DEVICE FOR TREATING MALIGNANT DISEASES WITH THE HELP OF TUMOR - DESTRUCTIVE MECHANICAL PULSES (TMI)

Abstract

A device and a method, which is individual to a patient, treat malignant diseases by using selectively acting tumor-destructive mechanical pulses (TMI). The tumor-destructive pulse shapes and frequency are determined using physical cell properties, which are individual to each patient. The device is controlled in such that lethal pulse fields are applied in the tumor area.

Claims

1. A device for the treatment of malignant diseases, the device comprising: an impulse generator for generating tumor-destructive impulses, and a control that is configured to generate a pressure shock repetition frequency of 0.2-30 Hz and an energy flux density of 0.1 to 10 mJ/mm.sup.2.

2. The device of claim 1, further comprising an intermediate segment that is used to produce negative pressure pulses.

3. A method of treating a tumor with shock waves, comprising: providing the device as claimed in claim 1; applying pressure shocks of 0.2-30 Hz to the tumor to selectively damage tumor cells using alternating mechanical fields and an energy flux density of 0.1 to 10 mJ/mm2.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0094] In the drawings:

[0095] FIG. 1 is a schematic view showing the construction of a TMI device;

[0096] FIG. 2 shows a schematic representation of a TMI treatment applicator;

[0097] FIG. 3 is a view showing the construction of a TMI cancer treatment center (CTC);

[0098] FIG. 4 is a view showing the AFT determining of the patient-individual cell data;

[0099] FIG. 5 is a graph showing a validating comparison of TMI-treated melanoma cells;

[0100] FIG. 6 is a graph showing a validating comparison of TMI treated prostate carcinoma cells, vemurafenib-resistant melanoma cells and rhabdomio sarcoma cells;

[0101] FIG. 7 is a view showing a validating TMI treatment of tumor-carrying, immune-competent animals (hares) and a comparative comparison of the results (untreated animal with aggressively growing tumor);

[0102] FIG. 8 is a view showing a validating TMI treatment of tumor-carrying, immunocompetent animals (hares) and a comparative comparison of the results (tumor regression after three TMI treatments);

[0103] FIG. 9 is a view showing a validating TMI treatment of tumor-carrying, immune-competent animals (hares) and a comparative comparison of the results (tumor regression after three TMI treatments in combination with Nivolumab);

[0104] FIG. 10 is a view showing a validating TMI treatment of tumor-carrying, immune-competent animals (hares) and a comparative comparison of the results (increase of the immune-markers after three TMI treatments):

[0105] FIG. 11 is a graph showing a validating TMI treatment of tumor-carrying immune-competent animals (mice) and a comparative comparison of the results (tumor progression with the untreated animals and the TMI-treated animals);

[0106] FIG. 12 is a schematic view showing a TMI device for the treatment of brain metastases;

[0107] FIG. 13 is a schematic view showing a TMI device for the treatment of brain metastases with a unilateral arrangement of treatment applicators;

[0108] FIG. 14 is a perspective view showing a TMI device for the treatment of a mammary carcinoma;

[0109] FIG. 15 is a sectional view showing a TMI device for the treatment of the mammary carcinoma;

[0110] FIG. 16 is a graph showing steepened impulse flanks in the tumor region and continuous sinusoidal oscillations, with a TMI device for the treatment of the mammary carcinoma;

[0111] FIG. 17 is a graph showing lethal impulse flanks in the tumor region, said impulse flanks having been produced by a TMI device;

[0112] FIG. 18 is a graph showing lethal impulse flanks in the tumor region, said impulse flanks having been produced with a TMI device;

[0113] FIG. 19 is a schematic view showing the effect of TMI treatment and response of the immune system;

[0114] FIG. 20 shows TMI treatment of affected lymph nodes and response of the immune system in combination with PD1 immunomodulators;

[0115] FIG. 21 shows a simulation of the patient specific shock waves propagation:

[0116] FIG. 22 shows a schematic view of an electrohydraulic TMI device for shock waves induced destruction of carcinoma cells in use;

[0117] FIG. 23 is a view similar to FIG. 22 showing the patient specific shock waves propagation;

[0118] FIG. 24 shows an AFM analysis of patients healthy and malignant cells;

[0119] FIG. 25 shows a FEM model of malignant BLM cells;

[0120] FIG. 26 is a prior art image of the cellular structure of malignent cells;

[0121] FIG. 27 shows shock waves propagation through cellular microstructure;

[0122] FIG. 28 shows selective damaging of MCF7 tumor cells in alternating mechanical fields;

[0123] FIG. 29 illustrates dead melanoma cells, FM melanocytes and FF fibroblasts;

[0124] FIG. 30 shows enlarged views of untreated (control) and treated malignant melanoma tissue;

[0125] FIG. 31 shows untreated control (top) and treated tissue (middle and enlarged detailed view below) of surgical tissue from a pancreatic carcinoma;

[0126] FIG. 32 shows results of the trials with immunocompetent, tumor-bearing animals;

[0127] FIG. 33 is a schematic view of a TMI device for the shock waves destruction of tumor cells and tumor areas;

[0128] FIG. 34 is a schematic view of a TMI shock waves device for extracorporeal treatment of pancreatic cancer in combination with checkpoint inhibitor immunotherapy;

[0129] FIG. 35 is a schematic view of a miniature TMI electohydraulic device for shock waves induced destruction of colon carcinoma cells;

[0130] FIG. 36 shows views of Bone metastases (red arrow, left) before shock wave treatments and after shock wave treatments (right);

[0131] FIG. 37 is a schematic view of a TMI ultrasound device for generating mainly negative pressure fields;

[0132] FIG. 37-1 shows exemplary shock waves that are generated;

[0133] FIG. 37-2 is a schematic illustration of the TMI ultrasound device of FIG. 37 showing a range of preferred exemplary dimensions of some of the elements;

[0134] FIG. 38 is a schematic view of a further TMI electrohydraulic device.

[0135] FIGS. 39-42 show further embodiments of TMI ultrasound devices for treatment of breast carcinoma.

DETAILED DESCRIPTION

[0136] Referring to the drawings, one embodiment of a TMI device is schematically represented in FIG. 1. The device comprises a central control unit or central processing unit (CPU) 1, a TMI impulse generator 2, a positioning mechanism 3, diagnostic units 4 and treatment applicators 5 with a transmission medium.

[0137] The treatment applicators 5 are provided with suitable positioning mechanisms 3 and a diagnostic unit 4. The alignment and positioning of the treatment applicators 5 is effected with the positioning mechanisms 3. The treatment applicators 5 are connected to the skin of a tissue region which is to be treated, via a transmission medium (not shown) in the form of a coupling membrane or gel layer. The control of the impulse generators 2 is configured such that tumor-destructive impulse shapes and impulse sequences are applied. The treatment applicators 5 which are flexibly integrated in a treatment dome or a treatment ring (cf. FIG. 12) in a regular manner are aligned onto the tumor region, and are subjected to tumor-destructive impulse sequences via the control unit 1. Tumor nodes are treated via several treatment applicators 5 which are focused upon the nodes. The tissue which surrounds the tumor, with tumor-protective fibroblasts (TAFS) which are activated by the tumor are scanned by way of lethal impulse shapes which are applied in a pointwise manner and are treated in a concomitant or time-staggered manner.

[0138] The application of TMI treatment applicators 5 with a point-like focus is advantageous. Herein, the positioning mechanisms 3 are activated with the help of the diagnostic unit 4 such that the point-like focus of the TMI device scans the complete tumor region. A pulsed control of the TMI treatment applicators 5 is advantageous in order to avoid an overheating in the focus region.

[0139] A TMI treatment applicator is schematically represented by way of example in FIG. 2. 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.

[0140] A diagram showing cells which are lethally damaged by the TMI treatment is shown in FIG. 5. What are shown are FM-human melanocytes, human fibroblasts and W3734 vermurafenib-resistant melanoma cells.

[0141] A diagram showing lethally damaged cells caused by TMI treatment is shown in FIG. 6. What is shown are DU145 prostate carcinoma cells, ME1617 vermurafenib-resistant melanoma cells and ZF rabdomyo-sarcoma cells.

[0142] Healthy cells survive the TMI treatment without any damage, as can be derived from FIG. 5 to FIG. 9.

[0143] 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 disease with the help of mechanical impulse fields. The TMI device BV comprises a treatment ring BR which is fastened to the head of a patient and on which a number of treatment applicators BA are arranged. The reference numeral PM indicates a positioning mechanism which belongs to each treatment applicator BA.

[0144] The TMI device BV also comprises at least one therapy-accompanying diagnostic unit (not represented) and a positioning mechanism or several positioning mechanisms. The treatment applicators BA are adjustably arranged thereon and transmit the mechanical impulse fields onto the skull via the respective coupling membrane (not shown) which is typically provided with a transmission gel. The various treatment applicators BA are herein attached to a treatment ring BR and in the shown example are directed onto a tumor region. Targeted mechanical impulse fields which ensure a destruction of the tumor can be produced at the location of the tumor by way of the targeted control of the individual treatment applicators BA.

[0145] A variant of the TMI treatment device of FIG. 12 is shown in FIG. 13. Furthermore, the skull SK of a patient and a tumor region TA which is located therein are represented. The treatment device BV according to FIG. 13 differs from that of FIG. 12 in that the treatment ring BR merely surrounds a part of the skull SK. This treatment ring, as is shown in FIG. 13, can be configured in the shape of a semicircle wherein other variants are not to be ruled out. A unilateral arrangement of the TMI treatment applicators BA is shown in FIG. 13. Herein, the treatment ring BR is configured in a completely peripheral manner, as is shown in FIG. 13, wherein however only one side of the treatment device BV is provided with treatment applicators BA.

[0146] As is shown in FIGS. 12 and 13, typically more than three treatment applicators are arranged extracorporeally with the help of positioning mechanism and are positioned on the skullcap via a coupling gel, for the extracorporeal, selective TMI treatment of central metastases and primary cerebral tumor disease. The skull absorbs between 50 and 80% of the energy of the impulse fields. The remaining impulse energy is so low that healthy brain regions are not damaged. The superimposed and modulated impulse fields and impulse sequences are sufficient to effect lethal damage for primary cerebral tumor cells and cerebral metastasis cells. What is particularly relevant here are the focused treatment of the tumor regions and the subsequent treatment of possible micro-metastases by way of a uniform distribution of impulse fields in the complete healthy brain mass. The impulse shape, the impulse sequence and the modulation of the impulse fields are herein selected accordingly.

[0147] A special TMI device according to the invention, for the extracorporeal, selective treatment of the mammary carcinoma is described hereinafter. Such a treatment device can be constructed schematically similarly as is shown in FIG. 14 and FIG. 15.

[0148] The TMI device in FIG. 14 again comprises impulse generators, a control device, several treatment applicators and imaging therapy-accompanying components.

[0149] The treatment applicators of the TMI device for the treatment of the mammary carcinoma induce tumor-destructive impulse shapes and impulse sequences in the tumor region. Concerning the focused applicators, a pronounced pressure increase occurs in the focus. The tissue is compressed. A non-liner increase of the sonic speed, a steepening of the pressure flanks and a classic pressure shock with highly tumor-destructive characteristics occurs. Pressure shocks can be induced via capacitive discharges in piezoelectric or electromagnetic applicators or be applied via focused, pulsed sine oscillations (p-HIFU) in the tumor region. Such an arrangement is particularly advantageous for the selective, non-thermal treatment of the mammary carcinoma since our own computations and validating tumor trials have led to the recognition that tumor-destructive impulses have a maximal tumor-destructive effect when the tumor region is heated to 39-41 C. before the actual treatment. Pulses which heat the tumor region to 39-41 C., preferably about 40 C. are applied before the actual treatment.

[0150] The device in FIG. 15 can comprise several different impulse generators. Herein, it can be useful to apply electrohydraulic, piezoelectric, ballistic or electromagnetic impulse generators or a combination of the mentioned impulse generators. With the extracorporeal treatment of tumor regions of the mammary carcinoma, the arrangements of at least two electrohydraulic, electromagnetic or piezoelectric treatment applicators are preferred for organ-specific reasons. These treatment applicators can be operated synchronously or asynchronously.

[0151] The focused treatment of the tumor regions and the subsequent treatment of possible micro-metastases by the uniform distribution of the impulse fields in the complete region are of relevance to the invention concerning the TMI device for the treatment of the mammary carcinoma. Affected lymph nodes are not excised, but treated by way of TMI.

[0152] The TMI device for the treatment of the mammary carcinoma according to FIG. 14 is configured as a vacuum treatment bell and comprises a threaded plunger 1, the bell wall 2, an ultrasound lower part 3, piezo-discs 4, a transmission medium 5, the ultrasound threaded disc 8, a membrane 9 and applicators with positioning mechanism 10. The reference numeral 6 indicates the tumor region. 7 the breast tissue.

[0153] The construction of a vacuum treatment bell for the destruction of micro-metastases in breast tissue 7 (cf. FIG. 15) and which is represented in FIGS. 14 and 15 comprises pressure shock applicators 10 which are integrated in the wall 2. The breast is sucked into the treatment bell which is configured in a hollow-walled manner. The pressure shock applicators 10 are aligned onto the tumor region 6 with the help of an imaging diagnostic unit (not shown). Vacuum oscillations are applied in the complete breast tissue 7 via the ultrasound converter, in a concomitant or time-shifted manner. The selectively acting oscillations (preferably 14-40 kHz) are not focused and affect the complete breast tissue 7. The frequency of the tumor-destructive oscillations is determined in prior FEM analyses. Healthy cells of the breast tissue 7 survive the treatment without any damage.

[0154] FIG. 16 shows steepened impulse flanks in the tumor region (curve with reference numeral 11) and continuous sine oscillations (curve with reference numeral 12), these having been produced by way of a TMI device for the treatment of the mammary carcinoma, in particular according to FIG. 14 or 15.

[0155] Tumor-destructive impulse shapes and impulse sequences with sequentially applied impulses in the low intensity range (10 MPA-60 MPA) and the high intensity range (20 MPA-120 MPA), as are producible or are produced with a device according to the invention, are represented by way of example in FIG. 17. The control of the device is herein configured such that a sequence of low-energetic impulse shapes (t.sub.1-t.sub.2) for the destruction of cellular bonding proteins is applied before the actual treatment (t.sub.10-t.sub.11). The pre-treatment is necessary for the necrotic destruction of malignant tumor cells which are embedded in the extracellular matrix.

[0156] Combined impulse sequences of pressure shock impulse shapes (V1) and ballistic impulse shapes (B1) with sequentially applied, inverted impulses (0.20 MPA-10.0 MPA) and ballistic impulses (0.0 MPA-40.0 MPA) are represented in FIG. 18. The represented impulse sequence is of relevance to the treatment of therapy-resistant rabdomyo-sarcoma diseases.

[0157] According to FIG. 19, malignant cell fragments arise due to the TMI treatment and lead to a maturation of dentritic cells and the induction of tumor-toxic characteristics in T-cells of the immune system.

[0158] According to FIG. 20, metastasis cells, dentritic cells as well as T-cells of the immune system are located in the affected lymph node. The targeted TMI treatment of affected lymph nodes can lead to a large number of tumor-toxic T-cells. Tumor-protective binding locations of the numerous, newly arisen tumor-toxic T-cells are blocked by way of the simultaneous or time-staggered dosage of PD1 immune modulators, and a systematic tumor-destructive effect unfolds.

ADDITIONAL TESTING AND EMBODIMENTS

[0159] The vibration-induced destruction of malignant cells in ultrasound fields is based on the different dynamic behavior of malignant and healthy cells. However, sinusoidal ultrasound oscillations contain a single frequency band in the frequency domain. In contrast, tumor tissue contains many different cells. Therefore, only tumor cells of a certain size, stiffness, and density will be destroyed by ultrasound waves of a given frequency.

[0160] Shock waves, on the other hand, contain many different frequency bands and have improved tumor-destroying properties.

[0161] The DICOM/FEM data of the patient and the TMI shock wave generator are shown in FIG. 21, where Patient DICOM/FEM data 101 and shock waves generator 102 are shown, while the results of the simulation are shown in FIG. 22, where an electrohydraulic TMI device for shock waves induced destruction of carcinoma cells is shown with a spark discharge 111, a reflector 112, a primary wave 113, and a reflected wave 114.

[0162] Patient specific shock waves propagation is shown in FIG. 23 where strains fields in patient tissue 121 are indicated, and the TMI shock wave generator 102 is again shown.

[0163] At the boundaries of the tumor region, the patient-specific FEM simulation of the shock wave propagation is extended to the cellular level. Here, the time function of the resulting pressure fields and the mechanical properties and geometric dimensions of the cancer cells are introduced into the FEM model computations.

[0164] The simulation-relevant physical values are determined from atomic force microscopy (AFM) measurements of patient cells. AFM patient data are shown in FIG. 24. The values are transferred to FEM models and the dynamic behavior as well as the lethal stresses and strains at the cellular level are obtained. FEM data and strains in the cellular structures are presented in FIGS. 25-27. In FIG. 25, a FEM model of malignant BLM cells is shown with an extracellular matrix 131, cellular membrane 132, actin filaments 133, a nuclear membrane 134, a nuclear structure 135, and micro filaments 136. FIG. 26 shows a prior art image from https://imagej.nih.gov/ij/images/FluorescentCells.jpg with the cellular structure of malignent cells, in which an extracellular matrix 141, a cellular membrane 142, actil filaments 143, a nuclear membrane 144, a nuclear structure 145, and micro filaments 146 are indicated. FIG. 27 shows shock waves propagation through cellular microstructure. Strains in cellular microstructures at t=4 ns (left) and t=8 ns (right) after induced shock wave at the FEM model border.

[0165] Cell mechanics is mainly determined by both the mechanics of the largest organelle in the cell, the nucleus, and the cytoskeletal architecture of the cell.

[0166] In most cancer cells, the cytoskeletal architecture is disrupted. The structural actin filaments are largely clumped and less bundled on the inner surface of the membrane.

[0167] It is well known that cell mechanics plays an important role in cell and tissue biology, from tissue and organ development to wound healing and cancer cell metastasis and migration.

[0168] In general, it is possible to distinguish between cancer cells and normal cells, as well as between primary and metastatic cancer cells.

[0169] Metastatic tumor cells were on average significantly softer than normal cells, breast cancer cells are 34% softer, lung cancer cells are 40% softer, and cervical cancer cells are 50% softer than their normal counterparts.

[0170] Actin filaments are composed of F-actin, which forms thin, polar fibers about 7 nm in diameter. They form a network of short filaments (called the actin cortex) localized beneath the cell membrane. The other components of the cytoskeleton are long and thick fibers that extend throughout the cell volume (stress fibers). A single microtubule is formed from laterally bounded protofilaments. Microtubules spread radially from a microtubule organizing center (MTOC) near the nucleus to become anchored in the cell membrane. During cancer progression, cells adapt their structure by reorganizing actin filaments and microtubules.

[0171] F-actin is mainly distributed at the periphery of cancer cells, and its content was mostly lower than that of normal cells.

[0172] Cytoskeletal morphology plays a key role in the regulation of cell mechanics. In particular, cellular mechanical properties are directly regulated by the highly cross-linked and dynamic cytoskeletal structure of F-actin and microtubules presented in the cytoplasm.

[0173] To validate the working hypotheses described, numerous tumor and vital surgical tissue experiments were performed. Numerous experiments with tumor-bearing animals (immunocompetent New Zealand rabbits) were also performed. Electromagnetic, piezoelectric, and electrohydraulic systems were used and their tumor-destroying effects were compared with those of sinusoidal ultrasound systems.

[0174] It was shown that specific alternating mechanical fields lead to necrotic destruction of malignant cells and can induce apoptotic processes.

[0175] Experiment one. The sensitivity of tumor cells (MCF7) and healthy melanocytes to pressure shocks that can be in the range of 0.2-30 Hz, and are more preferably in a range of 1-3 Hz is shown in FIG. 28. Here, selective damaging of MCF7 tumor cells in alternating mechanical fields occurs and dead MCF7 cells at different impulses frequencies and energy flux density that can be in the range of 0.1-10 mJ/mm2, and are more preferably in the range of 1-2 mJ/mm2, and in can be about 1.24 mJ/mm2 as is shown

[0176] Experiment two. Melanoma cells, FM melanocytes, and FF fibroblasts were exposed to 2 Hz pressure shock waves at an energy flux density of 1.24 mJ/mm2. The result is shown in FIG. 29. Here, dead melanoma cells, FM melanocytes and FF fibroblasts after 0-1030 min shocks waves at 2 Hz pressure shock frequency and energy flux density of 1.24 mJ/mm.sup.2 are shown. The experiments show that vemurafenib-resistant melanoma cells (MeIR) are 100% destroyed at a pressure shock frequency of 2 Hz, while very few skin fibroblasts (11.7%) are destroyed.

[0177] Experiment three. Comparison of vital surgical tissue of malignant melanoma. Untreated control (top) and treated tissue (bottom) are shown in FIG. 30. The treatment was carried out with 4000 pressure shocks at a pressure shock repetition frequency of 2 Hz and an energy flux density of 1.24 mJ/mm.sup.2.

[0178] Experiment four. Vital surgical tissue of pancreatic carcinoma. Untreated control (shown at the top) and treated tissue (shown in the middle and enlarged detailed view below). Treatment was done with 4000 shock waves at 2 Hz and an energy flux density of 1.24 mJ/mm2. The results are shown in FIG. 31.

[0179] Experiment five. Animal trials. FIG. 32 shows the results of the trials with immunocompetent, tumor-bearing animals (New Zealand rabbits). The tumor regression after 3 SW treatments without nivolumab is shown in red. Blue shows tumor regression after 3 pressure shock treatments with the co-administered nivolumab, and black at the top show's tumor progression in untreated animals. Unexpected immunosurveillance was observed after 3 shock waves treatments. No further metastasis was observed after shock waves treatments.

[0180] With appropriate shock waves, tumor cells and entire tumor areas can be completely destroyed. Anyway, they may not be able to destroy untreated distant metastases. However, in combination with checkpoint inhibitors, tumor toxic activated T cells are enabled to destroy untreated distant metastases (abscopal effects). For radiotherapy, there are already initial data that show in individual cases or in smaller series that tumors that have not been irradiated also regress after irradiation. A possibility to improve shockwave treatment is the combination with grid irradiation.

[0181] The stretching rate of malignant cells plays an important role in the necrotic failure of tumor cells. After impingement of the first shock waves, the cellular skeletal filaments of malignant cells are stretched. Significantly more than healthy cells. The rate of re-stretching of malignant cells is slower than that of healthy cells. The second shock wave should be delivered before complete re-expansion. The second and subsequent shock waves cause further stretching of the tumor cells until lethal stretching is reached. Consequently, the second shock wave should be delivered after re-expansion of healthy cells and before complete re-expansion of malignant cells. The second and subsequent shock waves cause further stretching of the tumor cells until lethal stretching is reached.

[0182] During propagation through the cell membrane, noticeable forces can be exerted on the wall because there are immediate pressure differences in front of and behind the wall. The same pressure differences act during the propagation of shock waves through mitochondria.

[0183] Cytoskeletal forces of both immune cells and tumor cells regulate immune cell infiltration into tumors and immune cell polarity. In summary, induced variation in cell stiffness may enhance tumor response to immunotherapies.

[0184] Mechanotransduction describes the transmission of a mechanical stimulus to a tissue and its transformation into a biological reaction. The effect of mechanotransduction can be shown in immediate responses, such as the opening of ion channels or the release of substances, but also in later visible properties, such as modifications in proliferation, apoptosis and gene expression. For instance, muscles respond to mechanical stimuli by increasing the size of muscle cells.

[0185] After shock wave application, reactive oxygen species lead to vasodilation, an increase in eNOS, and a decrease in the inflammatory substances NF-B and TNF- [27-30]. In addition, vascular endothelial growth factor (VEGF) is increased, which plays a critical role in the formation and growth of new tissue.

[0186] The immune system is an essential part of the tumor microenvironment. Cytotoxic lymphocytes, such as cytolytic T cells and natural killer cells, control tumor growth and disease progression by interacting with tumor cells and eliminating them.

[0187] The actin cytoskeleton has been recognized as a central mediator of the formation and maturation of the immunological synapse and cytolytic activities.

[0188] The principle of immunotherapy with checkpoint inhibitors (CPI) is the blockade of inhibitory receptors on T cells, which lead to an inactivation of the immune response. This is a non-specific immunotherapy that can be used for various tumors and has been established with success for melanoma. Here, tumor regressions with long-term tumor remission are achieved in up to 50% of patients.

[0189] However, primary resistance to therapy with checkpoint inhibitors is also observed in 40-50% of patients. The reason for this is probably that a specific immune response to the tumor has not yet developed, which can then be released by checkpoint inhibition. In this respect, the central question for these patients is how to induce a tumor-specific immune response. Various strategies can be considered, in particular (a) tumor-specific vaccinations, (b) radiation therapy for tumor destruction and (c) mechanical destruction of the tumor with alternating mechanical fields, especially shock waves. For radiotherapy, there are already initial data that show in individual cases or in smaller series that tumors that have not been irradiated also regress after irradiation (abscopal effect).

[0190] It is important to perform another shock wave treatment before the malignant cell fragments and tumor antigens are degraded.

[0191] After shock wave treatments immunosurveillance may occur. No further metastasis occurs after complete destruction of malignant cells in the tumor region.

[0192] In the context of shock wave treatment in combination with CPI, the CPI infusion should be given simultaneously or close after the shock waves treatment.

[0193] For successful immunotherapy with CPI, it is sufficient to treat only one metastasis of the tumor. Even untreated distant metastases go into remission and disappear after shock waves treatment (abscopal effects).

[0194] The shock wave treatments are free of side effects and can be repeated until all the tumor cells have been destroyed and no more circulating metastatic cells can be detected in the blood.

[0195] Certain parameters improve the tumor-destroying effect of shock waves. Heating of the tumor area before and during shock wave treatment is one such parameter. Healing alters the cytoskeletal properties of tumor cells, causing softer cytoskeletal filaments and thus more rapid membrane failure. The temperature-induced cell softening and fluidization may be due to an increase in cytoskeletal cross-linking at higher temperatures.

[0196] Another possibility to improve shockwave treatment is the combination of shockwaves with lipid-based nanoparticles, especially liposomes. The combination of shockwaves with thermally responsive polymeric nanoparticles encapsulating curcumin also improves cancer treatment.

[0197] Also, the combination of shock waves with hyperthermia and iron oxide nanoparticles significantly improves the shock wave treatment.

[0198] Pancreatic cancer has a 5-year survival rate of only 8% due to a lack of effective treatment options. Shockwaves combined with systemic administration of a low-temperature sensitive liposomal formulation of doxorubicin improve the prognostic factor for treating pancreatic cancer.

[0199] Magnetic nanoparticles can be directed and concentrated to the tumor cells or site by the apposition of a magnet. Moreover, these nanoparticles can respond to an alternating magnetic field by developing hyperthermia around 43 C., a temperature to which tumor cells, but not healthy cells, are particularly sensitive and thus induced to die. Cancer treatment is significantly improved by shock waves in combination with magnetic nanoparticles.

[0200] Intravenous administration of thermosensitive liposomes loaded with doxorubicin (TSL-Dox) during magnetic hyperthermia may improve shock wave treatment of cancer.

[0201] Hyperthermia therapy (40-44 C.) is a promising option to enhance radiotherapy/chemotherapy efficacy in brain tumors, especially pediatric ones. For this purpose, the Chalmers Hyperthermia Helmet has been developed. Chalmers Hyperthermia in combination with shock waves may improve the treatment of cancer.

[0202] Contrast-enhanced ultrasound (CEUS) is increasingly being used. One of the most common referrals for CEUS performance is characterization of indeterminate focal liver lesions and follow-up of known liver lesions. CEUS is performed with intravenous administration of ultrasound contrast agents (UCAs). Shock waves treatment of cancer diseases could be enhanced with the concomitant application of UCAs.

[0203] As an emerging noninvasive ultrasound imaging technology, CEUS can dynamically and sensitively display the morphology and flow of small blood vessels in real time to reflect the blood supply in tumors. CEUS is extensively applied in clinical practice. Shear wave elastography (SWE) quantitatively evaluates information on tissue hardness using the Young's modulus value of tissues obtained from real-time SWE based on 2-dimensional images. A higher Young's modulus value and redder color indicate harder tissue, whereas a lower Young's modulus value and bluer color indicate softer tissue. SWE is extensively applied in the diagnosis of tumors of the thyroid gland and mammary gland. SWE can differentiate between benign and malignant tumors because the hardness of biological tissues reflects their nature to a certain extent. Shock waves treatment of cancer may be enhanced with CEUS and SWE.

[0204] Another parameter for improving shock wave treatment is the concomitant or upstream shock wave-based destruction of tumor-associated fibroblasts (TAF's).

[0205] TAF's are recruited by cancer cells and promote proliferation and migration by alignment of the actin cytoskeleton.

[0206] In order to damage the TAFs, shock waves are used to destroy the TAFs. The parameters for the shock wave induced destruction of TAF's are determined by the mechanical properties of TAFs and validated experimentally. Frequency-dependent damping properties of TAFs and specific material properties of TAFs enable selective destruction.

[0207] No shock wave-induced metastatic processes were detected in tumor experiments with tumor-bearing animals or in individual patient treatments.

[0208] Regarding the discussion that alternating mechanical fields could promote metastasis, current knowledge indicates that the tumor requires a certain molecular makeup for metastatic spread. This includes the presence of receptors for cell migration and membrane penetration (adhesion molecules and metalloproteinases). If the tumor cell does not have this molecular equipment, even mechanical entrainment of the cell will not induce metastasis. If the tumor cell has the molecular equipment with the appropriate adhesion molecules, the mechanical component is not necessary.

[0209] A TMI device for the shock waves destruction of tumor cells and entire tumor regions is shown in FIG. 33 and includes the following components: Capacitive discharge control 151, Shock waves generator 152, Shock waves applicator 153, and a device location system 154.

[0210] A device for the extracorporeal shock wave treatment of pancreatic cancer is shown in FIG. 34 in combination with checkpoint inhibitor immunotherapy, and includes the following components: patient DICOM data 161, patient rigid body 162, optical localization 163, treatment applicator rigid body 164, shock waves applicator 165, and a FEM simulation model of the patient specific shocks wave propagation 166.

[0211] FIG. 35 shows a detail picture of the miniature electrohydraulic device for the shock wave treatment of colon carcinoma cells. Shown are a colon wall 171, a tumor area 172, a head of the shock wave miniature device with protective cover 173 and miniature camera (not shown) and colonoscopy endoscope 174, 175.

[0212] FIG. 36 shows bone metastases (red arrow, left) before SW treatments and after SW treatments (right). Treatments were performed at the tumor pelvis (red arrow, down). Abscopal effects.

[0213] According to the disclosure, tumor-destroying shock waves break up tumor cells, release tumor antigens and activate the immune system. Tumor cells are made recognizable to the body's immune system. In combination with checkpoint inhibitors, cytotoxically activated T cells are protected from destruction by tumor cells via inhibitory receptors. Therapies have shown that when a single metastasis is treated, untreated distant metastases are also destroyed by activated cytotoxic T cells (abscopal effects).

[0214] Combined treatments to improve tumor destructive and immunological effects are provided above.

[0215] Preferred constructive features of electrohydraulic applicators are described which lead to pressure fields with predominantly tensile components.

[0216] Design features of a TMI device with amplified abscopal effects are described below in connection with the TMI device shown in FIG. 37, which shows an asymmetric ultrasonic generator in which mainly tensile components are generated. Here, the ultrasound device 180 has free support 181 in longitudinal direction which acts as an intermediate element, piezo elements 182, a fixed support 183, a connecting arm 184, and is shown with a transmission medium 185, gel 186, and tissue 187. The ultrasonic generator is operated in the high intensity power range (>20 MPa). Expansion of the piezoelectric ring elements 182 only load the connecting arm 184 in tension via the free support 181 being acted upon axially by the piezo elements 182. This is due to the design: the piezo ring elements 182 that lying freely on the free support 181 that acts as the intermediate segment. When the piezo elements 182 are subsequently contracted, they lift off the free support 181 that acts as the intermediate segment. Compressive forces are therefore not transmitted. This results in a splitting of the pressure flanks and the desired shock wave characteristics (i.e., the generation negative pressure pulses). In addition, the edges of the tumor area can be scanned via phased array control in order to destroy the tumor vein-dense fibroblasts and subsequently break up the tumor cells in the tumor area.

[0217] FIG. 37-1 shows shockwaves 11 generated by increasing the flux density over 1-2 mJ/mm2 of the sinusoidal ultrasound 12.

[0218] FIG. 37-2 is a schematic illustration of the TMI ultrasound device 190 of FIG. 37 showing a range of preferred exemplary dimensions (in mm) for the elements described above. These preferred dimensions are the mean values. However, the dimensions may vary depending on the tumor to be treated. The lower values of the dimensions shown can be used in a device for superficial soft tissue metastases. The upper values of the dimensions shown may be used in a device for treatment of deeper tumor areas. These upper values are also to be preferred when the device is operated in high intensity mode (over 2 W/mmmm) and boiling histotripsy treatment is sought.

[0219] FIG. 38 shows another electrohydraulic TMI device 190 for shockwave treatments having spark electrodes 191, a medium 192, a reflector 193, as well as an intermediate reflector 194.

[0220] FIG. 39 shows another TMI ultrasound device 200 with mainly negative pressure fields for the treatment of breast carcinoma, with a connecting element 201, a treatment vessel 202, a piezo-ring fixed support 203, piezo elements 204, shown with a transmission medium 205 (water at 38-39.5 C.), a tumor region 206, tissue 207, a piezo-ring support that acts as a transmission element 208, a membrane 209, and regeneration ultrasound elements 210. The piezo ring 204 is mounted for free movement on the transmission element 208 and, when activated, expands axially and only transmits compressive forces to the connecting element 201 via the transmission element 208 (which acts as an intermediate segment) by axially moving into contact with and pushing down on the transmission element 208, loading the connecting element 201 in tension. When the piezo elements 204 subsequently retract in the axial direction, contact with the transmission element 208 (which acts as an intermediate segment) is broken. The piezo elements 204 are freely supported at the bottom and fixed at the top. When pulled together, the piezo elements 204 move freely upwards. This means that only negative pressure pulses, i.e., tensile forces, are transmitted via the transmission element 208 through the connecting element 201, the transmission medium 205 and the tumor region 206 during the sine wave energy application.

[0221] FIGS. 40-42 show further embodiments of a TMI ultrasound device 220, similar to the TMI device 200 above, which generates mainly negative pressure fields for the treatment of breast carcinoma. As shown in FIGS. 40 and 41, which are sections taken through a solid model of the device, the TMI ultrasound device 220 includes a connecting element 221, a treatment vessel 222, a piezo-ring fixed support 223, piezo elements 224 (not shown in FIG. 40), shown with a transmission medium 225 (water at 38-39.5 C.), a tumor region 226, tissue 227, and a piezo-ring support that acts as a transmission element 228. Here, the connecting element 221, the transmission element 228, and the piezo-ring fixed support 223 are shown as being integrally formed or connected. The treatment vessel 222 can also be integrally formed or connected with these elements as well.

[0222] Exemplary preferred dimensional ranges for these components (in mm) are also shown in FIG. 42. Here, the possibility that a separate piezo-ring fixed support can be omitted is also illustrated.

[0223] Preferably, in order to accommodate different patient sizes, the treatment vessel (or bell) 202, 222 can be made in different sizes.

[0224] In one preferred treatment, predominantly negative pressure pulses, i.e., tensile force components are applied first (for the destruction of tumor cells) and then, by inverting the control, predominantly pressure components (for regenerative, muscle-building biological effects) are applied.

[0225] In summary, the invention discloses:

[0226] 1. Tumor destructive aspects of the shock wave systems. In particular, the tensile components of the pressure fields have cell-destructive effects. Design specific features, especially of electrohydraulic TMI systems are described. Pressure positive components have especially cell regenerative properties.

[0227] 2. Abscopal effects and properties. Only one (easily accessible) tumor area needs to be treated at a time. By breaking up tumor cells in the treated area, tumor toxic immune cells are activated which also destroy untreated distant metastases.

[0228] 3. In order to activate the immune system continuously, the shock wave treatment as described must take place before all malignant cell fragments have been physiologically degraded.

[0229] 4. The treatment of the easily accessible tumor area must not destroy the entire tumor area, but only parts of the area.

[0230] 5. Tumor-toxic programming of T cells takes place via dendritic cells in lymph nodes. For this reason, it is advantageous not to extract affected lymph nodes but to treat them with shock waves.

[0231] 6. It is advantageous to protect tumor toxic activated T cells via check point inhibitors.

[0232] 7. Tumor areas create a protective environment for themselves. In this area, normal fibroblasts are tumoraderently altered and form a stiff, tumor-protective environment. Shock wave treatment also includes high frequency components that destroy tumor-altered stiff fibroblasts.

[0233] 8. It is advantageous to generate tumor-toxic mechanical fields via asymmetrically acting ultrasound generators, for example as shown in FIG. 37, with dominant tensile components. It is advantageous to increase the tumor destructive properties of the ultrasound device in FIG. 37 by increasing the energy flux density to over 1 mJ/mm2 to 2 mJ/mm2 and thereby effect shock wave specific properties as shown in FIG. 37-1. FIG. 38 shows an embodiment of an electrohydraulic shockwaves generating device with mainly negative pressure fields. FIGS. 39-42 show embodiments of the ultrasound device with mainly negative pressure fields for the treatment of breast carcinoma.

[0234] While specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the invention, it will be understood that the invention may be embodied otherwise without departing from such principles.