Treatment of skin stimulation caused by application of alternating electric field

Abstract

An interleukin 23 (IL-23) inhibitor for use in a method of reducing skin irritation of a subject caused by application of an alternating electric field, the method comprising: delivering the interleukin 23 (IL-23) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency of between about 50 kHz and about 10,000 kHz.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 409,581 filed on September 23, 2022 and U.S. Patent Application No. 18 / 371,625 filed on September 22, 2023, the entire contents of the above two applications are incorporated herein by reference. Background Art

[0003] Tumor Treatment Fields (TT Fields) are low-intensity alternating electric fields in the medium frequency range that can be used to treat tumors, as described in U.S. Patent No. 7,565,205. TT Fields are non-invasively induced into a region of interest by transducers placed directly on the patient's body and applying an AC voltage between the transducers. An AC voltage is applied between a first pair of transducers for a first time interval to produce an electric field having field lines extending generally in an anterior-posterior direction. Then, an AC voltage is applied between a second pair of transducers at the same frequency for a second time interval to produce an electric field having field lines extending generally in a left-right direction. The system then repeats this two-step sequence throughout the treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0004] Figure 1 Depicted are example methods for treating a subject according to exemplary embodiments of the present disclosure.

[0005] Figure 2 Depicted are example methods for treating a subject according to exemplary embodiments of the present disclosure.

[0006] FIG. 3A to FIG. 3D The effects of alternating electric fields on the release of IL-17A and the development of epidermal thickness are depicted.

[0007] 4A to 4D The effects of alternating electric fields (eg, TT fields) on epidermal thickening and release of IL-17A in the no treatment, razor and veet only, electrode only, sham heat, and alternating electric field application groups are depicted.

[0008] FIG. 5A to FIG. 5B Depicted are example effects of alternating electric fields on the release of IL-17A, IL-22, and IL-23 in an ovarian cancer model.

[0009] Figure 6 Depicted are example effects of alternating electric fields on the release of IL-17A, IL-22, and IL-23 in the LLC-2 tumor model.

[0010] Fig. 7A and Figure 7B Epidermal proliferation in the no treatment group, shaving and veet only groups, electrode only group, sham heat group, and applied alternating electric field group is depicted.

[0011] FIG. 8A to FIG. 8C Figure 3. Effects of alternating electric field on epidermal thickness ( Fig. 8A ) and epidermal staining ( Figure 8B ) and skin biopsy ( Figure 8C ) Example effects on the release of IL-22 in .

[0012] Fig. 9 An example of an apparatus for applying an alternating electric field having a modulated electric field to a subject's body is depicted.

[0013] Fig.10 An example structure of a transducer array is depicted.

[0014] Fig.11 An example computer device is depicted. DETAILED DESCRIPTION

[0015] The inventors have discovered techniques for treating skin irritation following alternating electric field treatment of a subject. The present disclosure relates to systems and methods for treating skin irritation caused by tumor treating field (TT field) therapy. For example, the present disclosure provides methods and systems for reducing and / or preventing the release of inflammatory cytokines / proteins induced by alternating electric fields. As used herein, the terms "prevent," "prevent," or "prevent" refer to reducing the probability of a subject who does not have a disorder or condition but is at risk or susceptible to the disorder or condition developing the disorder or condition. Prevention can be complete (i.e., no detectable symptoms) prevention, or it can be partial prevention, such that fewer symptoms are observed than would occur without treatment.

[0016] Figure 1 An example method 100 for treating skin irritation caused by the application of an alternating electric field (e.g., a TT field) according to an exemplary embodiment of the present disclosure is depicted. At step 102, a subject may be diagnosed with a condition. In one example, the condition may include a tumor, cancer, or other condition that can be treated by an alternating electric field. As used herein, "subject," "subject in need thereof," "patient," and "patient in need thereof" are used interchangeably and refer to an animal or organism (human or non-human) suffering from or susceptible to a disease or condition that can be treated by the application of an alternating electric field. Non-limiting examples of subjects include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In certain embodiments, the subject is a human.

[0017] The disclosed alternating electric fields (e.g., TT fields) are physical factor therapies that can be used to treat various symptoms and indications (e.g., cancer, tumors, hormone disorders, etc.). When using alternating electric fields to treat subjects, a certain level of alternating electric field amplitude and / or frequency may be required for effective treatment. As used herein, "effective treatment" refers to treatment that is sufficient to affect the desired biological effect, such as a beneficial outcome (including clinical outcomes). Therefore, "effective treatment" depends on the context in which it is applied. The amount and / or conditions of the alternating electric field for effective treatment may vary according to factors known in the art, such as the disease state, age, sex, and weight of the individual being treated.

[0018] Application of an alternating electric field (e.g., TT field) with a specific frequency range and amplitude range may cause skin irritation by promoting the release of inflammatory cytokines and / or proteins. For example, application of an alternating electric field may stimulate the interleukin 17 (IL-17) / interleukin 23 (IL-23) pathway and promote the release of inflammatory cytokines / proteins.

[0019] IL-17 can be produced by helper T cells (Th) 17, γδ T lymphocytes, mucosa-associated invariant T (MAIT) cells, or innate lymphoid cells (ILC) 3 in response to inflammatory stimulation. The Th17 phenotype can be stabilized by IL-23, which can be synthesized by macrophages and dendritic cells under the stimulation of Toll-like receptors and C-type lectin receptors. In addition to Th17, other innate subsets (such as unconventional T cells) can also be the source of IL17 in psoriasis. Plasmacytoid dendritic cells (pDCs) can secrete type I interferons and tumor necrosis factor α (TNFα), thereby activating classical dendritic cells (cDCs). These cDCs can produce IL-12 and IL-23 and guide the differentiation of naive T cells into helper T cells (Th) 1, Th17, and Th22. The survival and expansion of Th17 cells depend on IL-23. Interleukin 23 receptor (IL-23R) can be induced in Th17 through IL-6 signaling via Janus kinases (JAKs) JAK1, JAK2, tyrosine kinase 2 (TYK2), STAT3, and RAR-related orphan receptor γt (RORγt). IL-23 plays an important role in the differentiation of IL-17 expression phenotypes via activation of transcription factors retinoic acid-related orphan receptor γt (ROR-γt) and signal transducer and activator of transcription 3 (STAT3). The key complex consists of IL-17A / A, IL-17A / F or IL-17F / F cytokines and IL-17RA or IL-17RC, which is the initiation mark of IL-17 signaling.

[0020] IL-23 can also promote epidermal hyperplasia, thereby activating the proliferation of keratinocytes. By acting in synergy with IL-17, IL-23 can promote the recruitment of neutrophils and the infiltration of IL-22 and IL-17 producing cells into damaged skin. Both IL-17 and IL-22 promote the proliferation of keratinocytes and the recruitment of macrophages and neutrophils. They can also reduce the expression of adhesion molecules (i.e., selectins and integrins), which is conducive to destroying the skin barrier. The recruitment of CD4+T cells that pathogenically produce IL-23 / IL-17 has been shown to be higher in joints, while CD4+T cells that produce IL-17 / IL-22 are strongly detected in the skin and circulation. The effect of IL-22 can be mainly confined to epithelial cells. The production of dysregulated IL-22 can be associated with certain inflammatory skin diseases, such as atopic dermatitis and psoriasis.

[0021] IL-22 also induces phosphorylation of Jak1 and Tyk2. Furthermore, activation of the MAP kinase pathway and serine phosphorylation of STAT3 may be required for IL-22-induced maximal transactivation of STAT-responsive promoters in these cells. IL-22 may collaborate with other soluble factors and cells to form an inflammatory circuit that otherwise exists as a constitutive or inducible pathway in normal skin and is pathologically amplified in psoriasis.

[0022] T lymphocytes, especially CD4+ T cells or helper T cells (Th), can serve as the main source of IL-22 production. A unidirectional flow of cytokine signals can be seen in the case of IL-22, as immune cells serve as the main secretion source of IL-22, and its main targets include non-hematopoietic epithelial cells. Therefore, IL-22 can be considered an important factor in immune-epithelial interactions. Th1 cells and Th17 cells can be the main producers of IL-22. The production of IL-22 by CD4+ cells can be mainly mediated by the following: cytokines (such as IL-23, IL-21, IL-12, IL-1β, IL-7, IL-6, TNF-α (tumor necrosis factor)), some other molecules (such as Notch, ROLyt), and aryl hydrocarbon receptor ligands (such as FICZ [6-formylindole [3,2-b] carbazole).

[0023] Application of alternating electric fields (eg, TT fields) may cause skin irritation by promoting the release of inflammatory cytokines and / or proteins.

[0024] exist Figure 1At step 104, an inhibitor for treating or preventing skin irritation and / or epidermal renewal and proliferation may be delivered to the subject. In one example, the inhibitor may include at least one of the following: an IL-23 inhibitor, an IL-17A inhibitor, an RAR-related orphan receptor gamma (RORγt) inhibitor, an interleukin 17F (IL-17F) inhibitor, an interleukin 17 receptor alpha (IL-17RA) inhibitor, an interleukin 12 receptor beta 1 (IL-12Rβ1 inhibitor), an interleukin 23 receptor (IL-23R) inhibitor, an IL-22 inhibitor, a Janus kinase (JAK) inhibitor, a non-receptor tyrosine protein kinase (TYK2) inhibitor, or an epithelial differentiation inhibitor (e.g., a vitamin D derivative (such as calcipotriol)).

[0025] In certain embodiments, the inhibitor can be delivered to the subject by various techniques. In one example, the inhibitor can be orally administered to the subject. For example, at least one of the following can be made into tablets, pills, capsules, liquids, gels, syrups, suspensions, suspensions, etc. for oral or nasal use by the subject to be treated: IL-23 inhibitors, IL-17A inhibitors, RAR-related orphan receptor γ (RORγt) inhibitors, interleukin 17F (IL-17F) inhibitors, interleukin 17 receptor α (IL-17RA) inhibitors, interleukin 12 receptor β1 (IL-12Rβ1) inhibitors, interleukin 23 receptor (IL-23R) inhibitors, IL-22 inhibitors, Janus kinase (JAK) inhibitors, non-receptor tyrosine protein kinase (TYK2) inhibitors or vitamin D derivatives. In one example, the disclosed inhibitor can be administered to the subject parenterally. As used herein, the terms "parenteral administration" and "administered parenterally" refer to administration other than enteral and topical administration, usually by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. For example, but not limited to, the disclosed inhibitors can be administered topically to a subject. In some examples of topical administration, the inhibitor can be formulated as an ointment, cream, hydrogel, nanoparticle, adhesive material, or bioactive glue.

[0026] In one example, the IL-23 inhibitor may include at least one of guselkumab, lisinqizumab or tirkizumab. The dosage of the IL-23 inhibitor may be in the range of about 5 mg to about 200 mg. In one example, after delivering at least a portion of the IL-23 inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, when delivering at least a portion of the IL-23 inhibitor, at least a portion of the alternating electric field may be applied simultaneously. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes or 30 minutes before applying the alternating electric field to the subject, a portion of the IL-23 inhibitor may be delivered to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the IL-23 inhibitor. For example, at least about 1 minute after applying the alternating electric field to the subject, a portion of the IL-23 inhibitor may be delivered to the subject. In one example, the IL-23 inhibitor may be delivered to the subject before or at least one day (e.g., 3 to 4 days) after the alternating electric field treatment is started.

[0027] In one example, the IL-17A inhibitor may include at least one of secukinumab, ixekizumab or berdalumab. In one example, the IL-17A inhibitor is a dual inhibitor of IL-17A and IL-17F (such as bimegizumab). The dosage of the IL-17A inhibitor may be in the range of about 45 mg to about 300 mg. In one example, after delivering at least a portion of the IL-17A inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, when delivering at least a portion of the IL-17A inhibitor, at least a portion of the alternating electric field may be applied simultaneously. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes or 30 minutes before applying the alternating electric field to the subject, a portion of the IL-17A inhibitor may be delivered to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the IL-17A inhibitor. For example, at least about 1 minute after applying the alternating electric field to the subject, a portion of the IL-17A inhibitor may be delivered to the subject. In one example, the IL-17A inhibitor can be delivered to the subject at least one day (eg, 3 to 4 days) prior to or after initiation of alternating electric field therapy.

[0028] In one example, the RORγt inhibitor may include at least one of JNJ-61803534, AZD0284, GSK2981278, ML209, or SR221. The dosage of the RORγt inhibitor may be in the range of about 5 mg to 600 mg, once or twice a day. In one example, after delivering at least a portion of the RORγt inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, at least a portion of the alternating electric field may be applied simultaneously when delivering at least a portion of the RORγt inhibitor. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes before applying the alternating electric field to the subject, a portion of the RORγt inhibitor may be delivered to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the RORγt inhibitor. For example, at least about 1 minute after applying the alternating electric field to the subject, a portion of the RORγt inhibitor may be delivered to the subject. In one example, a RORγt inhibitor can be delivered to a subject at least one day (eg, 3 to 4 days) prior to or after initiation of alternating electric field therapy.

[0029] In one example, the IL-17F inhibitor may include at least one IL-17A inhibitor of the disclosed IL-17A inhibitors. For example, the IL-17F inhibitor may include at least one of secukinumab, ixekizumab, or berdalumab. In one example, the IL-17F inhibitor is a dual inhibitor of IL-17A and IL-17F (such as bimegizumab). The dose of the IL-17F inhibitor may be in the range of about 45 mg to about 300 mg. In one example, after delivering at least a portion of the IL-17F inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, when delivering at least a portion of the IL-17F inhibitor, at least a portion of the alternating electric field may be applied simultaneously. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes before applying the alternating electric field to the subject, a portion of the IL-17F inhibitor may be delivered to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the IL-17F inhibitor. For example, a portion of the IL-17F inhibitor may be delivered to the subject at least about 1 minute after applying the alternating electric field to the subject. In one example, the IL-17F inhibitor may be delivered to the subject at least one day (e.g., 3 to 4 days) before or after starting the alternating electric field therapy.

[0030] In one example, the IL-12Rβ1 inhibitor may include at least one of ustekinumab, (R)-lisofylline, apimod mesylate, apimod, and isomicroconvex sword leaf alcohol. The dosage of the IL-12Rβ1 inhibitor may be in the range of about 45 mg once a week to about 200 mg twice a week. In one example, after delivering at least a portion of the IL-12Rβ1 inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, when delivering at least a portion of the IL-12Rβ1 inhibitor, at least a portion of the alternating electric field may be applied simultaneously. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes before applying the alternating electric field to the subject, a portion of the IL-12Rβ1 inhibitor may be delivered to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the IL-12Rβ1 inhibitor. For example, at least about 1 minute after applying the alternating electric field to the subject, a portion of the IL-12Rβ1 inhibitor may be delivered to the subject.

[0031] In one example, the IL-17RA inhibitor may include at least one of berdalumab, FM-202, or an anti-IL-12p40 / IL-23p40 human antibody. The dose of the IL-17RA inhibitor may be in the range of about 100 mg to about 700 mg. In one example, after delivering at least a portion of the IL-17RA inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, at least a portion of the alternating electric field may be applied simultaneously when delivering at least a portion of the IL-17RA inhibitor. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes before applying the alternating electric field to the subject, a portion of the IL-17RA inhibitor may be delivered to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the IL-17RA inhibitor. For example, at least about 1 minute after applying the alternating electric field to the subject, a portion of the IL-17RA inhibitor may be delivered to the subject.

[0032] In one example, the IL-23R inhibitor may include at least one of ustekinumab, brianukumab, FM-202, FM-303, IL-23 Adnectin, ADC-1012, anti-IL-12p40 / IL-23p40 HumAbs, anti-IL-23 HumAbs, apimod, LY-2525623, milizumab (LY3074828), lisenqizumab (BI655066 / ABBV066), bricupumab (MEDI2070, formerly AMG139), and guselkumab (CNTO1959). The dose of the IL-23R inhibitor may be in the range of about 18 mg to about 200 mg. In one example, after delivering at least a portion of the IL-23R inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, while delivering at least a portion of the IL-23R inhibitor, at least a portion of the alternating electric field may be applied simultaneously. For example, a portion of the IL-23R inhibitor may be delivered to the subject at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes before applying the alternating electric field to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the IL-23R inhibitor. For example, a portion of the IL-23R inhibitor may be delivered to the subject at least about 1 minute after applying the alternating electric field to the subject.

[0033] In one example, the IL-22 inhibitor may include at least one of the fezakinumabs (an IL-22 binding protein). The dosage of the IL-22 inhibitor may be in the range of about 100 mg to about 600 mg. In one example, after delivering at least a portion of the IL-22 inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, at least a portion of the alternating electric field may be applied simultaneously when delivering at least a portion of the IL-22 inhibitor. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes before applying the alternating electric field to the subject, a portion of the IL-22 inhibitor may be delivered to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the IL-22 inhibitor. For example, at least about 1 minute after applying the alternating electric field to the subject, a portion of the IL-22 inhibitor may be delivered to the subject.

[0034] In one example, the JAK inhibitor may include at least one of the following: Opzelura, tofacitinib, AZD4604, filgotinib, ruxolitinib, NVP-BSK805, serotoninib, phenylpyranocin C, delphinidin, GLPG0634, molotinib, baricitinib, dicitinib, SJ10542, XL019, pyridoxine 6, SHR0302, itatinib, piricitinib, deuterated ruxolitinib, PF-06263276, SAR-20347, WP1066, iginertinib, FM-381, BMS-911543, TG101209, fuzotinib, cucurbitacin I, FM-479, golitinib, B D750, Socitinib, MS-1020, Oclacitinib, CHZ868, Bressitinib, Baricitinib, SC99, WHI-P97, AZD-1480, Recursin, LFM-A13, TCS21311, G5-7, SD-1008, Abrocitinib, Upadacitinib, AZ-3, FLL32, GDC-4379, GDC-43, NSC33994, Ilotinib, CEP-33779, Pacultinib, Litactinib, Fosifidactinib, ZM29923, Ifidantinib, Pacultinib, Povocitinib, Ezecitinib, Coumacin A1, Nezucitinib, Gandotinib, NSC 42834, JANEX-1JAK2 / TYK2-IN-1, JAK-IN-1 / 3 / 4 / 5 / 10 / 11 / 14 / 15 / 17 / 18 / 20, JAK1-IN-4 / 8 / 9, JAK2-IN-4 / 6 / 7, JAK3-IN-1 / 6 / 7 / 9 / 11 / 13 / 20, JAK-1 / 3-IN-1, JAK3 / BTK-IN-1 / 2 / 3 / 4 / 5 / 6 or JAK2 / FLT3-IN-1. The dosage of the JAK inhibitor may be in the range of about 1.2 grams to about 37.6 grams for topical application twice a week; the oral dosage is 10 mg to 100 mg twice a day. In one example, after delivering at least a portion of the JAK inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, at least a portion of the alternating electric field may be applied simultaneously while delivering at least a portion of the JAK inhibitor. For example, a portion of the JAK inhibitor may be delivered to the subject at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes before applying the alternating electric field to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the JAK inhibitor. For example, a portion of the JAK inhibitor may be delivered to the subject at least about 1 minute after applying the alternating electric field to the subject.

[0035] In one example, the TYK2 inhibitor may include at least one of the following: deuterated lecitinib, selectinib, SAR-20347, BIO, RO495, JAK inhibitor I, GDC046, rosatinib, brecitinib, baricitinib, BMS-911543, oclacitinib, filgotinib, abrocitinib or socitinib. The dose of the TYK2 inhibitor may be in the range of about 3 mg to about 1600 mg. In one example, after delivering at least a portion of the TYK2 inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, when delivering at least a portion of the TYK2 inhibitor, at least a portion of the alternating electric field may be applied simultaneously. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes or 30 minutes before applying the alternating electric field to the subject, a portion of the TYK2 inhibitor may be delivered to the subject. In one example, before delivering at least a portion of the TYK2 inhibitor, at least a portion of the alternating electric field may be applied to the subject. For example, a portion of the TYK2 inhibitor can be delivered to the subject at least about 1 minute after applying the alternating electric field to the subject.

[0036] In one example, the epithelial differentiation inhibitor may include at least one vitamin D derivative (e.g., calcipotriol). The local formulation concentration of the epithelial differentiation inhibitor may be in the range of about 0.001% to about 0.01%. The dosage range of the epithelial differentiation inhibitor may be in the range of about 25g to about 100g per week. In one example, after delivering at least a portion of the epithelial differentiation inhibitor, at least a portion of the alternating electric field may be applied to the subject. In one example, when delivering at least a portion of the epithelial differentiation inhibitor, at least a portion of the alternating electric field may be applied simultaneously. For example, at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes before applying the alternating electric field to the subject, a portion of the epithelial differentiation inhibitor may be delivered to the subject. In one example, at least a portion of the alternating electric field may be applied to the subject before delivering at least a portion of the epithelial differentiation inhibitor. For example, at least about 1 minute after applying the alternating electric field to the subject, a portion of the epithelial differentiation inhibitor may be delivered to the subject.

[0037] In certain embodiments, more than one inhibitor may be delivered to a subject. For example, at least two, three, four, five, six, seven, eight, nine, or ten inhibitors may be delivered to a subject.

[0038] At step 106, an alternating electric field may be delivered to the subject. For example, an alternating electric field (e.g., a TT field) may be applied to a target tissue (e.g., a tumor or cancer), a cell, or an area of ​​the subject. In a non-limiting embodiment, the alternating electric field may be applied using predetermined parameters. As an example, the alternating electric field may include a frequency in the range of about 50 kHz to about 10,000 kHz. As an example, the frequency of the alternating electric field may be between about 50 kHz and about 1,000 kHz, or between about 100 kHz and about 300 kHz. As an example, the frequency of the alternating electric field may be about 100 kHz, about 150 kHz, about 200 kHz, about 250 kHz, or about 300 kHz. As an example, the alternating electric field (e.g., a TT field) may include an intensity in the range of about 1 V / cm to about 10 V / cm. As an example, the intensity of the alternating electric field may be between about 1 V / cm to about 4 V / cm. Other possible exemplary parameters of the alternating electric field may include an effective time, a dimming time, and a duty cycle (all of which may be measured, for example, in milliseconds), as well as other parameters. The parameters may be modified based on the subject's condition (e.g., the size of the target tissue, the type of tumor, the age or sex of the subject) or the purpose of the treatment. In one example, for treating tumor cells / cancer cells, the strength of the alternating electric field is between about 1 V / cm and about 4 V / cm, and the frequency of the alternating electric field is between about 150 kHz and about 250 kHz. In a non-limiting embodiment, the alternating electric field may be applied using two pairs of transducer arrays placed on the subject and directed toward the subject's target tissue (e.g., a tumor).

[0039] In certain embodiments, an alternating electric field may be applied to the subject before or after application of the disclosed inhibitor. In certain embodiments, an alternating electric field (e.g., a TT field) may be applied to the target tissue simultaneously with the disclosed inhibitor. As an example, at least a portion of the applying step 106 may be performed simultaneously / concomitantly with at least a portion of the delivering step 104. In a non-limiting embodiment, steps 104 and 106 may be repeated until the desired therapeutic effect is achieved.

[0040] Figure 2An example alternative method of treating a subject 200 is depicted. The method 200 includes: diagnosing a subject with a disease or condition (e.g., a tumor) 102; obtaining a first level of one or more cytokines in the subject 202; applying an alternating electric field (e.g., a TT field) to the subject for a first time period 204; obtaining a second level / subsequent level of the one or more cytokines in the subject 206; obtaining an increase in the one or more cytokines by comparing the first level and the second level / subsequent level of the one or more cytokines 208; delivering at least one of: an IL-23 inhibitor, an IL-17A inhibitor, a RORγt inhibitor, a TYK inhibitor, a JAK inhibitor, or an epithelial differentiation inhibitor (e.g., a vitamin D derivative or calcipotriol) 104; and / or applying a tumor treating field (TT field) to the subject for a second time period 210.

[0041] At step 202, a first level of one or more cytokines of a subject may be obtained. The one or more cytokines may include at least one of IL-17A, IL-18, IL-22, or IL-23. The level of the one or more cytokines may be measured by various techniques, such as biochemistry (e.g., enzyme-linked immunosorbent assay) and / or proteomics assays (e.g., Western blot). In one example, the first level of IL-17A may be between about 5pg / ml and about 100pg / ml. For example, the first level of the IL-17A may be about 52pg / ml. In one example, the first level of IL-23 may be between about 10pg / ml and about 600pg / ml. In one example, the first level of IL-23 may be between about 30pg / ml and about 50pg / ml. For example, the first level of the IL-23 may be about 580pg / ml. In one example, the first level of IL-22 may be between about 1pg / ml and about 150pg / ml. For example, the first level of the IL-22 can be about 10 pg / ml.

[0042] At step 204, an alternating electric field (e.g., a TT field) may be applied to the subject for a first period of time. The first period of time may be at least about 24 hours, 48 ​​hours, or 72 hours. For example, the first period of time may be between about 24 hours and about 72 hours. During the first period of time, the alternating electric field may be applied continuously or intermittently.

[0043] At step 206, a second level of the one or more cytokines of the subject may be obtained. The one or more cytokines may include at least one of IL-17A, IL-18, IL-22, or IL-23. The level of the one or more cytokines may be measured by various techniques, such as biochemistry (e.g., enzyme-linked immunosorbent assay) and / or proteomics assay (e.g., Western blot). At step 208, the increase of the one or more cytokines may be obtained by comparing the first level and the second level to assess the increase of skin irritation-related factors. In one example, the increase of at least one of IL-23, IL-18, IL-17A, or IL-22 may be at least about 5%, at least about 10%, at least about 25%, at least about 50%, or at least about 100%. For example, the increase of the IL-23 may be as high as about 50%. For example, the increase of the IL-17A, IL-18, or IL-22 may be between about 5% and about 120%. In a non-limiting embodiment, the increase of the IL-17A may be about 90%. In a non-limiting example, the first level and the second level of the one or more cytokines can be obtained from a serum sample of the subject.

[0044] In non-limiting embodiments, when an increase in one or more of the disclosed cytokines is detected, at least one of the disclosed inhibitors may be delivered to the subject. In one example, the dosage of the disclosed inhibitor may vary based on the elevated level of one or more of the disclosed cytokines. For example, the dosage of the disclosed inhibitor may be increased to eliminate, prevent, or reduce the level of one or more of the disclosed cytokines in the subject, thereby reducing skin irritation. In one example, the disclosed inhibitor may be delivered to the subject prior to delivering another alternating electric field therapy, and the subject exhibits an increase in at least one of the IL-23, IL-18, IL-17A, or IL-22.

[0045] In a non-limiting embodiment, an increase in one or more of the disclosed cytokines may be obtained before applying the alternating electric field. For example, an increase in one or more of the disclosed cytokines may be obtained by comparing the first level of the one or more cytokines disclosed with a known normal range of the one or more cytokines, which does not cause skin irritation. For example, a normal level of IL-17A may be between about 1 pg / ml and about 50 pg / ml. In one example, a normal level of IL-17A may be about 20 pg / ml. In one example, a normal level of IL-23 may be between about 10 pg / ml and about 600 pg / ml. In one example, a normal level of IL-23 may be between about 30 pg / ml and about 50 pg / ml. For example, a normal level of IL-23 may be about 580 pg / ml. In one example, a normal level of IL-22 may be between about 1 pg / ml and about 10 pg / ml. For example, a normal level of IL-22 may be about 3 pg / ml. In one example, the normal level of IL-18 can be between about 50 pg / ml and about 10,000 pg / ml. In one example, the normal level of IL-18 can be about 155 pg / ml. In one example, the increase in at least one of IL-23, IL-17A, or IL-22 can be at least about 5%, at least about 10%, at least about 25%, at least about 50%, at least about 100%, or at least about 150% between the first level and the normal level. For example, the increase in IL-23 can be as high as about 50%. For example, the increase in IL-17A can be between about 5% and about 120%. In a non-limiting embodiment, the increase in IL-17A can be about 90%. In one example, the disclosed inhibitor can be delivered to the subject prior to delivering another disclosed alternating electric field, and the subject exhibits an increase in at least one of the IL-23, IL-17A, or IL-22.

[0046] At step 210, the alternating electric field (e.g., TT field) may be applied to the subject for a second period of time. The second period of time may be at least about 24 hours, 48 ​​hours, or 72 hours. For example, the second period of time may be between about 24 hours and about 48 hours. During the second period of time, the alternating electric field may be applied continuously or intermittently.

[0047] Experimental Results

[0048] Applying an alternating electric field (e.g., a TT field) causes skin irritation by promoting the release of inflammatory cytokines and / or proteins. Using certain embodiments disclosed herein, an alternating electric field (e.g., a TT field) is applied to a subject. Various mouse models are exposed to an alternating electric field. For example, an orthotopic ovarian cancer mouse model is established by injecting MOSE-L-ffl cancer cells into 12-week-old female mice. Using the INOVIVO system (Novocure, Haifa, Israel), mice are treated for 10 days with an alternating electric field (e.g., a TT field, 200kHz) having a field strength of at least 1V / cm. At the end of treatment, blood samples are collected into designated serum tubes for immunoassay analysis.

[0049] Lewis lung carcinoma (LLC) model ovarian cancer mouse model was established. Mice were treated for 10 days using the INOVIVO system (Novocure, Haifa, Israel) with an alternating electric field (e.g., TT field, 150kHz) with a field strength of at least 1V / cm. At the end of the treatment, blood samples were collected into designated serum tubes. Safety rats (control group) were treated for 14 days using the INOVIVO system (Novocure, Haifa, Israel) with a field strength of at least 1V / cm at 150kHz.

[0050] The disclosed results suggest that upregulation of IL-17A / IL-23 levels may account for the increased skin inflammation seen in psoriasis patients and that administration of IL17A / IL23 inhibitors to patients may be beneficial in treating skin irritation.

[0051] The IL-23 heterodimer is formed by the combination of a p19 subunit and a p40 subunit and is most structurally similar to IL-12. A key immune function of IL-23 is to drive the differentiation process of naive T helper (Th) cells to Th17 cells, which are the main producers of IL-17. IL-23 inhibits the differentiation of regulatory T (Treg) cells, which produce IL-10 and suppress inflammation, thereby limiting the differentiation of Th17. IL-23 promotes the secretion of IL-17, IL-22, and TNF-a by Th17 cells.

[0052] The IL-23 / IL-17A pathway plays an important role in skin irritation. Keratinocytes constitutively express IL-23. Keratinocytes in psoriatic skin express higher levels of IL-23 compared to keratinocytes in normal skin. Psoriasis, hidradenitis suppurativa, atopic dermatitis, and alopecia areata are T cell immune axes and cytokines in the pathogenesis of skin inflammation. T helper cells (including Th1, Th17, and Th22) are the main producers of IL-22. The IL-22-IL-22 subunit (IL-22R1) axis shows high potential clinical relevance in inflammatory diseases such as psoriasis, ulcerative colitis, liver and pancreatic damage, graft-versus-host disease, certain infections, and tumors. In case of skin inflammation, the increase of IL-22 contributes to the proliferation of keratinocytes. Th17-type cytokines (IL-17A, IL-17F, and IL-22) drive keratinocyte hyperproliferation and chemokine production, and continue further leukocyte recruitment. Biologic agents targeting IL-17 may reduce disease burden in patients with moderate to severe psoriasis.

[0053] FIG. 3A to FIG. 3D Depicts the generation of thicker epidermis in the skin beneath electrodes for applying an alternating electric field (e.g., TT field). The skin sections were from a safety experiment in which male and female rats were treated with an alternating electric field (e.g., TT field, 150 kHZ) for two weeks. Figure 3A As shown, skin sections were taken from the skin under the electrodes and from the control skin (without electrodes) and stained with anti-17A antibody. FIG. 3B to FIG. 3D , the results showed that IL-17A staining and epidermal thickness of the skin under the electrodes were increased compared to the control skin. In addition, IL-23 in the skin under the electrodes was increased compared to the untreated group and the control skin (sham model). There are certain inhibitors that can be used to reduce skin irritation caused by the application of alternating electric fields (e.g., TT fields), such as IL-17 inhibitors (e.g., secukinumab, ixekizumab, and berdalumab) and IL-23 inhibitors (e.g., guselkumab, liscentizumab, and tiriquizumab).

[0054] like FIG. 3A to FIG. 3C In skin samples from safety experiment rats, the results showed that the expression of IL-17A was increased in the skin under the electrodes compared with the skin not under the electrodes. In addition, the epidermal thickness of the skin under the electrodes was significantly higher than that of the skin not under the electrodes, indicating excessive proliferation of keratinocytes.

[0055] like Figure 3D As shown, in serum samples from rats, a certain trend showed that two cytokines, namely, the levels of IL-17A and IL-23 in serum, were increased after application of an alternating electric field (eg, TT field) compared to the sham heat group.

[0056] Secukinumab, ixekizumab, and berdalumab are monoclonal antibody therapies that inhibit interleukin (IL)-17 activity and are widely used to treat psoriasis, psoriatic arthritis, and ankylosing spondylitis. Interleukin-23 inhibitors (e.g., ustekinumab, guselkumab, terekizumab, and risenkizumab) may be safe and effective options for treating moderate to severe psoriasis. Ustekinumab can be used to treat psoriatic arthritis. IL-23 inhibitors and IL-17A inhibitors can be administered by subcutaneous injection every few weeks.

[0057] Certain IL-23 inhibitors and IL-17A inhibitors have a large molecular weight, making them unsuitable for use as topical drugs because they cannot diffuse across the skin barrier. There are currently topical RORγt inhibitors (such as JNJ-61803534 and GSK2981278) in clinical trials to treat psoriasis. IL-23 inhibitors and IL-17A inhibitors may include topical JAK inhibitors, TYK2 inhibitors, or calcipotriol.

[0058] 4A to 4D The effects of alternating electric fields (e.g., TT fields) on epidermal thickening and IL-17A elevation in different groups (i.e., no treatment, razor and veet only, electrode only, sham heat, and alternating electric fields (e.g., TT fields)) are depicted. Figure 4A As shown, mice in the no treatment group did not receive any treatment. The hair of mice in the razor only and veet groups was removed physically and chemically. In the electrode group, the hair of mice was removed physically / chemically and then electrodes were applied without heat or alternating electric field (e.g., TT field). In the sham heat model group, electrodes with only heat were applied to the mice with hair removed. In the alternating electric field (e.g., TT field) group, TT field was applied to the (hair removed) mice via electrodes.

[0059] Skin under alternating electric fields (e.g., TTFields) was compared to untreated skin, sham heat-treated skin, skin treated with razor and Veet alone, and skin that had been treated with razor and Veet and had electrodes placed without alternating electric fields (e.g., TTFields) or heat attached. Figure 4B As shown, skin sections were taken from the no treatment group, the razor and veet only group, the electrode only group, the sham heat group, and the alternating electric field (e.g., TT field) group and stained with anti-17A antibody. Compared with untreated mice, increased epidermal thickness was detected in the alternating electric field (e.g., TT field). The skin treated with the alternating electric field (e.g., TT field) was significantly increased compared with all control groups. As Figure 4C and Figure 4DAs shown, the results showed that the skin epidermal thickness under the alternating electric field (e.g., TT field) increased compared with the no treatment group, the razor and veet groups only, the electrode group only, and the sham heat group. Compared with the sham heat group, an increase in IL-17A staining was detected in the alternating electric field (e.g., TT field) group.

[0060] FIG. 5A to FIG. 5B The effects of alternating electric fields (e.g., TT fields) on the release of IL-17A, IL-22, and IL-23 in an ovarian tumor model are depicted. Mice were orthotopically implanted with MOSE-FFL cells. During the subsequent 15 days, an alternating electric field (e.g., TT field) was applied to the mice using a 200kHz torso array for 10 days. Serum was extracted and a cytokine array was performed. Figure 5A and Figure 5B It is shown that circulating levels of IL-17A, IL-22, and IL-23 are increased in mice treated with alternating electric fields (eg, TT fields) compared to the heat-treated group.

[0061] Figure 6 Depicted is the effect of alternating electric fields (e.g., TT fields) on the release of IL-17A, IL-22, and IL-23 in the LLC-2 tumor model. Mice were implanted with LLC-2 cells in situ. During the subsequent 7 days, an alternating electric field (e.g., TT field) was applied to the mice using a 150kHz torso array for 10 days. Serum was extracted and a cytokine array was performed. Figure 6 It is shown that circulating levels of IL-17A, IL-22, and IL-23 are increased in mice treated with alternating electric fields (eg, TT fields) compared to the heat-treated group.

[0062] Fig. 7A and Figure 7B Depicted are the effects of alternating electric fields (eg, TT fields) on epidermal proliferation as a marker of rapid epidermal turnover, indicating increased epidermal differentiation. Fig. 7A Shown are different sets of skin sections stained with Ki67, a marker for epidermal cell proliferation. Figure 7B Quantitative results are provided showing Ki67 positive nuclei per length in the epidermis of different groups. The results show that epidermal proliferation is increased in epidermis treated with alternating electric fields (eg, TT fields) compared to the untreated group.

[0063] IL-22 increases when the skin is injured, and increased hyperproliferation of epidermal differentiation can cause elevated IL-22. Calcipotriol, tofacitinib 2% cream, or opzelura can be used to treat epidermal differentiation and epidermal thickening caused by rapid skin turnover following the wound healing process. Rapid turnover caused by alternating electric fields can lead to inflammation and thickening of the epidermis (but fragile skin). Therefore, calcipotriol, tofacitinib 2% cream, or opzelura can also be used to treat skin irritation caused by alternating electric fields (e.g., TT fields).

[0064] FIG. 8A to FIG. 8C The effects of alternating electric fields (e.g., TT fields) on epidermal thickening and IL-22 elevation in different groups (i.e., no treatment, razor and veet only, electrode only, sham heat, and alternating electric fields (e.g., TT fields)) are depicted. Fig. 8A Skin sections were taken from the no treatment group, the razor and veet only group, the electrode only group, the sham heat group, and the alternating electric field (e.g., TT field) group and stained with anti-IL22 antibody. A significant increase in IL-22 in epidermal staining was detected in the group where the alternating electric field (e.g., TT field) was applied compared to the other groups (e.g., no treatment group, the razor and veet only group, the electrode only group, and the sham heat group). Epidermal thickness was significantly increased in the group where the alternating electric field (e.g., TT field) was applied compared to all other experimental groups. Fig. 8A As shown, the results showed that the skin epidermal thickness under the alternating electric field (e.g., TT field) increased compared with the no treatment group, the razor and veet groups only, the electrode group only, and the sham heat group. Compared with the sham heat group, an increase in IL-22 staining was detected in the alternating electric field (e.g., TT field) group. Figure 8B Shown is a significant increase in IL-22 epidermal staining following alternating electric fields (eg, TT fields) compared to all other experimental groups. Figure 8C Shown is an increase in IL-22 staining in skin sections following alternating electric fields (eg, TT fields) compared to all other experimental groups.

[0065] Exemplary Devices

[0066] Fig. 9An example of an apparatus for applying an alternating electric field (e.g., a TT field) to a subject's body is depicted. A first transducer array 901 includes 13 electrode elements 903, which are located on a substrate 904, and the electrode elements 903 are electrically and mechanically connected to each other through conductive wires 909. A second transducer array 902 includes 13 electrode elements 905, which are located on a substrate 906, and the electrode elements 905 are electrically and mechanically connected to each other through conductive wires 910. The first transducer array 901 and the second transducer array 902 are connected to an AC voltage generator 907 and a controller 908. The controller 908 may include one or more processors and a memory accessible by the one or more processors. The memory may store instructions that, when executed by the one or more processors, control the AC voltage generator 907 to implement one or more embodiments of the present invention. In some embodiments, the AC voltage generator 907 and the controller 908 may be integrated in the first transducer array 901 and the second transducer array 902, and form a first electric field generator and a second electric field generator.

[0067] Fig.10 An example of an alternative design of a transducer array is depicted. Similarly, the transducer array 1001 includes 20 electrode elements 1002 , which are located on a substrate 1003 , and the electrode elements 1002 are electrically and mechanically connected to each other through conductive wires 1004 .

[0068] Fig.11 An example computer device for use with embodiments herein is depicted. As an example, device 1100 may be a computer implementing certain inventive techniques disclosed herein. As an example, device 1100 may be a controller device for applying an alternating electric field (e.g., a TT field) having a modulated electric field in embodiments herein. Controller device 1100 may be used as Fig. 9 The device 1100 may include one or more processors 1102 , a memory 1103 , one or more input devices, and one or more output devices 1105 .

[0069] In one example, based on input 1101, the one or more processors generate control signals to control the voltage generator to implement embodiments of the present invention. In one example, input 1101 is user input. In another example, input 1101 may come from another computer in communication with controller device 1100. Input 1101 may be received in conjunction with one or more input devices (not shown) of device 1100.

[0070] The output device 1105 may provide the operating status of the present invention, such as transducer array selection, voltages being generated, and other operational information. According to some embodiments of the present invention, the output device 1105 may provide visualization data.

[0071] The memory 1103 may be accessible by the one or more processors 1102 (e.g., via the link 1104) such that the one or more processors 1102 may read information from and write information to the memory 1103. The memory 1103 may store instructions that, when executed by the one or more processors 1102, implement one or more embodiments of the present invention. The memory 1103 may be a non-transitory processor-readable medium having a set of instructions contained thereon, which, when executed by a processor (such as the one or more processors 1102), causes the processor to perform one or more methods disclosed herein.

[0072] Device 1100 may be a device comprising: one or more processors (such as one or more processors 1102); and a memory (such as memory 1103) accessible by the one or more processors, the memory storing instructions that, when executed by the one or more processors, cause the device to perform one or more methods disclosed herein.

[0073] Illustrative Embodiments

[0074] The invention includes other illustrative embodiments such as those shown below.

[0075] Exemplary Embodiment 1 A method of treating a subject, the method comprising: delivering an interleukin 17A (IL-17A) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0076] Exemplary Embodiment 2 The method according to Exemplary Embodiment 1, wherein the subject has a tumor, and the alternating electric field is applied to the tumor of the subject.

[0077] Exemplary Example 3 The method according to Exemplary Example 1, wherein the IL-17A inhibitor comprises at least one of secukinumab, ixekizumab and berdalumab.

[0078] Exemplary embodiment 4 The method according to exemplary embodiment 1, wherein at least a portion of the alternating electric field applying step is performed after at least a portion of the interleukin 17A inhibitor delivering step.

[0079] Exemplary embodiment 5 The method according to exemplary embodiment 1, wherein at least a part of the alternating electric field applying step and at least a part of the interleukin 17A inhibitor delivering step are performed simultaneously.

[0080] Exemplary Embodiment 6 The method according to Exemplary Embodiment 1, wherein at least a portion of the applying step is performed before at least a portion of the conveying step.

[0081] Exemplary Example 7 A method of treating a subject, the method comprising: delivering a RAR-related orphan receptor gamma (RORγt) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0082] Exemplary Embodiment 8 The method according to Exemplary Embodiment 7, wherein the subject has a tumor, and the alternating electric field is applied to the tumor of the subject.

[0083] Exemplary embodiment 9 The method according to Exemplary embodiment 7, wherein the RORγt inhibitor comprises at least one of JNJ-61803534 or GSK2981278.

[0084] Exemplary Embodiment 10 The method according to Exemplary Embodiment 7, wherein the alternating electric field is applied at a frequency between about 50 kHz and about 1,000 kHz.

[0085] Exemplary Embodiment 11 The method according to Exemplary Embodiment 10, wherein the alternating electric field is applied at a frequency between about 100 kHz and about 300 kHz.

[0086] Exemplary Embodiment 12 The method according to Exemplary Embodiment 7, wherein the alternating electric field is applied using two pairs of transducers placed on the subject and directed toward the subject's tumor.

[0087] Exemplary Embodiment 13 A method for treating a subject, the method comprising: delivering an interleukin 23 (IL-23) inhibitor to the subject and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0088] Exemplary embodiment 14 The method according to Exemplary embodiment 13, wherein a portion of the IL-23 inhibitor is delivered to the subject at least 5 minutes before the alternating electric field applying step.

[0089] Exemplary Embodiment 15 The method according to Exemplary Embodiment 13, wherein the alternating electric field is applied for about 18 hours to about 96 hours, and the IL-23 inhibitor is applied at least once during the alternating electric field applying step.

[0090] Exemplary embodiment 16 The method according to Exemplary embodiment 13, wherein a portion of the IL-23 inhibitor is delivered to the subject about two days after the alternating electric field applying step.

[0091] Exemplary embodiment 17 The method according to exemplary embodiment 13, wherein a portion of the IL-23 inhibitor is delivered to the subject about two days after the alternating electric field applying step, wherein the dose of the IL-23 inhibitor is in the range of 5 mg to 200 mg.

[0092] Exemplary embodiment 18 According to the method described in exemplary embodiment 13, the method further includes: obtaining a first level of at least one of IL-23, IL-17A or IL-22 in the subject before delivering the IL-23 inhibitor to the subject; obtaining a second level of at least one of IL-23, IL-17A or IL-22 in the subject after applying the alternating electric field to the subject; detecting an increase in at least one of IL-23, IL-17A or IL-22 by comparing the first level and the second level of at least one of IL-23, IL-17A or IL-22; and delivering the IL-23 inhibitor to the subject based on the increase in at least one of IL-23, IL-17A or IL-22.

[0093] Exemplary Embodiment 19 The method according to Exemplary Embodiment 18, wherein the increase in at least one of IL-23, IL-17A or IL-22 is at least about 5%.

[0094] Exemplary embodiment 20 According to the method described in exemplary embodiment 18, the method further includes: before delivering another alternating electric field, delivering an inhibitor to the subject who exhibits the increase in at least one of IL-23, IL-17A or IL-22, wherein the inhibitor includes at least one of the following: an IL-23 inhibitor, an IL-17A inhibitor, an RAR-related orphan receptor γ (RORγt) inhibitor, an IL-17F inhibitor, an IL-17RA inhibitor, an IL-12Rβ1 inhibitor, an IL-23R inhibitor, an IL-22 inhibitor, a Janus kinase (JAK) inhibitor, a non-receptor tyrosine protein kinase (TYK2) inhibitor, or an epithelial differentiation inhibitor.

[0095] Exemplary embodiment 20a. The method according to Exemplary embodiment 20, wherein the epithelial differentiation inhibitor is a vitamin D derivative, optionally calcipotriol.

[0096] Exemplary embodiment 21 The method according to Exemplary embodiment 18, wherein the first level of IL-23 is about 30 pg / ml to about 50 pg / ml.

[0097] Exemplary embodiment 22 The method according to Exemplary embodiment 21, wherein the first level of IL-23 is about 580 pg / ml.

[0098] Exemplary embodiment 23 The method according to Exemplary embodiment 18, wherein the increase of IL-23 is up to about 50%.

[0099] Exemplary embodiment 24 According to the method described in exemplary embodiment 1, the method further includes: obtaining a first level of at least one of IL-23, IL-17A or IL-22 in the subject before delivering the IL-23 inhibitor to the subject; obtaining a second level of at least one of IL-23, IL-17A or IL-22 in the subject after applying the alternating electric field to the subject; detecting an increase in at least one of IL-23, IL-17A or IL-22 by comparing the first level and the second level of at least one of IL-23, IL-17A or IL-22; and delivering the IL-23 inhibitor to the subject based on the increase in at least one of IL-23, IL-17A or IL-22.

[0100] Exemplary embodiment 25 The method according to Exemplary embodiment 1, wherein the increase in at least one of IL-23, IL-17A or IL-22 is at least about 5%.

[0101] Exemplary Example 26 According to the method described in Exemplary Example 1, the method further includes: before delivering another alternating electric field, delivering an inhibitor to the subject exhibiting the increase in at least one of IL-23, IL-17A or IL-22, wherein the inhibitor includes at least one of the following: an IL-23 inhibitor, an IL-17A inhibitor, an RAR-related orphan receptor γ (RORγt) inhibitor, an IL-17F inhibitor, an IL-17RA inhibitor, an IL-12Rβ1 inhibitor, an IL-23R inhibitor, an IL-22 inhibitor, a Janus kinase (JAK) inhibitor, a non-receptor tyrosine protein kinase (TYK2) inhibitor, or an epithelial differentiation inhibitor.

[0102] Exemplary embodiment 27 The method according to Exemplary embodiment 24, wherein the first level of IL-17A is about 5 pg / ml to about 100 pg / ml.

[0103] Exemplary embodiment 28 The method according to Exemplary embodiment 27, wherein the first level of IL-17A is about 52 pg / ml.

[0104] Exemplary embodiment 29 The method according to Exemplary embodiment 25, wherein the increase of IL-17A is about 5% to about 120%.

[0105] Exemplary embodiment 30: The method according to Exemplary embodiment 25, wherein the increase of IL-17A is about 90%.

[0106] Exemplary Embodiment 31 The method according to Exemplary Embodiment 1, wherein the alternating electric field is applied to the subject for a period of at least about 3 days.

[0107] Exemplary embodiment 32 The method according to Exemplary embodiment 1, wherein the IL-17A inhibitor is formulated for topical administration, oral administration or parenteral administration, wherein the IL-17A inhibitor is formulated as a gel, a hydrogel, a gel containing nanoparticles, an adhesive tape or a band-aid.

[0108] Exemplary embodiment 33 The method according to Exemplary embodiment 1, wherein a portion of the IL-17A inhibitor is delivered to the subject about 30 minutes before the alternating electric field applying step.

[0109] Exemplary embodiment 34 The method according to Exemplary embodiment 1, wherein the alternating electric field is applied for between about 18 hours and about 48 hours, and the IL-17A inhibitor is applied at least once during the alternating electric field applying step.

[0110] Exemplary embodiment 35 The method according to Exemplary embodiment 1, wherein a portion of the IL-17A inhibitor is delivered to the subject about 30 minutes after the alternating electric field applying step.

[0111] Exemplary embodiment 36 The method according to Exemplary embodiment 1, wherein the dosage of the IL-17A inhibitor is in the range of about 100 mg to about 300 mg.

[0112] Exemplary embodiment 37 The method according to Exemplary embodiment 7, wherein the RORγt inhibitor is formulated for topical administration, oral administration or parenteral administration.

[0113] Exemplary Embodiment 38 The method according to Exemplary Embodiment 7, wherein at least a portion of the alternating electric field applying step is performed after at least a portion of the conveying step.

[0114] Exemplary embodiment 39 The method according to Exemplary embodiment 7, wherein a portion of the RORγt inhibitor is delivered to the subject about 30 minutes before the applying step.

[0115] Exemplary Embodiment 40 The method according to Exemplary Embodiment 7, wherein at least a portion of the applying step is performed simultaneously with at least a portion of the RORγt inhibitor delivering step.

[0116] Exemplary Embodiment 41 The method according to Exemplary Embodiment 7, wherein the alternating electric field is applied for about 18 hours to about 96 hours, and the RORγt inhibitor is delivered at least once during the applying step.

[0117] Exemplary Embodiment 42 The method according to Exemplary Embodiment 7, wherein at least a portion of the alternating electric field applying step is performed before at least a portion of the RORγt inhibitor delivering step.

[0118] Exemplary embodiment 43 The method according to Exemplary embodiment 7, wherein a portion of the RORγt inhibitor is delivered to the subject about 30 minutes after the alternating electric field applying step.

[0119] Exemplary embodiment 44 The method according to Exemplary embodiment 7, wherein the dosage of the RORγt inhibitor is in the range of about 5 mg to about 600 mg.

[0120] Exemplary embodiment 45 The method according to Exemplary embodiment 26, wherein the JAK inhibitor comprises at least one of Opzelura or Tofacitinib.

[0121] Exemplary Embodiment 46 An interleukin 23 (IL-23) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering an interleukin 23 (IL-23) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0122] Exemplary Embodiment 47 The IL-23 inhibitor for use according to Exemplary Embodiment 47, wherein the IL-23 inhibitor comprises at least one of guselkumab, risenkizumab, and teikizumab.

[0123] Exemplary embodiment 48 According to the IL-23 inhibitor for use as described in Exemplary embodiment 47, the IL-23 inhibitor also includes: obtaining a first level of at least one of IL-23, IL-17A or IL-22 in the subject before delivering the IL-23 inhibitor to the subject; obtaining a second level or subsequent level of at least one of IL-23, IL-17A or IL-22 in the subject after applying the alternating electric field to the subject; detecting an increase in at least one of IL-23, IL-17A or IL-22 by comparing the first level and the second level or subsequent level of at least one of IL-23, IL-17A and IL-22; and delivering the IL-23 inhibitor to the subject based on the increase in at least one of IL-23, IL-17A and IL-22.

[0124] Exemplary Embodiment 49 The IL-23 inhibitor for use according to any one of Exemplary Embodiments 46 to 48, wherein the increase in at least one of IL-23, IL-17A or IL-22 is at least about 5%.

[0125] Exemplary embodiment 50 An IL-23 inhibitor for use according to exemplary embodiment 49, the IL-23 inhibitor further comprising: delivering an inhibitor to the subject exhibiting the increase in at least one of IL-23, IL-17A and IL-22 prior to delivering another alternating electric field, wherein the inhibitor comprises at least one of the following: an IL-23 inhibitor, an IL-17A inhibitor, an RAR-related orphan receptor γ (RORγt) inhibitor, an IL-17F inhibitor, an IL-17RA inhibitor, an IL-12Rβ1 inhibitor, an IL-23R inhibitor, an IL-22 inhibitor, a Janus kinase (JAK) inhibitor, a non-receptor tyrosine protein kinase (TYK2) inhibitor, and a vitamin D derivative.

[0126] Exemplary embodiment 51 The IL-23 inhibitor according to Exemplary embodiment 46, wherein at least a portion of the alternating electric field applying step is performed before, simultaneously with, or after at least a portion of the interleukin 23 (IL-23) inhibitor delivering step.

[0127] Exemplary Embodiment 52 An interleukin 17A (IL-17A) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering an interleukin 17A (IL-17A) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0128] Exemplary embodiment 53 The method according to exemplary embodiment 52, wherein the IL-17A inhibitor comprises at least one of secukinumab, ixekizumab and berdalumab.

[0129] Exemplary Embodiment 54 A RAR-related orphan receptor gamma (RORγt) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering a RAR-related orphan receptor gamma (RORγt) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0130] Exemplary embodiment 55 The method according to Exemplary embodiment 54, wherein the RORγt inhibitor comprises at least one of JNJ-61803534 and GSK2981278.

[0131] Exemplary Embodiment 56 An interleukin 17F (IL-17F) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering an interleukin 17F (IL-17F) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0132] Exemplary Embodiment 57 An interleukin 17RA (IL17RA) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering an interleukin 17RA (IL17RA) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0133] Exemplary Embodiment 58 An interleukin 12Rβ1 (IL-12Rβ1) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering the interleukin 12Rβ1 (IL-12Rβ1) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0134] Exemplary Embodiment 59 An interleukin 23R (IL-23R) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering an interleukin 23R (IL-23R) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0135] Exemplary Embodiment 60 An interleukin 22 (IL-22) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering an interleukin 22 (IL-22) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0136] Exemplary Embodiment 61 A Janus kinase (JAK) inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering a Janus kinase (JAK) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0137] Exemplary Embodiment 62 The JAK inhibitor for use according to Exemplary Embodiment 61, wherein the JAK inhibitor comprises at least one of Opzelura or Tofacitinib.

[0138] Exemplary Embodiment 63 A non-receptor tyrosine protein kinase (TYK2) inhibitor for use in a method for reducing skin irritation of a subject caused by applying an alternating electric field, the method comprising: delivering a non-receptor tyrosine protein kinase (TYK2) inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0139] Exemplary Embodiment 64 An epithelial differentiation inhibitor for use in a method for reducing skin irritation in a subject caused by applying an alternating electric field, the method comprising: delivering an epithelial differentiation inhibitor to the subject; and applying an alternating electric field to the subject at a frequency between about 50 kHz and about 10,000 kHz.

[0140] Unless otherwise indicated herein or clearly contradicted by context, embodiments described under any heading or in any section of this disclosure may be combined with embodiments illustrated under the same or any other heading or other section of this disclosure.

[0141] Numerous modifications, changes and variations may be made to the described embodiments without departing from the scope of the invention as defined by the claims.It is intended that the present invention not be limited to the described embodiments, but rather has the full scope defined by the language of the following claims and their equivalents.

Claims

1. An interleukin 23 (IL-23) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering an interleukin 23 (IL-23) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

2. The IL-23 inhibitor for use according to claim 1, wherein the IL-23 inhibitor comprises at least one of guselkumab, risenkizumab and teikizumab.

3. The IL-23 inhibitor for use according to claim 1, wherein the method further comprises: obtaining a first level of at least one of IL-23, IL-17A, or IL-22 in the subject before delivering the IL-23 inhibitor to the subject; obtaining a second or subsequent level of at least one of IL-23, IL-17A, or IL-22 in the subject after applying the alternating electric field to the subject; detecting an increase in at least one of IL-23, IL-17A, or IL-22 by comparing the first level and the second or subsequent level of the at least one of IL-23, IL-17A, or IL-22; and Based on the increase in the at least one of IL-23, IL-17A, and IL-22, the IL-23 inhibitor is delivered to the subject.

4. The IL-23 inhibitor for use according to any one of claims 1 to 3, wherein the increase in said at least one of IL-23, IL-17A or IL-22 is at least about 5%.

5. The IL-23 inhibitor for use according to claim 4, wherein the method further comprises: Prior to delivering another alternating electric field, an inhibitor is delivered to the subject exhibiting the increase in at least one of IL-23, IL-17A and IL-22, wherein the inhibitor comprises at least one of the following: an IL-23 inhibitor, an IL-17A inhibitor, an RAR-related orphan receptor gamma (RORγt) inhibitor, an IL-17F inhibitor, an IL-17RA inhibitor, an IL-12Rβ1 inhibitor, an IL-23R inhibitor, an IL-22 inhibitor, a Janus kinase (JAK) inhibitor, a non-receptor tyrosine protein kinase (TYK2) inhibitor, and a vitamin D derivative.

6. The IL-23 inhibitor according to claim 1, wherein at least a portion of the alternating electric field applying step is performed before, simultaneously with, or after at least a portion of the interleukin 23 (IL-23) inhibitor delivering step.

7. An interleukin 17A (IL-17A) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering an interleukin 17A (IL-17A) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

8. The method of claim 7, wherein the IL-17A inhibitor comprises at least one of secukinumab, ixekizumab, and berdalumab.

9. A RAR-related orphan receptor gamma (RORγt) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering to the subject an inhibitor of RAR-related orphan receptor gamma (RORγt); and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz. 10 . The method of claim 9 , wherein the RORγt inhibitor comprises at least one of JNJ-61803534 and GSK2981278.

11. An interleukin 17F (IL-17F) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering an interleukin 17F (IL-17F) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

12. An interleukin 17RA (IL17RA) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering an interleukin 17RA (IL17RA) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

13. An interleukin 12Rβ1 (IL-12Rβ1) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering an interleukin 12Rβ1 (IL-12Rβ1) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

14. An interleukin 23R (IL-23R) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering an interleukin 23R (IL-23R) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

15. An interleukin 22 (IL-22) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering an interleukin 22 (IL-22) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

16. A Janus kinase (JAK) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering a Janus kinase (JAK) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

17. The JAK inhibitor for use according to claim 16, wherein the JAK inhibitor comprises at least one of Opzelura or Tofacitinib.

18. A non-receptor tyrosine protein kinase (TYK2) inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering a non-receptor tyrosine protein kinase (TYK2) inhibitor to the subject; and An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

19. An epithelial differentiation inhibitor for use in a method of reducing skin irritation in a subject caused by application of an alternating electric field, the method comprising: delivering an epithelial differentiation inhibitor to the subject; as well as An alternating electric field is applied to the subject at a frequency between about 50 kHz and about 10,000 kHz.

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