic cells. These present native T cells tumor toxic properties and can lead to a beneficial tumor toxic response of the immune system. Healthy cells survive the tumor-specific pulse fields without damage because they have an intact actin filament. The rigid cortical actin filament of healthy, non-degenerated cells supports the membranes of healthy cells and has a membrane-protective effect for them. The invention describes tumor-specific impulses and tumor-specific pulse sequences. Pulse trains are determined by the pulse frequency and the number of pulses. Relevant to the invention is the visco-elastic delay behavior of malignant cell structures. After the impact of the first pulses or pulse fields, significant elongations occur in malignant cells. These are more concise than in normal cells. The second, temporally subsequent pulse fields amplify the already established strain fields. As a result, the strains continue to build until they reach lethal levels and lead to lethal damage in malignant cells and cell organelles. Healthy, non-degenerated cells are - as already stated - much stiffer than malignant cells and require longer time intervals to lethal To reach strains. For short pulse sequences, they remain below critical, cell destructive values and survive the treatment without damage.

In a corresponding development of the invention, selectively acting mitochondria also have destructive pulse fields.

The mitochondria of malignant cells are significantly more pressure sensitive than mitochondria of healthy cells. They are embedded in an unbundled, relatively soft actin filament. They are torn apart by the applied impulses and pulse sequences and cause the release of cytochrome c. Cytochrome c binds to the APAF-1 protein which oligomerizes and activates the initiator caspase 9 and subsequently the effector caspase 3. It is the so-called death receptors that lead to an apoptotic failure of the tumor cells.

In ultrashort pulses (rise times <10 ns) in the focus area, which can be used with appropriate embodiment of the invention, the inertia of the cells and cell organelles is too large to build lethal strain fields. The cells and cell organelles can not follow the pulse front and remain as a whole. But at the mitochondrial level, the pulse front first encounters mitochondrial outer membranes. At the time of impact, the opposite mitochondrial membrane is unloaded in ultrashort pulses. Thus, mitochondrial membranes are exposed to extreme pressure differences. They cause complex mitochondrial signaling cascades and the release of free radicals (NO and hydroxyl OH). These are assigned an important role as signal and modulators in the formation of heat shock proteins. In malignant cells apoptotic processes are triggered. Another aspect of the device relevant to the invention is the concomitant or time-delayed treatment of tumor-dense fibroblasts (CAFs). CAFs are vital prerequisites for mitotic and metastatic malignancy Cells. They are assigned a significant role in the inactivation of the immune system in the tumor area. Therefore, it is imperative to completely destroy activated fibroblasts in the tumor area. For this purpose, specific pulse fields for the selective destruction of tumor-dense fibroblasts (CAFs) in the tumor area are applied concomitantly or with a time delay with appropriate embodiment of the invention. CAF specific pulse fields can be determined in upstream FEM analyzes. The selectivity is given by CAF's specific material properties and the spindle shape of tumor-dense fibroblasts. These material properties of CAFs can be determined using AFM measurements.

Also relevant to the invention is the activation of commercially available photosensitizers. It has surprisingly been found that the tumor-destructive pulse fields used in a corresponding embodiment of the invention have the ability to activate photosensitizers. There are selectively acting, tumor-toxic compounds. These, in conjunction with the applied pulse fields, can cause severe tumor-specific response reactions of the immune system. Our own simulation analyzes and validating experiments have led to the finding that tumor-specific impulses have tumor-destructive properties even in tumors with a reduced rate of apoptosis, such as, for example, colon carcinoma, pancreatic carcinoma and hepatocellular carcinoma. Our own studies indicate that special impulses are capable of selectively destroying tumor stem cells, including chemo- and radiation-resistant tumor stem cells.

It has surprisingly been found that TMI (tumor-destructive mechanical impulses) lead to an activation of the immune system. Numerous malignant cell fragments and secreted malignant protein structures induce T-cells of the immune system to have tumor-toxic properties via dendritic cells (D. cells). In the blood TMI-treated tumor-bearing immunocompetent In animals, a dramatic increase of CD8 T cells with tumor toxic properties was found.

Since tumor cells are able to successfully defend TMI-induced T cells with tumor-toxic properties, a development of the present invention preferably comprises a combination of the TMI treatment with PD1 inhibitors (eg nivolumab). PD1 inhibitors are administered concomitantly or after TMI treatment. The treatment is continued until no circulating metastatic cells (CM) can be detected in the patient's blood. In this case, a new acoustic method can be used in which ZM excited by short extracorporeal impulses to tumor-specific vibrations and then detected acoustically.

It is advantageous to realize the invention in the form of a CTC (Cancer Treatment Center) center and individual, globally positioned TF (Treatment Facilities), which will be discussed in greater detail below (see FIG. In this context, the invention may, with a corresponding development, comprise the following distinct steps:

• In the TF, tumor cells are taken from a patient on site and sent to the CTC.

• In the CTC, AFM measurements of patient cells are performed and the measured physical properties are integrated into predefined, stable FEM models. This results in patient-specific lethal pulse forms and pulse sequences.

• In a second step, MRI data from the tumor areas are transferred from the TF to the CTC and integrated into predefined, stable FEM models. This results in patient-specific treatment parameters, which are transmitted to a CPU (central processing unit) of the relevant TF. The treatment parameters include patient-individual Both control impulses and patient-specific position coordinates of the treatment applicators. This ensures that lethal pulse forms and pulse sequences are applied in the tumor area.

In a further step, patient-related diagnostic patient data are continuously transferred to the CTC and evaluated by spectral analysis. The treatment applicators preferably have a centrally located diagnostic unit. Between the pulses ultrasonic noise waves are evaluated and short pulses in the low intensity range are sent for excitation and evaluation of the pulse echo (spectral analysis).

It has surprisingly been found that TMI (tumor-destructive mechanical impulses) lead to an activation of the immune system. Numerous malignant cell fragments and secreted malignant protein structures induce T-cells of the immune system tumor-toxic properties via dendritic cells. In the blood of TMI-treated tumor-bearing immunocompetent animals, a dramatic increase of CD8 T cells with tumor toxic properties could be observed.

Since metastatic cells, dendritic cells as well as T cells of the immune system are present in affected lymph nodes, according to the invention, diagnostic patient data of tumor-related lymph nodes are sent to the CTC. These are integrated into predefined stable FEM models and solved numerically. This results in patient-specific treatment parameters, which are transmitted to the CPU (central processing unit) of the TF. The treatment parameters include patient-specific control pulses of the CPU and patient-specific position coordinates for the treatment of affected lymph nodes.

Since tumor cells are able to successfully defend TMI-induced T cells with tumor toxic properties, in the context of the present invention a combination of TMI treatment with PD1 Inhibitors (eg Nivolumab) take place. PD1 inhibitors are administered concomitantly or after TMI treatment.

• The treatment is continued until no circulating metastatic cells (CM) in the patient's blood can be detected. In this case, an acoustic method can be used, in which the ZM excited by short extracorporeal impulses to tumor-specific vibrations and detected acoustically.

It is advantageous if the components of the treatment applicators include in addition to focused electromagnetic or piezoelectric pulse generators, low frequency (20-30 kHz) planar pulse generators, a diagnostic unit, positioning mechanisms and a transmission medium (Figure 2).

The focused pulse generators can preferably generate continuous or pulsed high-intensity sinusoidal oscillations which generate pressure impulse impulses in the focus area by dividing the sine wave or low-intensity pulsed sinusoidal oscillations which induce resonance phenomena in the tumor area. It is advantageous to vary the power of the TMI pulse generators in order to apply sequentially positioned surge pressure pulses and continuous sinusoidal vibrations (Figure 16).

Also relevant to the invention are specific tumor-destructive or treatment-specific pulse fields, their temporal variation, modulation, combination, diagnostic monitoring and control with the aid of a preferably software-aided control and control unit.

Upstream or accompanying are visco-elastic FEM simulation models of the cellular structures and commercial areas to be treated. The input parameters of the FEM simulation analyzes are physical properties of the cells and cell structures to be treated. These preferably result from AFM measurements or electrical measurements of living cells and cell organelles or are taken from a separate CTC database. Own calculations and analyzes have further led to the realization that sickle cells can also be led into apoptotic processes with the TMl therapy. In sickle cell diseases, cell-supporting, apoptotic processes are particularly important, since a necrotic destruction leads to possible adhesions of the cell fragments and the already difficult blood circulation is further worsened. In addition, ultrashort pulse fields due to the NO release have vasodilatory capabilities that play an eminently important role in sickle cell disease.

In summary, it should be noted that specific patient-specific tumor-destructive mechanical impulses of the TMI device, and preferably its temporal variation, modulation, combination, diagnostic accompaniment and control define the essence of the invention. Patient-specific viscoelastic FEM simulation models of the cellular structures and commercial areas to be treated can be placed in front of them. The input parameters of the FEM simulation analyzes are physical properties of the cells and cell structures to be treated and are preferably determined via AFM measurements.

Breast cancer is the most common invasive malignancy in women worldwide. Worldwide, there are about 1, 50,000 new cases of illness per year. In Germany about 71,000 new cases per year. The TMI treatment of

Breast cancer can include the following distinct steps:

First, AFM measurements of the patient cells are carried out for the determination of the patient-specific physical properties. These are integrated into predefined, stable FEM models. This results in patient-specific lethal pulse forms and pulse sequences. In a second step, MRI / CT data from the tumor areas are integrated into predefined, stable FEM models. This results in patient-specific treatment parameters which are transmitted to the CPU (central processing unit) of the TMI device. The treatment parameters include patient-individual control pulses and patient-specific position coordinates for the positioning mechanisms of the treatment applicators for the sequential scanning of the entire tumor area. This ensures that lethal pulse forms and pulse sequences are applied in the tumor area. Since metastatic cells of breast carcinoma, dendritic cells and T cells of the immune system are present in affected lymph nodes of breast cancer, according to the invention, diagnostic MRI / CT patient data of tumor-affected lymph nodes are integrated into predefined stable FEM models and solved numerically. This results in patient-specific treatment parameters: These include patient-specific control impulses and patient-specific position coordinates for the TMI treatment of the affected lymph nodes of breast cancer.

Our own calculations and validating cell experiments, tissue experiments and animal experiments have led to the finding that breast cancer cells can be fatally damaged by specific, selective tumor-destructive mechanical impulses. Healthy cells survive the treatment without damage. The cells of metastases of breast cancer behave largely like the cells of the primary tumor and have the same or very similar therapy-determining mechanical properties.

Our own FEM analyzes of the pressure propagation through the breast tissue and accompanying tumor experiments have led to the finding that tumor-destructive pressure peaks can be built up in the affected area. This requires a patient-specific positioning of the treatment applicators. From the results of the FEM simulation analyzes of the pressure propagation, tumor-destructive pulse forms and pulse sequences result.

Prostate cancer is by far the most commonly diagnosed malignant tumor of the man. In Germany, approximately 26,500 new men develop prostate cancer each year. Prostate cancer ranks second in cancer-related, organ-related mortality statistics in men Job. The TMI device, in turn, operates by means of mechanical pulse fields and comprises the pulse generators, a control device and treatment applicators, which, however, may have a different shape in this application. The treatment applicators can be arranged on the positioning mechanism on an anatomically curved holding device. Pulses of the treatment applicators are transferred to the tumor area. The treatment applicators flexibly integrated in the holding device are aligned with the tumor area and acted upon by the control unit with tumor-destructive pulse trains. Tumor nodules are treated by multiple, focused on the node treatment applicators. Tissue-surrounding tissue with tumor-activated, fibroblasts (TAFS) activated by the tumor is scanned by punctiform lethal pulse forms and treated concomitantly or with a time delay. In the TMI device for the treatment of prostate cancer and bone metastases of prostate cancer is explicitly treated also affected lymph nodes. It is a nature of the invention that also affected lymph nodes of prostate cancer are treated. High-resolution MRI / CT patient data is integrated into predefined stable FEM models. These are solved numerically and the position of the treatment applicators is determined so that the pressure propagation is directed to the lymph nodes and in the lymph nodes lethal pulse shapes and pulse trains are applied. The TMI device may also contain several different pulse generators for the treatment of prostate cancer. It may be appropriate to use piezoelectric, ballistic or electromagnetic pulse generators or a combination of said pulse generators. From an organ-specific point of view, the provision of two electromagnetic treatment applicators BA is preferred in the extracorporeal treatment of prostate cancer. These can be operated synchronously or asynchronously. The TMI device for the treatment of bone metastases of prostate cancer is preferably characterized by low frequency treatment applicators (30 kHz - 800 kHz) operating in the high intensity range (20.0 MPA - 200 MPA). Because tumor areas of bone metastases are primarily positioned on the inside of the highly absorbent compact, pulse shapes with low frequency components in the frequency spectrum and the treatment parameters described above are needed to overcome the highly absorbent compacts of the affected bone structures.

Furthermore, tissue experiments and animal experiments have led to the finding that even bone metastasis cells can be fatally damaged by specific, selectively acting tumor-destructive mechanical impulses. Healthy cells survive the treatment without damage.

The cells of bone metastases behave largely like the cells of the primary tumor and have the same or very similar therapy-determining mechanical properties. According to the invention, the physical properties of patient-specific metastatic cells are determined by AFM (Atomic Force Microscopy) measurements, integrated into FEM simulation models of non-linear pressure propagation through the tumor area and treatment parameters determined by means of comparative comparisons of the simulation results that lead to lethal lesions malignant Lead cells in the tumor area.

Patients' own prostate cancer cells are removed from the tumor area, or circulating metastatic cells are separated from the patient's blood, and AFM measurements are used to determine therapy-determining physical properties. Our own FEM analyzes of pressure propagation through bone structures and accompanying tumor experiments have led to the realization that in the affected bone marrow tumor-destructive pressure peaks can be built up. For this purpose, a patient-specific positioning of the treatment applicators is required. The results of FEM simulation analyzes of pressure propagation through absorbent bone structures result in tumor-destructive pulse shapes and pulse sequences. In this case, tumor-destructive pulse fields can be generated with the aid of a series of capacitive discharges or with the aid of pulsed sinusoidal oscillations.

In addition, both ballistic treatment applicators, piezoelectric treatment applicators or a combined construction of ballistic treatment applicators and piezoelectric treatment applicator can be used.

The Applicant has recognized that selective tumor-specific pulse shapes can be used for different tumor identities. The selectivity, tumor-destructive pulse shapes result from the mechanical, visco-elastic properties of the tumor cells and the intertumoral or tumor-surrounding extracellular matrix (ECM). The propagation of tumor-specific pulse fields through the cells and cell organelles leads to an expansion of the cell membranes and cell organelles. If the value of the membrane strain (especially in the tangential direction) exceeds a lethal value, a necrotic failure occurs. The cell membrane ruptures and the cell plasma with the cell organelles contained therein flows into the surrounding ECM. Malignant cell fragments, malignant protein structures and especially mitochondrial fragments are released. This leads to a tumor-specific maturation of dendritic cells. These present native T cells with tumor-toxic properties and can lead to a tumor toxic response of the immune system. Healthy cells survive tumor-specific pulse propagation without damage. You have an intact actinfilad ment. The rigid cortical actin filament of healthy, non-degenerated cells supports the membrane healthier and has a membrane-protective effect.

In a corresponding embodiment, the invention preferably includes a tumor-specific pulse sequence in addition to the tumor-specific pulse shape. The pulse train is determined by the pulse frequency and the number of pulses. Significant here is the visco-elastic delay behavior of malignant cell structures. After the impact of the first impulse pulse occurs in malignant cells to significant strain fields. These are more concise than in normal cells. The second impulse pulse amplifies the already established strain fields. As a result, the strains continue to build until they reach lethal levels and lead to necrotic destruction. Healthy, non-degenerated cells require longer time intervals to achieve lethal strains. For short bursts of pulses, they remain below the critical cell destructing values and survive the bursts without damage.

In the context of the invention, it can be provided that a positive pressure surge is followed by an equally high negative pressure surge, or that two positive pressure surges can be emitted, between which a defined delay time (time between the pressure surges) is set. The variance of the delay time is used to search for an optimal pulse form for tumor destruction. We are looking for the time when the expansion fields in the tumor overlap and thus add up until they become lethal for the tumor cells. Each tumor cell has an individual elongation characteristic, which is represented in the individual delay time. Healthy cells survive tumor-specific pulse propagation without damage. They have an intact actin filament. The rigid cortical actin filament of healthy, non-degenerated cells supports the membrane healthier and has a membrane-protective effect. The rigidity of the cells is determined primarily by the cytoskeleton.

The cytoskeleton consists of a variety of different protein structures, especially actin filaments, microtubules, microfilaments and interfilaments. A special role is played by actin filaments and microtubules. Actin filaments are responsible for the overall rigidity of the cells. They support the cell membranes. In most malignant cells, especially on the cortical inside of the cell membranes, actin filaments are almost non-existent, less concentrated and can not fulfill their physiological protective supporting function of the cell membrane. Due to the lower stiffness, the tumor cell can be better stretched and torn.

In a corresponding development of the invention can be provided that at least two pressure sound heads or oppositely polarized piezo elements are used in the phased array technique for the generation of the pulse sequences and a defined delay time between the pulses.

In the context of the invention, it can further be provided that the TMI device can treat metastases of the skeleton, of the body trunk, of the liver, of the head, of the neck as well as tumor recurrences, operated and irradiated (treated) recurrences.

In summary, the invention relates to patient-specific destructive pulse shapes and pulse sequences in the tumor area. For the determination of lethal pulse shapes and pulse sequences, tumor cells from the primary tumor or circulating metastatic cells are preferably taken from the patient. In subsequent AFM measurements, the physical properties of the extracted cells can be determined and integrated into FEM simulation models. The results of the simulation analyzes are patient-specific pulse shapes and pulse sequences, which can be applied after validating experiments in the tumor area. For this purpose, in a second step, patient-specific MRT data are preferably integrated into a stable, predefined FEM model, and the non-linear pressure propagation in the tumor area is determined. The results of the FEM analyzes result in the relevant parameters and positions of the TMl treatment applicators, which can be used for sequential scanning of the entire tumor area.

Further features and embodiments will become apparent from the following explanation of embodiments with reference to the drawings.

Figure 1 shows schematically the structure of a TMI device;

Figure 2 shows a schematic representation of a TMI treatment applicator;

FIG. 3 shows the structure of a TMI Cancer Treatment Center (CTC);

FIG. 4 shows the AFM determination of the patient-specific cell data; FIG. 5 shows a validating comparison of TMI-treated melanoma cells;

FIG. 6 shows a validating comparison of TMI-treated prostate carcinoma cells, vemurafenib-resistant melanoma cells and rhabdomiosarcoma cells;

FIG. 7 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (rabbits) and comparative comparison of the results (untreated animal with a strongly growing tumor);

FIG. 8 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (rabbits) and comparative comparison of the results (tumor regression after three TMI treatments); FIG. 9 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (rabbits) and comparative comparison of the results (tumor regression after three TMI treatments in combination with nivolumab); FIG. 10 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (rabbits) and comparative comparison of the results (increase in immune markers after three TMI treatments);

FIG. 11 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (mice) and comparative comparison of the results (tumor progression in the untreated animals and the TMI-treated animals);

Figure 12 shows a TMI device for the treatment of brain metastases;

Figure 13 shows a TMI device for the treatment of brain metastases with unilateral placement of treatment applicators;

Figure 14 shows a TMI device for the treatment of breast cancer in an overall view;

Figure 15 is a sectional view of a TMI device for the treatment of breast cancer;

FIG. 16 shows tumor pulse pulse edges established in a TMI device for the treatment of breast cancer and continuous sinusoids;

Figure 17 shows lethal pulse edges generated in the tumor area with a TMI device;

FIG. 18 shows lethal pulse edges generated in the tumor area using a TMI device; Figure 19 shows schematically the effect of TMI treatment and response of the immune system; and

Figure 20 shows TMI treatment of affected lymph nodes and immune system response in combination with PD1 immunomodulators.

In Fig. 1, the possible embodiment of a TMI device is shown schematically. The device comprises a central control unit or central processing unit (CPU) 1, a TMI pulse generator 2, positioning mechanisms 3, diagnostic units 4 and treatment applicators 5 with transmission medium.

The treatment applicators 5 are equipped with corresponding positioning mechanisms 3 and a diagnostic unit 4. The alignment and positioning of the treatment applicators 5 is carried out with the positioning mechanisms 3. The treatment applicators 5 are connected to the skin of a tissue area to be treated via a transfer medium (not shown) in the form of a coupling membrane or gel layer. The control of the pulse generators 2 is designed so that tumor-destructive pulse shapes and pulse sequences are applied. The flexible integrated treatment applicators 5, which are regularly in a treatment dome or a treatment ring (see Fig. 12), are aligned with the tumor area and acted upon by the control unit 1 with tumor-destructive pulse trains. Tumor nodules are treated via a plurality of treatment applicators 5 focused on the nodule. Tissue-surrounding tissue with tumor-activated, tumor-protective fibroblasts (TAFS) is scanned by punctiform lethal pulse forms and treated concomitantly or with a time delay.

The use of TMI treatment applicators 5 with punctiform focus is advantageous. In this case, the positioning mechanisms 3 are controlled with the aid of the diagnostic unit 4 such that the punctiform focus of the TMI device scans the entire tumor area. To prevent overheating in the focus To avoid rich, a pulsed control of TMl treatment applicators 5 is advantageous.

In FIG. 2, a TMI treatment applicator is shown schematically by way of example. It comprises a positioning mechanism 1, a focused pulsed treatment applicator 2, a transmission medium 3 and a low frequency (20-30 kHz) treatment applicator.

FIG. 5 shows a diagram from which lethally damaged cells result from the TMI treatment. Shown are FM-human melanocytes, human fibroblasts and W3734 vemurafenibresistente melanoma cells.

FIG. 6 shows a diagram from which lethally damaged cells result from the TMI treatment. Shown are DU145 prostate carcinoma cells, Me1617 vemurafenibresistente melanoma cells and ZF rabdomyosarcoma cells.

Healthy cells survive the TMI treatment without damage, as shown in Figs. 5-9.

FIG. 12 shows a TMI device (or TMI treatment device) BV for the selective, extracorporeal treatment of therapy-resistant cerebral metastases and primary cerebral tumor diseases by means of mechanical pulse fields. The TMI device BV comprises a treatment ring BR to be fastened to the head of a patient, on which a number of treatment applicators BA are arranged. Reference PM denotes a positioning mechanism associated with each treatment applicator BA.

The TMI device BV also includes at least one therapy-accompanying diagnostic unit (not shown) and a positioning mechanism or multiple positioning mechanisms. The treatment applicators BA, which are arranged in an adjustable manner, are attached thereto and are connected via a respective coupling device. membrane (not shown), which is typically provided with a transfer gel that transmit mechanical pulse fields to the cranial bones. The various treatment applicators BA are attached to a treatment ring BR and in the example shown to be directed to a tumor area. The targeted control of the individual treatment applicators BA targeted mechanical pulse fields can be generated at the site of the tumor, which ensure destruction of the tumor.

FIG. 13 shows a variant of the TM1 treatment device from FIG. 12. Also shown are the skull bone SK of a patient and a tumor area TA located therein. The treatment device BV according to FIG. 13 differs from that of FIG. 12 in that the treatment ring BR surrounds only a part of the cranial bone SK. This can, as shown in Fig. 13, be designed in the form of a semicircle, with other variants should not be excluded. FIG. 13 shows a unilateral arrangement of the TMI treatment applicators BA. In this case, the treatment ring BR is executed completely circumferential, as shown in Fig. 13, but only one side of the treatment device BV is equipped with treatment applicators BA.

As shown in Figures 12 and 13, for extracorporeal, selective TMI treatment of cerebral metastases and primary cerebral cancers, several, typically more than three, treatment applicators are positioned extracorporeally by means of positioning mechanisms and positioned on the skull through a coupling gel. The cranial bone absorbs between 50 and 80% of the energy of the pulse fields. The remaining impulse energy is so low that healthy brain areas are not damaged. For primary cerebral tumor cells and cerebral metastatic cells, the superimposed and modulated pulse fields and pulse sequences are sufficient to cause lethal damage. Particularly relevant here are the focused treatment of the tumor areas and the subsequent treatment of possible micrometastases by the uniform distribution of the pulse fields in the whole sound brain mass. The pulse shape, the pulse train and the modulation of the pulse fields are selected accordingly.

A special TMI device according to the invention for the extracorporeal, selective treatment of breast cancer is described below. Such a treatment device may be constructed schematically similar to that shown in FIGS. 14 and 15.

The TMI device in Fig. 14, in turn, includes pulse generators, a controller, a plurality of treatment applicators, and imaging therapy-directing components.

The treatment applicators of the TMI device for the treatment of breast cancer induce tumor-destructive pulse shapes and pulse trains in the tumor area. For focused applicators, the focus is on a sharp increase in pressure. The tissue is compressed. There is a nonlinear increase in the speed of sound, a division of the pressure flanks and a classic pressure surge with strong tumor-destructive properties. Pressure surges can be induced via capacitive discharges in piezoelectric or electromagnetic applicators or applied to the tumor area via focused pulsed sinusoids (p-HIFU). Such an arrangement is particularly advantageous for the selective, non-thermal treatment of breast cancer since own calculations and validating tumor experiments have led to the finding that tumor-destructive impulses have a maximum tumor-destructive effect when the tumor area is heated to 39-41 ° C. before the actual treatment becomes. Before the actual treatment pulses are applied, which heat the tumor area to 39- 41 ° C, preferably about 40 ° C. The device in Fig. 15 may include a plurality of different pulse generators. It may be useful piezoelectric, ballistic or electromagnetic pulse generators or a combination of the above Use pulse generators. From an organ-specific point of view, the arrangements of at least two electromagnetic or piezoelectric treatment applicators are preferred in the extracorporeal treatment of tumor areas of mammary carcinoma. These can be operated synchronously or asynchronously.

Relevant to the invention in the TMI device for the treatment of breast cancer are the focused treatment of the tumor areas and the subsequent treatment of possible micrometastases by the uniform distribution of the pulse fields in the entire area. Affected lymph nodes are not excised, but treated by TMI.

The TMI device for the treatment of mammary carcinoma according to FIG. 14 is designed as a vacuum treatment bell and comprises a threaded ram 1, the bell wall 2, an ultrasonic lower part 3, piezo discs 4, a transmission medium 5, the ultrasonic threaded disc 8, a diaphragm 9 and applicators with positioning mechanisms 10. Reference numeral 6 denotes the tumor area, 7 the breast tissue. The construction of a negative-pressure treatment bell for the destruction of micrometastases in the breast tissue 7 (see Fig. 15) shown in Figures 14 and 15 comprises integrated push-pull applicators 10 in the wall 2. The breast is sucked into the hollow-walled treatment bell. With the aid of an imaging diagnostic unit (not shown), the pressure impact applicators 10 are aligned with the tumor area 6. Concomitant or delayed negative pressure vibrations are applied via the ultrasound converter in the entire breast tissue 7. The selectively acting vibrations (preferably 14-40 kHz) are not focused and cover the entire breast tissue. 7. The frequency of the tumor-destructive vibrations is determined in upstream FEM analyzes. Healthy breast tissue 7 cells survive the treatment without damage. 16 shows by means of a TMI device for the treatment of mammary carcinoma, in particular according to FIG. 14 or 15, generated pulse edges established in the tumor area (curve at reference numeral 11) and continuous sinusoidal oscillations (curve at reference numeral 12).

In FIG. 17, tumor-destructive pulse shapes and pulse sequences with sequentially applied pulses in the low-intensity range (-10 MPA-60 MPA) and high-intensity range (-20 MPa-120 MPA) are shown by way of example, as they can be generated with a device according to the invention or be generated. The control of the device is designed so that before the actual treatment (tio-tn) a series of low-energy pulse forms (trt.2) is applied for the destruction of cellular binding proteins. The pretreatment is required for the necrotic destruction of malignant tumor cells embedded in the extracellular matrix.

Shown in Fig. 18 are combined bursts of burst pulse shapes (Vi) and ballistic pulse shapes (B-i) with sequentially applied inverted pulses (-0.20 MPA - 10.0 MPA) and ballistic pulses (0.0 MPA - 40.0 MPA). The illustrated pulse train is relevant for the treatment of drug-resistant rabdomyosarcoma diseases.

According to FIG. 19, malignant cell fragments are formed by the TMI treatment, which lead to a maturation of dendritic cells and the induction of tumor-toxic properties in T cells of the immune system.

According to FIG. 20, metastatic cells, dendritic cells as well as T cells of the immune system are located in affected lymph nodes. The targeted TMI treatment of affected lymph nodes can lead to a large number of tumor toxic T cells. The simultaneous or time-delayed administration of PD1 immunomodulators blocks the tumor-protective binding sites of the numerous, newly formed tumor-toxic T cells and produces a systemic tumor-destroying effect.

Claims

claims

1 . Device for the treatment of malignant diseases with the aid of tumor-destructive mechanical impulses, with a cell biologically optimized, optimally destructive and tumor-selective patient-specific pulse shape and / or pulse sequences, which consist of the mechanical, visco-elastic properties of the tumor cells and the intertumoral or tumor-surrounding extracellular Matrix (ECM) results or results.

2. Apparatus according to claim 1, which is designed for applying a cell biologically optimized, optimally destructive and tumor-selective pressure impulse pulse sequence.

3. Apparatus according to claim 1 or 2, wherein between the pulses a cell biologically optimized, optimally destructive and tumor-selective delay time is set or adjustable.

4. Device according to one of claims 1 to 3, which by extending an impinged with the pulses target volume in healthy tissue for

Destruction of tumor-activated fibroblasts is formed.

5. Device according to one of claims 1 to 4, with at least one

Pressure sounding head and with at least one control unit for controlling the pressure sonic head for generating the tumor-destructive mechanical impulses or pulse trains.

6. Apparatus according to claim 5, comprising at least one positioning mechanism for positioning the pressure sonic head relative to an impulses acted upon by the target volume, preferably in accordance with the control unit.

7. Apparatus according to claim 5 and claim 6, wherein the pressure sonic head is positioned or positionable and modulated or modulated with respect to its pulse output such that arise in the target volume tumor destructive shear forces.

8. Device according to one of claims 1 to 7, characterized in that for the generation of the tumor-selective pulse shapes and pulse trains at least two pressure sound heads or oppositely polarized Piezoe- elements are provided in phased array technique, preferably with corresponding positioning mechanisms.

9. Device according to one of claims 1 to 8, characterized in that in particular for the treatment of mammary carcinoma or brain metastases at least three or more pressure sound heads are provided with corresponding positioning mechanisms, so that preferably the pressure sound heads are positioned or positioned and in terms of their Impulsabgabe are modulated or modulated so that tumor-destructive shear forces arise in a tumor area.

10. Apparatus according to claim 8 or 9, wherein the positioning mechanisms are controlled or controlled so that a preferably point-shaped focus area is first directed to a tumor edge and this scans, wherein the pulse edges preferably high frequency components of about 1 MHz to 10 MHz.

1 1. Device according to one of claims 6 to 10, wherein the positioning mechanisms are controlled such that a preferably point-shaped focus area is directed to the target volume and scans it, wherein pulse edges have patient-specific low-frequency components, preferably at about 0.1 MHz - 3 MHz ,

12. Device according to one of the preceding claims, wherein a target volume by suitable pulses or pulse trains to about 39 ° C to 41 ° C, preferably about 40 "degrees, is heated.

13. Device according to one of the preceding claims, characterized in that it comprises at least one ballistic and / or at least one electro-hydraulic or piezoelectric shock wave generator or corresponding treatment applicators, in particular for generating positive shock wave pulses.

14. The apparatus according to claim 13, characterized in that the at least one ballistic shock wave generator for generating second shock wave pulses (t10-t1 1) is provided.

15. Device according to one of the preceding claims, characterized in that it comprises at least two shock wave generators and a control unit, wherein the shock wave generators are so successively controlled or controlled by the control unit, that the respective pressure maxima of the shock wave pulses (t1 -t2), (t10- t1 1) follow one another at a time interval which is smaller than the pulse duration (t1-t2), (t10-t1 1) of the shockwave pulses.

16. Device according to one of the preceding claims with at least one diagnostic unit for continuously monitoring a treatment success, in particular for monitoring an ultrasonic echo image of a tumor area, a number of circulating tumor cells in the blood and / or immune parameters.

17. A method for operating and controlling a device according to any one of claims 1 to 16, wherein an optimal pulse shape and / or pulse sequence and / or other operating parameters before use of the device in a cell experiment on a patient extracted cells or by means of a Tissue testing is determined or taken from a database for cell experiments and tissue experiments, which are determined by measurements, in particular AFM measurements, physical properties of the extracted cells and integrated into FEM simulation models.

18. The method according to claim 17, wherein the operating parameters are determined individually for each patient with the aid of physical properties of cells taken from a patient and on the basis of MRI / CT data of the patient.

19. Method according to claim 17, wherein lethal pulse shapes and pulse sequences are determined with the aid of patient-individual numerical simulation models and experimentally validated.

20. The method according to any one of claims 17 to 19, wherein the operation of the TMI treatment via a central treatment center (CTC) and decentralized treatment facilities (TF) takes place.

21. The method of any one of claims 17 to 20, wherein the TMI device is aligned with tumor-affected lymph nodes to treat them individually.

22. The method according to any one of claims 17 to 21, wherein the TMI device is used simultaneously with the use of immunomodulators.