Electrode assembly for applying tumor treatment electric fields (TTFields) using anisotropic material sheets

Abstract

Alternating electric fields (e.g., TTFields) may be applied to the body of a subject using one or more electrode assemblies including a sheet of anisotropic material, at least one conductive material layer disposed on a front surface of the sheet of anisotropic material, and an electrode element disposed behind the sheet of anisotropic material. The electrode element has a front surface disposed in electrical contact with a rear surface of the sheet of anisotropic material. The sheet of anisotropic material spreads both heat and current in a direction parallel to the front surface of the sheet, eliminating or at least minimizing hot spots on the electrode assembly. This in turn allows for increased current flow without exceeding a temperature safety threshold (e.g., 41°C).

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 230438 (filed Aug. 6, 2021), U.S. Provisional Application No. 63 / 275841 (filed Nov. 4, 2021), and U.S. Provisional Application No. 63 / 275843 (filed Nov. 4, 2021), which are hereby incorporated by reference in their entirety.

Background Art

[0002] Tumor Treating Fields (TTFields) therapy is a proven approach for treating tumors using an alternating electric field at a frequency between 50 kHz and 1 MHz such as for example 100 - 500 kHz. The alternating electric field is induced by an electrode assembly (an array of capacitive electrodes, also called a transducer array for example) placed on opposite sides of the subject's body. When an AC voltage is applied between the opposing electrode assemblies, an AC current is coupled through the electrode assembly into the subject's body. And a higher current is strongly correlated with a higher treatment effect.

[0003] FIG. 1A is a schematic view of a prior - art electrode assembly 40 including nine prior - art electrode elements labeled X1 - X9. FIG. 1B is a cross - sectional schematic view of electrode elements X7 - X9 of electrode assembly

[0004] taken along the dashed line of FIG. 1A.

[0004] As shown in FIG. 1B, electrode element X7 (taken as an example) includes a metal layer (shown by diagonal hatching) and a ceramic (dielectric material) layer. A layer of conductive hydrogel is provided between each ceramic layer and the subject's skin to ensure good electrical contact of the electrode element with the body. An AC voltage from an AC voltage generator (not shown) is applied to the metal layer of the electrode elements of the opposing electrode assemblies to generate TTFields in the subject's body.

[0005] During use, the skin beneath the hydrogel and electrode elements gradually heats up, so for safety reasons, it is necessary to keep the skin temperature below a safety threshold (e.g., 41°C). Since most of the heat appears directly beneath electrode elements X1-X9 (as shown in Figure 1C), conventional electrode assemblies have hot spots directly beneath the electrode elements, and cold regions located between the electrode elements. These hot spots then limit the amount of current that can be supplied through conventional electrode assemblies. [Overview of the project] [Means for solving the problem]

[0006] One aspect of the present invention is directed to a first apparatus for applying an alternating electric field to the body of a subject. The first apparatus comprises a sheet of anisotropic material, at least one conductive material layer, and a first electrode element. The sheet of anisotropic material has a front and a rear surface. The sheet has a first thermal conductivity in a direction perpendicular to the front surface, and the thermal conductivity of the sheet in a direction parallel to the front surface is at least twice as high as the first thermal conductivity. At least one conductive material layer is disposed on the front surface of the sheet and has a biocompatible front surface. The first electrode element is positioned behind the sheet and has a first front surface disposed to be in electrical contact with the rear surface of the sheet.

[0007] In some embodiments of the first apparatus, the first electrode element comprises (i) a first dielectric material layer having a front and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer (rear layer) positioned between the first front surface of the first electrode element and the rear surface of the sheet, the first conductive material rear layer facilitating electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. Optionally, in these embodiments, the first conductive material rear layer may include a conductive hydrogel.

[0008] In some embodiments of the first apparatus, the first electrode element comprises (i) a first dielectric material layer having a front and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, the first conductive material rear layer facilitating electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. These embodiments also further include a second electrode element positioned behind the sheet. The second electrode element has a second front surface disposed to be in electrical contact with the rear surface of the sheet. The second electrode element comprises (i) a second dielectric material layer having a front and a rear surface, and (ii) a second metal layer disposed on the rear surface of the second dielectric material layer. The front surface of the second dielectric material layer is the second front surface of the second electrode element. The first conductive material rear layer is positioned between the second front surface of the second electrode element and the rear surface of the sheet, and the first conductive material rear layer facilitates electrical contact between the second front surface of the second electrode element and the rear surface of the sheet.

[0009] In some embodiments of the first apparatus, the first electrode element comprises (i) a first dielectric material layer having a front and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, the first conductive material rear layer facilitating electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. These embodiments also further include a second electrode element positioned behind the sheet. The second electrode element has a second front surface disposed to be in electrical contact with the rear surface of the sheet. The second electrode element comprises (i) a second dielectric material layer having a front and a rear surface, and (ii) a second metal layer disposed on the rear surface of the second dielectric material layer. The front surface of the second dielectric material layer is the second front surface of the second electrode element. These embodiments also further include a second conductive material rear layer positioned between the second front surface of the second electrode element and the rear surface of the sheet. The second conductive material rear layer facilitates electrical contact between the second front surface of the second electrode element and the rear surface of the sheet.

[0010] In some embodiments of the first apparatus, the first electrode element comprises (i) a first dielectric material layer having a front and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, the first conductive material rear layer facilitating electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. In these embodiments, the first conductive material rear layer is a conductive adhesive. Optionally, in these embodiments, the conductive adhesive may comprise an adhesive polymer and carbon powder, particles, fibers, flakes, or nanotubes. Optionally, in these embodiments, the conductive adhesive has a thickness between 10 and 2000 μm.

[0011] In some embodiments of the first apparatus, the first electrode element includes a metal piece having a front surface, the front surface of the metal piece being the first front surface of the first electrode element. Optionally, these embodiments may further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, the first conductive material rear layer facilitating electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. Optionally, in these embodiments, the first front surface of the first electrode element may be positioned in direct contact with the rear surface of the sheet.

[0012] In some embodiments of the first apparatus, the anisotropic material sheet is a sheet of graphite. In some embodiments of the first apparatus, the anisotropic material sheet is a sheet of pyrolytic graphite, a graphite foil made of compressed high-purity exfoliated mineral graphite, or a graphitized polymer film. In some embodiments of the first apparatus, the anisotropic material sheet is nonmetallic.

[0013] In some embodiments of the first apparatus, the thermal conductivity of the sheet in the direction parallel to the front surface is more than 10 times higher than the first thermal conductivity. In some embodiments of the first apparatus, the sheet has a first resistance in the direction perpendicular to the front surface, and the resistance of the sheet in the direction parallel to the front surface is less than half of the first resistance.

[0014] In some embodiments of the first apparatus, at least one conductive material layer comprises a hydrogel. In some embodiments of the first apparatus, at least one conductive material layer comprises a layer of hydrogel having a thickness between 50 and 2000 μm.

[0015] In some embodiments of the first apparatus, at least one conductive material layer comprises a conductive adhesive. Optionally, in these embodiments, the conductive adhesive may comprise an adhesive polymer and carbon powder, particles, fibers, flakes, or nanotubes. Optionally, in these embodiments, the conductive adhesive has a thickness between 10 and 2000 μm.

[0016] Some embodiments of the first apparatus further include a sheet, a first electrode element, and a flexible self-adhesive backing configured to support at least one conductive material layer, so that the front surface of at least one conductive material layer can be in contact with and positioned against the skin of a subject.

[0017] In some embodiments of the first apparatus, the sheet has a center of gravity, and the center of gravity of the first front surface of the first electrode element is positioned less than 3 cm away from the center of gravity of the sheet. In some embodiments of the first apparatus, the sheet has a center of gravity and a dimension parallel to the rear surface of the sheet, and the center of gravity of the first front surface of the first electrode element is positioned less than 30% of this dimension away from the center of gravity of the sheet.

[0018] Some embodiments of the first apparatus further include leads electrically connected to the first electrode element.

[0019] Another aspect of the present invention is directed to a first method for applying an alternating electric field to a target region inside a subject's body. The first method includes positioning a first electrode assembly at a first location on or inside the subject's body. The first electrode assembly includes a first sheet of an anisotropic material having a first front and a first rear surface. The first sheet has a first thermal conductivity in a direction perpendicular to the first front surface. The thermal conductivity of the first sheet in a direction parallel to the first front surface is at least twice as high as the first thermal conductivity. The first electrode assembly is positioned such that the first front surface of the first sheet faces the target region. The first method also includes positioning a second electrode assembly at a second location on or inside the subject's body. The second electrode assembly includes a second sheet of anisotropic material having a second front and a second rear surface. The second sheet has a second thermal conductivity in a direction perpendicular to the second front surface. The thermal conductivity of the second sheet in a direction parallel to the second front surface is more than twice as high as the thermal conductivity of the second sheet. The second electrode assembly is positioned such that the second front surface of the second sheet faces the target area. The first method also includes applying an alternating voltage between the first electrode assembly and the second electrode assembly. This application is performed after the first electrode assembly and the second electrode assembly have been positioned.

[0020] In some examples of the first method, the application is carried out by applying an alternating voltage between (i) a first electrode element disposed in electrical contact with the first rear surface and (ii) a second electrode element disposed in electrical contact with the second rear surface.

[0021] Some examples of the first method further include measuring a first temperature of a first electrode element, measuring a second temperature of a second electrode element, and controlling the applied temperature based on the first and second temperatures.

[0022] In some examples of the first method, the first electrode assembly further includes a first conductive material layer disposed on a first front surface. In these examples, the second electrode assembly further includes a second conductive material layer disposed on a second front surface.

[0023] In some cases of the first method, each of the first and second sheets of anisotropic material is a sheet of graphite. In some cases of the first method, each of the first and second sheets of anisotropic material is a sheet of pyrolytic graphite, graphite foil made of high-purity compression-exfoliated mineral graphite, or a graphitized polymer film. In some cases of the first method, each of the first and second sheets of anisotropic material is a nonmetal.

[0024] In some cases of the first method, the thermal conductivity of the first sheet in the direction parallel to the first front surface is more than 10 times higher than the thermal conductivity of the first sheet, and the thermal conductivity of the second sheet in the direction parallel to the second front surface is more than 10 times higher than the thermal conductivity of the second sheet.

[0025] In some cases of the first method, the first sheet has a first resistance in a direction perpendicular to the first front surface, and the resistance of the first sheet in a direction parallel to the first front surface is less than half of the first resistance. The second sheet has a second resistance in a direction perpendicular to the second front surface, and the resistance of the second sheet in a direction parallel to the second front surface is less than half of the second resistance.

[0026] Another aspect of the present invention is directed to a second apparatus for applying an alternating electric field to the body of a subject. The second apparatus comprises a sheet of anisotropic material, at least one conductive material layer, and a first electrode element. The sheet of anisotropic material has a front and a rear surface. The sheet has a first resistance in a direction perpendicular to the front surface, and the resistance of the sheet in a direction parallel to the front surface is less than half of the first resistance. At least one conductive material layer is disposed on the front surface of the sheet and has a biocompatible front surface. The first electrode element is positioned behind the sheet and has a first front surface disposed to be in electrical contact with the rear surface of the sheet.

[0027] In some embodiments of the second device, the first electrode element comprises (i) a first dielectric material layer having a front surface and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, and the first conductive material rear layer facilitates electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. Optionally, in these embodiments, the first conductive material rear layer may include a conductive hydrogel.

[0028] In some embodiments of the second device, the first electrode element comprises (i) a first dielectric material layer having a front surface and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, and the first conductive material rear layer facilitates electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. These embodiments also further include a second electrode element positioned behind the sheet. The second electrode element has a second front surface disposed to be in electrical contact with the rear surface of the sheet. The second electrode element comprises (i) a second dielectric material layer having a front surface and a rear surface, and (ii) a second metal layer disposed on the rear surface of the second dielectric material layer. The front surface of the second dielectric material layer is the second front surface of the second electrode element. The first conductive material rear layer is positioned between the second front surface of the second electrode element and the rear surface of the sheet, and the first conductive material rear layer facilitates electrical contact between the second front surface of the second electrode element and the rear surface of the sheet. [[ID=⑧]] [[ID=⑨]]

[0029] [[ID=⑩]] In some embodiments of the second device, the first electrode element comprises (i) a first dielectric material layer having a front surface and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, and the first conductive material rear layer facilitates electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. These embodiments also further include a second electrode element positioned behind the sheet. The second electrode element has a second front surface disposed to be in electrical contact with the rear surface of the sheet. The second electrode element comprises (i) a second dielectric material layer having a front surface and a rear surface, and (ii) a second metal layer disposed on the rear surface of the second dielectric material layer. The front surface of the second dielectric material layer is the second front surface of the second electrode element. The device further includes a second conductive material rear layer positioned between the second front surface of the second electrode element and the rear surface of the sheet, and the second conductive material rear layer facilitates electrical contact between the second front surface of the second electrode element and the rear surface of the sheet.

[0030] In some embodiments of the second device, the first electrode element comprises (i) a first dielectric material layer having a front surface and a rear surface, and (ii) a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element. These embodiments further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, and the first conductive material rear layer facilitates electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. In these embodiments, the first conductive material rear layer includes a conductive adhesive. Optionally, in these embodiments, the conductive adhesive may include an adhesive polymer and a powder, particles, fibers, flakes, or nanotubes of carbon. Optionally, in these embodiments, the conductive adhesive has a thickness between 10 and 2000 μm.

[0031] In some embodiments of the second apparatus, the first electrode element includes a metal piece having a front surface, the front surface of the metal piece being the first front surface of the first electrode element. Optionally, these embodiments may further include a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the sheet, the first conductive material rear layer facilitating electrical contact between the first front surface of the first electrode element and the rear surface of the sheet. Optionally, in these embodiments, the first front surface of the first electrode element may be positioned in direct contact with the rear surface of the sheet.

[0032] In some embodiments of the second apparatus, the anisotropic material sheet is a sheet of graphite. In some embodiments of the second apparatus, the anisotropic material sheet is a sheet of pyrolytic graphite, graphite foil made of high-purity compression-exfoliated mineral graphite, or a graphitized polymer film. In some embodiments of the second apparatus, the anisotropic material sheet is nonmetallic.

[0033] In some embodiments of the second apparatus, the resistance of the sheet in the direction parallel to the front is less than 10% of the resistance of the first apparatus.

[0034] In some embodiments of the second apparatus, the sheet has a first thermal conductivity in a direction perpendicular to the front surface, and the thermal conductivity of the sheet in a direction parallel to the front surface is more than twice as high as the first thermal conductivity.

[0035] In some embodiments of the second apparatus, at least one conductive material layer comprises a hydrogel.

[0036] In some embodiments of the second apparatus, at least one conductive material layer comprises a conductive adhesive. Optionally, in these embodiments, the conductive adhesive comprises an adhesive polymer and carbon powder, particles, fibers, flakes, or nanotubes. Optionally, in these embodiments, the conductive adhesive has a thickness between 10 and 2000 μm.

[0037] Some embodiments of the second apparatus further include a sheet, a first electrode element, and a flexible self-adhesive backing configured to support at least one conductive material layer, so that the front surface of at least one conductive material layer can be in contact with and positioned against the skin of a subject.

[0038] In some embodiments of the second apparatus, the sheet has a center of gravity, and the center of gravity of the first front surface of the first electrode element is positioned less than 3 cm away from the center of gravity of the sheet. In some embodiments of the second apparatus, the sheet has a center of gravity and a dimension parallel to the rear surface of the sheet, and the center of gravity of the first front surface of the first electrode element is positioned less than 10% of this dimension away from the center of gravity of the sheet.

[0039] Some embodiments of the second apparatus further include leads electrically connected to the first electrode element.

[0040] Another aspect of the present invention relates to a second method for applying an alternating electric field to a target region inside the body of a subject. The second method includes positioning a first electrode assembly at a first location on or inside the body of the subject. The first electrode assembly includes a first sheet of an anisotropic material having a first front and a first rear surface. The first sheet has a first resistance in a direction perpendicular to the first front surface. The resistance of the first sheet in a direction parallel to the first front surface is less than half of the first resistance. The first electrode assembly is positioned such that the first front surface of the first sheet faces the target region. The second method also includes positioning a second electrode assembly at a second location on or inside the body of the subject. The second electrode assembly includes a second sheet of anisotropic material having a second front and a second rear surface. The second sheet has a second resistance in a direction perpendicular to the second front surface. The resistance of the second sheet in a direction parallel to the second front surface is less than half the resistance of the second sheet. The second electrode assembly is positioned so that the second front surface of the second sheet faces the target area. The second method also includes applying an alternating voltage between the first electrode assembly and the second electrode assembly. This application is performed after the first electrode assembly and the second electrode assembly have been positioned.

[0041] In some examples of the second method, the application is carried out by applying an alternating voltage between (i) a first electrode element disposed in electrical contact with the first rear surface and (ii) a second electrode element disposed in electrical contact with the second rear surface.

[0042] Some examples of the second method further include measuring a first temperature of a first electrode element, measuring a second temperature of a second electrode element, and controlling the applied temperature based on the first and second temperatures.

[0043] In some examples of the second method, the first electrode assembly further includes a first conductive material layer disposed on a first front surface. The second electrode assembly further includes a second conductive material layer disposed on a second front surface.

[0044] In some cases of the second method, each of the first and second sheets of anisotropic material is a sheet of graphite. In some cases of the second method, each of the first and second sheets of anisotropic material is a sheet of pyrolytic graphite, graphite foil made of high-purity compression-exfoliated mineral graphite, or a graphitized polymer film. In some cases of the second method, each of the first and second sheets of anisotropic material is a nonmetal.

[0045] In some cases of the second method, the resistance of the first sheet in the direction parallel to the first front surface is less than 10% of the resistance of the first sheet, and the resistance of the second sheet in the direction parallel to the second front surface is less than 10% of the resistance of the second sheet.

[0046] In some cases of the second method, the first sheet has a first thermal conductivity in a direction perpendicular to the first front surface, and the thermal conductivity of the first sheet in a direction parallel to the first front surface is more than twice as high as the first thermal conductivity. Furthermore, the second sheet has a second thermal conductivity in a direction perpendicular to the second front surface, and the thermal conductivity of the second sheet in a direction parallel to the second front surface is more than twice as high as the second thermal conductivity.

[0047] Another aspect of the present invention is directed to a third method for treating a disease in a subject by applying an alternating electric field to a target area within the subject's body. The third method includes positioning a first electrode assembly at a first location on or inside the subject's body. The first electrode assembly includes a first sheet of conductive anisotropic material having a first front surface and a first rear surface. The first sheet has a first thermal conductivity in a direction perpendicular to the first front surface, and the thermal conductivity of the first sheet in a direction parallel to the first front surface is at least twice as high as the first thermal conductivity. The first electrode assembly is positioned such that the first front surface of the first sheet faces the target area. The third method also includes positioning a second electrode assembly at a second location on or inside the subject's body. The second electrode assembly includes a second sheet of conductive anisotropic material having a second front surface and a second rear surface. The second sheet has a second thermal conductivity in a direction perpendicular to the second front surface, and the thermal conductivity of the second sheet in a direction parallel to the second front surface is more than twice as high as the second thermal conductivity. The second electrode assembly is positioned such that the second front surface of the second sheet faces the target area. The third method also includes applying an alternating voltage between the first electrode assembly and the second electrode assembly. This application is performed after the first electrode assembly and the second electrode assembly have been positioned.

[0048] In some instances of the third method, the application is carried out by applying an alternating voltage between (i) a first electrode element disposed in electrical contact with a first rear surface and (ii) a second electrode element disposed in electrical contact with a second rear surface. In some instances of the third method, the target region is within a region selected from one of the torso, brain, and abdomen of the subject.

[0049] In some cases of the third method, the disease is cancer. At random selection, in these cases, the cancer is selected from glioblastoma multiforme, lung cancer, malignant pleural mesothelioma, non-small cell lung cancer, brain metastasis, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, intestinal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, uveal cancer, and liver cancer.

[0050] In some cases of the third method, the disease is cancer, and the method further includes administering one or more anticancer agents. Optionally, in these cases, one or more anticancer agents are selected from temozolomide, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, doxorubicin, cyclophosphamide, trastuzumab, atezolizumab, gemcitabine, mebendazole, sorafenib, oxaliplatin, capecitabine, fluorouracil, leucovorin, depatuxizumab-mafodotin, and ABT-751.

[0051] In some cases of the third method, the disease is cancer, and the method further includes the administration of an immune checkpoint inhibitor. Optionally, in these embodiments, the immune checkpoint inhibitor is selected from one or more of pembrolizumab, nivolumab, semipirimab, atezolimmab, durvalumab, avelumab, and ipilimumab.

[0052] In some cases of the third method, the disease is cancer, and the cancer is glioblastoma multiforme, and this method further includes the administration of temozolomide.

[0053] In some cases of the third method, the disease is cancer, and the method further includes the administration of radiotherapy. Optionally, these cases may further include the administration of one or more of the following: E2F inhibitors, CDK4 / 6 inhibitors, and PARP inhibitors.

[0054] Some examples of the third method further include administering one or more of the following: E2F inhibitors, CDK4 / 6 inhibitors, and PARP inhibitors.

[0055] In some cases of the third method, the disease is a neurodegenerative disease. At random selection, in these cases, the neurodegenerative disease is chosen from among amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, neurofibromatosis, multiple sclerosis, or dementia.

[0056] In some cases of the third method, the disease is an autoimmune disease. At random selection, in these cases, the autoimmune disease is chosen from among Rasmussen's encephalitis (RE), lupus nephritis, type 1 diabetes, rheumatoid arthritis, and polymyositis.

[0057] Some examples of the third method further include measuring a first temperature of a first electrode element, measuring a second temperature of a second electrode element, and controlling the applied temperature based on the first and second temperatures.

[0058] In some examples of the third method, the first electrode assembly further includes a first conductive material layer disposed on a first front surface. The second electrode assembly further includes a second conductive material layer disposed on a second front surface.

[0059] In some cases of the third method, each of the first and second sheets of anisotropic material is a sheet of pyrolytic graphite. In some cases of the third method, each of the first and second sheets of anisotropic material is a graphite foil or graphitized polymer film made of high-purity compression-exfoliated mineral graphite.

[0060] In some cases of the third method, the thermal conductivity of the first sheet in the direction parallel to the first front surface is more than 10 times higher than the thermal conductivity of the first sheet, and the thermal conductivity of the second sheet in the direction parallel to the second front surface is more than 10 times higher than the thermal conductivity of the second sheet.

[0061] In some cases of the third method, the first sheet has a resistance in a direction parallel to the first front surface that is less than half the resistance of the first sheet in a direction perpendicular to the first front surface, and the second sheet has a resistance in a direction parallel to the second front surface that is less than half the resistance of the second sheet in a direction perpendicular to the second front surface.

[0062] In some cases of the third method, the first sheet has a resistance in a direction parallel to the first front surface that is less than 10% of the resistance of the first sheet in a direction perpendicular to the first front surface, and the second sheet has a resistance in a direction parallel to the second front surface that is less than 10% of the resistance of the second sheet in a direction perpendicular to the second front surface.

[0063] Another aspect of the present invention is directed toward chemotherapeutic agents selected from one or more of temozolomide, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, doxorubicin, cyclophosphamide, trastuzumab, atezolizumab, gemcitabine, mebendazole, sorafenib, oxaliplatin, capecitabine, fluorouracil, leucovorin, depatuxizumab-mafodotin, and ABT-751, which are used for the treatment of cancers selected from glioblastoma multiforme, lung cancer, malignant pleural mesothelioma, non-small cell lung cancer, brain metastases, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, intestinal cancer, colon cancer, rectal cancer, liver cancer, hepatocellular carcinoma, and uveal cancer. The chemotherapy drug is administered using an electrode assembly containing a sheet of anisotropic material, in combination with the application of an alternating electric field having a frequency of 50 kHz to 1 MHz.

[0064] Optionally, the application of an alternating current field is carried out by applying an alternating current voltage between (i) a first electrode assembly including a first sheet of anisotropic material and (ii) a second electrode assembly including a second sheet of anisotropic material.

[0065] Optionally, chemotherapy drugs may be administered in combination with immune checkpoint inhibitors. Optionally, chemotherapy drugs may be administered in combination with immune checkpoint inhibitors selected from one or more of the following: pembrolizumab, nivolumab, semipirimab, atezolimmab, durvalumab, avelumab, and ipilimumab.

[0066] Optionally, the cancer is glioblastoma multiforme, and the chemotherapy drug includes temozolomide. Optionally, the cancer is glioblastoma multiforme, and the chemotherapy drug includes temozolomide, further administered in combination with an immune checkpoint inhibitor. Optionally, the cancer is glioblastoma multiforme, and the chemotherapy drug includes temozolomide, further administered in combination with pembrolizumab.

[0067] Optionally, chemotherapy drugs may be administered in combination with radiation therapy.

[0068] Optionally, chemotherapy drugs may be administered in combination with one or more of the following: E2F inhibitors, CDK4 / 6 inhibitors, and PARP inhibitors.

[0069] Optionally, chemotherapy drugs are administered using an electrode assembly containing a graphite sheet, in combination with the application of an alternating electric field having a frequency of 50 kHz to 1 MHz.

[0070] Optionally, chemotherapy drugs are administered in combination with the application of an alternating electric field having a frequency of 50 kHz to 1 MHz using an electrode assembly containing a graphite foil sheet or graphitized polymer film made of pyrolytic graphite or high-purity compression-exfoliated mineral graphite.

[0071] Optionally, the application of an alternating current field is carried out by applying an alternating current voltage between (i) a first electrode assembly comprising a first sheet of anisotropic material having a first front and a first rear surface and (ii) a second electrode assembly comprising a second sheet of anisotropic material having a second front and a second rear surface. The thermal conductivity of the first sheet in the direction parallel to the first front surface is more than twice as high as the thermal conductivity in the direction perpendicular to the first front surface, and the thermal conductivity of the second sheet in the direction parallel to the second front surface is more than twice as high as the thermal conductivity in the direction perpendicular to the second front surface.

[0072] Optionally, the application of an alternating current field is carried out by applying an alternating current voltage between (i) a first electrode assembly comprising a first sheet of anisotropic material having a first front and a first rear surface and (ii) a second electrode assembly comprising a second sheet of anisotropic material having a second front and a second rear surface. The thermal conductivity of the first sheet in the direction parallel to the first front surface is more than 10 times higher than the thermal conductivity in the direction perpendicular to the first front surface, and the thermal conductivity of the second sheet in the direction parallel to the second front surface is more than 10 times higher than the thermal conductivity in the direction perpendicular to the second front surface.

[0073] Optionally, the application of an alternating electric field is carried out by applying an alternating voltage between (i) a first electrode assembly comprising a first sheet of anisotropic material having a first front and a first rear surface and (ii) a second electrode assembly comprising a second sheet of anisotropic material having a second front and a second rear surface. The first sheet has a resistance in a direction parallel to the first front surface that is less than half the resistance of the first sheet in a direction perpendicular to the first front surface, and the second sheet has a resistance in a direction parallel to the second front surface that is less than half the resistance of the second sheet in a direction perpendicular to the second front surface.

[0074] Optionally, the application of an alternating current field is carried out by applying an alternating current voltage between (i) a first electrode assembly comprising a first sheet of anisotropic material having a first front and a first rear surface and (ii) a second electrode assembly comprising a second sheet of anisotropic material having a second front and a second rear surface. The first sheet has a resistance in a direction parallel to the first front surface that is less than 10% of the resistance of the first sheet in a direction perpendicular to the first front surface, and the second sheet has a resistance in a direction parallel to the second front surface that is less than 10% of the resistance of the second sheet in a direction perpendicular to the second front surface.

[0075] Another aspect of the present invention is directed toward immune checkpoint inhibitors selected from one or more of pembrolizumab, nivolumab, semipirimab, atezolimmab, durvalumab, avelumab, and ipilimumab, which are used to treat cancers selected from glioblastoma multiforme, lung cancer, malignant pleural mesothelioma, non-small cell lung cancer, brain metastases, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, intestinal cancer, colon cancer, rectal cancer, liver cancer, hepatocellular carcinoma, and uveal cancer. The immune checkpoint inhibitors are administered using an electrode assembly containing a sheet of anisotropic material in combination with the application of an alternating electric field having a frequency from 50 kHz to 1 MHz.

[0076] Another aspect of the present invention is HLM006474, MRT00033659, YKL-5-124-TFA, YKL-5-124, abemaciclib, ribociclib, trilaciclib, Ibrance, relociclib, arbosidib, roniciclib, ribiciclib, milicib, RGB-286638, NSN3106729, PHA-793887, R547, indirubin, NU610 2. Bohemin, CDK9-IN-7, CGP60474, Pulvalanol A, PF-06873600, Nimboride, FN-1501, AG-024322, ON123300, G1T28, G1T38, AMG925, SHR-6390, BPI-1178, BPI-16350, FCN437, Birocyclib, BEBT-209, Ty-302, TQB-3616, HS-10342, PF-06842874, CS-2002, MM-D37K, CDK4 / The E2F inhibitors, CDK4 / 6 inhibitors, or PARP inhibitors selected from one or more of 6-IN-2, SU9516, AT7519, niraparib, olaparib, and rucaparib are targeted, and these are used to treat cancers selected from among glioblastoma multiforme, lung cancer, malignant pleural mesothelioma, non-small cell lung cancer, brain metastases, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, intestinal cancer, colon cancer, rectal cancer, liver cancer, hepatocellular carcinoma, and uveal cancer. The E2F inhibitors, CDK4 / 6 inhibitors, or PARP inhibitors are administered using an electrode assembly containing a sheet of anisotropic material in combination with the application of an alternating electric field having a frequency from 50 kHz to 1 MHz.

[0077] Another aspect of the present invention is directed toward the use of chemotherapeutic agents selected from temozolomide, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, doxorubicin, cyclophosphamide, trastuzumab, atezolizumab, gemcitabine, mebendazole, sorafenib, oxaliplatin, capecitabine, fluorouracil, leucovorin, depatuxizumab-mafodotin, and ABT-751, which are used in the manufacture of agents for the treatment of cancers selected from glioblastoma multiforme, lung cancer, malignant pleural mesothelioma, non-small cell lung cancer, brain metastases, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, intestinal cancer, colon cancer, rectal cancer, liver cancer, hepatocellular carcinoma, and uveal cancer. The chemotherapy drug is administered using an electrode assembly containing a sheet of anisotropic material, in combination with the application of an alternating electric field having a frequency of 50 kHz to 1 MHz.

[0078] Another aspect of the present invention is directed toward the use of immune checkpoint inhibitors selected from one or more of pembrolizumab, nivolumab, semipirimab, atezolimmab, durvalumab, avelumab, and ipilimumab, which are used in the manufacture of agents for the treatment of cancers selected from among glioblastoma multiforme, lung cancer, malignant pleural mesothelioma, non-small cell lung cancer, brain metastases, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, intestinal cancer, colon cancer, rectal cancer, liver cancer, hepatocellular carcinoma, and uveal cancer. The immune checkpoint inhibitors are administered using an electrode assembly containing a sheet of anisotropic material in combination with the application of an alternating electric field having a frequency from 50 kHz to 1 MHz.

[0079] Another aspect of the present invention is HLM006474, MRT00033659, YKL-5-124-TFA, YKL-5-124, abemaciclib, ribociclib, trilaciclib, Ibrance, relociclib, arbosidib, roniciclib, ribiciclib, milicib, RGB-286638, NSN3106729, PHA-793887, R547, indirubin, NU610 2. Bohemin, CDK9-IN-7, CGP60474, Pulvalanol A, PF-06873600, Nimboride, FN-1501, AG-024322, ON123300, G1T28, G1T38, AMG925, SHR-6390, BPI-1178, BPI-16350, FCN437, Birocyclib, BEBT-209, Ty-302, TQB-3616, HS-10342, PF-06842874, CS-2002, MM-D37K, CDK4 / 6-IN-2 The E2F inhibitor, CDK4 / 6 inhibitor, or PARP inhibitor selected from one or more of SU9516, AT7519, niraparib, olaparib, and rucaparib is intended for use in the manufacture of drugs for use in the treatment of cancers selected from glioblastoma multiforme, lung cancer, malignant pleural mesothelioma, non-small cell lung cancer, brain metastases, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, intestinal cancer, colon cancer, rectal cancer, liver cancer, hepatocellular carcinoma, and uveal cancer. The E2F inhibitor, CDK4 / 6 inhibitor, or PARP inhibitor is administered in combination with the application of an alternating electric field having a frequency of 50 kHz to 1 MHz using an electrode assembly containing a sheet of anisotropic material. Optionally, the E2F inhibitor, CDK4 / 6 inhibitor, or PARP inhibitor may be further administered in combination with radiotherapy.

[0080] Another aspect of the present invention is directed to a third apparatus for applying an alternating current electric field to a target region within the body of a subject. The third apparatus comprises a first electrode assembly, a second electrode assembly, and an alternating current voltage generator. The first electrode assembly includes a first sheet of an anisotropic material having a first front and a first rear surface. The first sheet has a first thermal conductivity in a direction perpendicular to the first front surface, and the thermal conductivity of the first sheet in a direction parallel to the first front surface is at least twice as high as the first thermal conductivity. The second electrode assembly includes a second sheet of anisotropic material having a second front and a second rear surface. The second sheet has a second thermal conductivity in a direction perpendicular to the second front surface, and the thermal conductivity of the second sheet in a direction parallel to the second front surface is at least twice as high as the second thermal conductivity. The alternating current voltage generator is configured to apply an alternating current voltage between the first electrode assembly and the second electrode assembly.

[0081] In some embodiments of the third apparatus, the thermal conductivity of the first sheet in the direction parallel to the first front surface is more than 10 times higher than the thermal conductivity of the first sheet, and the thermal conductivity of the second sheet in the direction parallel to the second front surface is more than 10 times higher than the thermal conductivity of the second sheet.

[0082] In some embodiments of the third apparatus, the first electrode assembly further includes a first conductive material layer disposed on a first front surface, and the second electrode assembly further includes a second conductive material layer disposed on a second front surface.

[0083] In some embodiments of the third apparatus, each of the first and second sheets of anisotropic material is a sheet of graphite. In some embodiments of the third apparatus, each of the first and second sheets of anisotropic material is a sheet of pyrolytic graphite, a graphite foil made of high-purity compression-exfoliated mineral graphite, or a graphitized polymer film.

[0084] Another aspect of the present invention is directed to a fourth apparatus for applying an alternating current electric field to a target region within the body of a subject. The fourth apparatus comprises a first electrode assembly, a second electrode assembly, and an alternating current voltage generator. The first electrode assembly includes a first sheet of anisotropic material having a first front and a first rear surface. The first sheet has a first resistance in a direction perpendicular to the first front surface, and the resistance of the first sheet in a direction parallel to the first front surface is less than half of the first resistance. The second electrode assembly includes a second sheet of anisotropic material having a second front and a second rear surface. The second sheet has a second resistance in a direction perpendicular to the second front surface, and the resistance of the second sheet in a direction parallel to the second front surface is less than half of the second resistance. The alternating current voltage generator is configured to apply an alternating current voltage between the first electrode assembly and the second electrode assembly.

[0085] In some embodiments of the fourth apparatus, the resistance of the first sheet in the direction parallel to the first front surface is less than 10% of the first resistance, and the resistance of the second sheet in the direction parallel to the second front surface is less than 10% of the second resistance.

[0086] In some embodiments of the fourth apparatus, the first electrode assembly further includes a first conductive material layer disposed on a first front surface, and the second electrode assembly further includes a second conductive material layer disposed on a second front surface.

[0087] In some embodiments of the fourth apparatus, each of the first and second sheets of anisotropic material is a sheet of graphite. In some embodiments of the fourth apparatus, each of the first and second sheets of anisotropic material is a sheet of pyrolytic graphite, a graphite foil made of high-purity compression-exfoliated mineral graphite, or a graphitized polymer film. [Brief explanation of the drawing]

[0088] [Figure 1A] This is a schematic diagram of a conventional electrode assembly. [Figure 1B]Figure 1A is a cross-sectional view of an electrode element of a conventional electrode assembly, taken along the dashed line. [Figure 1C] This is a cross-sectional view showing the heat generation characteristics of a conventional electrode element. [Figure 1D] This is a cross-sectional view showing the heat generation characteristics of the electrode element in Figure 1B with a hypothetical modification applied. [Figure 2] This is a schematic plan view of an electrode assembly comprising electrode elements used to apply TTFields to a subject's body. [Figure 3A] Figure 2 is a cross-sectional view of the first embodiment, including electrode elements E1 and E2, taken along the dashed line. [Figure 3B] This is a cross-sectional view showing the heat generation characteristics of the embodiment of Figure 3A. [Figure 4A] This is a thermal image of a conventional electrode assembly. [Figure 4B] This is a thermal image of the electrode assembly corresponding to the embodiment shown in Figure 3A. [Figure 4C] This graph compares the thermal characteristics of conventional electrode assemblies with the embodiment shown in Figure 3A. [Figure 4D] This figure shows a thermal camera image of a simulated electrode array constructed using metal (aluminum) sheets. [Figure 4E] This figure shows a thermal camera image of a simulated electrode array constructed using sheets of anisotropic material (thermolytic graphite). [Figure 4F] This figure shows the experimental results when electrode arrays with and without graphite sheets were used to apply TTFields to the torso of a rat. [Figure 5] Figure 2 is a cross-sectional view of a second embodiment including electrode elements E1 and E2, taken along the dashed line. [Figure 6] This is a cross-sectional view of a third embodiment including a single electrode element E1. [Figure 7] This is a cross-sectional view of a fourth embodiment including a single electrode element E1. [Figure 8] This is a cross-sectional view of a fifth embodiment including a single electrode element E1. [Figure 9] This is a block diagram of a system incorporating two electrode assemblies used to apply TTFields to the subject's body. [Modes for carrying out the invention]

[0089] Various embodiments are described in detail below with reference to the attached drawings, and similar reference numbers represent similar elements.

[0090] This application describes an exemplary electrode assembly that may be used, for example, to deliver TTFields to the body of a subject and treat one or more cancers or tumors located within the body of the subject.

[0091] When TTFields are applied to a subject's body, the temperature of the subject's body may rise in proportion to the induced electric field. Regulation limits the amount of current that can be driven through the transducer array to an amount that keeps the measured temperature at the placement on the subject's body below a temperature threshold. As practiced in the art, the temperature at the placement of the transducer array on the subject's body is controlled to remain below the temperature threshold by reducing the operating current driven by the transducer array, and consequently weakening the intensity of the TTFields. This then becomes a critical limit on the intensity of TTFields that may be used to treat tumors. Therefore, it is necessary in the art to be able to safely access higher TTField intensities without exceeding the temperature threshold at the subject's skin.

[0092] In a transducer array with multiple electrode elements, the portion of the transducer array positioned directly beneath the electrode elements becomes hotter than the portion positioned between the electrode elements. Furthermore, in a transducer array with multiple electrode elements, a larger current flows through the electrode elements positioned along the edges of the array compared to the electrode elements positioned in the center of the array. Moreover, electrode elements positioned at the corners or similar sharp bends of the array's edges have a larger current than other electrode elements along the edges and near the center. This tendency of transducer arrays to conduct higher currents through electrode elements positioned along the edges, particularly at corners, is referred to herein as the “edge effect.”

[0093] Non-uniform current distribution through a transducer array, either due to electrode element distribution or edge effects, can create higher temperature zones (or "hot spots"), for example, at the corners or edges of the transducer array. These hot spots are the first to reach a threshold temperature and therefore control the requirement to reduce the current. As such, the occurrence of hot spots limits the maximum operating current that can be driven by the transducer array, and the resulting intensity of TTFields.

[0094] The inventors now recognize the need for transducer arrays that reduce or minimize the non-uniform distribution of current, thereby enabling the application of larger operating currents. Transducer arrays operating at high currents can induce stronger TTFields within the subject's body, potentially leading to better patient outcomes. The electrode assemblies disclosed herein allow current and heat to be uniformly diffused across the array, thereby minimizing or eliminating hot spots.

[0095] Embodiments described herein incorporate a sheet of material having anisotropic thermal and / or anisotropic electrical properties into an electrode assembly, as described below. If the sheet of material has anisotropic thermal properties, the sheet diffuses heat more uniformly over a larger surface area. If the sheet of material has anisotropic electrical properties, the sheet diffuses current more uniformly over a larger surface area. In each case, this lowers the temperature of hot spots and raises the temperature of colder areas (compared to the prior art configurations described above) when a given AC voltage is applied to the electrode assembly. Thus, the current can be increased without exceeding a safe temperature threshold at any point on the subject's skin (thereby enhancing the therapeutic effect).

[0096] In some embodiments, the anisotropic material is anisotropic with respect to its electrical conductivity. In some embodiments, the anisotropic material is anisotropic with respect to its thermal conductivity. In some preferred embodiments, the anisotropic material is anisotropic with respect to both its electrical conductivity and its thermal conductivity.

[0097] Anisotropic thermal properties include directional thermal properties. In particular, a sheet of anisotropic material has a first thermal conductivity in a direction perpendicular to its front surface. The thermal conductivity of the sheet in a direction parallel to the front surface is at least twice as high as the first thermal conductivity. In some preferred embodiments, the thermal conductivity in the parallel direction is at least 10 times higher than the first thermal conductivity. For example, the thermal conductivity of the sheet in a direction parallel to the front surface may be 1.5 times, 2 times, 3 times, 5 times, 10 times, 20 times, 30 times, 100 times, 200 times, or even 1,000 times higher than the first thermal conductivity. In some embodiments, the thermal conductivity of the sheet of anisotropic material in a direction parallel to the front surface is 5 to 30 times higher than the first thermal conductivity. In some embodiments, the thermal conductivity of the sheet of anisotropic material in a direction parallel to the front surface is 1.5 to 10 times higher than the first thermal conductivity. For example, the thermal conductivity of a sheet of pyrolytic graphite in the xy-plane is 10 to 20 times higher than its thermal conductivity in the perpendicular z-direction.

[0098] Anisotropic electrical properties include directional electrical properties. In particular, the sheet has a first resistance in the direction perpendicular to the front surface, and the resistance of the sheet in the direction parallel to the front surface is less than the first resistance. In some preferred embodiments, the resistance in the parallel direction is less than half of the first resistance or less than 10% of the first resistance. For example, the resistance of sheet 70 in the direction parallel to the front surface may be less than 75%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.5%, 0.1%, or even less than 0.05% of the first resistance. In some embodiments, the resistance of the sheet of anisotropic material in the direction parallel to the front surface is between 10% and 75% of the first resistance. In some embodiments, the resistance of the sheet of anisotropic material in the direction parallel to the front surface is between 0.05% and 10% of the first resistance. For example, the electrical resistivity of a sheet of pyrolytic graphite in the xy-plane is approximately three orders of magnitude (1,000 times) lower than its electrical resistivity in the perpendicular z-direction.

[0099] In some embodiments (for example, when the sheet of anisotropic material is a sheet of pyrolytic graphite), the sheet of anisotropic material has both anisotropic electrical properties and anisotropic thermal properties.

[0100] In some embodiments (for example, when the anisotropic material sheet is a sheet of pyrolytic graphite), the anisotropic material sheet is nonmetallic. These embodiments are particularly advantageous in situations where it is desirable to prevent the movement of ions into the body of the subject. More specifically, using a metal sheet may result in the movement of metal ions into the body of the subject. In situations where this is undesirable, embodiments using a nonmetallic sheet of anisotropic material are preferred.

[0101] The present invention may be more readily understood by referring to the following detailed description, examples, drawings, and claims, as well as the preceding and following descriptions thereof. However, it should be understood that the present invention is not limited to any particular apparatus, device, system, and / or method disclosed unless otherwise specified, and may, of course, be modified as such.

[0102] The headings are provided for convenience and should not be construed as limiting the invention in any way. Embodiments illustrated in any heading or portion of this disclosure may be combined with embodiments illustrated under the same heading or other headings or portions of this disclosure.

[0103] Any combination of the elements described herein in all possible variations of the elements is incorporated herein unless otherwise indicated herein or unless clearly contradicted by the context.

[0104] As used herein and in the accompanying claims, the singular forms indicated by “one” and “it” (corresponding to the articles “a,” “an,” and “the” in the original English text) include the plural form unless the context clearly indicates otherwise.

[0105] Figure 2 is a schematic diagram of an electrode assembly 50 of one embodiment, comprising electrode elements used to apply TTFields to the body of a subject. In Figure 2, only two electrode elements labeled E1 and E2 are shown, but additional electrode elements may be included in the electrode assembly 50. In an alternative embodiment, the electrode assembly 50 includes only a single electrode element. In particular, Figure 2 is a general depiction of the electrode assembly 50, and those electrode assemblies E1 and E2 may have different configurations (as described below, for example, in relation to Figures 3A to 8).

[0106] Figure 3A is a cross-sectional view of a first embodiment of the electrode assembly 50a, including electrode elements E1 and E2, taken along the dashed line in Figure 2.

[0107] In the embodiment shown in Figure 3A, the electrode assembly 50a includes a sheet 70 of an anisotropic material having a front surface (facing the subject's skin in Figure 3A) and a rear surface. This sheet 70 has a first thermal conductivity in the direction perpendicular to the front surface. The thermal conductivity of the sheet 70 in the direction parallel to the front surface is more than twice as high as the first thermal conductivity. In some preferred embodiments, the thermal conductivity of the sheet 70 in the direction parallel to the front surface is more than 10 times higher than the first thermal conductivity. The sheet 70 in the embodiment of Figure 3A is also anisotropic in another respect. More specifically, the sheet 70 has a first resistance in the direction perpendicular to the front surface, and the resistance of the sheet in the direction parallel to the front surface is less than half of the first resistance. In some embodiments, the resistance of the sheet in the direction parallel to the front surface is less than 10% of the first resistance.

[0108] The electrode assembly 50a includes a sheet 70 of a conductive anisotropic material having a front surface (facing the subject's skin in Figure 3A) and a rear surface. The sheet 70 of the conductive anisotropic material may be a sheet of graphite. Examples of preferred forms of graphite include synthetic graphite such as pyrolytic graphite (including, but not limited to, pyrolytic graphite sheets (PGS) available from Panasonic Industries, Ltd., Kadoma City, Osaka Prefecture), other forms of synthetic graphite, including, but not limited to, graphite foil made of high-purity compression-exfoliated mineral graphite (including, but not limited to, those supplied by MinGraph® 2010A Flexible Graphite available from Mineral Seal Corp., Tucson, Arizona, USA), or synthetic graphite such as graphitized polymer films, such as graphitized polyimide films (including, but not limited to, those supplied by Tochigi Kaneka Corporation, Mooka City, Tochigi Prefecture). In alternative embodiments, a conductive anisotropic material other than graphite may be used instead of graphite.

[0109] In some embodiments, the anisotropic material sheet 70 is a sheet of pyrolytic graphite. The thermal conductivity of the pyrolytic graphite sheet in the direction parallel to the front surface of the sheet (i.e., in the xy-plane) is typically 50 times higher than the thermal conductivity of the sheet in the direction perpendicular to the front surface (i.e., the z-direction). The electrical resistivity of the pyrolytic graphite sheet in the direction parallel to the front surface of the sheet (i.e., in the xy-plane) is typically less than 2% of the electrical resistivity of the sheet in the direction perpendicular to the front surface (i.e., the z-direction).

[0110] In other embodiments, the anisotropic material sheet 70 is a graphite foil made of high-purity compression-exfoliated mineral graphite. In other embodiments, the anisotropic material may be pyrolytic carbon or a graphitized polymer film. In other embodiments, the anisotropic material may be boron nitride. In other embodiments, a sheet of another conductive material having anisotropy may be used. In some embodiments (for example, when the anisotropic material sheet is a sheet of synthetic graphite such as pyrolytic graphite, high-purity compression-exfoliated mineral graphite, or a graphitized polymer film), the anisotropic material sheet 70 is nonmetallic.

[0111] The electrode assembly 50a further includes at least one conductive material layer 60 disposed on the front surface of the sheet 70, the at least one conductive material layer 60 having a biocompatible front surface. Note that in the embodiment shown in Figure 3, there is only a single layer 60 of conductive material, and that single layer is biocompatible. However, in alternative embodiments (not shown), there may be multiple layers, in which case only the front layer must be biocompatible. At least one layer 60 of material is configured to ensure good electrical contact between the device and the body. In some embodiments, at least one conductive material layer 60 should cover the entire front surface of the sheet 70 of anisotropic material. At least one conductive material layer 60 may be the same size as or larger than the sheet 70 of anisotropic material. In some embodiments (and as shown in Figure 3A), at least one conductive material layer 60 includes a single layer of hydrogel. In these embodiments, the hydrogel may have a thickness between 50 and 2000 μm, such as 100 to 1000 μm, or even 300 to 500 μm. In some embodiments, at least one conductive material layer 60 is a single layer of non-hydrogel biocompatible conductive adhesive. In some embodiments, at least one conductive material layer 60 is a single layer of non-hydrogel biocompatible conductive adhesive such as product FLX068983 - FLEXcon® OMNI-WAVE® TT 200 BLACK H-502 150 POLY H-9 44PP-8 developed by FLEXcon, Inc., located in Spencer, Massachusetts, USA, or other such OMNI-WAVE products from FLEXcon, Inc., or ARcare® 8006 conductive adhesive composition manufactured and sold by Adhesives Research, Inc., located in Glenrock, Pennsylvania, USA. Non-hydrogel conductive adhesives may contain anhydrous polymers having adhesive properties, and carbon particles, powders, fibers, flakes, or nanotubes. The adhesive polymer may be, for example, an acrylic polymer, a silicone polymer, or a combination thereof, which may be available as acrylic or silicone-based carbon-filled adhesive tapes.The adhesive may also contain one or more conductive polymers (for example, polyaniline (PANI), poly(3,4-ethylenedioxythiophene (PEDOT), or others known in the art). The conductive filler in at least one conductive material layer 60 should be nonmetallic. In these embodiments, the biocompatible conductive adhesive may have a thickness between 10 and 2000 μm, such as 20 to 1000 μm, or even 30 to 400 μm.

[0112] The electrode assembly 50a further includes a first electrode element E1 positioned behind the sheet 70. The first electrode element E1 has a first front surface disposed to be in electrical contact with the rear surface of the sheet 70. In the embodiment of Figure 3A, the first electrode element E1 comprises a first dielectric material layer 310 of a dielectric (e.g., ceramic) material having a front and a rear surface, and a first metal layer 320 disposed on the rear surface of the first dielectric material layer 310. The front surface of the first dielectric material layer 310 is the first front surface of the first electrode element E1. Although the figure (e.g., Figure 3A) depicts the dielectric material 310 as "ceramic," it should be noted that a variety of other suitable dielectric materials may be used instead of the ceramic material. Examples include a polymer layer having a dielectric constant of at least 10, or another material having a dielectric constant of at least 10.

[0113] In some embodiments, the dielectric material layer 310 can have a dielectric constant in the range of 10 to 50,000. In some embodiments, the dielectric material layer 310 comprises a highly dielectric polymer material such as poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) and / or poly(vinylidene fluoride-trifluoroethylene-1-chlorofluoroethylene). These two polymers are abbreviated herein as "poly(VDF-TrFE-CTFE)" and "poly(VDF-TrFE-CFE)", respectively. These embodiments are particularly advantageous because the dielectric constants of these materials are on the order of 40. In some embodiments, the polymer layer may be poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) or "poly(VDF-TrFE-CTFE-CFE)".

[0114] In some embodiments, the dielectric material layer 310 comprises a terpolymer containing polymerization units of monomers such as VDF, TrFE, CFE, and / or CTFE in any preferred molar ratio. Preferred terpolymers include, for example, those having 30 to 80 mol% VDF, 5 to 60 mol% TrFE, and CFE and / or CTFE constituting the remaining mol% of the terpolymer.

[0115] In some embodiments, the sheet 70 has a center of gravity, and the center of gravity of the first front surface of the first electrode element E1 is positioned less than 3 cm away from the center of gravity of the sheet 70. In some embodiments, the sheet 70 has a center of gravity and a dimension (e.g., length or width) parallel to the rear surface of the sheet 70, and the center of gravity of the first front surface of the first electrode element E1 is positioned less than 30% or less than 10% of this dimension away from the center of gravity of the sheet 70.

[0116] The electrode assembly 50a further includes a first conductive material rear layer 80 positioned between the first front surface of the first electrode element E1 (i.e., the front surface of the first dielectric material layer 310) and the rear surface of the sheet 70. The first conductive material rear layer 80 facilitates electrical contact between the first front surface of the first electrode element E1 and the rear surface of the sheet 70. In the embodiment illustrated, the conductive material rear layer 80 is a layer of hydrogel. However, in alternative embodiments, different conductive materials (e.g., conductive grease, conductive adhesive, conductive tape, conductive composite material, etc.) may be used. In some embodiments, the conductive material 80 may be a non-hydrogel conductive adhesive as described above.

[0117] The electrode assembly 50a may optionally include one or more additional electrode elements. In the embodiment illustrated, the electrode assembly 50a includes a second electrode element E2 positioned behind the sheet 70. The second electrode element E2 has a second front surface disposed to be in electrical contact with the rear surface of the sheet 70. The two electrode elements E1 and E2 in Figure 3A have the same structure. Thus, the second electrode element E2 comprises a second dielectric material layer 310 of a dielectric (e.g., ceramic) material having a front and a rear surface, and a second metal layer 320 disposed on the rear surface of the second dielectric material layer 310. The front surface of the second dielectric material layer 310 is the second front surface of the second electrode element E2. In some embodiments, the combined area of ​​all electrode elements is less than the area of ​​the sheet 70, less than half the area of ​​the sheet 70, less than one-quarter of the area of ​​the sheet 70, or less than one-tenth of the area of ​​the sheet 70.

[0118] The first conductive material rear layer 80 is positioned between the second front surface of the second electrode element E2 (i.e., the front surface of the second dielectric material layer 310) and the rear surface of the sheet 70. The first conductive material rear layer 80 facilitates electrical contact between the second front surface of the second electrode element E2 and the rear surface of the sheet 70. As described for E1 and as shown in Figure 3A, the conductive material 80 may be a layer of hydrogel, but in alternative embodiments, different conductive materials may also be used (e.g., conductive grease, conductive adhesives including the non-hydrogel conductive adhesive described above, conductive tape, conductive composite material, etc.).

[0119] The metal layers 320 of all electrode elements (i.e., E1 and E2 in the illustrated embodiment) can be wired together to leads 90 (e.g., using wires, traces on a flexible circuit, etc.). The leads 90 supply AC voltage from an AC voltage generator (not shown) to the electrode elements to generate TTFields when the electrode assembly 50a is attached to the subject's body for treatment.

[0120] Optionally, the electrode assembly 50a includes a sheet 70, a first electrode element E1 (and other electrode elements present in the electrode assembly), and a flexible self-adhesive backing 55 configured to support at least one conductive material layer 60 such that the front surface of at least one conductive material layer 60 can be positioned relative to the skin of the subject.

[0121] As described above, Figure 2 is a schematic plan view of the electrode assembly 50 including electrode elements E1 and E2. This diagram in Figure 2 (not to scale) also shows that the area of ​​sheet 70 is larger than the combined area of ​​electrode elements E1 and E2 (for example, at least twice as large, at least four times as large, or at least ten times as large). When an AC voltage is applied to electrode elements E1 and E2, the heat diffuses throughout sheet 70, minimizing or eliminating hot spots. In addition to the diffusion and redirection of heat (minimizing heat in specific locations), diffusion has an additional effect on heat dissipation, but it is because most of it is directed towards the edges of the sheet in the xy plane, which ends up at a room temperature (cooler) heat sink rather than traveling to fairly warm body temperature in the z direction. This area, therefore, cools considerably faster.

[0122] This reduction in hot spots (compared to the conventional technology) becomes more apparent when comparing Figure 1C and Figure 3B. More specifically, Figure 1C shows the current distribution and heat generation for conventional electrode elements, each positioned on a conductive hydrogel layer covering approximately the same area (in the xy plane) as the electrode element. As shown in Figure 1C, all current passes through the hydrogel layer directly beneath the electrode element, resulting in a hot spot directly beneath the electrode element.

[0123] One might initially think that this problem could be solved by increasing the area of ​​the hydrogel to cover all regions between the electrode elements (i.e., by covering a significantly larger area in the xy-plane compared to the area of ​​the electrode elements). However, this is not the case. More specifically, Figure 1D shows the current distribution and heat generation for this hypothetical electrode assembly. As shown in Figure 1D, all the current passes straight through the hydrogel layer directly beneath the electrode elements, resulting in a hot spot directly beneath the electrode elements.

[0124] In contrast, Figure 3B shows the current distribution for the embodiment in Figure 3A. As shown in Figure 3B, the current is still distributed only within the post-conductive material layer (e.g., 80 in Figure 3B) in the region beneath the electrode element. However, the anisotropic material sheet 70 diffuses heat throughout its entire region because its thermal conductivity in the horizontal direction (i.e., parallel to the plane of the sheet) is much higher than its thermal conductivity in the vertical direction. In addition to diffusing heat, the low electrical resistance of the sheet 70 in the horizontal direction diffuses the current outward throughout the sheet 70, and this diffused current distribution continues within the conductive material layer 60 (hydrogel in both Figures 3A and 3B), from there to the skin of the subject. In this embodiment, both current and heat are diffused over a wider area of ​​the conductive material layer 60, so that hot spots are eliminated (or at least minimized). This means that for a given applied AC voltage, the hottest point beneath the electrode assembly in the embodiment in Figure 3A / B has a lower temperature than the hottest point beneath the electrode assembly in the prior art example in Figure 1. Therefore, the current can be increased (with respect to the current of the prior art) without exceeding the safe temperature threshold at any point under the electrode assembly in the embodiment of Figure 3A. This increase in current advantageously enhances the efficacy of TTFields treatment. Similar results can also be achieved when the hydrogel is replaced with a conductive adhesive composite material.

[0125] The superior performance of the embodiment shown in Figure 3A is demonstrated in Figures 4A, 4B, and 4C. Figure 4A is a thermal image of a prior art electrode assembly including two electrode elements and a layer of hydrogel disposed in front of the electrode elements (see, for example, Figure 1B). There is no sheet of anisotropic material between the front of the electrode elements and the rear of the hydrogel layer. During use, the front of the hydrogel layer is positioned on the skin of the subject. Figure 4A shows a hot spot generated within the region corresponding to the electrode element.

[0126] Figure 4B is a thermal image of the electrode assembly corresponding to the embodiment in Figure 3A in which pyrolytic graphite was used as the anisotropic material. Figure 4B shows that hot spots, which occurred in the conventional electrode assembly, are minimized, and the maximum temperature is reduced. Figure 4C is a graph showing a comparison of the thermal performance of the embodiment in Figure 3A (using pyrolytic graphite as the anisotropic material) and the conventional technology (no anisotropic material) for the same applied current (500 mA). In particular, the hottest part of the conventional electrode assembly was 41°C. However, when the same 500 mA current was applied to the embodiment in Figure 3A, the hottest part of the electrode assembly was only 32°C. Similar experiments were performed using graphite foil made of high-purity compression-exfoliated mineral graphite as the anisotropic material, and similar results were obtained.

[0127] In the relevant experiments, the optimized conventional array (without anisotropic material) rose to an average temperature of up to 40°C with an applied current of 2A, but this was limited. The same type of array with added pyrolytic graphite sheets (in the configuration of the embodiment in Figure 3A) was able to operate at increased power levels (applied current of 3A) and operated at an average temperature of 38°C, 2–3°C below the temperature threshold limit. These results suggest that the apparatus and methods of the present invention described herein may achieve more beneficial therapeutic outcomes by operating with higher applied currents.

[0128] In experimental simulations of electrodes for therapeutic target placement within the body, the heat distribution obtained using pyrolytic graphite sheets was compared with that obtained using metal sheets. In half of the experiment, a phantom gel was implanted sandwiched between two sheets of metal (aluminum), and a voltage was applied between the two metal sheets (directly to the center of the sheets). In the other half of the experiment, a phantom gel was implanted sandwiched between two sheets of pyrolytic graphite, and a voltage was applied between the two pyrolytic graphite sheets (directly to the center of the sheets). Metals are generally excellent conductors (both thermal and electrical). Pyrolytic graphite sheets also have good electrical conductivity (and their electrical conductivity in the xy-plane is higher than that in the perpendicular z-direction). However, the electrical conductivity of pyrolytic graphite in the xy-plane is two orders of magnitude lower than that of conventional metals. When a voltage is applied between a pair of metal sheets (aluminum), the high conductivity and equipotential properties of the aluminum sheets result in a higher current density at the edges of the sheets, leading to uneven heating in different regions. In contrast, applying a voltage between two graphite sheets results in a more uniform current density at the center and edges of the sheets (due to the higher resistance in the xy plane compared to metal), and a more uniform temperature profile of the sheets.

[0129] Figures 4D and 4E show thermal camera images of simulated electrode arrays using metal (aluminum) sheets and simulated electrode arrays using anisotropic material (pyrolytic graphite) sheets, respectively. The aluminum sheets result in a non-uniform thermal distribution, which controls the requirements by causing the outer edges to reach the threshold temperature first and thus reduce the current. In contrast, the pyrolytic graphite sheets result in a very uniform thermal distribution across the entire sheet.

[0130] Figure 4F shows experimental results when electrode arrays with and without graphite sheets were used to apply TTFields to the torso of rats (using a small animal array). The two lower traces show the measured currents for two rats when the conventional electrode arrays depicted in Figure 1A / 1B were used, and the two upper traces show the measured currents for two rats when the electrode elements depicted in Figure 3A (using graphite sheets as a layer of anisotropic material) were used. The temperature setpoint was the same for all implementations. In particular, when the graphite sheet was included, the resistance was 20% lower and the current was 50% higher at the same temperature setpoint, resulting from improved heat and current distribution attributable to the graphite. And since the higher current is associated with improved results, these experiments indicate that incorporating a layer of anisotropic material into the electrode array can lead to improved results.

[0131] Figure 5 is a cross-sectional view of a second embodiment of electrode assembly 50b, including electrode elements E1 and E2, taken along the dashed line in Figure 2. The embodiment in Figure 5 is similar to the embodiment in Figure 3A in all respects except for the following: The embodiment in Figure 3A includes a broad rear layer 80 of conductive material (e.g., hydrogel) positioned between the sheet 70 and the front surfaces of both the first and second electrode elements E1 and E2. In contrast, the embodiment in Figure 5 includes separate regions 380 of conductive material for each individual electrode element. Thus, the embodiment in Figure 5 includes a first conductive material rear layer 380 positioned between the first front surface of the first electrode element E1 and the rear surface of the sheet 70, and also includes a second conductive material rear layer 380 positioned between the second front surface of the second electrode element E2 and the rear surface of the sheet 70. The first and second rear layers 380 of conductive material facilitate electrical contact between the front surfaces of the respective electrodes and the rear surface of the sheet 70. In the embodiments illustrated, the rear layer 380 of the conductive material is a layer of hydrogel. However, in alternative embodiments, different conductive materials (e.g., conductive grease, conductive adhesives including the non-hydrogel conductive adhesives described above, conductive tapes, conductive composite materials, etc.) may be used. In some embodiments, the combined area of ​​all electrode elements is less than the area of ​​sheet 70, less than half the area of ​​sheet 70, less than one-quarter the area of ​​sheet 70, or less than one-tenth the area of ​​sheet 70.

[0132] Similar to the embodiment in Figure 3A, the current in the embodiment in Figure 5 is still concentrated in the rear layer 380 of the conductive material only in the region beneath the electrode element. The sheet 70 of the anisotropic material diffuses heat and current as described above in relation to the embodiment in Figure 3A, which eliminates or at least minimizes hot spots. This means that for a given applied AC voltage, the hottest point under the electrode assembly in the embodiment in Figure 5 is at a lower temperature than the hottest point under the electrode assembly in the prior art example in Figure 1. Thus, the current can be increased (with respect to the current in the prior art) without exceeding the safe temperature threshold at any point under the electrode assembly in the embodiment in Figure 5. And this increase in current is advantageous in that it enhances the effectiveness of the TTFields treatment.

[0133] Figure 6 is a cross-sectional view of a third embodiment of an electrode assembly 50c including a single electrode element E1. The embodiment in Figure 6 is similar to the embodiment in Figure 3A, except that the embodiment in Figure 6 does not include a layer of dielectric material. In the embodiment in Figure 6, the electrode assembly 50c includes a sheet 70 of an anisotropic material having a front surface (facing the skin of the subject in Figure 6) and a rear surface. This sheet 70 is similar to the sheet 70 described above in relation to Figure 3A. In some embodiments, the sheet 70 of the anisotropic material is a sheet of synthetic graphite. In some embodiments, the sheet 70 of the anisotropic material is a sheet of pyrolytic graphite. In other embodiments, the sheet 70 of the anisotropic material is graphite foil made of high-purity compression-exfoliated mineral graphite (e.g., MinGraph® 2010A Flexible Graphite). In other embodiments, the sheet 70 of the anisotropic material is a sheet of graphitized polymer film. In other embodiments, the sheet 70 of the anisotropic material is a sheet of pyrolytic carbon. In other embodiments, the anisotropic material may be boron nitride. In other embodiments, the anisotropic material sheet 70 is a sheet of another conductive anisotropic material. In some embodiments (for example, when the anisotropic material sheet is a sheet of synthetic graphite such as pyrolytic graphite, high-purity compression-exfoliated mineral graphite, or a graphitized polymer film), the anisotropic material sheet 70 is nonmetallic.

[0134] The electrode assembly 50c further includes at least one biocompatible conductive material layer 60 disposed on the front surface of the sheet 70, the at least one conductive material layer 60 having a biocompatible front surface. Note that in the embodiment shown in Figure 6, there is only a single layer 60 of conductive material, and that single layer is biocompatible. However, in alternative embodiments (not shown), there may be multiple layers, in which case only the front layer must be biocompatible. The at least one conductive material layer 60 is configured to ensure good electrical contact between the device and the body. In one preferred embodiment, the at least one conductive material layer 60 should cover the entire front surface of the anisotropic material sheet 70. The at least one conductive material layer 60 may be the same size as the anisotropic material sheet 70 or larger (i.e., covering the same or a larger area). In some embodiments, the at least one conductive material layer 60 includes a single layer of hydrogel. In these embodiments, the hydrogel may have a thickness between 50 and 2000 μm, such as 100 to 1000 μm, or even 300 to 500 μm. In some embodiments, at least one conductive material layer 60 is a single layer of a non-hydrogel biocompatible conductive adhesive, such as FLEXcon's OMNI-WAVE product or Adhesives Research, Inc.'s ARcare® product, as described above. The non-hydrogel conductive adhesive may comprise an anhydrous polymer having adhesive properties (e.g., an acrylic polymer, a silicone polymer, or a combination thereof) and a conductive filler. The conductive filler in at least one conductive material layer 60 should be nonmetallic. In these embodiments, the biocompatible conductive adhesive may have a thickness between 10 and 2000 μm, such as 20 to 1000 μm, or even 30 to 400 μm.

[0135] The electrode assembly 50c further includes a first electrode element E1 positioned behind the sheet 70. The first electrode element E1 includes a metal piece 500 having a front surface disposed to electrically contact the rear surface of the sheet 70. In the embodiment of Figure 6, the front surface of the metal piece 500 is the first front surface of the first electrode element E1. Thus, the embodiment of Figure 6 differs from the embodiments of Figure 3A or Figure 5 in that it lacks a layer of dielectric material. The positional relationship between the first electrode element E1 and the sheet 70 in this embodiment of Figure 6 may be as described above in relation to Figure 3A.

[0136] The electrode assembly 50c further includes a first conductive material rear layer 80 positioned between the first front surface of the first electrode element E1 (i.e., the front surface of the metal piece 500) and the rear surface of the sheet 70. The first conductive material rear layer 80 facilitates electrical contact between the first front surface of the first electrode element E1 and the rear surface of the sheet 70. In the embodiment illustrated, the conductive material rear layer 80 is a layer of hydrogel. However, in alternative embodiments, different conductive materials (e.g., conductive grease, conductive adhesives including the non-hydrogel conductive adhesives described above, conductive tapes, conductive composite materials, etc.) may be used.

[0137] The metal piece 500 of the electrode element E1 is wired to a lead 90 (for example, using a wire, trace on a flexible circuit, etc.), which supplies an AC voltage to the electrode element from an AC voltage generator (not shown) to generate TTFields when the electrode assembly 50c is attached to the subject's body for treatment.

[0138] The electrode assembly 50c may optionally include one or more additional electrode elements (not shown) that have the same structure and function as electrode element E1 and are positioned to have the same function. In such a case, the metal pieces 500 of all electrode elements may be wired together to the lead 90 (for example, using wires, traces on a flexible circuit, etc.).

[0139] In some embodiments including only a single electrode element E1, the area of ​​the sheet 70 is larger than the area of ​​the electrode element E1 (for example, at least twice as large, at least four times as large, or at least ten times as large). In some embodiments including multiple electrode elements (not shown), the area of ​​the sheet 70 is larger than the combined area of ​​all the electrode elements (for example, at least two, four, or ten times as large). When an AC voltage is applied to the electrode elements, heat is diffused throughout the sheet 70, minimizing or eliminating hot spots.

[0140] Similar to the embodiment in Figure 3A, the anisotropic material sheet 70 in the embodiment in Figure 6 diffuses heat and current, as described above in relation to the embodiment in Figure 3A, which eliminates or at least minimizes hot spots. This means that for a given applied AC voltage, the hottest point under the electrode assembly in the embodiment in Figure 6 has a lower temperature than the hottest point under the electrode assembly in the prior art example in Figure 1. Thus, the current can be increased (with respect to the current in the prior art) without exceeding the safe temperature threshold at any point under the electrode assembly in the embodiment in Figure 6. And this increase in current is advantageous in that it enhances the effectiveness of TTFields treatment.

[0141] Figure 7 is a cross-sectional view of a fourth embodiment of an electrode assembly 50d including a single electrode element E1. The embodiment in Figure 7 is similar to the embodiment in Figure 6, except that the first front surface of the first electrode element E1 (i.e., the front surface of the metal piece 600) is positioned in direct contact with the rear surface of the sheet 70 (instead of being electrically connected via an intervening layer of conductive material).

[0142] Similar to the embodiment in Figure 6, the anisotropic material sheet 70 in the embodiment in Figure 7 diffuses heat and current, as described above in relation to the embodiment in Figure 3A, which eliminates or at least minimizes hot spots. This means that for a given applied AC voltage, the hottest point under the electrode assembly in the embodiment in Figure 7 has a lower temperature than the hottest point under the electrode assembly in the prior art example in Figure 1. Thus, the current can be increased (with respect to the current in the prior art) without exceeding the safe temperature threshold at any point under the electrode assembly in the embodiment in Figure 7. And this increase in current is advantageous in that it enhances the effectiveness of TTFields treatment.

[0143] Figure 8 is a cross-sectional view of a fifth embodiment of the electrode assembly 50e, which includes a single electrode element E1. The embodiment in Figure 8 is similar to the embodiment in Figure 7, except that a capacitor 700 is added in series with the metal piece 600, after which it is connected. A similar addition of a capacitor 700 connected after the metal piece 600, in series with the metal piece 600, could also be considered for the embodiment in Figure 6.

[0144] Figure 9 shows how the pair of electrode assemblies 50a shown in Figure 3A are used to apply an alternating electric field to a target area within the body of a subject. The subject may be a human or other mammal, including but not limited to rats and mice. (Note that any of the electrode assemblies described above in relation to Figures 5-8 may be used instead of the electrode assemblies 50a shown in Figure 3A.)

[0145] This method involves positioning a first electrode assembly 50a at a first location on or inside the body of a subject. (In the example shown in Figure 9, the first electrode assembly 50a is positioned on the skin of the subject on the right side of the subject's head facing a target area, for example, a tumor). The first electrode assembly 50a may be configured as described above herein. In the embodiment of Figure 9, the first electrode assembly 50a includes a first sheet 70 of an anisotropic material having a first front surface and a first rear surface. The first sheet 70 has a first thermal conductivity in a direction perpendicular to the first front surface. The thermal conductivity of the first sheet 70 in a direction parallel to the first front surface is more than twice as high as the first thermal conductivity. The first sheet 70 has a first resistance in a direction perpendicular to the front surface, and the resistance of the first sheet in a direction parallel to the front surface is less than half of the first resistance. During use, the first electrode assembly 50a is positioned such that the first front surface of the first sheet 70 faces the target area.

[0146] This method also includes positioning the second electrode assembly 50a at a second location inside or on the body of the subject. (In the example shown in Figure 9, the second electrode assembly 50a is positioned on the skin of the subject on the left side of the subject's head facing the target area.) The second electrode assembly 50a may be configured as described above herein. In the embodiment of Figure 9, the second electrode assembly 50a includes a second sheet 70 of an anisotropic material having a second front surface and a second rear surface. The second sheet 70 has a second thermal conductivity in a direction perpendicular to the second front surface. The thermal conductivity of the second sheet 70 in a direction parallel to the second front surface is more than twice as high as the second thermal conductivity. The second sheet 70 has a second resistance in a direction perpendicular to the front surface, and the resistance of the second sheet in a direction parallel to the front surface is less than half of the second resistance. During use, the second electrode assembly 50a is positioned so that the second front surface of the second sheet 70 faces the target area.

[0147] The method further includes applying an alternating current voltage between the first electrode assembly 50a and the second electrode assembly 50a. This application is performed after the first electrode assembly 50a and the second electrode assembly 50a have been positioned. This application can be carried out by applying an alternating current voltage between (i) a first electrode element disposed in electrical contact with the first rear surface of the first sheet 70 and (ii) a second electrode element disposed in electrical contact with the second rear surface of the second sheet 70.

[0148] In some embodiments, the first electrode assembly 50a further includes a first layer of biocompatible conductive material 60 disposed on the first front surface of the first sheet 70. Correspondingly, the second electrode assembly further includes a second layer of biocompatible conductive material 60 disposed on the second front surface of the second sheet 70. As described above, the biocompatible conductive material 60 may be a hydrogel, or it may be a conductive grease, a conductive adhesive including the non-hydrogel conductive adhesive described above, a conductive tape, a conductive composite material, etc.

[0149] In some embodiments, the first electrode assembly 50a further includes a first conductive material rear layer 80 (as described above) positioned between the first front surface of the first electrode element of the first electrode assembly 50a and the first rear surface of the first sheet 70. Correspondingly, the second electrode assembly further includes a second conductive material rear layer 80 (as described above) positioned between the second front surface of the second electrode element of the second electrode assembly and the second rear surface of the second sheet 70.

[0150] In some embodiments, each of the first and second sheets of the anisotropic material 70 is a sheet of synthetic graphite. In some embodiments, the sheet of anisotropic material 70 is a sheet of pyrolytic graphite. In other embodiments, each of the first and second sheets of the anisotropic material 70 is a graphite foil made of high-purity compression-exfoliated mineral graphite (for example, MinGraph® 2010A Flexible Graphite, available from Mineral Seal Corp. in Tucson, Arizona). In other embodiments, the sheet of anisotropic material 70 is a sheet of graphitized polymer film. In other embodiments, the anisotropic material may be pyrolytic carbon. In other embodiments, the anisotropic material may be boron nitride. In other embodiments, sheets of other conductive materials having anisotropy may be used. In some embodiments (for example, when the sheet of anisotropic material is a sheet of synthetic graphite such as pyrolytic graphite, high-purity compression-exfoliated mineral graphite, or graphitized polymer film), the sheet of anisotropic material 70 is nonmetallic.

[0151] An AC voltage between the first electrode assembly and the second electrode assembly can be applied by an AC voltage generator 820. In some embodiments, the frequency of the AC voltage is between 50 kHz and 1 MHz, or between 100 kHz and 500 kHz. In the illustrated example, the AC voltage generator is controlled by a controller 822. The controller 822 may control the amplitude of the current supplied through the first and second electrode assemblies 50a using temperature measurements to maintain the temperature below a safety threshold (e.g., 41°C). This can be achieved, for example, by measuring a first temperature of the first electrode element, measuring a second temperature of the second electrode element, and controlling the application of the AC voltage based on the first and second temperatures, as described below.

[0152] Figure 9 shows an example of hardware suitable for this purpose. More specifically, a temperature sensor 800 (e.g., a thermistor) is positioned to make thermal contact with each electrode element (e.g., dielectric material 310 / metal layer 320) in each of the electrode assemblies 50a. The temperature sensor 800 measures the respective first and second temperatures (e.g., in the first and second electrode elements in the first and second electrode assemblies, respectively), and the controller 822 controls the output of the AC voltage generator 820 based on these temperatures.

[0153] Similar embodiments and methods are conceivable that utilize any of the electrode assemblies 50a-e, or a combination thereof, instead of either or both of the first electrode assembly 50a and the second electrode assembly 50a.

[0154] The electrode assemblies described herein may be used to treat a disease present in a subject by applying an alternating electric field to a target area of ​​the subject's body. Such a method includes positioning a first electrode assembly and a second electrode assembly opposite the target area of ​​the subject's body, the first and second electrode assemblies being as described herein, and applying an alternating electric field between the first and second electrode assemblies to treat the subject's disease. The target area may be any area of ​​the subject's body that is damaged by disease or exhibits pathological symptoms. Preferred target areas include, but are not limited to, the subject's brain, torso, abdomen, lungs, breasts, ovaries, prostate, pancreas, stomach, intestines, colon, rectum, liver, or kidneys. In some embodiments, the target area may include a tumor or cancer (one or more cancer cells).

[0155] "To treat" means administering or applying therapeutic means, such as an alternating electric field, to a subject, such as a human or other mammal (e.g., an animal model), who has a tumor (cancer) or is at increased susceptibility to developing cancer, in order to prevent or delay the worsening of the effects of the tumor (cancer), or to partially or completely reverse the effects of the tumor (cancer).

[0156] The alternating current electric fields used in the methods and / or embodiments described herein may have frequencies between 50 kHz and 2 MHz, 50 kHz and 1 MHz, 100 kHz and 1 MHz, 100 kHz and 500 kHz, 100 kHz and 300 kHz, or 150 kHz and 400 kHz. In some embodiments, the alternating current electric field has frequencies of about 100 kHz, about 150 kHz, about 175 kHz, about 200 kHz, about 225 kHz, about 250 kHz, about 275 kHz, about 300 kHz, about 325 kHz, about 350 kHz, about 375 kHz, about 400 kHz, about 425 kHz, about 450 kHz, about 475 kHz, about 500 kHz, about 550 kHz, about 600 kHz, about 650 kHz, about 700 kHz, about 750 kHz, about 800 kHz, about 850 kHz, about 900 kHz, about 950 kHz, or about 1 MHz. The frequencies and frequency ranges described above may be useful in any of the methods described herein.

[0157] In some methods and / or embodiments, the alternating electric field has an electric field strength between 0.1 V / cm and 20 V / cm, 0.1 V / cm and 10 V / cm, or 1 V / cm and 4 V / cm. The above electric field strength ranges may be useful in any of the methods and / or embodiments described herein.

[0158] Some methods and / or embodiments include positioning a first electrode assembly and a second electrode assembly opposite a target site on the body of a subject, the first and second electrode assemblies being as described herein, and applying an alternating electric field between the first and second electrode assemblies to treat a tumor or cancer (an area containing cancer cells) in the subject.

[0159] The methods and embodiments described herein may be used to treat tumors or cancers in subjects. Such tumors (cancers) include, but are not limited to, brain cancers such as glioblastoma multiforme, lung cancers (e.g., malignant pleural mesothelioma, non-small cell lung cancer), brain metastases (e.g., from non-small cell lung cancer or melanoma), breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancers (e.g., gastroesophageal junction adenocarcinoma, gastric adenocarcinoma), intestinal cancer, colon cancer, rectal cancer, liver cancer, hepatocellular carcinoma, and uveal cancer (ocular cancer).

[0160] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering one or more therapeutic agents, such as anticancer agents. Suitable anticancer agents include, but are not limited to, temozolomide, pemetrexed, cisplatin, carboplatin, paclitaxel, nab-paclitaxel, doxorubicin, cyclophosphamide, trastuzumab, atezolizumab, gemcitabine, mebendazole, sorafenib, oxaliplatin, capecitabine, fluorouracil, leucovorin, ABT-751, ABT-414 (depatuxizumab-mafodotin), and bevicizumab.

[0161] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering one or more checkpoint inhibitors. Preferred checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, PDL-1 inhibitors, and CTLA-4 inhibitors. For example, one or more of pembrolizumab, nivolumab, semipirimab, atezolimmab, durvalumab, avelumab, and ipilumab may be administered.

[0162] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, and applying an alternating electric field between the first and second electrode assemblies, and further comprising administering radiotherapy. Radiotherapy may include, but is not limited to, photon radiation (e.g., X-ray therapy, gamma-ray therapy) and particle radiation (e.g., electron beam therapy, proton beam therapy, neutron beam therapy, carbon ion therapy, alpha particle therapy, beta particle therapy). Radiotherapy may be administered, for example, externally or internally (e.g., close-range irradiation).

[0163] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering one or more agents that inhibit or block DNA repair mechanisms. For example, agents that inhibit or block DNA repair mechanisms include E2F inhibitors, CDK inhibitors, and PARP inhibitors. Preferred E2F inhibitors include, but are not limited to, HLM006474, MRT00033659, YKL-5-124-TFA, and YKL-5-124. Suitable CDK inhibitors include, but are not limited to, abemaciclib, ribociclib, trilaciclib, Ibrance, rerocyclib, arbosidib, roniciclib, ribiciclib, miliclib, RGB-286638, NSN3106729, PHA-793887, R547, indirubin, NU6102, bohemin, CDK9-IN-7, CGP60474, purvalanol A, PF-06873600, and nimbococcus. This includes Lido, FN-1501, AG-024322, ON123300, G1T28, G1T38, AMG925, SHR-6390, BPI-1178, BPI-16350, FCN437, birociclib, BEBT-209, Ty-302, TQB-3616, HS-10342, PF-06842874, CS-2002, MM-D37K, CDK4 / 6-IN-2, SU9516, and AT7519. Preferred PARP inhibitors include, but are not limited to, niraparib, olaparib, and lucaparib. In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first electrode assembly and the second electrode assembly, and further comprising administering an E2F inhibitor.In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, on the opposite side of a target area of ​​the subject's body, applying an alternating electric field between the first electrode assembly and the second electrode assembly, and further comprising administering a CDK4 / 6 inhibitor. In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, on the opposite side of a target area of ​​the subject's body, applying an alternating electric field between the first electrode assembly and the second electrode assembly, and further comprising administering a PARP inhibitor.

[0164] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body; applying an alternating electric field between the first electrode assembly and the second electrode assembly; administering radiotherapy, as described herein; and further administering one or more agents that inhibit or block DNA repair mechanisms.

[0165] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering an aurora kinase inhibitor. Suitable aurora kinase inhibitors include, but are not limited to, AZD1152, danucertib (PHA-739358), AT9283, PF-03814735, and AMG900.

[0166] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, and applying an alternating electric field between the first and second electrode assemblies, and further comprising administering a drug that increases the sensitivity of the tumor or cancer (or cancer cells containing the tumor, or cancer cells or cancer cell clusters not associated with the tumor) to treatment with the alternating electric field. In some embodiments, the sensitivity of tumor or cancer cells to the alternating electric field can be increased by altering the cyclin D1 pathway. In some embodiments, the cyclin D1 pathway can be altered by administering one or more of the following: a mammalian target of rapamycin (mTOR) inhibitors, an Akt inhibitor, a phosphatidylinositol 3-kinase (PI3K) inhibitor, a Src inhibitor, a focal adhesion kinase (FAK) inhibitor, or a glycogen synthase kinase 3β (GSK3β) inhibitor.

[0167] Therefore, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering an mTOR inhibitor. Suitable mTOR inhibitors include, but are not limited to, tolkinib, everolimus, temsirolimus, everolimus, CC-223, MKK-1, AZD8055, AZD02114, INK-128, 051-027, dactricib, BGT226, SF1126, PKI-587, NVPBE235, sapanicertib, AZD2014, BEZ235, XL765, GDC0980, SF1 126, PF-04691502, PF-05212384 (Gedatricib, PKI-587), LY3023414, XL795 (Voxtasilib), Vimiralisib (PQR309), Paxalisib (GDC-0084), DS-7423, PKI-179, GSK458V, P7170, SB2343, PI-103, NU7441, KU-0063794, Lidafollicular (Deforolimus, MK-8669), Trin 1, Trin 2, OSI-027, GSK1059615, WYE-354, Vistausertib (AZD2014), WYE-125132, Palomide 529 (P529), WYE-687, XL388, MHY1485, LY3023414 (Samotricib), GNE-447, CC-115, Zotarolimus (ABT-578), Contains PQR620, SF2523, mTor inhibitor-1,2,3 or 8, PQR626, WAY-600, PF-04979064, 3BDO, dihydromyricetin, ETP-46464, PKI-402, cyclovir buxin D, CZ415, VS-5584, (+)-usnic acid, RMC-5552, PQR530, JR-AB2-011, alnicolide D or TML-6.

[0168] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering an Akt inhibitor. Suitable Akt inhibitors include, but are not limited to, any composition or compound that inhibits Akt, inhibits the phosphorylation of Akt, inhibits phosphorylated Akt, or inhibits the degradation of cyclin D1. In some methods and / or embodiments, the Akt inhibitor is, but is not limited to, lapatinib, H8, H-89, NL-71-101, GSK690693, 7-azaindole, 6-phenylpurine derivatives, pyrrolo[2,3-d]pyrimidine derivatives, CCT128930, 3-aminopyrrolidine, anilinotriazole derivatives, spiroindoline derivatives, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, Afrecertib (GSK2110183), 2-Pyrimidyl-5-Amidothiophene derivative (DC120), Uprosertib (GSK2141795), 2,3-Diphenylquinoxaline derivative, Triazolo[3,4-f][1,6]Naphthyridine-3(2H)-one derivative (MK 2206), Edelfosine (1-O-Octadecyl-2-O-methyl-rac-glycerol-3-phosphocholine, ET-18-OCH3) Irmofosine (BM 41.440), Miltefosine (Hexadecylphosphocholine, HePC), Perifosine (D21266), Elucylphosphocholine (ErPC), Elhosine (ErPC3, Elucylphosphomocholine), Indole-3-carbinol, 3-chloroacetylindole, Diindolylmethane, Diethyl-6-methoxy-5,7-dihydroindoro-[2,3b]carbazole-2,10-dicarboxylate (SR13668), OSU-A9, PH-316, PHT-427, PIT-1, PIT-2, M-PIT-1, [(1-methyl-1H-pyrazole-4-yl)carbonyl]-N'-(3-bromophenyl)-thiourea, Trisilibine (TCN, NSC-154020), Trisilibine monophosphate active analog ( TCN-P), 4-amino-pyrido[2,3-d]pyrimidine derivative, API-1, 3-phenyl-3H-imidazo[4,5-b]pyridine derivative, ARQ-092, BAY-1125976, 3-methyl-xanthine, quinolone-4-carboxamide and 2-[4-(cyclohexa1,3-dien-1-yl)-1H-pyrazole-3-yl]phenol, 3-oxy This product contains saccharin, 3α- and 3β-acetoxycylcaric acid, acetoxycylcaric acid, lactokinomycin, frenolicin B, carafungin, medelmycin, Boc-Phe-vinyl ketone, 4-hydroxynonenal (4-HNE), 1,6-naphthilidinone derivatives, imidazo-1,2-pyridine derivatives, ligosertib (ON-01910), trisirivine, honokiol, mirancertib (ARQ-092), boluscertib, SC66, A-674563, TIC10 analog, urolithin B, ABTL-0821, laurelin A, homosalate, deguerin, recibfogenin, telameprocol, oroxin B, LM22B-10, amarogentin, oridonin, praeruptorin A, or scutellarin.

[0169] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first electrode assembly and the second electrode assembly, and further comprising administering a PI3K inhibitor. Suitable PI3K inhibitors include, but are not limited to, GDC-0941, TG100-115, CH5132799, PX-866, XL147, ZSTK474, BKM-120, BAY80-6946, AZD8835, WX-037, AZD8186, KA2237, CAL-120, ME401, AMG319, GSK2636771, INCB050465, INK-1117, TGR-1202, RP6530, GDC-0032, BYL719, BGT226, IPI-145, CAL-101, AMG511, ADZ6482, MLN1117, 3-hydroxyanthranilic acid, hispiduline, pectolinalin, or synovuffagin.

[0170] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first electrode assembly and the second electrode assembly, and further comprising administering a Src inhibitor. Suitable Src inhibitors are not limited to, but include dasatinib (BMS-354825), ponatinib (AP24534), salakatinib (AZD0530), bosutinib (SKI-606), dehydroabietic acid (DAA, DHAA), PP2, ginkgolic acid C17:1 (GAC17:1), DGY-06-116, dramapimod (BIRB 796), apatinib, peritinib (EKB-569), resveratrol, KX2-391 (tilavanibrin), NVP-BHG712, ENMD-2076, PRT062607 (P505-15, BIIB057, PRT-2607), PP1, MNS (3,4-methylenedioxy-β-nitrostyrene), and dramapimod (BIRB Contains 796), WH-4-023, RK24466, KX1-004, 7-hydroxychromone, AD-80, repotrectinib (TPX-0005), quercetin (NSC 9221, soforetin, CI75720), SU 6656, Src inhibitor 1 (CAS 179248-59-0), CCT196969, myristic acid (tetradecanoic acid), eCF506, 1-naphthyl PP1 (1-NA-PP 1), AMG-47a, ON123300, UM-164, MLR-1023, PD173955, AZD0424, PD180970, or HG-7-85-01.

[0171] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first electrode assembly and the second electrode assembly, and further comprising administering a focal adhesion kinase (FAK) inhibitor. Suitable FAK inhibitors include, but are not limited to, defectanib (VS-6063), solanesol (nonaiisoprenol), PF-00562271 besylate (PF-562271), PF-562271 (PF-00562271), PRT062607 (P505-15, BIIB057, PRT-2607), PF-573228 TAE226 (NVP-TAE226), PF-562271 HCl, BI-4464, Y15, GSK2256098, PND-1186 (VS-4718), PF-431396, FAK inhibitor 14 (cas 4506-66-5), or levastinib.

[0172] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering a glycogen synthase kinase 3β (GSK3β) inhibitor. Suitable GSK3β inhibitors include, but are not limited to, lithium, zinc, tungstate, naproxen, cromolyn, famotidine, olanzapine, pyrimidine derivatives, CT98014, CT98023, CT99021, TWS119, indirubin, 6-BIO, himelniazicin, dibromocantarreline, melidianin, arylindolemaleimide, SB-216763, SB-41528, thiazole, AR-A014418, AZD-1080, Paullones, Kenpaulon, Alsta - Contains paulowne, kazpaulowne, alosin, manzamine, manzamine A, furanosequiterpenes, parinulin, tricanthine, L803-mts, thiadiazolidinedione, TDZD-8, NP00111, NP031115, NP031112 (tideglucib), halomethyl ketone (HMK-32), L803-mts, CH1R99021, CT99021, TWS119, aloysin, 9-ING-41, 1-azakenepaulowne, IM-12, CHIR-98014, or LY2090314.

[0173] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering a chloride intracellular channel (e.g., CLIC1 and / or CLIC4) inhibitor. Suitable CLIC inhibitors include, but are not limited to, indanyloxyacetic acid-94 (IAA94), diflumic acid, diphenylamine-2-carboxylic acid (DPC), 4,4'-diisothiocyano-2,2'-stilbenidisulfonic acid, disodium salt (DIDS), anthracene derivatives, stilbenes, and heavy metal ions, blocked benzimidazole, clofibric acid, benzofuran, propionic acid (CPP), 4-acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid (SITS), 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), chlorotoxin, mibefuradil, calix[4]arene, clomiphene, Cd2+, Gd3+, glibencraimide, flufenamic acid, inositol-tetrabisphosphate, mefloquinand, or fluoxetine.

[0174] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target area of ​​the subject's body, applying an alternating electric field between the first and second electrode assemblies, and further comprising administering a fibroblast growth factor (FGF) inhibitor. In some methods and / or embodiments, the FGF inhibitor specifically inhibits or reduces FGF expression. In some methods and / or embodiments, the FGF inhibitor specifically binds to nucleic acids encoding FGF. In some methods and / or embodiments, FGF is FGF-21, FGF-19, FGF-7, or FGF-basic. In some methods and / or embodiments, the FGF inhibitor may be a small molecule, a peptide, a protein, an antibody, or a nucleic acid (e.g., siRNA). Examples of FGF inhibitors include, but are not limited to, soluble fibroblast growth factor receptors (FGFRs), such as soluble FGFR3, and soluble decoy receptors, such as FGF-Trap, which is a soluble decoy receptor fusion protein that binds to FGF-2.

[0175] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly opposite a target area of ​​the subject's body, applying an alternating electric field between the first electrode assembly and the second electrode assembly, and further comprising administering a fibroblast growth factor receptor (FGFR) inhibitor. Preferred examples of FGFR inhibitors, though not limited to them, include BAY1179470, FPA144, PRO-001, RG7444, SSR128129E, AZD4547, BAY1163877, BGJ398, CH5183284, erdafitinib, LY2874455, lusitanib / E3810, nintedanib, pazopanib, lovritinib, PD-161570, CP-547632, infiglatinib (BGJ398), PD173074, SSR Includes 128129E, PD-166866, ASP5878, H3B-6527, NSC12, BO-264, sulfatinib, fisogatinib (BLU-554), FIIN-2, futibatinib (TAS-120), BLU9931, pemigatinib (INCB054828), zoliglatinib (Debio-1347), allofanib (RPT835), PRN1371, ferulic acid, ODM-203, and delazantinib (ARQ-087).

[0176] In some embodiments, a method for treating a tumor or cancer in a subject comprises positioning a first electrode assembly and a second electrode assembly opposite a target area of ​​the subject's body, applying an alternating electric field between the first electrode assembly and the second electrode assembly, and further comprising administering one or more of lenvatinib and bevacizumab.

[0177] In some embodiments, a method for treating non-small cell lung cancer includes positioning a first electrode assembly and a second electrode assembly on opposite sides of the torso of a subject, and applying an alternating electric field between the first electrode assembly and the second electrode assembly, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz. In some embodiments, a method for treating non-small cell lung cancer includes applying an alternating electric field to the torso of a subject using two or more electrode assemblies as described herein, and further includes administering docetaxel. In some embodiments, a method for treating non-small cell lung cancer includes applying an alternating electric field to the torso of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz, and further includes administering a checkpoint inhibitor. Suitable checkpoint inhibitors include, but are not limited to, pembrolizumab, nivolumab, semiprimab, atezolimmab, durvalumab, avelumab, and ipilumab. In some embodiments, a method for treating non-small cell lung cancer comprises applying an alternating electric field to the torso of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz, and further comprising administering docetaxel and pembrolizumab.

[0178] In some embodiments, a method for treating malignant pleural mesothelioma involves applying an alternating electric field to the torso of a subject (e.g., the lungs) using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz, and further comprising administering a chemotherapeutic agent. In some embodiments, a method for treating malignant pleural mesothelioma comprises applying an alternating electric field to the torso of a subject (e.g., the lungs) using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz, and further comprising administering one or more of pemetrexed, cisplatin, and carboplatin.

[0179] In some embodiments, a method for treating ovarian cancer includes positioning a first electrode assembly and a second electrode assembly on the opposite side of the abdomen of a subject, and applying an alternating electric field between the first electrode assembly and the second electrode assembly, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz. In some embodiments, a method for treating ovarian cancer includes applying an alternating electric field to the abdomen of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz, and further includes administering paclitaxel.

[0180] In some embodiments, a method for treating glioblastoma multiforme (GBM) includes positioning a first electrode assembly and a second electrode assembly on opposite sides of the subject's head, and applying an alternating electric field between the first and second electrode assemblies, wherein the alternating electric field has a frequency of approximately 100–400 kHz, such as approximately 200 kHz. In some embodiments, a method for treating glioblastoma multiforme includes applying an alternating electric field to a target region of the subject's brain using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of approximately 100–400 kHz, such as approximately 200 kHz, and further includes administering one or more of temozolomide and checkpoint inhibitors. Preferred checkpoint inhibitors include, but are not limited to, pembrolizumab, nivolumab, semiprimab, atezolimmab, durvalumab, avelumab, and ipilumab.

[0181] In some embodiments, a method for treating glioblastoma multiforme includes applying an alternating electric field to the head of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz, and further includes administering temozolomide. In some embodiments, a method for treating glioblastoma multiforme includes applying an alternating electric field to the head of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz, and further includes administering pembrolizumab. In some embodiments, a method for treating glioblastoma multiforme comprises applying an alternating electric field to the head of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz, and further comprising administering temozolomide and pembrolizumab.

[0182] In some embodiments, a method for treating glioblastoma multiforme is to apply an alternating electric field to the head of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz, and further comprises administering radiotherapy (e.g., 60 Gy is given in 30 fractions of 2 Gy). In some embodiments, a method for treating glioblastoma multiforme is to apply an alternating electric field to the head of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz, and further comprises administering radiotherapy (e.g., 60 Gy is given in 30 fractions of 2 Gy) and administering temozolomide.

[0183] In some embodiments, a method for treating glioblastoma multiforme includes applying an alternating electric field to the head of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz, and further includes administering bevacizumab. In some embodiments, a method for treating glioblastoma multiforme includes applying an alternating electric field to the head of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 to 400 kHz, such as about 200 kHz, and further includes administering niraparib.

[0184] In some embodiments, a method for treating gastric cancer involves applying an alternating electric field to the abdomen of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz. In some embodiments, a method for treating gastric cancer involves applying an alternating electric field to the abdomen of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz, and further includes administering trastuzumab.

[0185] In some embodiments, a method for treating gastric cancer involves applying an alternating electric field to the abdomen of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz, and further comprising administering one or more chemotherapeutic agents, such as oxaliplatin and capecitabine.

[0186] In some embodiments, a method for treating pancreatic cancer involves applying an alternating electric field to the abdomen (e.g., the pancreas) of a subject using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz, and further comprising administering one or more of gemcitabine and nab-paclitaxel.

[0187] In some embodiments, a method for treating hepatocellular carcinoma involves applying an alternating electric field to the torso of a subject (e.g., the liver) using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz. In some embodiments, a method for treating hepatocellular carcinoma involves applying an alternating electric field to the torso of a subject (e.g., the liver) using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 50 to 350 kHz, such as about 150 kHz, and further includes administering sorafenib.

[0188] In some embodiments, a method for treating metastatic uveal melanoma includes applying an alternating electric field to the head of a subject (e.g., the eyeball) using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency of about 100 kHz to about 500 kHz (e.g., about 150 kHz, about 200 kHz, or about 250 kHz), and further including administering a checkpoint inhibitor. Suitable checkpoint inhibitors include, but are not limited to, pembrolizumab, nivolumab, semiprimab, atezolimmab, durvalumab, avelumab, and ipilumumab. In some embodiments, a method for treating metastatic uveal melanoma comprises applying an alternating electric field to the head of a subject (e.g., the eyeball) using two or more electrode assemblies as described herein, wherein the alternating electric field has a frequency from about 100 kHz to about 500 kHz (e.g., about 150 kHz, about 200 kHz, or about 250 kHz), and further comprising administering one or more of nivolumab and ipilumumab.

[0189] Some methods and / or embodiments involve applying an alternating electric field to a target area of ​​a subject's body to increase the permeability of intercellular tight junctions between epithelial cells. For example, some methods involve positioning a first electrode assembly and a second electrode assembly, as described herein, on the opposite side of the subject's head, and applying an alternating electric field between the first and second electrode assemblies to increase the permeability of intercellular tight junctions (TJs) (i.e., the blood-brain barrier) between brain capillary endothelial cells. In other embodiments, these methods involve positioning a first electrode assembly and a second electrode assembly on the opposite side of the subject's abdomen, and applying an alternating electric field between the first and second electrode assemblies to increase the permeability of intestinal epithelium. Such increased permeability of intercellular tight junctions between epithelial cells may help enhance the absorption of substances such as pharmaceuticals. In some embodiments, such methods further involve administering a therapeutic agent to the subject. In some embodiments, the alternating electric field that helps to increase the permeability of intercellular tight junctions has frequencies between approximately 50 kHz and approximately 500 kHz, approximately 100 kHz and approximately 300 kHz, or approximately 100 kHz and approximately 190 kHz. In some embodiments, the frequencies are approximately 150 kHz, approximately 160 kHz, approximately 170 kHz, approximately 180 kHz, or approximately 190 kHz.

[0190] Some methods and / or embodiments include positioning a first electrode assembly and a second electrode assembly, as described herein, on opposing sides of a target area of ​​a subject's body, and applying an alternating electric field between the first and second electrode assemblies to increase the permeability of cell membranes, particularly cancer cell membranes. Such cancer cell membranes may be the membranes of any cancer cells, e.g., brain cancer cells such as glioblastoma multiforme, lung cancer cells (e.g., malignant pleural mesothelioma, non-small cell lung cancer), brain metastasis cells (e.g., from non-small cell lung cancer or melanoma), breast cancer, ovarian cancer cells, prostate cancer cells, pancreatic cancer cells, gastric cancer cells (e.g., gastroesophageal junction adenocarcinoma, gastric adenocarcinoma), intestinal cancer cells, colon cancer cells, rectal cancer cells, liver cancer, hepatocellular carcinoma cells, and uveal cancer cells. In some embodiments, such methods further include administering a therapeutic agent to or near the cancer cells. In some embodiments, the alternating electric field that helps increase the permeability of the cell membrane has a frequency between about 50 kHz and about 1 MHz, between about 50 kHz and about 500 kHz, or between about 100 kHz and about 300 kHz.

[0191] Some methods and / or embodiments include positioning a first electrode assembly and a second electrode assembly, as described herein, on the opposite side of the subject's head, and applying an alternating electric field between the first and second electrode assemblies to treat or alleviate symptoms of a neurodegenerative disease. For example, such a neurodegenerative disease may be one or more of, but are not limited to, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis (MS), neurofibromatosis, or dementia. In some embodiments, a method for treating a neurodegenerative disease includes applying an alternating electric field to the subject's brain to inhibit GSK3β.

[0192] Some methods and / or embodiments include positioning a first electrode assembly and a second electrode assembly, as described herein, on opposite sides of the body of a subject, and applying an alternating electric field between the first electrode assembly and the second electrode assembly to treat or alleviate symptoms of a neurodegenerative disease, and further including administering a therapeutic agent for the treatment of a neurodegenerative disease. The therapeutic agents for the treatment of a neurodegenerative disease include, but are not limited to, GSK3β inhibitors, cholinesterase inhibitors, anti-amyloid monoclonal antibodies (e.g., aducanumab), dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, catechol O-methyltransferase inhibitors, or anticholinergic agents. In some embodiments, the therapeutic agent is 9-ING-41, HY-130795, TWS119, tideglucib, SAR502250, AR-A014418, TDZD8, kaempaulon, chromoib sodium, SB415286, IM-12, CP21R7, GNF4877, 1-azakempaulon, or indirubin-3'-monoxime, tacrine, galantamine, liquilitigenin, memantine, rivastigmine, donepezil, ciprofloxacin, celecoxib, tauroursodeoxycholic acid, sodium phenylbutyrate, levodopa, carbidopa, pramipexole, ropinirole, rotigotine, apomorphine, or selegiline. It is one or more of rasagiline, safinamide, entacapone, opicapon, tolcapone, benztropine, trihexyphenidyl, amantadine, riluzole, edaravone, and l-3,4-dihydroxyphenylalanine.

[0193] Some methods and / or embodiments include positioning a first electrode assembly and a second electrode assembly, as described herein, on the opposite side of a target region, and applying an alternating electric field between the first and second electrode assemblies to treat or alleviate symptoms of an autoimmune disease, wherein the target region includes tissue being attacked by the autoimmune disease. For example, in Rasmussen's encephalitis (RE), the immune system attacks one hemisphere of a person's brain, so in a method for treating RE, the target region could be the subject's head or brain. In lupus nephritis, the immune system attacks a person's kidneys. The target site for lupus nephritis involves placing a pair of electrodes on the subject's body, anterior and posterior to the kidney and / or associated aspiration lymph nodes, and optionally, placing a second pair of electrodes on the side of the subject's body, at the level corresponding to the kidney and / or associated aspiration lymph nodes. A method for treating type 1 diabetes may include a target region of the subject's pancreas. Methods for treating rheumatoid arthritis may include target areas of the affected joints and / or associated lymph nodes in the region of lymphatic drainage. Methods for treating polymyositis may include target areas of the affected muscles of the subject and / or associated lymph nodes in the region of lymphatic drainage.

[0194] Some methods and / or embodiments include positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target region of a subject, and applying an alternating electric field between the first and second electrode assemblies to treat a subject infected with a virus that relies on electrostatic interaction with receptors, the target region comprising one or more cells infected with the virus. For example, the virus may be a coronavirus or a lentivirus. In some embodiments, the alternating electric field has a frequency between 50 kHz and 1 MHz, or between 100 kHz and 500 kHz. In some embodiments, the alternating electric field has a frequency of about 150 kHz.

[0195] Some methods and / or embodiments include positioning a first electrode assembly and a second electrode assembly, as described herein, opposite a target region of a subject, and applying an alternating electric field between the first and second electrode assemblies to treat a subject infected with a lentivirus or coronavirus, further including administering an antiviral drug to the subject. Preferred examples of antiviral drugs, but are not limited to, remdesivir (Vecryly), Avigan (Faviravir), Olumiant and Baricinix (Baricitinib), hydroxychloroquine / chloroquine, cacilibimab and imudevimab (formerly REGN-COV2), PTC299, leronlimab (PRO140), bamranivimab (LY-CoV555), renzilumab, ivermectin, RLF-100. (Aviptadil), Metformin (Glucophage, Gourmetza, Riomet), AT-527, Actemra (Tocilizumab), Nicloside (Niclosamide), Convalescent Plasma, Pepsid (Famotidine), Kaletra (Lopinavir-Ritonavir), Remicade (Infliximab), AZD7442, AZD7442, CT-P59, Heparin (UF and LMW), VIR-7831 (GSK4182136), JS016, Kevzara (sarilumab), SACCOVID (CD24Fc), Humira (adalimumab), COVI-GUARD (STI-1499), Dexamethasone (Dextenza, Ozuldex, etc.), PB1046, Galidesivir, Bucillamine, PF-00835321 (PF-07304814), Elixir (apixaban), Taxylo (lanadelmab), Hydrocortisone, Ilaris (ca This includes nakinumab, colchicine (mitigare, colcris), BLD-2660, avigan (faviravir / avifavir), Rhu-pGSN (gelsolin), MK-4482, TXA127, LAM-002A (apirimodomesylate), DNL758 (SAR443122), INOpulse, ABX464, AdMSCs, rosmapimod, maprilimumab, and calkens (acalabrutinib).

[0196] Some methods and / or embodiments include positioning a first electrode assembly and a second electrode assembly, as described herein, on the opposite side of the torso of a subject (e.g., the lungs), and applying an alternating electric field between the first and second electrode assemblies to treat or alleviate symptoms of acute respiratory distress. In some embodiments, acute respiratory distress syndrome may also be caused by a viral infection, such as a coronavirus infection.

[0197] While the present invention is disclosed with reference to several embodiments, numerous modifications, alterations, and changes are possible to the embodiments described without departing from the scope and realm of the invention, as defined in the supplementary claims. Therefore, the present invention should not be limited to the embodiments described, but is intended to have the entire scope defined by the wording of the following claims and their equivalents. [Explanation of Symbols]

[0198] 50 electrode assemblies 50a Electrode Assembly 50b Electrode Assembly 50c electrode assembly 50d Electrode Assembly 50e Electrode Assembly 60 layers 70 seats 80 First conductive material rear layer 310 First dielectric material layer 320 First metal layer 380 Different areas of conductive materials 500 metal pieces 600 metal pieces 700 Capacitor 800 Temperature Sensor 820 AC voltage generator 822 Controller

Claims

1. A device for applying an alternating electric field to the body of a test subject, A first electrode assembly comprising a first sheet of an anisotropic material having a first front surface and a first rear surface, wherein the first sheet has a first thermal conductivity in a direction perpendicular to the first front surface, and the thermal conductivity of the first sheet in a direction parallel to the first front surface is at least twice as high as the first thermal conductivity, A second electrode assembly comprising a second sheet of an anisotropic material having a second front surface and a second rear surface, wherein the second sheet has a second thermal conductivity in a direction perpendicular to the second front surface, and the thermal conductivity of the second sheet in a direction parallel to the second front surface is at least twice as high as the second thermal conductivity, Disposed on the first front surface of the first sheet, at least one conductive material layer having a biocompatible first front surface, Disposed on the second front surface of the second sheet, at least one conductive material layer having a biocompatible second front surface, A first electrode element positioned behind the first sheet, the first electrode element having a first front surface disposed to electrically contact the first rear surface of the first sheet, A second electrode element positioned behind the second sheet, the second electrode element having a second front surface disposed to electrically contact the second rear surface of the second sheet, An AC voltage generator, wherein the AC voltage generator is An AC voltage is provided to the first electrode element of the first electrode assembly and the second electrode element of the second electrode assembly. It is configured to generate an alternating electric field between the first electrode assembly and the second electrode assembly, The AC voltage generator comprises an AC electric field whose frequency is between 50 kHz and 1 MHz. The aforementioned alternating electric field is a tumor treatment electric field, and the device is configured accordingly.

2. The first electrode element comprises a first dielectric material layer having a front and a rear surface, and a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element, The apparatus according to claim 1, further comprising a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the first sheet, wherein the first conductive material rear layer electrically contacts the first front surface of the first electrode element and the rear surface of the first sheet.

3. The present invention further comprises an additional electrode element positioned behind the first sheet, the additional electrode element having an additional front surface disposed to electrically contact the rear surface of the first sheet, The additional electrode element comprises an additional dielectric material layer having a front and a rear surface, and an additional metal layer disposed on the rear surface of the additional dielectric material layer. The front surface of the additional dielectric material layer is the additional front surface of the additional electrode element, The apparatus according to claim 2, wherein the first conductive material rear layer is positioned between the additional front surface of the additional electrode element and the rear surface of the first sheet, and the first conductive material rear layer is in electrical contact with the additional front surface of the additional electrode element and the rear surface of the first sheet.

4. The present invention further comprises an additional electrode element positioned behind the first sheet, the additional electrode element having an additional front surface disposed to electrically contact the rear surface of the first sheet, The additional electrode element comprises an additional dielectric material layer having a front and a rear surface, and an additional metal layer disposed on the rear surface of the additional dielectric material layer. The front surface of the additional dielectric material layer is the additional front surface of the additional electrode element, The apparatus according to claim 2, further comprising an additional conductive material rear layer positioned between an additional front surface of the additional electrode element and the rear surface of the first sheet, wherein the additional conductive material rear layer electrically contacts the additional front surface of the additional electrode element and the rear surface of the first sheet.

5. The first electrode element includes a metal piece having a front surface, The apparatus according to claim 1, wherein the front surface of the metal piece is the first front surface of the first electrode element.

6. The apparatus according to claim 1, wherein the thermal conductivity of the first sheet in a direction parallel to the first front surface is 10 times or more higher than the first thermal conductivity.

7. The apparatus according to claim 1, wherein the at least one conductive material layer includes a conductive adhesive.

8. A device for applying an alternating electric field to the body of a test subject, A first electrode assembly comprising a first sheet of an anisotropic material having a first front surface and a first rear surface, wherein the first sheet has a first resistance in a direction perpendicular to the first front surface, and the resistance of the first sheet in a direction parallel to the first front surface is less than half of the first resistance, A second electrode assembly comprising a second sheet of an anisotropic material having a second front surface and a second rear surface, wherein the second sheet has a second resistance in a direction perpendicular to the second front surface, and the resistance of the second sheet in a direction parallel to the second front surface is less than half of the second resistance, Disposed on the first front surface of the first sheet, at least one conductive material layer having a biocompatible first front surface, Disposed on the second front surface of the second sheet, at least one conductive material layer having a biocompatible second front surface, A first electrode element positioned behind the first sheet, the first electrode element having a first front surface disposed to electrically contact the first rear surface of the first sheet, A second electrode element positioned behind the second sheet, the second electrode element having a second front surface disposed to electrically contact the second rear surface of the second sheet, An AC voltage generator, wherein the AC voltage generator is An AC voltage is provided to the first electrode element of the first electrode assembly and the second electrode element of the second electrode assembly. It is configured to generate an alternating electric field between the first electrode assembly and the second electrode assembly, The AC voltage generator comprises an AC electric field whose frequency is between 50 kHz and 1 MHz. The aforementioned alternating electric field is a tumor treatment electric field, and the device is configured accordingly.

9. The first electrode element comprises a first dielectric material layer having a front and a rear surface, and a first metal layer disposed on the rear surface of the first dielectric material layer. The front surface of the first dielectric material layer is the first front surface of the first electrode element, The apparatus according to claim 8, further comprising a first conductive material rear layer positioned between the first front surface of the first electrode element and the rear surface of the first sheet, wherein the first conductive material rear layer electrically contacts the first front surface of the first electrode element and the rear surface of the first sheet.

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