Treatment of autoimmune diseases using alternating electric fields to reduce proliferation of t cells

Abstract

By positioning a plurality of electrodes within or on the body of a subject and applying an AC voltage between the plurality of electrodes so as to apply an alternating electric field through a tissue under attack by an autoimmune disease and / or draining lymph nodes associated with the tissue, damage from the autoimmune disease can be prevented or minimized. The frequency and field strength of the alternating electric field are selected so that the alternating electric field suppresses the proliferation of T cells in the tissue to the extent that damage caused by the autoimmune disease is reduced.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application 62 / 728,174, filed September 7, 2018, which is incorporated herein by reference in its entirety. Background Technology

[0003] In autoimmune diseases, a person's own immune system mistakenly attacks specific parts of the body. Examples of T-cell-dependent autoimmune diseases include: type 1 diabetes (where the immune system attacks beta cells in the pancreas); rheumatoid arthritis (where the immune system attacks the synovium of joints); multiple sclerosis (where the immune system attacks the central nervous system); polymyositis (where the immune system attacks certain muscles); lupus nephritis (where the immune system attacks glomeruli in the kidneys); and Rasmussen's encephalitis (where the immune system attacks parts of the brain).

[0004] In individual fields, it has been established that tumors (e.g., glioblastoma) can be treated by applying an alternating electric field of 200 kHz to the tumor. This is described in U.S. Patents 7,016,725 and 7,565,205, each of which is incorporated herein by reference in its entirety. And in the context of treating tumors, these alternating electric fields are referred to as “tumor treatment fields” or “TTFields.” TTFields utilize a device called Optune manufactured by Novocure™. ® Wearable and portable devices are used for delivery. Summary of the Invention

[0005] One aspect of the present invention relates to a first method for preventing or minimizing damage from an autoimmune disease in a target area of ​​a subject's body. The first method includes positioning a plurality of electrodes within or on the subject's body, the electrodes positioned relative to the target area, such that applying an AC voltage between the electrodes applies an alternating electric field through tissue in the target area being attacked by the autoimmune disease; and applying the AC voltage between the electrodes at time intervals, such that the alternating electric field is applied through the tissue during the time intervals. The alternating electric field has a specific frequency and field strength such that when the alternating electric field is applied in the tissue during the time intervals, it inhibits the proliferation of T cells in the tissue, thereby reducing the degree of damage caused by the autoimmune disease.

[0006] In some instances of the first method, multiple electrodes are also positioned relative to the subject’s body such that an alternating electric field is applied to at least one draining lymph node associated with the tissue being attacked.

[0007] In some instances of the first method, the autoimmune disease is type 1 diabetes, and multiple electrodes are positioned relative to the subject's body to apply an alternating electric field to the pancreas. In some of these instances, multiple electrodes are also positioned relative to the subject's body to apply an alternating electric field to at least one pancreatic draining lymph node.

[0008] In some instances of the first method, the autoimmune disease is multiple sclerosis, and multiple electrodes are positioned relative to the subject's body such that an alternating electric field is applied to at least one lesion in the subject's central nervous system.

[0009] In some instances of the first method, the autoimmune disease is polymyositis, and multiple electrodes are positioned relative to the subject's body such that an alternating electric field is applied to at least one muscle of the subject. In some of these instances, multiple electrodes are also positioned relative to the subject's body such that an alternating electric field is applied to at least one draining lymph node associated with at least one muscle.

[0010] In some instances of the first method, the autoimmune disease is rheumatoid arthritis, and multiple electrodes are positioned relative to the subject's body such that an alternating electric field is applied in at least one joint of the subject. In some of these instances, multiple electrodes are also positioned relative to the subject's body such that an alternating electric field is applied in at least one draining lymph node associated with at least one joint.

[0011] In some instances of the first method, the autoimmune disease is Rasmussen encephalitis, and multiple electrodes are positioned relative to the subject's body to apply an alternating electric field in the affected hemisphere of the subject's brain.

[0012] In some instances of the first method, the autoimmune disease is lupus nephritis, and multiple electrodes are positioned relative to the subject's body such that an alternating electric field is applied to at least one kidney of the subject. In some of these instances, multiple electrodes are also positioned relative to the subject's body such that an alternating electric field is applied to at least one draining lymph node associated with at least one kidney.

[0013] In some instances of the first method, localization includes positioning a first set of electrodes within or on the subject's body and positioning a second set of electrodes within or on the subject's body. The first set of electrodes is positioned relative to a target region such that applying an AC voltage between the electrodes of the first set applies an alternating electric field with a first orientation through tissue in the target region being attacked by an autoimmune disease. The second set of electrodes is positioned relative to the target region such that applying an AC voltage between the electrodes of the second set applies an alternating electric field with a second orientation through the tissue. The first and second orientations are different. Application includes repeating in an alternating sequence: (a) applying a first AC voltage between the electrodes of the first set, applying an alternating electric field with a first orientation through the tissue, and (b) applying a second AC voltage between the electrodes of the second set, applying an alternating electric field with a second orientation through the tissue. The alternating electric field with the first orientation has a specific frequency and field strength such that when the alternating electric field with the first orientation is applied in the tissue, it inhibits the proliferation of T cells in the tissue. An alternating electric field with a second orientation has a specific frequency and field strength, which, when applied to tissue, inhibits the proliferation of T cells. This inhibited T cell proliferation reduces damage caused by autoimmune diseases.

[0014] Optionally, in an example of the first method described in the preceding paragraphs, the first and second sets of electrodes may also be positioned relative to the subject's body such that alternating electric fields having first and second orientations are also applied to at least one draining lymph node associated with the tissue being attacked. Optionally, in an example of the first method described in the preceding paragraphs, the first orientation is offset from the second orientation by at least 60°.

[0015] Another aspect of the invention relates to a second method for preventing or minimizing damage from an autoimmune disease in tissue being attacked by the disease. The second method includes positioning a plurality of electrodes within or on the body of a subject, the electrodes being positioned relative to at least one draining lymph node associated with the attacked tissue, such that applying an AC voltage between the electrodes applies an alternating electric field through the at least one draining lymph node; and applying the AC voltage between the electrodes at time intervals, such that the alternating electric field is applied through the at least one draining lymph node during the time intervals. The alternating electric field has a specific frequency and field strength, such that when the alternating electric field is applied in the at least one draining lymph node during the time intervals, the alternating electric field inhibits the proliferation of T cells in the at least one draining lymph node, thereby reducing the degree of damage caused by the autoimmune disease.

[0016] In some instances of the second method, positioning includes positioning a first set of electrodes within or on the subject's body and positioning a second set of electrodes within or on the subject's body. The first set of electrodes is positioned relative to at least one draining lymph node associated with the tissue being attacked, such that applying an AC voltage between the electrodes of the first set will apply an alternating electric field with a first orientation through at least one draining lymph node, and the second set of electrodes is positioned relative to at least one draining lymph node, such that applying an AC voltage between the electrodes of the second set will apply an alternating electric field with a second orientation through at least one draining lymph node. The first and second orientations are different. The application includes repeating in an alternating sequence: (a) applying a first AC voltage between the electrodes of the first set, such that an alternating electric field with a first orientation is applied through at least one draining lymph node, and (b) applying a second AC voltage between the electrodes of the second set, such that an alternating electric field with a second orientation is applied through at least one draining lymph node. An alternating electric field with a first orientation has a specific frequency and field strength, such that when applied to at least one draining lymph node, it inhibits the proliferation of T cells in that lymph node. An alternating electric field with a second orientation has a specific frequency and field strength, such that when applied to at least one draining lymph node, it inhibits the proliferation of T cells in that lymph node. The inhibited proliferation of T cells in at least one draining lymph node reduces damage caused by autoimmune diseases.

[0017] Optionally, in an instance of the second method described in the preceding paragraphs, the first orientation is offset from the second orientation by at least 60°.

[0018] Optionally, in any of the examples of the first or second method described above, each of the plurality of electrodes is capacitively coupled to the subject's body. Optionally, in any of the examples of the first or second method described above, positioning and application are performed after the acute phase of the autoimmune disease has been determined.

[0019] Optionally, any of the examples of the first or second method described above further includes treating autoimmune diseases with a therapeutically effective drug regimen.

[0020] Optionally, in any of the examples of the first or second method described above, the alternating electric field has a frequency of approximately 200 kHz. Optionally, in any of the examples of the first or second method described above, the alternating electric field has a frequency between 50 and 500 kHz. Optionally, in any of the examples of the first or second method described above, the alternating electric field has a field strength between 1 and 5 V / cm RMS. Optionally, in any of the examples of the first or second method described above, the tissue is tumor-free. Attached Figure Description

[0021] Figure 1 It is a schematic representation of a system for applying alternating electric fields to tissues in the human brain, a system designed to minimize damage to brain tissue caused by autoimmune diseases.

[0022] Various embodiments are described in detail below with reference to the accompanying drawings, wherein the same reference numerals denote the same elements. Detailed Implementation

[0023] In the embodiments described below, a system similar to the Optune® system used for treating tumors with TTFields is used to treat an autoimmune disease rather than a tumor. Although the use of the Optune® system to treat glioblastoma is well known to those skilled in the art, it will be briefly described here for completeness. An array of four capacitively coupled electrodes (also referred to as a “transducer array”) is positioned on the shaved head of the subject (e.g., one on the front, one on the back, one on the right, and one on the left). An AC voltage generator applies an AC voltage at 200 kHz between the front / back pairs of the electrode array for one second, and then applies an AC voltage at the same frequency between the right / left pairs of the electrode array for one second, repeating this two-step sequence for the duration of treatment. This alternating sequence of TTFields senses the subject’s brain in the first and second orientations. The electrode array is positioned such that the first orientation and second orientation are offset by a significant amount (e.g., at least 60°, or at least 80°).

[0024] T cells in the body's immune system play a crucial role in fighting tumors. Given this, research has been conducted to determine whether TTFields might interfere with T cell operation. One such study concluded that, "Since the presence of pluripotent T cells is associated with an effective anti-tumor response, a single-cell-level pluripotency analysis was performed on activated T cells. The analysis showed that, under TTFields conditions, non-proliferating cells retained all other combinations of immune function. TTFields were found to have a small effect on the survival of inactivated T cells. In activated cells, there was a moderate effect on cells that did not attempt to proliferate, but TTFields essentially reduced the survival rate of already proliferating cells. These findings are true for both helper and cytotoxic T cells." (Evaluating the In-Vitro Effects of Tumor TreatingFields on T Cell Responses, G. Diamant et al., AACR Proceedings, Vol. 58, Abstract #617, April 2017.)

[0025] In the context of treating tumors, reducing T cell proliferation is a disadvantage because fewer T cells are available to attack tumor cells. However, in the context of treating autoimmune diseases, this exact same disadvantage is advantageously transformed into a benefit. More specifically, this application explains how autoimmune diseases can be treated by using an alternating electric field (“AEF”) to inhibit T cell proliferation; T cells are key players in the immune system's attack on the body. Because AEF can inhibit T cell proliferation, it can prevent or reduce the damage caused by T cells to the body in the context of autoimmune diseases, which can slow disease progression.

[0026] Furthermore, many autoimmune diseases exhibit different phases during which the immune system attacks tissues within the subject's body. For these autoimmune diseases, the application of the AEF can be timed to coincide with the intervals during which the immune system is actively attacking the relevant tissues. In many preferred embodiments, the electrodes are positioned to maximize the electric field in the tissues being attacked by the immune system. The concepts described herein are applicable to a wide range of autoimmune diseases, including but not limited to the diseases individually identified below.

[0027] In type 1 diabetes, the immune system damages pancreatic beta cells in stages 1 (when the subject still has normal blood sugar) and 2 (when blood sugar is abnormal due to loss of functional beta cell mass). Therefore, AEF (autoimmune ejection fraction) should be applied to the relevant anatomy during those stages of the disease to slow disease progression. However, once type 1 diabetes has progressed to stage 3, the subject's beta cells are already damaged beyond repair, so continuing treatment is pointless. Because the immune system is attacking the pancreas, the optimal positioning of the electrodes is to place one pair of electrodes on the subject's body in front of and behind the pancreas and / or pancreatic draining lymph nodes, and a second pair of electrodes on the side of the subject's body at the height of the pancreas and / or pancreatic draining lymph nodes.

[0028] In multiple sclerosis (MS), the immune system attacks myelinated axons in the central nervous system. For this disease, an autoimmune electrode (AEF) should be applied to relevant anatomical structures in subjects diagnosed with secondary progressive MS, primary progressive MS, relapsing-remitting MS, or progressive relapsing MS to slow disease progression. Regarding electrode placement, since applying the AEF to the entire central nervous system may be impractical, MRI can be used to detect lesions in the CNS, and the AEF can be applied only to those areas where lesions are detected. Alternatively, the AEF can be continuously applied to the subject's scalp as a precaution to prevent the formation of brain lesions.

[0029] In polymyositis (PM), the immune system attacks the muscles, particularly those in the hips, thighs, upper arms, shoulders, neck, and top of the back. For this disease, an autoimmune electronic (AEF) should be applied to these areas and / or to the associated draining lymph nodes to slow disease progression. Electrodes can be positioned along a strip-shaped area extending proximally to distally along the aforementioned body parts; for example, one pair of electrodes may be positioned in front of and behind the relevant body part, and a second pair of electrodes may be positioned on the right and left sides of the relevant body part.

[0030] In rheumatoid arthritis (RA), the immune system attacks a person's joints (e.g., knees, hips, shoulders, elbows, wrists, ankles, etc.). For this disease, an autoimmune electrode (AEF) should be applied to the aforementioned areas and / or to associated draining lymph nodes in subjects already diagnosed with polycyclic or progressive RA to slow disease progression. During active disease, the electrode should be positioned near the joint, and it should be used as a precautionary measure during remission periods in polycyclic RA. Note that the electrode positioning configuration disclosed in US 2018 / 0001075 can be used to apply the AEF to certain joints (e.g., knees, elbows, and wrists), US 2018 / 0001075, which is incorporated herein by reference in its entirety.

[0031] In Rasmussen encephalitis (RE), the immune system attacks a single hemisphere of the brain. The disease typically progresses through three phases: a prodromal phase, an acute phase, and a residual phase. For this disease, an aeroelectric electrode (AEF) should be applied to the affected hemisphere of the brain in a subject diagnosed with the acute phase of RE to slow disease progression. Once the disease has progressed to the residual phase, treatment can be discontinued. Electrodes should be positioned on the subject's scalp to maximize the field in the affected hemisphere. Many methods for determining optimal electrode placement in the context of glioblastoma can also be used in the context of RE.

[0032] In lupus nephritis, the immune system attacks a person's kidneys. For this disease, the optimal positioning of the electrodes is to place one pair of electrodes on the subject's body in front of and behind the kidneys and / or associated draining lymph nodes, and to place a second pair of electrodes on the side of the subject's body at the height corresponding to the kidneys and / or associated draining lymph nodes.

[0033] For any of the above-mentioned diseases, it is preferred to treat the afflicted portion of the subject's body with AEF for a significant duration (e.g., at least 75% of the time, which reaches at least 18 hours per day).

[0034] Many autoimmune diseases, including some of those listed above, affect body sites with associated draining lymph nodes (e.g., pancreas, kidneys, etc.). Since most T-cell proliferation occurs in draining lymph nodes, treatment of these autoimmune diseases with AEF can be achieved by: (a) applying AEF alone to the relevant body site (e.g., pancreas, kidneys, etc.); (b) applying AEF alone to one or more associated draining lymph nodes; or (c) applying AEF to both the relevant body site and one or more associated draining lymph nodes. The decision regarding which lymph nodes are associated with the relevant body site can be based on literature (i.e., where the association between the body site and a particular lymph node is known in the medical literature) or personalized for each individual subject using imaging (e.g., CT, MRI, ultrasound, etc.).

[0035] Figure 1 An example system 20 for applying AEF to tissue in the human brain is depicted. This system 20 is designed to minimize damage to brain tissue caused by autoimmune diseases such as Rasmussen's encephalitis. System 20 includes an AC voltage generator 30, a first set of electrodes 44 positioned on the right and left sides of the head, and a second set of electrodes 42 positioned on the front and back of the head. (Because...) Figure 1 A frontal view of the scalp 40 is depicted, so the electrodes 42, positioned on the back of the head, are not visible in this view. In the illustrated embodiment, each of the electrodes 42, 44 includes nine circular elements arranged in parallel. However, in alternative embodiments, depending on the anatomical location where the electrodes will be positioned for any given autoimmune disease, different numbers of elements and / or elements of different shapes may be used.

[0036] To use the system, a first set of electrodes 44 is applied to the subject's body (i.e., on the right and left sides of the head in the illustrated embodiment). The first set of electrodes 44 is positioned relative to the target region such that applying an AC voltage between the electrodes 44 will apply an alternating electric field with a first orientation (i.e., right to left in the illustrated embodiment) through the tissue in the target region (i.e., the brain in the illustrated embodiment) being attacked by an autoimmune disease. A second set of electrodes 42 is also applied to the subject's body (i.e., on the front and back of the head in the illustrated embodiment). The second set of electrodes is positioned relative to the target region such that applying an AC voltage between the electrodes 42 will apply an alternating electric field with a second orientation (i.e., front to back in the illustrated embodiment) through the tissue. The first and second orientations are different (and are substantially perpendicular in the illustrated embodiment).

[0037] After the first and second sets of electrodes 42, 44 have been applied to the subject's body, the AC voltage generator 30 repeats the following steps in an alternating sequence: (a) applying a first AC voltage between the electrodes 44 of the first set, such that an alternating electric field with a first orientation is applied through the tissue; and (b) applying a second AC voltage between the electrodes 42 of the second set, such that an alternating electric field with a second orientation is applied through the tissue. The alternating electric field with the first orientation has a specific frequency and field strength, such that when applied to the tissue, it inhibits the proliferation of T cells in the tissue. Similarly, the alternating electric field with the second orientation has a specific frequency and field strength, such that when applied to the tissue, it inhibits the proliferation of T cells in the tissue. This inhibition of T cell proliferation in the tissue reduces damage caused by autoimmune diseases.

[0038] In some embodiments, all electrodes are positioned on the subject's body (e.g., Figure 1 As described in [the original text]); in other embodiments, all electrodes may be implanted inside the subject's body (e.g., just under the subject's skin, or near the organ being treated); and in other embodiments, some of the electrodes are positioned on the subject's skin, while the remaining electrodes are implanted inside the subject's body.

[0039] The same frequency (i.e., 200 kHz) used in the Optune® system for treating glioblastoma can also be used to treat autoimmune diseases by inhibiting T cell proliferation, as described above. However, in alternative embodiments, different frequencies can be used. For example, the frequency of the AEF used to treat autoimmune diseases can be between 100 and 300 kHz, between 50 and 500 kHz, or between 25 kHz and 1 MHz. The optimal frequency can be experimentally determined for each individual autoimmune disease. Preferably, care is taken to ensure that the AEF at the selected frequency does not adversely heat any part of the subject's body.

[0040] The field strength of the AEF can be between 0.2 and 1 V / cm RMS, between 1 and 5 V / cm RMS, or between 5 and 25 V / cm RMS. The optimal field strength can be experimentally determined for each individual with an autoimmune disease. Here again, it is preferable to ensure that the AEF at the field strength being used does not adversely heat any part of the subject's body.

[0041] By applying an AC voltage between two different sets of electrodes, the orientation of the AEF can be switched between two different orientations at one-second intervals, as done in the Optune® system. However, in alternative embodiments, the orientation of the AEF can be switched at a faster rate (e.g., at intervals between 1 and 1000 ms) or a slower rate (e.g., at intervals between 1 and 100 seconds). In other alternative embodiments, the electrodes do not need to be arranged in pairs. See, for example, electrode positioning described in U.S. Patent 7,565,205, which is incorporated herein by reference. In other alternative embodiments, the orientation of the switching field is not required at all; in this case, only a single pair of electrodes is needed.

[0042] In some embodiments, the electrodes are capacitively coupled to the subject's body (e.g., by using electrodes that include a conductive plate and also have a dielectric layer disposed between the conductive plate and the subject's body). However, in alternative embodiments, the dielectric layer may be omitted, in which case the conductive plate will be in direct contact with the subject's body.

[0043] Optionally, a thermal sensor (not shown) may be included at the electrode, and the AC voltage generator 30 may be configured to reduce the magnitude of the AC voltage applied to the electrode if the temperature sensed at the electrode becomes too high.

[0044] In some embodiments, one or more additional pairs of electrodes may be added and included in the sequence. In other embodiments, the field is applied to the target region in a single orientation, in which case the above-described alternating sequence can be replaced by a continuous AC signal applied to a single set of electrodes (e.g., positioned on opposite sides of the target region).

[0045] Note that, although Figure 1 An embodiment in which AEF is applied to the brain is described, but AEF can be applied to different parts of the subject's body, as described above in the alternative embodiments.

[0046] AEF can be used to treat autoimmune diseases in tissues without tumors (e.g., the brain of the first person to have RE). Alternatively, AEF can be used to treat autoimmune diseases in tissues containing tumors (e.g., the brains of different people with both RE and glioblastoma).

[0047] Finally, AEF-based autoimmune therapies can be optionally combined with conventional drugs used to treat the corresponding diseases.

[0048] Although the invention has been disclosed with reference to certain embodiments, many modifications, alterations, and variations of the described embodiments are possible without departing from the scope and domain of the invention as defined in the appended claims. Therefore, the invention is intended to be limited to the described embodiments, but rather to have the full scope defined by the language of the following claims and their equivalents.

Claims

1. A device for treating autoimmune diseases, comprising: Multiple electrodes (42, 44) are placed inside or on the body of a subject relative to a target region, such that applying an AC voltage between the multiple electrodes (42, 44) will apply an alternating electric field through the tissue being attacked by an autoimmune disease in the target region and at least one draining lymph node associated with said tissue. as well as An AC voltage generator (30) is used to apply an AC voltage between a plurality of electrodes (42, 44) at time intervals, such that an alternating electric field is applied through the tissue during the time intervals. The alternating electric field has a certain frequency and field strength, such that when the alternating electric field is applied to the tissue and at least one draining lymph node associated with the tissue during the time interval, the alternating electric field inhibits the proliferation of T cells in the tissue, thereby reducing the degree of damage caused by autoimmune diseases.

2. The device according to claim 1, wherein, Autoimmune diseases are: (i) Type 1 diabetes, and multiple electrodes (42, 44) can be positioned relative to the subject’s body to apply an alternating electric field in the pancreas; (ii) Multiple sclerosis, and multiple electrodes (42, 44) can be positioned relative to the subject’s body such that an alternating electric field is applied to at least one lesion in the subject’s central nervous system; (iii) Polymyositis, and multiple electrodes (42, 44) can be positioned relative to the subject's body so that an alternating electric field is applied in at least one muscle of the subject; (iv) Rheumatoid arthritis, and multiple electrodes (42, 44) can be positioned relative to the subject's body such that an alternating electric field is applied in at least one joint of the subject; (v) Rasmussen encephalitis, and multiple electrodes (42, 44) can be positioned relative to the subject's body to apply an alternating electric field in the affected hemisphere of the subject's brain; or (vi) Lupus nephritis, and multiple electrodes (42, 44) can be positioned relative to the subject’s body such that an alternating electric field is applied to at least one kidney of the subject.

3. The device of claim 1, wherein the plurality of electrodes (42, 44) comprises: The first set of electrodes (44) is placed inside or on the body of the subject relative to the target area, such that applying an AC voltage between the first set of electrodes (44) will apply a first alternating electric field with a first orientation through the tissue; And a second set of electrodes (42) for placement within or on the body of the subject relative to the target area, such that applying an AC voltage between the second set of electrodes (42) will apply a second alternating electric field with a second orientation through the tissue, wherein the first orientation and the second orientation are different, and the first and second alternating electric fields are applied in an alternating sequence by applying a first AC voltage between the first set of electrodes (44) such that a first alternating electric field with a first orientation is applied through the tissue; A second AC voltage is applied between the second set of electrodes (42) such that a second alternating electric field with a second orientation is applied through the tissue.

4. The device according to claim 3, wherein, The first and second sets of electrodes (44, 42) can be positioned relative to the subject's body such that first and second alternating electric fields with first and second orientations are applied to at least one draining lymph node associated with the tissue.

5. The device according to claim 3, wherein, The first orientation is offset from the second orientation by at least 60°.

6. The device of claim 3, wherein the first and second alternating electric fields switch at intervals between 1 ms and 1000 ms.

7. The device of claim 3, wherein the first and second alternating electric fields switch at intervals between 1 s and 100 s.

8. The device according to any one of claims 1 to 7, wherein, Multiple electrodes (42, 44) can each be capacitively coupled to the subject's body.

9. The device according to any one of claims 1 to 7, wherein, Each alternating electric field is applied after the acute phase of the autoimmune disease has been identified.

10. The device according to any one of claims 1 to 7, in combination with a therapeutically effective drug regimen.

11. The device according to any one of claims 1 to 7, wherein each alternating electric field has a frequency between 50 kHz and 500 kHz.

12. The device according to any one of claims 1 to 7, wherein each alternating electric field has a frequency between 100 kHz and 300 kHz.

13. The device according to any one of claims 1 to 7, wherein each alternating electric field has a frequency of 200 kHz.

14. The device according to any one of claims 1 to 7, wherein the electric field strength is between 0.2 V / cm RMS and 5 V / cm RMS.

15. The device according to any one of claims 1 to 7, wherein the electric field strength is between 0.2 V / cm RMS and 1 V / cm RMS.

16. The device according to any one of claims 1 to 7, wherein the electric field strength is between 1 V / cm RMS and 5 V / cm RMS.

17. The device according to any one of claims 1 to 7, wherein the tissue is tumor-free.

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