Compositions, systems, and methods for treating cancer using tumor treating fields (ttfields) and NF-Κb inhibitors

Abstract

Compositions, kits, systems, and methods for reducing viability of cancer cells and treating cancer, as well as reducing a volume of a tumor and / or preventing an increase in volume of a tumor present in a body of a living subject, are disclosed. The systems and methods involve application of an alternating field in combination with administration of at least one composition comprising at least one NF-κB inhibitor.

Description

TITLE OF INVENTIONCOMPOSITIONS, SYSTEMS, AND METHODS FOR TREATING CANCER USING TUMOR TREATING FIELDS (TTFIELDS) AND NF-KB INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The subject application claims benefit under 35 USC 119(e) of US Provisional Application No. 63 / 664,925, filed June 27, 2024. The entire contents of the above-referenced patent application(s) are hereby expressly incorporated herein by reference.BACKGROUND

[0002] Tumor Treating Fields (TTFields) are low intensity (e.g., 1-3 V / cm) alternating electric fields within the intermediate frequency range (such as, but not limited to, 100-500 kHz) that target solid tumors by disrupting mitosis. This non-invasive treatment targets solid tumors and is described, for example, in US Patent Nos. 7,016,725; 7,089,054; 7,333,852; 7,565,205; 8,244,345; 8,715,203; 8,764,675; 10,188,851; and 10,441,776. TTFields are typically delivered through two pairs of transducer arrays that generate perpendicular fields within the treated tumor; the electrode arrays that make up each of these pairs are positioned on opposite sides of the body part that is being treated. More specifically, for the OPTUNE® system, one pair of electrodes is located to the left and right (LR) of the tumor, and the other pair of electrodes is located anterior and posterior (AP) to the tumor. TTFields are approved for the treatment of glioblastoma multiforme (GBM), and may be delivered, for example, via the OPTUNE® system (Novocure Limited, St. Helier, Jersey), which includes transducer arrays placed on the patient's shaved head.

[0003] Each transducer array used for the delivery of TTFields in the OPTUNE® device comprises a set of ceramic disk electrodes, which are coupled to the patient's skin (such as, but not limited to, the patient's shaved head for treatment of GBM) through a layer of conductive medical gel. The purpose of the medical gel is to deform to match the body's contours and to provide good electrical contact between the arrays and the skin; as such, the gel interface bridges the skin and reduces interference. The device is intended to be continuously worn by the patient for 2-4 days before removal for hygienic care and re-shaving(if necessary), followed by reapplication with a new set of arrays. As such, the medical gel remains in substantially continuous contact with an area of the patient's skin for a period of 2-4 days at a time. In addition, the arrays can be shifted a few centimeters in either direction to allow the skin to heal from one period of treatment to the next. Therefore, a portion of skin that was covered by electrodes / gel for a 2-4 day period could then be uncovered for 2-4 days when the replaced electrodes are shifted slightly; then the device may be reapplied to the original portion of skin for the next 2-4 day period.

[0004] Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) is a transcription factor responsible for transcription of many inflammation-related genes and serves as a pivotal mediator of inflammatory response (Albensi (2019) Front Cell Dev Biol, 7:154; Liu et al. (2017) Sig Transduct Target Ther, 2:17023). Dysregulation of NF-KB signaling is associated with inflammatory diseases and certain cancers (Miller et al. (2010) Biochemical Pharmacology, 79(9):1272-1280).

[0005] Under physiological conditions, the NF-KB pathway is constitutively active only in a few types of cells, including neurons, B cells, and thymocytes, and is always inactive in all other cell types. However, in cancer cells such as breast, colon, pancreatic, ovarian, lymphoma, and melanoma, the NF-KB pathway has been reported to be constitutively active. Constitutive activity of NF-KB signaling in tumor cells is involved in cellular proliferation, blocking apoptosis, promotion of angiogenesis, and invasion and metastasis (Miller et al., supra).

[0006] Although many approved drugs such as proteosome inhibitors have been shown to downregulate NF-KB, there are currently no NF-KB direct inhibitors used in the clinic, since there is concern that the immune response will be drastically blocked.

[0007] The effects of TTFields on NF-KB have been considered and indicate an upregulation of NF-KB that would lead to a positive outcome because the immune system is recruited. For example, Chen et al. (J. Clin Invest (2022) 132(8):el49258) demonstrate an upregulation of the NF-KB factor p65 and thus an upregulation of NF-KB signaling and associate these findings with activated immune system and better survival. Also, Guo et al. (Cancers (Basel) (2022) 14(15):3669) demonstrate that TTFields elevates the expression levels of proinflammatory cytokines in macrophages via the MAPK and NF-kB signaling pathways.

[0008] Dexamethasone is a potent anti-inflammatory corticosteroid. Wong et al. (British J Cancer (2015) 113:232-241) demonstrated that dexamethasone exerted profound effectson both TTFields and chemotherapy efficacy in glioblastoma patients, resulting in lower patient overall survival. The analysis revealed a cutoff of less than 4.1 mg dexamethasone / day, which correlated with better outcomes in both TTFields-treated patients as well as the control arm. Wong et al. concluded that global immunosuppression by dexamethasone likely interferes with immune functions that are necessary for the treatment of glioblastoma.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 illustrates various classes of NF-KB inhibitors and their mechanisms of action (taken from D'Acquisto et al. (2002) Mol Interv, 2(l):22-35).

[0010] FIG. 2 illustrates an analysis of overall survival in newly diagnosed glioblastoma (GBM) treated with temozolomide alone versus temozolomide plus TTFields.

[0011] FIG. 3 illustrates an analysis of overall survival in newly diagnosed GBM treated with TTFields alone versus TTFields plus Aprepitant and / or TMZ. Hazard Ratio = 0.725 (0.340- 1.543); Log Rank p TTFields + TMZ vs TTFields + TMZ+ APREPITANT = 0.1180568823.

[0012] FIG. 4 illustrates an analysis of overall survival in newly diagnosed GBM treated with TTFields alone versus TTFields plus Azithromycin and / or TMZ. Hazard Ratio = 0.784(0.454-1.353); Log Rank p TTF+TMZ vs TTF+TMZ+AZITHROMYCIN = 0.1989639461.

[0013] FIG. 5 illustrates an analysis of overall survival in newly diagnosed GBM treated with TTFields alone versus TTFields plus Loratadine and / or TMZ. Hazard Ratio = 0.662(0.350- 1.251); Log Rank p TTF+TMZ vs TTF+TMZ+LORATADINE = 0.2825428032.

[0014] FIG. 6 illustrates an analysis of RnD657 count at 72 hours in AsPCl cells following treatment with TTFields alone versus TTFields plus BAY 11-7082 (an NF-KB inhibitor).

[0015] FIG. 7 illustrates an analysis of RnD657 apoptosis at 72 hours in AsPCl cells following treatment with TTFields alone versus TTFields plus BAY 11-7082.

[0016] FIG. 8 illustrates an overall effect in AsPCl cells following treatment with TTFields alone versus TTFields plus BAY 11-7082.DETAILED DESCRIPTION

[0017] Before explaining at least one embodiment of the inventive concept(s) in detail by way of exemplary language and results, it is to be understood that the inventive concept(s) is not limited in its application to the details of construction and the arrangement of thecomponents set forth in the following description. The inventive concept(s) is capable of other embodiments or of being practiced or carried out in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments are meant to be exemplary - not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

[0018] Unless otherwise defined herein, scientific and technical terms used in connection with the presently disclosed inventive concept(s) shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. The nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses and chemical analyses.

[0019] All patents, published patent applications, and non-patent publications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this presently disclosed inventive concept(s) pertains. All patents, published patent applications, and non-patent publications referenced in any portion of this application are herein expressly incorporated by reference in their entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

[0020] All of the compositions, assemblies, systems, kits, and / or methods disclosed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions, assemblies, systems, kits, and methods of the inventive concept(s) have been described in terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit, and scope of the inventive concept(s). All such similar substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the inventive concept(s) as defined by the appended claims.

[0021] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0022] The use of the term "a" or "an" when used in conjunction with the term "comprising" in the claims and / or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." As such, the terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" may refer to one or more compounds, two or more compounds, three or more compounds, four or more compounds, or greater numbers of compounds. The term "plurality" refers to "two or more."

[0023] The use of the term "at least one" will be understood to include one as well as any quantity more than one, including but not limited to, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. The term "at least one" may extend up to 100 or 1000 or more, depending on the term to which it is attached; in addition, the quantities of 100 / 1000 are not to be considered limiting, as higher limits may also produce satisfactory results. In addition, the use of the term "at least one of X, Y, and Z" will be understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z. The use of ordinal number terminology (e.g., "first," "second," "third," "fourth," etc.) is solely for the purpose of differentiating between two or more items and is not meant to imply any sequence or order or importance to one item over another or any order of addition, for example.

[0024] The use of the term "or" in the claims is used to mean an inclusive "and / or" unless explicitly indicated to refer to alternatives only or unless the alternatives are mutually exclusive. For example, a condition "A or B" is satisfied by any of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0025] As used herein, any reference to "one embodiment," "an embodiment," "some embodiments," "one example," "for example," or "an example" means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. The appearance of the phrase "in some embodiments" or "one example" in various places in the specification is not necessarily all referring to the same embodiment, for example. Further, all references to one or more embodiments or examples are to be construed as non-limiting to the claims.

[0026] Throughout this application, the term "about" is used to indicate that a valueincludes the inherent variation of error for a composition / apparatus / device, the method being employed to determine the value, or the variation that exists among the study subjects. For example, but not by way of limitation, when the term "about" is utilized, the designated value may vary by plus or minus twenty percent, or fifteen percent, or twelve percent, or eleven percent, or ten percent, or nine percent, or eight percent, or seven percent, or six percent, or five percent, or four percent, or three percent, or two percent, or one percent from the specified value, as such variations are appropriate to perform the disclosed methods and as understood by persons having ordinary skill in the art.

[0027] As used in this specification and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0028] The term "or combinations thereof" as used herein refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0029] As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance occurs to a great extent or degree. For example, when associated with a particular event or circumstance, the term "substantially" means that the subsequently described event or circumstance occurs at least 80% of the time, or at least 85% of the time, or at least 90% of the time, or at least 95% of the time. For example, the term "substantially adjacent" may mean that two items are 100% adjacent to one another, or that the two items are within close proximity to one another but not 100% adjacent to one another, or that a portion of one of the two items is not 100% adjacent to the other item but is within close proximity to the other item.

[0030] The term "pharmaceutically acceptable" refers to compounds and compositionswhich are suitable for administration to humans and / or animals without undue adverse side effects such as (but not limited to) toxicity, irritation, and / or allergic response commensurate with a reasonable benefit / risk ratio.

[0031] The term "patient" or "subject" as used herein includes human and veterinary subjects. "Mammal" for purposes of treatment refers to any animal classified as a mammal, including (but not limited to) humans, domestic and farm animals, nonhuman primates, and any other animal that has mammary tissue.

[0032] The term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include, but are not limited to, individuals already having a particular condition / disease / infection as well as individuals who are at risk of acquiring a particular condition / disease / infection (e.g., those needing prophylactic / preventative measures). The term "treating" refers to administering an agent / element / method to a patient for therapeutic and / or prophylactic / preventative purposes.

[0033] The term "therapeutic composition" or "pharmaceutical composition" as used herein refers to an agent that may be administered in vivo to bring about a therapeutic and / or prophylactic / preventative effect.

[0034] Administering a therapeutically effective amount or prophylactically effective amount is intended to provide a therapeutic benefit in the treatment, prevention, and / or management of a disease, condition, and / or infection. The specific amount that is therapeutically effective can be readily determined by the ordinary medical practitioner, and can vary depending on factors known in the art, such as (but not limited to) the type of condition / disease / infection, the patient's history and age, the stage of the condition / disease / infection, and the co-administration of other agents.

[0035] The term "effective amount" refers to an amount of a biologically active molecule or conjugate or derivative thereof, or an amount of a treatment protocol (e.g., an alternating electric field), sufficient to exhibit a detectable therapeutic effect without undue adverse side effects (such as (but not limited to) toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio when used in the manner of the inventive concept(s). The therapeutic effect may include, for example but not by way of limitation, preventing, inhibiting, or reducing the occurrence of at least one condition, disease, and / or infection. The effective amount for a subject will depend upon the type of subject, the subject's size andhealth, the nature and severity of the condition / disease / infection to be treated, the method of administration, the duration of treatment, the nature of concurrent therapy (if any), the specific formulations employed, and the like. Thus, it is not possible to specify an exact effective amount in advance. However, the effective amount for a given situation can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein.

[0036] As used herein, the term "concurrent therapy" is used interchangeably with the terms "concomitant therapy" and "adjunct therapy," and will be understood to mean that the patient in need of treatment is treated or given another drug for the condition / disease / infection in conjunction with the treatments of the present disclosure. This concurrent therapy can be sequential therapy, where the patient is treated first with one treatment protocol / pharmaceutical composition and then the other treatment protocol / pharmaceutical composition, or the two treatment protocols / pharmaceutical compositions are given simultaneously. In addition, it will be understood that one administration step (such as, but not limited to, administration of the TTFields) may occur over a longer period of time than the other administration step (i.e., oral administration or injection of a substance). In these instances of varying administration time periods, the term "simultaneously" will be understood to mean that the shorter administration step wholly overlaps with the longer administration step. However, the term "simultaneously" will include performing the shorter administration step at any point during the longer administration step (e.g., the beginning, middle, or end of the longer administration step, or any other time period therebetween), as well as performing the shorter administration step one or more times wholly within the time period of the longer administration step. Therefore, the term "simultaneously" does not require that the two administration steps be performed over the exact same length of time.

[0037] The terms "administration" and "administering," as used herein, will be understood to include all routes of administration known in the art, including but not limited to, oral, topical, transdermal, parenteral, subcutaneous, intranasal, mucosal, intramuscular, intraperitoneal, intratumoral, intravitreal, intratumoral, and intravenous routes, and including both local and systemic applications. In addition, the compositions of the present disclosure (and / or the methods of administration of same) may be designed to provide delayed, controlled, or sustained release using formulation techniques which are well knownin the art.

[0038] The term "target region," as used herein, refers to a region containing all or a portion of the cancer, cancer cells, and / or tumor to be treated.

[0039] Turning now to the inventive concept(s), a concurrent therapy for cancer is disclosed herein. The concurrent therapy includes the use of alternating electric fields (e.g., TTFields) in combination with at least one NF-KB inhibitor. The combination of alternating electric fields (e.g., TTFields) with the at least one NF-KB inhibitor provides a synergistic result in the treatment of cancer.

[0040] Certain non-limiting embodiments of the present disclosure are directed to a method of reducing viability of cancer cells. The method includes the steps of: (1) administering at least one composition to the cancer cells, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to the cancer cells for a period of time. Said method may be an in vitro method or an in vivo method.

[0041] Certain non-limiting embodiments of the present disclosure are directed to a method of enhancing the cytotoxicity of at least one NF-KB inhibitor against cancer cells. The method includes the steps of: (1) administering at least one composition to the cancer cells, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to the cancer cells for a period of time. Said method may be an in vitro method or an in vivo method.

[0042] Certain non-limiting embodiments of the present disclosure are directed to a method of inhibiting NF-KB in cancer cells. The method includes the steps of: (1) administering at least one composition to the cancer cells, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to the cancer cells for a period of time.

[0043] Certain additional non-limiting embodiments of the present disclosure are directed to a method of treating cancer in a subject. The method includes the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to a target region of the subject.

[0044] Certain additional non-limiting embodiments of the present disclosure are directed to a method of reducing a volume of a tumor, wherein the tumor is present in a bodyof a living subject and includes a plurality of cancer cells. The method includes the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to a target region of the subject.

[0045] Certain additional non-limiting embodiments of the present disclosure are directed to a method of preventing an increase of volume of a tumor, wherein the tumor is present in a body of a living subject and includes a plurality of cancer cells. The method includes the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to a target region of the subject.

[0046] Certain additional non-limiting embodiments of the present disclosure are directed to a method of extending overall survival (OS) in a living subject with cancer, the method comprising the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to a target region of the subject. The overall survival in the living subject is increased when compared to treatment with (1) or (2) alone.

[0047] Steps (1) and (2) of any of the methods of the present disclosure may be performed concomitantly or sequentially, and in particular, substantially simultaneously or wholly or partially sequentially. When the steps are performed wholly or partially sequentially, the at least one composition comprising at least one NF-KB inhibitor may be administered before or after application of the alternating electric field has begun.

[0048] The methods of the present disclosure may be utilized to treat any types of cancer cells / cancers / tumors that respond to treatment with alternating electric fields (e.g., TTFields) and / or NF-KB inhibitor(s). Non-limiting examples of cancer cells / cancers / tumors that can be treated in accordance with the present disclosure include hepatocellular carcinoma / carcinoma cells, glioblastoma / glioblastoma cells, pleural mesothelioma / mesothelioma cells, differentiated thyroid cancer / cancer cells, advanced renal cell carcinoma / carcinoma cells, ovarian cancer / cancer cells, breast cancer / cancer cells, pancreatic cancer / cancer cells, lung cancer / cancer cells (such as, but not limited to, non-small cell lung cancers), and the like, as well as any combination thereof.

[0049] In a particular (but non-limiting) embodiment, the cancer may be a solid tumor.

[0050] Any type of conductive or non-conductive electrode(s) and / or transducer array(s)that can be utilized for generating an alternating electric field that are known in the art or otherwise contemplated herein may be utilized for generation of the alternating electric field in accordance with the methods of the present disclosure. Non-limiting examples of electrodes and transducer arrays that can be utilized for generating an alternating electric field in accordance with the present disclosure include those that function as part of an alternating electric field-generating system (e.g., TTFields system) as described, for example but not by way of limitation, in US Patent Nos. 7,016,725; 7,089,054; 7,333,852; 7,565,205; 8,244,345; 8,715,203; 8,764,675; 10,188,851; and 10,441,776; and in US Patent Application Publication Nos. US 2018 / 0160933; US 2019 / 0117956; US 2019 / 0307781; and US 2019 / 0308016.

[0051] The alternating electric field may be generated at any frequency in accordance with the present disclosure. For example (but not by way of limitation), the alternating electric field may have a frequency of about 50 kHz, about 60 kHz, about 70 kHz, about 75 kHz, about 80 kHz, about 90 kHz, about 100 kHz, about 105 kHz, about 110 kHz, about 115 kHz, about 120 kHz, about 125 kHz, about 130 kHz, about 135 kHz, about 140 kHz, about 145 kHz, about150 kHz, about 155 kHz, about 160 kHz, about 165 kHz, about 170 kHz, about 175 kHz, about180 kHz, about 185 kHz, about 190 kHz, about 195 kHz, about 200 kHz, about 225 kHz, about250 kHz, about 275 kHz, about 300 kHz, about 325 kHz, about 350 kHz, about 375 kHz, about400 kHz, about 425 kHz, about 450 kHz, about 475 kHz, about 500 kHz, about 550 kHz, about600 kHz, about 650 kHz, about 700 kHz, about 750 kHz, about 800 kHz, about 850 kHz, about900 kHz, about 950 kHz, about 1 MHz, about 2 MHz, about 3 MHz, about 4 MHz, about 5 MHz, about 6 MHz, about 7 MHz, about 8 MHz, about 9 MHz, about 10 MHz, and the like, as well as a range formed from any of the above values (e.g., a range of from about 50 kHz to about 10 MHz, a range of from about 50 kHz to about 1 MHz, a range of from 50 kHz to about 500 kHz, a range of from about 100 kHz to about 500 kHz, a range of from about 150 kHz to about 300 kHz, etc.), and a range that combines two integers that fall between two of the abovereferenced values (e.g., a range of from about 122 kHz to about 313 kHz, a range of from about 78 kHz to about 298 kHz, etc.).

[0052] In certain particular (but non-limiting) embodiments, the alternating electric field may be imposed at two or more different frequencies. When two or more frequencies are present, each frequency is selected from any of the above-referenced values, or a range formed from any of the above-referenced values, or a range that combines two integers thatfall between two of the above-referenced values.

[0053] In certain particular (but non-limiting) embodiments, the following frequencies may be utilized for specific cancers: GBM, about 200 kHz; NSCLC, about 150 kHz; breast cancer, about 200 kHz; pancreatic cancer, about 150 kHz; brain metastases from NSCLC, about 150 kHz; hepatic cancer, about 150 kHz; and the like.

[0054] The alternating electric field may have any field strength in the target region / subject / cancer cells, so long as the alternating electric field is capable of functioning in accordance with the present disclosure. For example (but not by way of limitation), the alternating electric field may have a field strength in the target region / subject / cancer cells of at least about 1 V / cm, about 1.5 V / cm, about 2 V / cm, about 2.1 V / cm, about 2.2 V / cm, about 2.3 V / cm, about 2.4 V / cm, about 2.5 V / cm, about 2.6 V / cm, about 2.7 V / cm, about 2.8 V / cm, about 2.9 V / cm, about 2.5 V / cm, about 3 V / cm, about 3.5 V / cm, about 4 V / cm, about 4.5 V / cm, about 5 V / cm, about 5.5 V / cm, about 6 V / cm, about 6.5 V / cm, about 7 V / cm, about 7.5 V / cm, about 8 V / cm, about 9 V / cm, about 9.5 V / cm, about 10 V / cm, about 10.5 V / cm, about 11 V / cm, about 11.5 V / cm, about 12 V / cm, about 12.5 V / cm, about 13 V / cm, about 13.5 V / cm, about 14 V / cm, about 14.5 V / cm, about 15 V / cm, about 15.5 V / cm, about 16 V / cm, about 16.5 V / cm, about 17 V / cm, about 17.5 V / cm, about 18 V / cm, about 18.5 V / cm, about 19 V / cm, about 19.5 V / cm, about 20 V / cm, and the like, as well as a range formed from any of the above values (e.g., a range of from about 1 V / cm to about 20 V / cm, a range of from about 1 V / cm to about 10 V / cm, a range of from about 1 V / cm to about 4 V / cm, etc.), and a range that combines two integers that fall between two of the above-referenced values (e.g., a range of from about 1.1 V / cm to about 18.6 V / cm, a range of from about 1.2 V / cm to about 9.8 V / cm, a range of from about 1.3 V / cm to about 4.7 V / cm, etc.). Generally, it is desired to utilize the highest field strength possible without causing overheating, with field intensity typically being capped by temperature measurements.

[0055] In some instances, the electric field in at least a portion of the target region / subject / cancer cells is induced by an applied voltage that is determined by computer simulation of the target region / subject / cancer cells. In some instances, the electric field in at least a portion of the target region / subject / cancer cells is induced by an applied voltage of at least 50 V RMS (root mean squared) or at least 50 V p2p (peak-to-peak), and optionally, the applied voltage is at least 100 V RMS or at least 100 V p2p. In some embodiments, an applied voltage of at least 50 V induces an electric field with a field strength of at least 1 V / cm (e.g.,at least 5 V / cm) in at least a portion of the target region / subject / cancer cells.

[0056] The alternating electric field may be applied in a single direction between a pair of arrays or may be alternating in two or more directions / channels between two or more pairs of arrays (e.g., front-back and left-right). For example, certain TTFields devices (such as, but not limited to, the OPTUNE® system (Novocure Limited, St. Helier, Jersey)) operate in two directions in order to increase the chances that a dividing cell will be aligned with the electric field such that the electric field can have the desired anti-mitotic effect. However, it will be understood that the scope of the present disclosure also includes the application of the alternating electric field in a single direction. The term "alternating electric field" as used herein will be understood to include application in a single direction / channel as well as in two or more directions / channels; in addition, the term "alternating electric field" as used herein will be understood to include both application of a single alternating electric field as well as application of a plurality of alternating electric fields in succession for a duration of time.

[0057] The alternating electric field may be applied for any continuous or cumulative period of time sufficient to achieve an enhancement in the cytotoxicity of the NF-KB inhibitor(s), a reduction in viability of cancer cells, a reduction in tumor volume, and / or a prevention of increase in tumor volume. The period of time that the alternating electric field is applied includes both a continuous period of time as well as a cumulative period of time. That is, the period of time that the alternating electric field is applied includes a single session (i.e., continuous application of the field over the session) as well as multiple sessions with minor breaks in between sessions (i.e., consecutive application for a cumulative period, wherein during breaks, the device is not positioned on the body and / or is not operational). For example, a subject is allowed to take breaks during treatment with an alternating electric field device and is only expected to have the device positioned on the body and operational for at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the total treatment period (e.g., over a course of one day, one week, two weeks, one month, two months, three months, four months, five months, etc.).

[0058] For example, but not by way of limitation, the alternating electric field may be applied for a continuous or cumulative period of time of at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, and the like, as well as a range formed from any of the above values (e.g., a range of from about 1 hour to about six months, a range of from about 1 hour to about 7 days, a range of from about 24 hours to about 72 hours, etc.), and a range that combines two integers that fall between two of the above-referenced values (e.g., a range of from about 14 hours to about 68 hours, etc.).

[0059] In a particular (but non-limiting) embodiment, the period of time that the alternating electric field is applied is at least about 24 hours, with the device positioned on the body and operational for at least about 80% of that period.

[0060] The total period of time that the alternating electric field is applied may be achieved in a continuous or intermittent manner. That is, when the alternating electric field is applied for a shorter period of time (such as, but not limited to, less than about 12 or 24 hours), the alternating electric field may be continuously applied over that period of time. However, when the alternating electric field is applied for a longer period of time (such as, but not limited to, a period of about 24 hours or greater), the treatment period may include one or more breaks during the application cycle that separate two or more application sections, whereby the application sections and breaks combine to form the total application period. When breaks are present, the alternating electric field is applied for at least about 50%, about 60%, about 70%, about 80%, or about 90% or more of the treatment time, so that the breaks typically constitute only about 10%, about 20%, about 30%, about 40%, about 50%, or less of the treatment time. In a particular (but non-limiting) embodiment, when breaks are present, the breaks should typically constitute about 20% or less of the treatment time, so that the alternating electric field is applied for at least about 80% or more of the treatment time. For example, but not by way of limitation, the alternating electric field should be applied for at least about 19 hours of each 24-hour period. In addition, the longer that the alternating electric field is applied, the higher the efficacy will be.

[0061] Any NF-KB inhibitor known in the art or otherwise contemplated herein may be utilized in accordance with the present disclosure, so long as the NF-KB inhibitor is capable of concurrent therapy with alternating electric fields to reduce the viability of cancer cells, reduce the volume of a tumor, prevent an increase in a volume of a tumor, and / or extend the overall survival rate of the subject. Non-limiting examples of NF-KB inhibitors that can be utilized in accordance with the present disclosure include an IL-6 inhibitor (such as, but not limited to, Tocilizumab), a proteosome inhibitor (such as, but not limited to, bortezomib, carfilzomib, proteosome inhibitor 1 (PSI), MG132, and the like), an NSAID (such as, but not limited to, sodium salicylate, sulindac, a coxl inhibitor, and the like) a RANK-RANKL inhibitor, an Ikk inhibitor, an IL-ip inhibitor, emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, lestaurtinib, pristimerin, KINK-1, DHMEQ, Aprepitant, Loratadine, Azithromycin, BAY 11-7082, and the like, as well as any combinations thereof.

[0062] In a particular (but non-limiting) embodiment, the at least one NF-KB inhibitor is selected from the group consisting of Aprepitant, Loratadine, Azithromycin, BAY 11-7082, and combinations thereof.

[0063] The composition comprising at least one NF-KB inhibitor may be provided with any formulation known in the art or otherwise contemplated herein. In certain particular (but non-limiting) embodiments, the composition comprising NF-KB inhibitor(s) contains one or more pharmaceutically acceptable carriers (and as such, the composition may also be referred to as a "pharmaceutical composition"). Non-limiting examples of suitable pharmaceutically acceptable carriers that may be utilized in accordance with the present disclosure include water; saline; dextrose solutions; fructose or mannitol; calcium carbonate; cellulose; ethanol; oils of animal, vegetative, or synthetic origin; carbohydrates, such as glucose, sucrose, or dextrans; antioxidants, such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; detergents; liposomal carriers; conductive and non- conductive nanoparticles; buffered solutions, such as sodium chloride, saline, phosphate- buffered saline, and / or other substances which are physiologically acceptable and / or safe for use; diluents; excipients such as polyethylene glycol (PEG); or any combination thereof. Suitable pharmaceutically acceptable carriers for pharmaceutical formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 23rd ed. (2020).

[0064] In certain particular (but non-limiting) embodiments, the composition comprising NF-KB inhibitor(s) may further contain one or more additional active agents. Various activeagents that can be utilized concurrently with alternating electric fields and / or NF-KB inhibitor(s) are known in the art, and certain combination therapies are approved by the FDA or currently in clinical trials testing. Non-limiting examples of therapeutic agents that can be utilized in accordance with the present disclosure include anti-PD-1 therapeutics such as (but not limited to) Pembrolizumab (KEYTRUDA®, Merck & Co., Inc., Rahway, NJ), Tislelizumab, Nivolumab, and Cemiplimab; anti-PD-Ll therapeutics such as atezolizumab, avelumab, and durvalumab; chemotherapeutic agents, such as (but not limited to) Lenvatinib, Paclitaxel, Doxorubicin, Cisplatin, sorafenib, Docetaxel, Ifosamide, Etoposide (VEPESID®, Bristol-Myers Squibb Co, New York, NY), Gemcitabine, Lomustine, Nab Paclitaxel, Temozolomide, and Carboplatin; immune checkpoint inhibitors, such as (but not limited to) Cemiplimab, Nivolumab, Pembrolizumab, and Tislelizumab; TKI inhibitors, such as (but not limited to) lenvatinib and everolimus; mTOR inhibitors; Akt inhibitors; PI3K inhibitors; PARP inhibitors; VEGF inhibitors; FGF inhibitors; anti-LAB3 agents; aromatase inhibitors, such as (but not limited to) Letrozole; biologies, such as monoclonal antibodies (such as, but not limited to, Denosumab and pembrolizumab)); anti-LAG3 agents, such as (but not limited to) OPDUALAG™ and Relatimab; anti-CTLA-4 therapeutic agents, such as (but not limited to) Ipilimumab; and the like, as well as any combinations thereof.

[0065] In certain particular (but non-limiting) embodiments, the NF-KB inhibitor(s) present in the composition is conjugated to another substance. For example, but not by way of limitation, the NF-KB inhibitor(s) may be conjugated to a particle or other substance for targeted delivery of the drug to a specific location in the body. In another particular (but nonlimiting) embodiment, the composition may comprise at least one NF-KB inhibitor encapsulated in a nanoparticle for phototherapy.

[0066] In addition, any of the compositions of the present disclosure may contain other agents that allow for administration of the compositions via a particular administration route. For example, but not by way of limitation, the compositions may be formulated for administration by oral, topical, transdermal, parenteral, subcutaneous, intranasal, mucosal, intramuscular, intraperitoneal, intravitreal, intratumoral, and / or intravenous routes. Based on the route of administration, the compositions may also contain one or more additional components in addition to the active agent(s) (e.g., NF-KB inhibitor and / or additional therapeutic agent). Examples of additional secondary compounds that may be present include, but are not limited to, fillers, gels, adhesives, salts, buffers, preservatives, stabilizers,solubilizers, wetting agents, emulsifying agents, dispersing agents, and other materials well known in the art.

[0067] In particular (but non-limiting) embodiments, the at least one composition comprising at least one NF-KB inhibitor is administered orally, locally, intradermally, subcutaneously, intravenously, intratumorally, and / or intranodally to the cells / subject / tumor.

[0068] The at least one composition comprising at least one NF-KB inhibitor may be administered before or after application of the alternating electric field has begun. In certain particular (but non-limiting) embodiments, the at least one composition comprising at least one NF-KB inhibitor may be administered after the application of the alternating electric field has begun. In particular (but not by way of limitation), the at least one composition comprising at least one NF-KB inhibitor may be administered during application of the alternating electric field (e.g., before the period of time that the alternating electric field is applied has elapsed) and / or after application of the alternating electric field has elapsed.

[0069] For example (but not by way of limitation), the at least one composition comprising at least one NF-KB inhibitor may be administered before application of the alternating electric field has commenced by a period of at least about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, and the like, as well as a range formed from any of the above values (e.g., a range of from about 1 minute to about 24 hours, a range of from about 24 hours to about 96 hours, etc.), and a range that combines two integers that fall between two of the above-referenced values (e.g., a range of from about 14 hours to about 94 hours, etc.). In a particular (but non-limiting) embodiment, the at least one composition comprising at least one NF-KB inhibitor is administered at least about 24 hours before application of the alternating electric field has begun.

[0070] In other non-limiting examples, the at least one composition comprising at least one NF-KB inhibitor may be administered after application of the alternating electric field has commenced by a period of at least about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, and the like, as well as a range formed from any of the above values (e.g., a range of from about 1 minute to about 24 hours, a range of from about 24 hours to about 96 hours, etc.), and a range that combines two integers that fall between two of the above-referenced values (e.g., a range of from about 14 hours to about 94 hours, etc.). In a particular (but non-limiting) embodiment, the at least one composition comprising at least one NF-KB inhibitor is administered at least about 24 hours after application of the alternating electric field has begun.

[0071] In yet other non-limiting examples, the at least one composition comprising at least one NF-KB inhibitor may be administered after the period of time that the alternating electric field is applied has elapsed, wherein the at least one composition comprising at least one NF-KB inhibitor is administered within about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, and the like, of when the period of time elapsed.

[0072] In a particular (but non-limiting) embodiment, the at least one compositioncomprising at least one NF-KB inhibitor is administered within about 96 hours of when the period of time elapsed.

[0073] The composition comprising at least one NF-KB inhibitor may be administered to the cancer cells / subject at any concentration that provides a therapeutically effective concentration of the at least one NF-KB inhibitor. In certain non-limiting embodiments, the application of the alternating electric field reduces the amount of NF-KB inhibitor(s) required to be therapeutically effective when compared to a normal therapeutically effective amount administered in the absence of an alternating electric field. For example, but not by way of limitation, the therapeutically effective concentration of NF-KB inhibitor(s) may be reduced by at least about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more with respect to a dosage of NF-KB inhibitor known to be therapeutically effective in the absence of application of an alternating electric field. In a particular (but non-limiting) embodiment, the therapeutically effective concentration of NF-KB inhibitor(s) is reduced by at least about 50% when compared to a dosage of NF-KB inhibitor known to be therapeutically effective in the absence of an alternating electric field.

[0074] The therapeutically effective concentration of each NF-KB inhibitor(s) utilized in accordance with the present disclosure may be, for example (but not by way of limitation), about 1 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, about 100 nM, about 125 nM, about 150 nM, about 175 nM, about 200 nM, about 250 nM, about 300 nM, about 350 nM, about 400 nM, about 450 nM, about 500 nM, about 550 nM, about 600 nM, about 650 nM, about 700 nM, about 750 nM, about 800 nM, about 850 nM, about 900 nM, about 950 nM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, and the like, as well as a range formed from any of the above values (e.g., a range of from about 12.5 nM to about 100 nM, a range of from about 1 mM to about 20 mM, etc.), and a range that combines two integers that fall between two of the above-referenced values (e.g., a range of from about 17 nM to about 83 nM, etc.).

[0075] In a particular (but non-limiting) embodiment, the therapeutically effectiveconcentration of each NF-KB inhibitor is from about 12.5 nM to about 100 nM.

[0076] In particular (but non-limiting) embodiments, the therapeutically effective concentration of each NF-KB inhibitor utilized in accordance with the present disclosure may be, for example (but not by way of limitation), about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, and the like, as well as a range formed from any of the above values (e.g., a range of from about 10 mg / kg to about 50 mg / kg, a range of from about 1 mg / kg to about 40 mg / kg, a range of from about 1 mg / kg to about 30 mg / kg, a range of from about 1 mg / kg to about 25 mg / kg, a range of from about 1 mg / kg to about 20 mg / kg, a range of from about 1 mg / kg to about 10 mg / kg, etc.).

[0077] In certain particular (but non-limiting) embodiments, the NF-KB inhibitor may be administered by any dosage regimen known in the art. For example, but not by way of limitation, the composition comprising the NF-KB inhibitor may be administered in a single dosage or multiple dosages over a defined treatment period. For example (but not by way of limitation), a therapeutically effective concentration of the composition may be administered about once every 4 hours, about once every 8 hours, about once every 12 hours, about once every day, about once every other day, about once every three days, about once a week, about twice a week, about three times a week, about once every two weeks, about once every three weeks, about once a month, and the like, as well as a range formed from any of the above values (a range of about once every 4 to 8 hours, a range of from about once a week to about once a month, etc.).

[0078] In certain particular (but non-limiting) embodiments, the method includes one or more additional steps. For example (but not by way of limitation), the method may further include the step of (3) discontinuing the application of the alternating electric field (such as, but not limited to) to allow the cells / tissue to recover. In addition, any of steps (1) and / or (2) may be repeated one or more times.

[0079] In certain particular (but non-limiting) embodiments, the method involves concurrent therapy with two or more compositions. As such, the method may include an additional step of (4) administering at least a second composition to the cancer cells / subject. In one particular (but non-limiting) embodiment, the at least second composition may contain one or more of any of the active substances disclosed or otherwise contemplated herein for use with NF-KB inhibitor(s).

[0080] Various substances and therapies that can be utilized in combination with NF-KB inhibitor(s) are known in the art or otherwise contemplated herein. Non-limiting examples of therapeutic agents that can be present in the second composition and utilized in combination with NF-KB inhibitor(s) in accordance with the present disclosure include anti-PD-1 therapeutics such as (but not limited to) Pembrolizumab (KEYTRUDA®, Merck & Co., Inc., Rahway, NJ), Tislelizumab, Nivolumab, and Cemiplimab; anti-PD-Ll therapeutics such as atezolizumab, avelumab, and durvalumab; chemotherapeutic agents, such as (but not limited to) Lenvatinib, Paclitaxel, Doxorubicin, Cisplatin, sorafenib, Docetaxel, Ifosamide, Etoposide (VEPESID®, Bristol-Myers Squibb Co, New York, NY), Gemcitabine, Lomustine, Nab Paclitaxel, Temozolomide, and Carboplatin; immune checkpoint inhibitors, such as (but not limited to) Cemiplimab, Nivolumab, Pembrolizumab, and Tislelizumab; TKI inhibitors, such as (but not limited to) lenvatinib and everolimus; mTOR inhibitors; Akt inhibitors; PI3K inhibitors; PARP inhibitors; VEGF inhibitors; FGF inhibitors; anti-LAB3 agents; anti-CTLA-4 therapeutics; aromatase inhibitors, such as (but not limited to) Letrozole; biologies, such as monoclonal antibodies (such as, but not limited to, Denosumab and pembrolizumab)); anti-LAG3 agents, such as (but not limited to) OPDUALAG™ and Relatimab; anti-PD-Ll therapeutic agents, such as (but not limited to) Atezolizumab, Avelumab, and Durvalumab; anti-CTLA-4 therapeutic agents, such as (but not limited to) Ipilimumab; and the like, as well as any combinations thereof.

[0081] When present, step (4) may be performed substantially simultaneously or wholly or partially sequentially with the administration of the first composition in step (1), wherebythe two (or three) separate compositions are administered simultaneously or wholly or partially sequentially. In addition, the two (or three) compositions administered in steps (1) and (4) may be administered via the same route (e.g., both orally administered or injected), or the two (or three) compositions may be administered by different routes (e.g., one composition orally administered and another composition intravenously administered, etc.).

[0082] When present, the optional additional administration step (4) may be performed before or after the application of the alternating electric field has begun, and during application of the alternating electric field and / or after application of the alternating electric field has elapsed, in the same manner(s) and time frame(s) as described above for the first composition.

[0083] That is, for example (but not by way of limitation), the second composition (and / or third composition, when present) may be administered before application of the alternating electric field has commenced by a period of at least about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, and the like, as well as a range formed from any of the above values (e.g., a range of from about 1 minute to about 24 hours, a range of from about 24 hours to about 96 hours, etc.), and a range that combines two integers that fall between two of the abovereferenced values (e.g., a range of from about 14 hours to about 94 hours, etc.). In a particular (but non-limiting) embodiment, the second (and / or third) composition(s) is / are administered at least about 24 hours before application of the alternating electric field has begun.

[0084] In other non-limiting examples, the second composition (and / or third composition, when present) may be administered after application of the alternating electric field has commenced by a period of at least about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, and the like, as well as a range formed from any of the above values (e.g., a range of from about 1 minute to about 24 hours, a range of from about 24 hours to about 96 hours, etc.), and a range that combines two integers that fall between two of the abovereferenced values (e.g., a range of from about 14 hours to about 94 hours, etc.). In a particular (but non-limiting) embodiment, the second (and / or third) composition(s) is / are administered at least about 24 hours after application of the alternating electric field has begun.

[0085] In yet other non-limiting examples, the second composition (and / or third composition, when present) may be administered after the period of time that the alternating electric field is applied has elapsed, wherein the second (and / or third) composition(s) is / are administered within about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, and the like, of when the period of time elapsed.

[0086] In addition, for example (but not by way of limitation), the second composition (and / or third composition, when present) may be administered after administration of the first composition by a period of at least about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours,about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, and the like, as well as a range formed from any of the above values (e.g., a range of from about 24 hours to about 96 hours, etc.), and a range that combines two integers that fall between two of the above-referenced values (e.g., a range of from about 14 hours to about 94 hours, etc.). In a particular (but non-limiting) embodiment, the second (and / or third) compositions is / are administered at least about 12 hours after administration of the first composition.

[0087] In certain particular (but non-limiting) embodiments, the method may further comprise the step of (5) administering at least one additional therapy to the cells / subject. Any therapies known in the art or otherwise contemplated herein for use with alternating electric fields (e.g., TTFields) and / or NF-KB inhibitor therapy may be utilized in accordance with the methods of the present disclosure. Non-limiting examples of additional therapies that may be utilized include radiation therapy (such as, but not limited to, ionizing radiation therapy), photodynamic therapy, transarterial chemoembolization (TACE), or combinations thereof.

[0088] In certain particular (but non-limiting) embodiments, the method includes one or more additional steps. For example (but not by way of limitation), the method may further include repeating any of the steps (e.g., steps (1) and (2) and optional steps (3), (4), and (5)) one or more times. Each of the steps can be repeated as many times as necessary. When step (2) of applying the alternating electric field is repeated, the transducer arrays may be placed in slightly different positions on the subject than their original placement; relocation of the arrays in this manner may further aid in treatment of the tumor / cancer. In addition, step (1) and optional steps (4) and (5) (when present) of administering compositions / additional therapies may be repeated various times and at various intervals to follow any known and / or generally accepted dosage / treatment regimen for the composition(s) / therapy(ies).

[0089] The use of ordinal references to the optional steps is for purpose of example only; the methods of the present disclosure may include one or more of the optional steps (3), (4), and (5), either alone or in combination with one another. That is, the methods of the present disclosure include performing step (3) in the absence of steps (4) or (5), performing step (4) in the absence of steps (3) or (5), and performing step (5) in the absence of steps (3) and (4).In other words, the scope of the methods disclosed herein includes performing steps (l)-(2) (as well as repeating each step as many times as necessary), performing steps (l)-(3) (as well as repeating one or more steps as many times as necessary), performing steps (l)-(2) and (4) (as well as repeating one or more steps as many times as necessary), performing steps (l)-(2) and (5) (as well as repeating one or more steps as many times as necessary), performing steps (l)-(4) (as well as repeating one or more steps as many times as necessary), performing steps (l)-(3) and (5) (as well as repeating one or more steps as many times as necessary), performing steps (l)-(2) and (4)-(5) (as well as repeating one or more steps as many times as necessary), and performing all of steps (l)-(5) (as well as repeating one or more steps as many times as necessary).

[0090] While the use of concurrent therapy with two substances is explicitly described above, it will be understood that the scope of the present disclosure further includes concurrent therapy with three or more compositions. As such, the method can include one or more additional steps of administering an additional composition to the subject (similar to steps (1) and (4)). Any additional substances administered in the method may be selected from any of the substances disclosed or otherwise contemplated herein for use concurrently with NF-KB inhibitor(s) (as disclosed herein above with respect to optional step (4)). Also, administration of any additional substances can be performed substantially simultaneously or wholly or partially sequentially with the administration of the first and / or second compositions / substances and in the same manner(s) and time frame(s) as described above for the first and second compositions / substances.

[0091] While the methods described herein above are related to use of the combination of alternating electric fields (e.g., TTFields) with at least one of NF-KB inhibitor in cancer treatment, it will be understood that the scope of the present disclosure is not limited to use in cancer treatment. Rather, the present disclosure encompasses treatment of any other related diseases, infections, or conditions for which NF-KB inhibitor treatment and / or alternating electric field treatment is beneficial.

[0092] Certain non-limiting embodiments of the present disclosure are related to kits that include any of the components of the alternating electric field-generating systems disclosed or otherwise contemplated herein (such as, but not limited to, one or more transducer arrays and / or one or more hydrogel compositions, as disclosed in US Patent Nos. 7,016,725; 7,089,054; 7,333,852; 7,565,205; 8,244,345; 8,715,203; 8,764,675; 10,188,851; and10,441,776; and in US Patent Application Nos. US 2018 / 0160933; US 2019 / 0117956; US 2019 / 0307781; and US 2019 / 0308016) in combination with at least one of any of the compositions comprising NF-KB inhibitor(s) disclosed or otherwise contemplated herein. The kits may optionally further include one or more of any of the optional compositions disclosed or otherwise contemplated herein (such as, but not limited to, one or more compositions utilized in one or more optional concurrent therapy step(s)). The kits may optionally further include one or more devices (or one or more components of devices) utilized in one or more additional therapy steps.

[0093] In a particular (but non-limiting) embodiment, the kit may further include instructions for performing any of the methods disclosed or otherwise contemplated herein. For example (but not by way of limitation), the kit may include instructions for applying one or more components of the alternating electric field-generating device to the skin of the patient, instructions for applying the alternating electric field to the patient, instructions for when and how to administer the composition(s) comprising at least one NF-KB inhibitor and optionally how to administer one or more optional additional compositions, and / or instructions for when to activate and turn off the alternating electric field in relation to the administration of the composition(s) comprising at least one NF-KB inhibitor and / or administration of one or more optional compositions.

[0094] In addition to the components described in detail herein above, the kits may further contain other component(s) / reagent(s) for performing any of the particular methods described or otherwise contemplated herein. For example (but not by way of limitation), the kits may additionally include: (i) components for preparing the skin prior to disposal of the hydrogel compositions and / or transducer arrays thereon (e.g., a razor, a cleansing composition or wipe / towel, etc.); (ii) components for removal of the gel / transducer array(s);(iii) components for cleansing of the skin after removal of the gel / transducer array(s); and / or(iv) other components utilized with the system (e.g., conductive material, nonconductive material, a soothing gel or cream, a bandage, etc.). The nature of these additional component(s) / reagent(s) will depend upon the particular treatment format, and identification thereof is well within the skill of one of ordinary skill in the art; therefore, no further description thereof is deemed necessary. Also, the components / reagents present in the kits may each be in separate containers / compartments, or various components / reagents can be combined in one or more containers / compartments, depending on the sterility, cross-reactivity, and stability of the components / reagents.

[0095] The kit may be disposed in any packaging that allows the components present therein to function in accordance with the present disclosure. In certain non-limiting embodiments, the kit further comprises a sealed packaging in which the components are disposed. In certain particular (but non-limiting) embodiments, the sealed packaging is substantially impermeable to air and / or substantially impermeable to light.

[0096] In addition, the kit can further include a set of written instructions explaining how to use one or more components of the kit. A kit of this nature can be used in any of the methods described or otherwise contemplated herein.

[0097] In certain non-limiting embodiments, the kit has a shelf life of at least about six months, such as (but not limited to), at least about nine months, or at least about 12 months.

[0098] Certain non-limiting embodiments of the present disclosure are related to systems that include any of the components of the alternating electric field-generating systems disclosed or otherwise contemplated herein (such as, but not limited to, one or more transducer arrays and / or one or more hydrogel compositions, as disclosed in US Patent Nos. 7,016,725; 7,089,054; 7,333,852; 7,565,205; 8,244,345; 8,715,203; 8,764,675; 10,188,851; and 10,441,776; and in US Patent Application Nos. US 2018 / 0160933; US 2019 / 0117956; US 2019 / 0307781; and US 2019 / 0308016) in combination with at least one of any of the compositions comprising at least one NF-KB inhibitor disclosed or otherwise contemplated herein. The systems may optionally further include one or more of any of the optional compositions disclosed or otherwise contemplated herein. The systems may optionally further include one or more devices (or one or more components of devices) utilized in one or more additional therapy steps.

[0099] Certain non-limiting embodiments of the present disclosure are related to any of the NF-KB inhibitor-containing compositions disclosed or otherwise contemplated herein for use in any of the methods disclosed or otherwise contemplated herein.

[0100] Certain non-limiting embodiments of the present disclosure are related to a combination treatment comprising any of the NF-KB inhibitor-containing compositions disclosed or otherwise contemplated herein in combination with at least one of any of the alternating electric field-generating devices disclosed or otherwise contemplated herein for use in any of the methods disclosed or otherwise contemplated herein.T1EXAMPLES

[0101] Examples are provided hereinbelow. However, the present disclosure is to be understood to not be limited in its application to the specific experimentation, results, and laboratory procedures disclosed herein after. Rather, the Examples are simply provided as one of various embodiments and are meant to be exemplary, not exhaustive.Example 1

[0102] The repurposing of drugs currently used to treat other conditions to improve survival in cancer patients being treated with TTFields was analyzed in this Example based on clinical trials and in vitro work. The analysis was performed to determine overall survival comparison of TTFields-treated GBM patients that had not received the drug in question during TTFields treatment to GBM patients that had been prescribed the drug in question sometime during TTFields treatment. Temozolomide (TMZ) is the standard of care for GBM. FIG. 2 illustrates an analysis of TMZ in accordance with this Example; this graph provides a "baseline" for this study in the absence of the NF-KB inhibitors.

[0103] Three drugs have been identified in this Example that have shown improved survival when administered in combination with TTFields (versus TTFields alone). All three drugs are currently administered to subjects for completely different purposes and are not known to possess anti-cancer activity. In addition, the three drugs have only one factor in common: they all possess the "side effect" of inhibiting the NF-KB pathway.

[0104] The first drug is Aprepitant, which is used to prevent chemotherapy-induced nausea and is classified as an NK1 antagonist. Aprepitant is known to inhibit NF-KB.

[0105] The second drug is Loratadine, an anti-histamine drug that is an antagonist of peripheral histamine Hl receptors. Loratadine exhibits anti-inflammatory properties of suppression of NF-kB.

[0106] The third drug is Azithromycin, which is an antibiotic that binds to the 50S subunit of the bacterial ribosome. Azithromycin modulates transcription of transcription factors such as AP-1 and NF- kB.

[0107] Analysis of median overall survival of patients in the study is shown in FIGS. 3-5 and Tables 1-4. As can be seen, the combination of TTFields and TMZ with any one of these three drugs (which only share the "side effect" of NF-KB inhibition) had a substantial effect on overall survival. Indeed, the use of the anti-histamine drug Loratadine with TTFields and TMZincreased median overall survival by 82% over TTFields and TMZ alone.TABLE 1: Overall Survival Results from FIG. 3TABLE 2: Overall Survival Results from FIG. 4TABLE 3: Overall Survival Results from FIG. 5TABLE 4

[0108] These results are surprising and unexpected, given the prior art teachings that upregulation of NF-KB signaling leads to a positive outcome because the immune system is recruited, and that the activated immune system is associated with better survival. In contrast, the present disclosure has demonstrated the exact opposite - the combination of TTFields with multiple drugs that only shared the activity of NF-KB inhibition substantially increased overall survival when compared to TTFields-treatment alone. Therefore, the combination of TTFields with NF-KB inhibitor(s) provides a surprising and unexpected new avenue of cancer treatment that has a drastic effect on overall survival rates for cancers with very high mortality rates.Example 2

[0109] In this Example, the effects of TTFields and an NF-KB inhibitor (BAY 11-7082) on pancreatic cancer were examined.

[0110] 40,000 AspC-1 human pancreatic cancer cells (CRL-1682, ATCC) were plated in 0.5 ml RPMI complete media in Inovitro™ dishes (Novocure GmbH, Baar, CH). 24 hours after seeding, 1 pM BAY 11-7082 in DMSO was added. Dishes were connected to the Inovitro™ system (Novocure GmbH, Baar, CH) at 18°C and 150 kHz. For the control and BAY 11-7082, 2 ml media was added.

[0111] After 72 hours, the supernatant was removed, and cells were washed with PBS. 0.5 ml trypsin was added for 6 minutes at 37°C and diluted in 0.5 ml media, then 200 pl was taken for count, while 200 pl was taken for colony and apoptosis.

[0112] For apoptosis staining, 0.15pl Annexin V and 1 pl 7-AAD were added to 100 pl binding buffer. The plate was centrifuged at 470 g for 5 minutes at 4°C. The media was discarded, and the 100 pl binding buffer containing Annexin V and 7-AAD was added. The plate was incubated in the dark at room temperature for 10 minutes, and then the plate was read in a Cytek flow cytometer.

[0113] As can be seen in FIGS. 6-8, the concomitant treatment of TTFields application plus the NF-KB inhibitor BAY 11-7082 had a synergistic anti-cancer effect on human pancreatic cancer cells. In particular, FIG. 6 contains results of cell count performed by flow cytometry. The data demonstrates that, while there was no statistically significant reduction in cell count following either TTFields application or NF-kB inhibition in this application setting, there was a significant reduction in cell survival when the two treatments were applied concomitantly; therefore, this data indicates that there is at least an additive effect for concomitant treatment. FIG. 7 demonstrates that apoptosis was significantly increased in the concomitant treatment when compared to control and treatment only with the NF-kB inhibitor. FIG. 8 demonstrates an overall effect when calculating cell count (indicating cytotoxicity) and colony assay results (indicating colonogenic abilities following treatment). This Figure demonstrates that, when calculating the colonogenic abilities, the statistical significance was dramatically increased in the concomitant treatment compared to control and single treatments.Example 3

[0114] This Example lists other drugs and drug groups that are known to inhibit NF-KB and thus can be utilized in accordance with the present disclosure. FIG. 1 illustrates the various classes of NF-KB inhibitors and, while not wishing to be bound by any theory, their proposedmechanisms of action.

[0115] IL-6 inhibiting drugs, such as (but not limited to) Tocilizumab, are NF-KB inhibitors.

[0116] Proteosome inhibitors, such as (but not limited to), bortezomib, carfilzomib, proteosome inhibitor 1 (PSI), and MG132 modulate the NF-KB pathway. Bortezomib is one of the first ever proteosome inhibitors approved by the FDA for treatment of cancer.

[0117] Aspirin, sodium salicylate, and sulindac are classical examples of non-steroidal anti-inflammatory drugs (NSAIDs), and these drugs act through regulation of the mediators of inflammation, namely COX-1 and COX-2. These targets also act by blocking the NF-KB pathway via inhibition of proteasomal degradation of IKB.

[0118] RANK-RANKL inhibitors are also NF-KB inhibitors. It has been reported that even overexpression of RANK may itself activate the NF-KB pathway.

[0119] Ikk inhibitors include small molecules designed to target IKK, a key regulator of NF- KB activation, and these small molecules have shown promise in preclinical studies. These inhibitors block the phosphorylation and degradation of IKB proteins, preventing NF-KB from entering the nucleus.

[0120] IL1-P inhibitors are another class of NF-KB inhibitors that can be utilized in accordance with the present disclosure.

[0121] In addition, at least nineteen drugs that inhibited NF-KB signaling have been identified, with potencies as low as 20 nM. Many of these drugs, including (but not limited to) emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, and lestaurtinib, inhibited NF-KB signaling via inhibition of li<Bot phosphorylation. Others, such as (but not limited to) ectinascidin, chromomycin A3, and bortezomib utilized other mechanisms

[0122] Several other non-limiting inhibitors of NF-KB signaling include pristimerin, KINK- 1, and DHMEQ. These compounds were reported to block tumor growth through various mechanisms such as (but not limited to) inhibition of IKK and prevention of NF-KB activation.NON-LIMITING ILLUSTRATIVE EMBODIMENTS OF THE INVENTIVE CONCEPT(S)

[0123] Illustrative embodiment 1. A method of reducing viability of cancer cells, the method comprising the steps of: (1) administering at least one composition to the cancer cells, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to the cancer cells for a period of time.

[0124] Illustrative embodiment 2. The method of illustrative embodiment 1, wherein themethod is an in vitro method.

[0125] Illustrative embodiment 3. The method of illustrative embodiment 1, wherein the method is an in vivo method.

[0126] Illustrative embodiment 4. A method of treating cancer in a subject, the method comprising the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to a target region of the subject.

[0127] Illustrative embodiment 4A. A method of treating a subject having cancer, the method comprising the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to a target region of the subject, wherein the target region comprises cancer cells.

[0128] Illustrative embodiment 5. A method of reducing a volume of a tumor, wherein the tumor is present in a body of a living subject and includes a plurality of cancer cells, the method comprising the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to a target region of the subject.

[0129] Illustrative embodiment 6. A method of preventing an increase in volume of a tumor, wherein the tumor is present in a body of a living subject and includes a plurality of cancer cells, the method comprising the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and (2) applying an alternating electric field to a target region of the subject.

[0130] Illustrative embodiment 7. A method of extending overall survival (OS) in a living subject with cancer, the method comprising the steps of: (1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF- KB inhibitor; and (2) applying an alternating electric field to a target region of the subject; and wherein overall survival in the living subject is increased when compared to treatment with (1) or (2) alone.

[0131] Illustrative embodiment 8. The method of any of illustrative embodiments 4-7, wherein the at least one composition is orally or intravenously administered to the subject.

[0132] Illustrative embodiment 9. The method of any of illustrative embodiments 4-8, wherein the at least one composition is locally or intratumorally administered to the subject.

[0133] Illustrative embodiment 10. The method of any of illustrative embodiments 1-9, wherein at least one of: the alternating electric field is applied at a frequency in a range of from about 50 kHz to about 1 MHz; the alternating electric field has a field strength of at least about 1 V / cm in at least a portion of the cancer cells / target region / subject; and the period of time that the alternating electric field is applied is at least about 50% of at least about a 24 consecutive hour time period.

[0134] Illustrative embodiment 10A. The method of any of illustrative embodiments 1-9, wherein at least one of: the alternating electric field is applied at a frequency in a range of from about 50 kHz to about 1 MHz; and optionally the period of time that the alternating electric field is applied is at least about 50% of at least about a 24 consecutive hour time period.

[0135] Illustrative embodiment 11. The method of any one of illustrative embodiments 1- 10A, wherein steps (1) and (2) are performed substantially simultaneously.

[0136] Illustrative embodiment 12. The method of any one of illustrative embodiments 1- 10A, wherein steps (1) and (2) are performed wholly or partially sequentially, and wherein the at least one composition is administered before the application of the alternating electric field has begun.

[0137] Illustrative embodiment 13. The method of any one of illustrative embodiments 1- 10A, wherein steps (1) and (2) are performed wholly or partially sequentially, and wherein the at least one composition is administered after the application of the alternating electric field has begun.

[0138] Illustrative embodiment 14. The method of any one of illustrative embodiments 1- 10A and 13, wherein the at least one composition is administered after the period of time has elapsed.

[0139] Illustrative embodiment 15. The method of any one of illustrative embodiments 1- 10A and 13, wherein the at least one composition is administered before the period of time the alternating electric field is applied has elapsed.

[0140] Illustrative embodiment 16. The method of any one of illustrative embodiments 1-15, wherein steps (1) and (2) are repeated one or more times.

[0141] Illustrative embodiment 17. The method of any one of illustrative embodiments 1-16, wherein the cancer / cancer cells is / are selected from the group consisting of hepatocellular carcinoma / hepatocellular carcinoma cells, glioblastoma / glioblastoma cells,pleural mesothelioma / pleural mesothelioma cells, differentiated thyroid cancer / differentiated thyroid cancer cells, advanced renal cell carcinoma / advanced renal cell carcinoma cells, ovarian cancer / ovarian cancer cells, breast cancer / breast cancer cells, pancreatic cancer / pancreatic cancer cells, lung cancer / lung cancer cells, and combinations thereof.

[0142] Illustrative embodiment 18. The method of any of illustrative embodiments 1-17, wherein the at least one NF-KB inhibitor is selected from the group consisting of an IL-6 inhibitor, a proteosome inhibitor, a RANK-RANKL inhibitor, an Ikk inhibitor, an IL-ip inhibitor, and combinations thereof.

[0143] Illustrative embodiment 19. The method of any of illustrative embodiments 1-18, wherein the at least one NF-KB inhibitor is selected from the group consisting of Tocilizumab, bortezomib, carfilzomib, proteosome inhibitor 1 (PSI), MG132, sodium salicylate, sulindac, a coxl inhibitor, emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, lestaurtinib, pristimerin, KINK-1, DHMEQ, Aprepitant, Loratadine, Azithromycin, BAY 11-7082, and combinations thereof.

[0144] Illustrative embodiment 20. The method of any of illustrative embodiments 1-19, wherein the at least one NF-KB inhibitor is selected from the group consisting of Aprepitant, Loratadine, Azithromycin, BAY 11-7082, and combinations thereof.

[0145] Illustrative embodiment 21. The method of any of illustrative embodiments 1-20, wherein the alternating electric field has a field strength in a range of from about 1 V / cm to about 10 V / cm in at least a portion of the cancer cells / target region / subject.

[0146] Illustrative embodiment 22. The method of any of illustrative embodiments 1-21, wherein the period of time that the alternating electric field is applied is in a range of from about 24 hours to about 72 hours.

[0147] Illustrative embodiment 23. The method of any of illustrative embodiments 1-22, wherein the method further comprises the step of discontinuing the application of the alternating electric field.

[0148] Illustrative embodiment 24. The method of any of illustrative embodiments 1-23, wherein the at least one composition is administered at least 24 hours after application of the alternating electric field has begun.

[0149] Illustrative embodiment 25. The method of any of illustrative embodiments 1-24, wherein the at least one composition is administered within about 96 hours of when theperiod of time elapsed.

[0150] Illustrative embodiment 26. The method of any of illustrative embodiments 1-25, wherein the at least one composition further comprises a pharmaceutically acceptable carrier.

[0151] Illustrative embodiment 27. The method of any of illustrative embodiments 1-26, wherein the composition comprising the at least one NF-KB inhibitor is administered to the cancer cells / subject at a therapeutically effective concentration of the at least one NF-KB inhibitor.

[0152] Illustrative embodiment 28. The method of illustrative embodiment 27, wherein the therapeutically effective concentration of the at least one NF-KB inhibitor is from about 10 mg / kg to about 50 mg / kg.

[0153] Illustrative embodiment 29. The method of any of illustrative embodiments 1-28, wherein the at least one composition further comprises at least one additional therapeutic agent.

[0154] Illustrative embodiment 30. The method of any of illustrative embodiments 1-29, wherein the method further comprises the step of administering a second composition to the cancer cells / subject, wherein the second composition comprises at least one additional therapeutic agent.

[0155] Illustrative embodiment 31. The method of illustrative embodiment 30, wherein the first and second compositions are administered substantially simultaneously.

[0156] Illustrative embodiment 32. The method of illustrative embodiment 30, wherein the first and second compositions are administered wholly or partially sequentially.

[0157] Illustrative embodiment 33. The method of any of illustrative embodiments 29-32, wherein the at least one additional therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an immune checkpoint inhibitor, an anti-PD-1 therapeutic agent, a TKI inhibitor, an mTOR inhibitor, an Akt inhibitor, a PI3K inhibitor, a PARP inhibitor, a VEGF inhibitor, an FGF inhibitor, an aromatase inhibitor, a radiotherapy agent, a biologic, an anti- LAG3 agent, an anti-PD-Ll therapeutic agent, an anti-CTLA-4 therapeutic agent, and combinations thereof.

[0158] Illustrative embodiment 34. The method of illustrative embodiment 33, wherein the at least one additional therapeutic agent is selected from the group consisting of Paclitaxel, Doxorubicin, Cisplatin, sorafenib, Docetaxel, Ifosamide, Etoposide (Vepesid),Gemcitabine, Lomustine, Nab Paclitaxel, Temozolomide, Carboplatin, Cemiplimab, Nivolumab, Pembrolizumab, Tislelizumab, lenvatinib, everolimus, Letrozole, Denosumab, Relatimab, Atezolizumab, Avelumab, Durvalumab, Ipilimumab, and combinations thereof.

[0159] Illustrative embodiment 34A. The method of any of Illustrative embodiments 1- 34, wherein the cancer / cancer cells is / are glioblastoma / glioblastoma cells, and wherein the at least one composition of (1) further comprises Temozolomide.

[0160] Illustrative embodiment 34B. The method of any of Illustrative embodiments 1- 34A, wherein the cancer / cancer cells is / are glioblastoma / glioblastoma cells, and wherein the method further comprises the step of administering a second composition to the cancer cells / subject, wherein the second composition comprises Temozolomide.

[0161] Illustrative embodiment 35. The method of any of illustrative embodiments 1-34B, further comprising the step of administering at least one additional therapy to the cancer cells / subject.

[0162] Illustrative embodiment 36. The method of illustrative embodiment 35, wherein the at least one additional therapy is selected from the group consisting of radiation therapy, photodynamic therapy, transarterial chemoembolization (TACE), and combinations thereof.

[0163] Illustrative embodiment 37. The method of any of illustrative embodiments 1-36, further comprising the step of exposing the cancer cells / subject to radiation therapy.

[0164] Illustrative embodiment 38. The method of illustrative embodiment 37, wherein the radiation therapy is applied before step (1), after step (1), before step (2), and / or after step (2).

[0165] Illustrative embodiment 39. The method of any of illustrative embodiments 1-38, further comprising the step of exposing the cancer cells / target region of the subject to ionizing radiation (IR), wherein the IR is applied before step (1), after step (1), before step (2), and / or after step (2).

[0166] Illustrative embodiment 39A. The method of any of illustrative embodiments 1-39, wherein the alternating electric field is a tumor treating field.

[0167] Illustrative embodiment 40. Use of at least one composition comprising at least one NF-KB inhibitor in a concomitant therapy method of any of illustrative embodiments 1- 39A.

[0168] Illustrative embodiment 40A. The use of Illustrative embodiment 40, wherein the at least one composition comprises at least one additional therapeutic agent selected fromthe group consisting of Paclitaxel, Doxorubicin, Cisplatin, sorafenib, Docetaxel, Ifosamide, Etoposide (Vepesid), Gemcitabine, Lomustine, Nab Paclitaxel, Temozolomide, Carboplatin, Cemiplimab, Nivolumab, Pembrolizumab, Tislelizumab, lenvatinib, everolimus, Letrozole, Denosumab, Relatimab, Atezolizumab, Avelumab, Durvalumab, Ipilimumab, and combinations thereof.

[0169] Illustrative embodiment 40B. The use of Illustrative embodiment 40A, wherein the at least one additional therapeutic agent is Temozolomide.

[0170] Illustrative embodiment 40C. Use of at least one composition comprising at least one NF-KB inhibitor in the manufacture of a medicament for the treatment of cancer, optionally wherein the medicament is for use in a concomitant therapy method of any of illustrative embodiments 1-39A.

[0171] Illustrative embodiment 41. A composition comprising at least one NF-KB inhibitor for use in any of the methods of illustrative embodiments 1-39A.

[0172] Illustrative embodiment 42. A combination treatment comprising an alternating electric field and at least one composition comprising at least one NF-KB inhibitor.

[0173] Illustrative embodiment 42A. The combination treatment of illustrative embodiment 42, for use in the method of any of illustrative embodiments 1-39A.

[0174] Illustrative embodiment 43. A kit, comprising: an alternating electric fieldgenerating device; and at least one composition comprising at least one NF-KB inhibitor.

[0175] Illustrative embodiment 44. A system, comprising: an alternating electric fieldgenerating device; and at least one composition comprising at least one NF-KB inhibitor.

[0176] Illustrative embodiment 45. The kit of illustrative embodiment 43 or the system of illustrative embodiment 44, for use in the method of any of illustrative embodiments 1-39A.

[0177] Illustrative embodiment 46. The composition / combination treatment / kit / system of any of illustrative embodiments 41-45, wherein the composition further comprises at least one pharmaceutically acceptable carrier.

[0178] Illustrative embodiment 47. The composition / combination treatment / kit / system of any of illustrative embodiments 41-46, wherein the composition further comprises at least one additional therapeutic agent.

[0179] Illustrative embodiment 48. The composition / combination treatment / kit / system of illustrative embodiment 47, wherein the at least one additional therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an immune checkpointinhibitor, an anti-PD-1 therapeutic agent, a TKI inhibitor, an mTOR inhibitor, an Akt inhibitor, a PI3K inhibitor, a PARP inhibitor, a VEGF inhibitor, an FGF inhibitor, an aromatase inhibitor, a radiotherapy agent, a biologic, an anti-LAG3 agent, an anti-PD-Ll therapeutic agent, an anti- CTLA-4 therapeutic agent, and combinations thereof.

[0180] Illustrative embodiment 49. The composition / combination treatment / kit / system of illustrative embodiment 47 or 48, wherein the at least one additional therapeutic agent is selected from the group consisting of Paclitaxel, Doxorubicin, Cisplatin, sorafenib, Docetaxel, Ifosamide, Etoposide (Vepesid), Gemcitabine, Lomustine, Nab Paclitaxel, Temozolomide, Carboplatin, Cemiplimab, Nivolumab, Pembrolizumab, Tislelizumab, lenvatinib, everolimus, Letrozole, Denosumab, Relatimab, Atezolizumab, Avelumab, Durvalumab, Ipilimumab, and combinations thereof.

[0181] Illustrative embodiment 50. The composition / combination treatment / kit / system of illustrative embodiment 49, wherein the at least one additional therapeutic agent is Temozolomide.

[0182] Illustrative embodiment 51. The combination treatment / kit / system of any of illustrative embodiments 42-50, further comprising at least a second composition comprising at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an immune checkpoint inhibitor, an anti-PD-1 therapeutic agent, a TKI inhibitor, an mTOR inhibitor, an Akt inhibitor, a PI3K inhibitor, a PARP inhibitor, a VEGF inhibitor, an FGF inhibitor, an aromatase inhibitor, a radiotherapy agent, a biologic, an anti-LAG3 agent, an anti-PD-Ll therapeutic agent, an anti-CTLA-4 therapeutic agent, and combinations thereof.

[0183] Illustrative embodiment 52. The combination treatment / kit / system of illustrative embodiment 51, wherein the at least one additional therapeutic agent is selected from the group consisting of Paclitaxel, Doxorubicin, Cisplatin, sorafenib, Docetaxel, Ifosamide, Etoposide (Vepesid), Gemcitabine, Lomustine, Nab Paclitaxel, Temozolomide, Carboplatin, Cemiplimab, Nivolumab, Pembrolizumab, Tislelizumab, lenvatinib, everolimus, Letrozole, Denosumab, Relatimab, Atezolizumab, Avelumab, Durvalumab, Ipilimumab, and combinations thereof.

[0184] Illustrative embodiment 53. The combination treatment / kit / system of illustrative embodiment 52, wherein the at least one additional therapeutic agent is Temozolomide.

[0185] While the attached disclosures describe the inventive concept(s) in conjunctionwith the specific experimentation, results, and language set forth hereinafter, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the present disclosure.

Claims

CLAIMS1. A combination treatment comprising an alternating electric field and at least one composition comprising at least one NF-KB inhibitor.

2. The combination treatment of claim 1, wherein the at least one NF-KB inhibitor is selected from the group consisting of an IL-6 inhibitor, a proteosome inhibitor, a RANK-RANKL inhibitor, an Ikk inhibitor, an IL-ip inhibitor, and combinations thereof.

3. The combination treatment of claim 1 or 2, wherein the at least one NF-KB inhibitor is selected from the group consisting of Aprepitant, Loratadine, Azithromycin, BAY 11-7082, and combinations thereof.

4. The combination treatment of any one of claims 1-3, wherein the at least one composition further comprises Temozolomide.

5. A method of reducing viability of cancer cells, the method comprising the steps of:(1) administering at least one composition to the cancer cells, wherein the at least one composition comprises at least one NF-KB inhibitor; and(2) applying an alternating electric field to the cancer cells for a period of time.

6. A method of treating cancer in a subject, the method comprising the steps of:(1) administering at least one composition to the subject, wherein the at least one composition comprises at least one NF-KB inhibitor; and(2) applying an alternating electric field to a target region of the subject.

7. The method of claim 6, further defined as a method of reducing a volume of a tumor and / or preventing an increase in volume of the tumor, wherein the tumor is present in a body of a living subject and includes a plurality of cancer cells.

8. The method of claim 6 or 7, further defined as a method of extending overall survival (OS) in a living subject with cancer, and wherein overall survival in the living subject is increased when compared to treatment with (1) or (2) alone.

9. The method of any one of claims 5-8, wherein the at least one NF-KB inhibitor is selected from the group consisting of an IL-6 inhibitor, a proteosome inhibitor, a RANK-RANKL inhibitor, an Ikk inhibitor, an IL-ip inhibitor, and combinations thereof.

10. The method of any one of claims 5-9, wherein the at least one NF-KB inhibitor is selected from the group consisting of Aprepitant, Loratadine, Azithromycin, BAY 11-7082, and combinations thereof.

11. The method of any one of claims 5-10, wherein the at least one composition is orally or intravenously administered to the subject.

12. The method of any one of claims 5-11, wherein the at least one composition is locally or intratumorally administered to the subject.

13. The method of any one of claims 5-12, wherein at least one of: the alternating electric field is applied at a frequency in a range of from about 50 kHz to about 1 MHz; the alternating electric field has a field strength of at least about 1 V / cm in at least a portion of the target region; the period of time that the alternating electric field is applied is at least about 50% of at least about a 24 consecutive hour time period; and steps (1) and (2) are repeated one or more times.

14. The method of any one of claims 5-13, wherein the cancer / cancer cells is / are selected from the group consisting of hepatocellular carcinoma, glioblastoma, pleural mesothelioma, differentiated thyroid cancer, advanced renal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, lung cancer, and combinations thereof.

15. A composition comprising at least one NF-KB inhibitor, wherein the composition is for use in the method of any one of claims 5-14.

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