Composition for treating cancer

Abstract

[Problem] To elucidate the mechanism of an anti-tumor effect of a ketogenic diet therapy to discover a novel cancer treatment method. [Solution] Provided is a composition for treating cancer, the composition comprising a ketogenic diet therapy composition and is used in combination with an inflammatory cytokine inhibitor. Also provided is a novel cancer immunotherapy comprising a combination of the administration of an inflammatory cytokine inhibitor and a ketogenic diet therapy. The ketogenic diet therapy composition is a composition containing a fat in an amount of 55% or more. The inflammatory cytokine inhibitor is preferably an IL-1 inhibitor, an IL-6 inhibitor or a TNF-α inhibitor. When used in combination with the inflammatory cytokine inhibitor, the anti-tumor effect of the ketogenic diet therapy is enhanced.

Description

Compositions for treating cancer

[0001] The present invention relates to the treatment of cancer.

[0002] Ketone bodies are biosynthesized in the liver through the beta-oxidation of fatty acids. When glucose supply is insufficient due to fasting or prolonged exercise, lipids are broken down to produce ketone bodies from fatty acids, which are then used as an energy source (Non-Patent Document 1). The ketogenic diet, a high-fat, low-carbohydrate diet designed to increase the body's production of ketone bodies, such as acetoacetate, beta-hydroxybutyrate, and acetone, has long been known. Intake of a ketogenic diet increases the blood ketone body concentration. Dietary therapy using a ketogenic diet is known to be useful for treating intractable epilepsy and GLUT1 deficiency, as well as for suppressing seizures in intractable epilepsy (Non-Patent Document 2).

[0003] As dietary habits become more Westernized, cancers commonly seen in Europe and the United States, such as colon cancer, breast cancer, lung cancer, prostate cancer, and pancreatic cancer, are on the rise. However, existing cancer treatments, such as surgical resection, chemotherapy, and radiation therapy, are not sufficiently effective for lung cancer and pancreatic cancer. There is a particular need for the development of effective treatments for patients with inoperable advanced cancers.

[0004] The inventors of the present invention have discovered that cancer treatment with a carbohydrate-restricted, high-fat diet (hereinafter also referred to as ketogenic diet therapy) is highly effective in patients with advanced cancer (Patent Document 1). They also discovered a biomarker for selecting cancer patients for whom ketogenic diet therapy is effective (Patent Document 2). Furthermore, they developed a ketogenic diet therapy ABC score that can determine the prognosis of cancer patients receiving ketogenic diet therapy using albumin, blood glucose levels, and CRP, an inflammation marker, which are measured in routine clinical practice (Patent Document 3). Furthermore, they developed a new ketogenic diet therapy that is effective for patients with advanced cancer (Non-Patent Document 3, Patent Document 4). However, the mechanism of action of ketogenic diet therapy in cancer patients is currently unclear.

[0005] International Publication No. 2017 / 038101 International Publication No. 2019 / 059349 International Publication No. 2021 / 006276 Japanese Patent Application Laid-Open No. 2020-059699

[0006] Vidali S, et al., Int J Biochem Cell Biol. 63, 55-59 (2015) Tatsuya Fujii, "From the Basics to Practice of the Ketogenic Diet", Shindan to Chiryousha (2011) Hagihara, K., et al., Nutrients 12, 1473 (2020)

[0007] The objective of the present invention is to discover a new cancer treatment method by elucidating the mechanism of the antitumor effect of ketogenic diet therapy.

[0008] To elucidate the mechanism of the antitumor effect of the ketogenic diet, the inventors analyzed genes that are altered by the ketogenic diet. As a result, they discovered that the ketogenic diet is involved in cytokine signaling, and have invented a new cancer immunotherapy that combines the ketogenic diet with an inflammatory cytokine inhibitor.

[0009] 1. A composition for cancer treatment, comprising a ketogenic dietary composition used in combination with an inflammatory cytokine inhibitor. 2. The composition according to item 1, wherein the ketogenic dietary composition contains a lipid. 3. The composition according to item 2, wherein the lipid content relative to the total solid content of the ketogenic dietary composition is 55% by mass or more. 4. The composition according to item 3, wherein the carbohydrate content relative to the total solid content of the ketogenic dietary composition is 0 to 15% by mass. 5. The composition according to any one of items 2 to 4, wherein the lipid contains a medium-chain fatty acid oil. 6. The composition according to any one of items 1 to 5, wherein the inflammatory cytokine inhibitor is an IL-1 inhibitor, an IL-6 inhibitor, or a TNF-α inhibitor. 7. The composition according to any one of items 1 to 5, wherein the inflammatory cytokine inhibitor is an IL-1β inhibitor. 8. The composition according to item 7, wherein the IL-1β inhibitor is an anti-IL-1β antibody. 9. 10. The composition according to any one of the preceding items 1 to 8, which is a pharmaceutical composition. 10. A combination for cancer treatment, comprising an inflammatory cytokine inhibitor and a ketogenic diet composition. 11. A composition for cancer treatment, comprising an inflammatory cytokine inhibitor, used in combination with a ketogenic diet composition. 12. A composition for enhancing the anti-cancer effect of a ketogenic diet, comprising an inflammatory cytokine inhibitor. 13. A method for treating cancer, comprising administering an inflammatory cytokine inhibitor and a ketogenic diet. 14. The method according to the preceding item 13, wherein the ketogenic diet is a therapy using a ketogenic diet composition containing lipids. 15. Use of a ketogenic diet composition for preparing a composition for cancer treatment, to be used in combination with an inflammatory cytokine inhibitor. 16. The use according to the preceding item 15, wherein the ketogenic diet composition is a composition containing lipids. 17. A kit for cancer treatment, comprising an inflammatory cytokine inhibitor and a ketogenic diet composition.

[0010] When used in combination with an inflammatory cytokine suppressor, the antitumor effect of the ketogenic diet is enhanced. This enhanced antitumor effect is thought to be due to the inflammatory cytokine suppressor amplifying the effects of the ketogenic diet, which is involved in cytokine signaling. This invention makes possible a groundbreaking new cancer immunotherapy that demonstrates antitumor effects without the use of cytotoxic anticancer drugs. This will improve the quality of life and contribute to improving survival rates for many patients with advanced or refractory cancers.

[0011] Figure 1 shows the antitumor effect of ketogenic diet therapy in tumor-bearing mice subcutaneously implanted with Colon-26 cells. The graph shows the change in tumor volume after the initiation of the ketogenic diet. A high-dose cisplatin (CDDP) group was used as a positive control. From Day 13 onward, tumor volume in the ketogenic diet-CDDP combination group was significantly lower than that in the CDDP-administered group. It was revealed that the combination of CDDP administration and ketogenic diet suppressed tumor growth more than CDDP administration alone. Control: control group; KF: ketogenic diet group; KF + CDDP 3.75 mg / kg: ketogenic diet-CDDP combination group; CDDP 3.75 mg / kg: CDDP-administered group; CDDP 5.0 mg / kg: high-dose CDDP-administered group; n = 12 per group; Dunnett's multiple comparison test was performed. Day 6: Compared to the control group, the ketogenic diet group, the ketogenic diet-CDDP combination group, the CDDP-administered group, and the high-dose CDDP-administered group showed p<0.05 (*). Compared to the ketogenic diet-CDDP combination group, the control group showed p<0.05 (#). Day 9: Compared to the control group, the ketogenic diet group, the ketogenic diet-CDDP combination group, the CDDP-administered group, and the high-dose CDDP-administered group showed p<0.05 (*). Compared to the ketogenic diet-CDDP combination group, the control group and the ketogenic diet group showed p<0.05 (#). Day 13: Compared to the control group, the ketogenic diet group, the ketogenic diet-CDDP combination group, the CDDP-administered group, and the high-dose CDDP-administered group showed p<0.05 (*). Compared to the ketogenic diet-CDDP combination group, the control group, the ketogenic diet group, and the CDDP-administered group showed p<0.05 (#). Day 16: Compared to the control group, the ketogenic diet-CDDP combination group, the CDDP administration group, and the high-dose CDDP administration group showed p<0.05 (*). Compared to the ketogenic diet-CDDP combination group, the control group, the ketogenic diet group, and the CDDP administration group showed p<0.05 (#). Day 21: Compared to the control group, the ketogenic diet-CDDP combination group, the CDDP administration group, and the high-dose CDDP administration group showed p<0.05 (*). Compared to the ketogenic diet-CDDP combination group, the control group, the ketogenic diet group, and the CDDP administration group showed p<0.05 (#). ; Bars represent standard error of the mean. Figure 2 shows the antitumor effect of ketogenic diet therapy using tumor-bearing mice subcutaneously implanted with Colon-26 cells.The tumor weights for each group 21 days after the initiation of a ketogenic diet are shown. Tumor weights in the ketogenic diet-CDDP combination group were significantly lower than those in the CDDP-administered group. This demonstrates that the combination of CDDP administration and a ketogenic diet suppresses tumor growth more than CDDP administration alone. n = 12 per group; *p < 0.05, **p < 0.01, Dunnett's multiple comparison test; bars represent standard error of the mean. Figure 3 shows the involvement of a ketogenic diet in apoptosis. Tumor tissue from tumor-bearing mice subcutaneously implanted with Colon-26 cells was excised 21 days after the initiation of a ketogenic diet, and the number of apoptotic cells was counted. Apoptosis was suppressed by high-dose CDDP administration (5.0 mg / kg), but this suppression was alleviated by ketogenic diet intervention. The ketogenic diet demonstrated an apoptosis-inducing effect. Control: control group, KF: ketogenic diet group, KF + CDDP 3.75 mg / kg: ketogenic diet-CDDP combination group, CDDP 3.75 mg / kg: CDDP administration group, CDDP 5.0 mg / kg: high-dose CDDP administration group; n = 12 for each group; **p < 0.01; t-test; bars represent standard error of the mean. Figure 4 shows the expression status of each gene in the pathway "Mm_Type_II_interferon_signaling_(IFNG)_WP1253_71753" in the CDDP-administered group. A change in color from yellow to red indicates higher expression levels. On the grayscale, darker gray indicates higher expression levels. Figure 5 shows the expression status of each gene in the pathway "Mm_Type_II_interferon_signaling_(IFNG)_WP1253_71753" in the ketogenic diet-CDDP combination group. A change in color from yellow to red indicates a higher level of expression. On the grayscale, darker gray indicates a higher level of expression. Comparison with Figure 4 revealed that the expression levels of genes marked with an * were increased by the ketogenic diet. This demonstrated that the ketogenic diet enhances interferon signaling activity. Figure 6 shows the expression status of each gene in the pathway "Mm_Apoptosis_WP1254_89986" in the CDDP-administered group. A change in color from yellow to red indicates a higher level of expression. On the grayscale, darker gray indicates a higher level of expression.Figure 7 shows the expression status of each gene in the pathway "Mm_Apoptosis_WP1254_89986" in the ketogenic diet-CDDP combination group. A change in color from yellow to red indicates higher expression levels. On the grayscale, darker shades of gray indicate higher expression levels. Comparison with Figure 6 revealed that the expression levels of genes marked with an * were increased by the ketogenic diet. The ketogenic diet was shown to activate signals to caspase 3. Figure 8 shows the results of NLP analysis of gene expression in PBMCs from patients before and 3 months after the introduction of a ketogenic diet, and of the 12 genes whose expression levels were altered, NLP analysis was performed. The results suggest that the ketogenic diet is involved in the immune response mediated by PTGS2-IL1b-CXCL10 and cytokine signaling mediated by IL1b-CXCL10-IFIT1. Of the 12 identified genes, 8 genes were suggested to have a relationship originating from PTGS2. Figure 9 shows the results of an analysis of the time course of expression levels of the eight genes shown to be correlated in Figure 8 in PBMCs from patients divided into three groups based on the therapeutic effect three months after the introduction of a ketogenic diet. The Response group consisted of nine patients with complete remission (CR) or partial response (PR), the Stable group consisted of 12 patients with stable disease (SD), and the Progress group consisted of 10 patients with progressive disease (PD). CXCL10, which is downstream of PTGS2, showed increased expression in the Response group (improved patients), exhibiting a different behavior from that of non-improved patients. This suggests that the PTGS2-to-IL1b transition is a unique variation in cancer ketogenic diet therapy. Bars represent the standard error of the mean. Figure 10 is a graph showing the antitumor effect of combined ketogenic diet therapy and anti-IL-1β antibody administration in tumor-bearing mice subcutaneously implanted with Colon-26 cells, showing changes in tumor volume. Fourteen days after the start of the ketogenic diet, the ketogenic diet + anti-IL-1β antibody group had lower tumor volume than the normal diet + control antibody group and the normal diet + anti-IL-1β antibody group, demonstrating that the combination of a ketogenic diet and anti-IL-β1 antibody can suppress tumor growth.Control IgG: normal diet + control antibody administration group, Anti-IL-1β: normal diet + anti-IL-1β antibody administration group, KF + Control IgG: ketogenic diet + control antibody administration group, KF + Anti-IL-1β: ketogenic diet + anti-IL-1β antibody administration group; n = 12 for each group; **p < 0.01, normal diet + control antibody administration group vs. ketogenic diet + anti-IL-1β antibody administration group, Dunnett's multiple comparison test; #p < 0.05, normal diet + anti-IL-1β antibody administration group vs. ketogenic diet + anti-IL-1β antibody administration group, Student's t-test; bars represent standard error of the mean. Figure 11 is a graph showing the antitumor effect of combined ketogenic diet therapy and anti-IL-1β antibody administration using tumor-bearing mice subcutaneously implanted with Colon-26 cells. The tumor weights shown are from 17 days after the start of the ketogenic diet. The ketogenic diet + anti-IL-1β antibody group had lower tumor weights than the normal diet + anti-IL-1β antibody group, demonstrating that the combination of a ketogenic diet and an anti-IL-β1 antibody can suppress tumor growth. Control IgG: normal diet + control antibody group, Anti-IL-1β: normal diet + anti-IL-1β antibody group, KF + Control IgG: ketogenic diet + control antibody group, KF + Anti-IL-1β: ketogenic diet + anti-IL-1β antibody group; n = 12 per group; p < 0.05, Student's t-test; bars represent standard error of the mean.

[0012] The composition of the present invention is a composition for cancer treatment, characterized in that it is used in combination with an inflammatory cytokine suppressor. The composition of the present invention is a composition for cancer treatment used in ketogenic diet therapy. The composition of the present invention is a cancer treatment composition comprising a ketogenic diet composition for use in combination with an inflammatory cytokine suppressor.

[0013] The ketogenic diet of the present invention is a cancer treatment method using carbohydrate-restricted, high-lipid nutrition with a ketone ratio of 1 or higher. The ketone ratio is expressed as the mass ratio of lipids to (protein + carbohydrates) in the nutrients ingested daily. The ketone ratio can be adjusted depending on the patient's condition and the timing of initiation of the ketogenic diet. For example, a ketone ratio of approximately 2 is preferred one week after the introduction of the ketogenic diet. Thereafter, preferred ketone ratios include 1 to 2. The ketone ratio may also be greater than 2.

[0014] The diet or nutrition used in the ketogenic diet therapy of the present invention is also referred to as a ketogenic diet. The ketogenic diet of the present invention is not limited in form as long as the ketone ratio of the nutrients ingested daily is 1 or greater. Examples include a regular diet prepared at home or in a facility using animal or plant ingredients, a composition with a desired ketone ratio that can be ingested directly or by dissolving in water, and a combination of a regular diet and a composition for achieving the desired ketone ratio.

[0015] The composition of the present invention includes a ketogenic diet composition. The composition of the present invention may be the same as a ketogenic diet composition. Alternatively, the composition of the present invention may be a composition containing a ketogenic diet composition and other components. As long as the composition of the present invention has a desired ketone ratio, the other components are not particularly limited. Examples of other components include micronutrients, excipients, etc.

[0016] The composition of the present invention is a composition for treating cancer that is used in combination with an inflammatory cytokine suppressor. The manner in which they are combined is not limited. Examples include a combination in which the inflammatory cytokine suppressor and the composition of the present invention are administered (ingested), a combination in which the inflammatory cytokine suppressor and the composition of the present invention are combined into a single formulation, and a combination in which the inflammatory cytokine suppressor and the composition of the present invention are combined into a kit.

[0017] The ketogenic dietary composition of the present invention is a composition used in ketogenic dietary therapy, and is, for example, a composition with a desired ketone ratio that can be ingested as is or by dissolving in water, etc., a composition that can be easily prepared with other ingredients to form a composition with a desired ketone ratio, and a composition that can be combined with a normal diet to achieve a desired ketone ratio.

[0018] The ketogenic dietary composition of the present invention is used in combination with an anti-inflammatory cytokine suppressor for the treatment of cancer. The ketogenic dietary composition is administered (ingested) to a subject (patient) as all or part of a ketogenic diet, and the inflammatory cytokine suppressor may be administered in combination.

[0019] One embodiment of the ketogenic diet composition of the present invention is a composition that can be used as the entire ketogenic diet of the ketogenic diet. The composition of this embodiment contains, in daily amounts, the energy, nutrients, and trace elements required by a subject (patient) per day.

[0020] Another embodiment of the ketogenic dietary composition of the present invention may be a composition that can be used as part of a ketogenic diet. In this embodiment, a subject (patient) ingests the ketogenic dietary composition of the present invention in combination with other foods. For example, the ketogenic dietary composition of the present invention may replace one or two meals a day, or the ketogenic dietary composition of the present invention may be ingested as a nutritional supplement. In the embodiment ingested as a nutritional supplement, the ketogenic dietary composition of the present invention may have a higher lipid content.

[0021] In the ketogenic diet of the present invention, a nutritional intake method can be planned to meet the ketone ratio required for each patient. The ketogenic diet composition of the present invention can be a composition whose component contents can be adjusted to meet the ketone ratio required by the patient. For example, it can be a kit in which each component or several components are packaged separately, allowing the component ratio to be adjusted to suit the patient and intake method.

[0022] The inflammatory cytokine inhibitor of the present invention is not limited as long as it is a substance that inhibits the function of inflammatory cytokines in vivo. Examples include substances that inhibit the activity of inflammatory cytokines, substances that inhibit the binding of inflammatory cytokines to their receptors, substances that suppress the expression of inflammatory cytokines, substances that inhibit inflammatory cytokine signaling, and substances that suppress the production of inflammatory cytokines. Examples include antibodies against inflammatory cytokines, inflammatory cytokine receptor antagonists, substances structurally similar to inflammatory cytokines, antisense RNA of inflammatory cytokine genes, and inhibitors of inflammatory cytokine-producing enzymes. More preferred inflammatory cytokine inhibitors include anti-inflammatory cytokine antibodies.

[0023] Examples of the inflammatory cytokine inhibitor of the present invention include an IL-1 inhibitor, an IL-6 inhibitor, an IL-8 inhibitor, an IL-17 inhibitor, a TNF-α inhibitor, and a JAK inhibitor involved in IL-6 signaling. Preferred examples include an IL-1 inhibitor, an IL-6 inhibitor, a TNF-α inhibitor, and a JAK inhibitor. More preferred examples are IL-1 inhibitors, and even more preferred examples are IL-1β inhibitors. Preferred examples of the IL-1β inhibitor include anti-IL-1β antibodies and IL-1β production inhibitors.

[0024] Inflammatory cytokine suppressors are widely used in clinical settings, and research and development of these suppressors is also progressing. The inflammatory cytokine suppressors of the present invention include all of these drugs. Examples of drugs used clinically include canakinumab, a human IL-1β monoclonal antibody, salazosulfapyridine, methotrexate, tacrolimus, mesalazine, and diaphenylsulfone, which suppress IL-1β production. Other examples include desloratadine and actarit, which have an inhibitory effect on IL-6 production, colchicine, which reduces IL-8, adalimumab, golimumab, certolizumab pegol, and infliximab, which are anti-TNF-α monoclonal antibodies, ixekizumab, an anti-human interleukin-17A monoclonal antibody, apremilast, which controls the expression of inflammatory cytokines such as IL-17, TNF-α, and IL-23, iguratimod, which suppresses the production of TNF-α and IL-6, etanercept, which acts as a TNF-α decoy receptor, pirfenidone, which suppresses the production of IL-2, TNF-α, IL-1, and IL-6, prednisolone and betamethasone, which suppress the production of TNF-α and IL-1, and ruxolitinibulin, which suppresses the increase in blood levels of IL-6 and TNF-α. Other examples of inflammatory cytokine suppressants in the present invention include JAK inhibitors that inhibit JAK phosphorylation in the JAK-STAT system downstream of IL-6 signaling, such as tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib.

[0025] The administration route, dosage, and frequency of administration of the inflammatory cytokine inhibitor vary depending on the drug and are not particularly limited. For example, an anti-IL-1β monoclonal antibody is administered by subcutaneous injection at 1 mg to 1 g once every 2 to 10 weeks. Salazosulfapyridine is orally administered at 100 mg to 2 g twice daily. There is no limitation on the timing of initiating administration of the inflammatory cytokine inhibitor; for example, administration can be initiated before the initiation of a ketogenic diet, on the same day or the day after the initiation of the ketogenic diet, or several days or weeks after the initiation of the ketogenic diet. Preferably, administration is initiated on the same day or the day after the initiation of the ketogenic diet, or several days or weeks after the initiation of the ketogenic diet. More preferably, administration is initiated several days or weeks after the initiation of the ketogenic diet. The formulation containing the inflammatory cytokine inhibitor is not particularly limited as long as it has a dosage form appropriate for the desired administration route, etc. The formulation may contain pharmaceutically acceptable excipients and stabilizers. The formulation may also contain other active ingredients.

[0026] The ketogenic dietary composition of the present invention contains a high lipid content, and the lower limit of the lipid content can be about 55% by mass, preferably about 60% by mass, and more preferably about 70% by mass or about 80% by mass, based on the total solid content (components excluding water) contained in the composition. The upper limit of the lipid content can be about 95% by mass or about 90% by mass, based on the total solid content contained in the composition. These lower and upper limits can be arbitrarily combined, and the lipid content of the ketogenic dietary composition of the present invention can be, for example, about 55% to about 95% by mass or about 55% to about 90% by mass, based on the total solid content.

[0027] The lipid content in the ketogenic dietary composition of the present invention can be expressed as the ratio of lipid energy (kcal) to the total energy (kcal) of the composition (% energy, sometimes simply referred to as "%" herein). The lower limit of this ratio can be about 70%, preferably about 80%, more preferably about 85% or about 90%, and the upper limit of this ratio can be about 95% or about 90%. These lower and upper limits can be arbitrarily combined, and the lipid ratio (ratio of lipid energy to the total energy of the composition) in the ketogenic dietary composition of the present invention can range, for example, from about 70% to about 95% or from about 80% to about 90%.

[0028] The lipids contained in the ketogenic dietary composition of the present invention include short-chain fatty acid oils, medium-chain fatty acid oils, long-chain fatty acid oils, and any combination thereof. The ketogenic dietary composition of the present invention preferably has a high medium-chain fatty acid oil content. For example, the lower limit of the ratio of medium-chain fatty acid oils to the total lipids can be about 10% by mass, about 20% by mass, about 30% by mass, about 40% by mass, about 50% by mass, about 60% by mass, about 70% by mass, or about 80% by mass, and the upper limit can be about 90% by mass, about 80% by mass, about 70% by mass, or about 60% by mass. These lower and upper limits can be combined in any desired manner, and the range of the ratio of medium-chain fatty acid oils to total lipids in the ketogenic dietary composition of the present invention can be, for example, about 10% by mass to about 90% by mass, about 20% by mass to about 80% by mass, about 30% by mass to about 80% by mass, or about 40% by mass to about 70% by mass, and preferably about 50% by mass to about 60% by mass.

[0029] In the present invention, "medium-chain fatty acid oils" refers to oils and fats in which the fatty acids constituting the oils and fats have a medium chain length, and are also called MCT (Medium Chain Triglyceride) or medium-chain fatty acid triglycerides. These oils and fats typically contain fatty acids having 6 to 12 carbon atoms, preferably 8 to 12 carbon atoms, 8 to 11 carbon atoms, or 8 to 10 carbon atoms. They are more easily digested and absorbed than common oils and are easily converted into energy. Examples of medium-chain fatty acids include hexanoic acid (caproic acid; C6), octanoic acid (caprylic acid; C8), nonanoic acid (pelargonic acid; C9), decanoic acid (capric acid; C10), and dodecanoic acid (lauric acid; C12).

[0030] Medium-chain fatty acid oils are found in oils and fats contained in plants such as palm plants, including coconuts and palm fruit, and in dairy products such as milk. Medium-chain fatty acid oils extracted (including crude extraction) or refined (including crude refinement) from these oils (preferably vegetable oils such as palm kernel oil) can be used as they are or as raw materials. Alternatively, chemically synthesized products or commercially available products may be used. Examples of medium-chain fatty acid oils that can be used include Nisshin MCT oil, Nisshin MCT powder, and extra virgin coconut oil (all manufactured by The Nisshin Oillio Group, Inc.).

[0031] The ketogenic dietary composition of the present invention may have a limited carbohydrate content. The lower limit of the carbohydrate content in the ketogenic dietary composition of the present invention may be about 0% by mass or about 5% by mass based on the total solid content of the composition, and the upper limit of the carbohydrate content may be about 15% by mass or about 10% by mass based on the total solid content of the composition. These lower and upper limits may be combined arbitrarily, and the carbohydrate content relative to the total solid content (components excluding water) of the composition may range, for example, from about 0% by mass to about 15% by mass or from about 5% by mass to about 10% by mass.

[0032] In the present invention, "carbohydrate" refers to carbohydrates that are not dietary fiber, and includes monosaccharides, disaccharides, and polysaccharides. Examples of monosaccharides include glucose (grape sugar), fructose (fruit sugar), and galactose. Examples of disaccharides include maltose (malt sugar), sucrose (cane sugar), and lactose (milk sugar). Examples of polysaccharides include starch (amylose, amylopectin), glycogen, and dextrin.

[0033] The ketogenic dietary composition of the present invention preferably contains lactose as a carbohydrate, more preferably contains lactose as a carbohydrate but not glucose, and particularly preferably contains substantially only lactose as a carbohydrate. When the ketogenic dietary composition of the present invention contains lactose, the ratio of lactose to the total carbohydrate can be, for example, about 10% by mass or more, about 20% by mass or more, about 30% by mass or more, about 40% by mass or more, about 50% by mass or more, about 60% by mass or more, about 70% by mass or more, about 80% by mass or more, or about 90% by mass or more, and preferably, all of the carbohydrate (100% by mass of the carbohydrate) can be lactose.

[0034] "Carbohydrate" as used in the context of the ketogenic dietary composition, ketogenic diet and ketogenic diet of the present invention refers to carbohydrates other than dietary fiber, i.e., sugars, and "carbohydrate" and "sugars" are used interchangeably.

[0035] The ketogenic dietary composition of the present invention may also contain protein. The lower limit of the protein content in the ketogenic dietary composition of the present invention may be about 5% by mass or about 10% by mass based on the total solid content of the composition, and the upper limit of the protein content may be about 40% by mass or about 20% by mass based on the total solid content of the composition. These lower and upper limits may be combined arbitrarily, and the protein content relative to the total solid content of the composition may be, for example, about 5% to about 40% by mass or about 10% to about 20% by mass.

[0036] A preferred embodiment of the ketogenic dietary composition of the present invention includes a composition containing, relative to the total solid content of the composition, about 25% to about 40% by mass of long-chain fatty acid oils and fats, about 30% to about 50% by mass of medium-chain fatty acid oils and fats, about 0% to about 15% by mass of carbohydrates, and about 10% to about 30% by mass of protein.

[0037] A preferred embodiment of the ketogenic dietary composition of the present invention is a composition having a ketone ratio (lipid / (protein + carbohydrate)) (mass ratio) of about 1 or more, preferably 2 or more, and more preferably 2.5 or more, and the upper limit of the ketone ratio can be, for example, about 4 or about 3.5. The ketone ratio of the ketogenic dietary composition of the present invention can be adjusted by the mode of ingestion of the composition of the present invention.

[0038] More preferred embodiments of the ketogenic dietary composition of the present invention include Ketone Formula (817-B; manufactured by Meiji Co., Ltd.; hereinafter, simply referred to as Ketone Formula (registered trademark)) and compositions with equivalent compositions. Also preferred are compositions based on Ketone Formula but with modified compositions. Examples include Ketone Formula compositions with further reduced carbohydrate and / or protein content, Ketone Formula compositions with each component independently modified by approximately ±5%, ±10%, ±15%, ±20%, or ±25%, and kit compositions in which two or three components of Ketone Formula or modified compositions are packaged separately and prepared immediately before use. The composition of Ketone Formula is as shown in Tables 1 and 2 below.

[0039] The composition of the present invention can be suitably used in a ketogenic diet in combination with medium-chain fatty acid oils and fats.

[0040] The composition of the present invention can be provided as a food composition for a ketogenic diet. When used for mammals other than humans, the term "food" can be used in the sense of including feed.

[0041] The composition of the present invention can be provided as a pharmaceutical composition for ketogenic diet therapy. The composition of the present invention can be orally ingested as a therapeutic diet. In another embodiment, the composition of the present invention can be administered intranasally or via a gastrostomy tube.

[0042] The composition of the present invention can be used in combination with an inflammatory cytokine inhibitor for ketogenic diet therapy to treat cancer, including tumor growth inhibition, tumor shrinkage, maintenance of tumor size, cancer recurrence inhibition, metastasis inhibition, symptom relief and remission, slowing the rate of symptom progression, and enhancing the effectiveness of other cancer treatments.

[0043] The composition of the present invention can be used to treat various cancers. It is suitable for use in the treatment of progressive cancers and refractory cancers that are difficult to treat with other treatment methods. Refractory cancers include terminal cancers at stage 4 (stage IV), cancers that are difficult to resect, cancers that are difficult to detect early, and metastatic cancers, such as pancreatic cancer, breast cancer, multiple bone metastases, malignant pharyngeal space tumors, malignant breast tumors, chondrosarcoma, astroblastoma, nasopharyngeal cancer, and abdominal wall liposarcoma.

[0044] The composition of the present invention can be ingested in combination with an inflammatory cytokine suppressor for the treatment of cancer. This treatment method is highly effective and can be used as a sole treatment, but it can also be carried out in parallel with other cancer treatments. The other cancer treatments are not limited as long as they are used in cancer treatment. Examples include surgical therapy (e.g., resection / excision), chemotherapy, and radiation therapy. By combining treatment with the composition of the present invention combined with an inflammatory cytokine suppressor with other cancer treatments, the effectiveness of the cancer treatment can be enhanced.

[0045] Surgical therapy involves removing the cancerous lesion, and if there is metastasis to the surrounding tissues or lymph nodes of the organ, removing these as well, or removing the organ itself. Even for early-stage cancer or cancer that has progressed to a certain extent, surgical therapy is actively performed if it is in a state where it can be removed. Methods that minimize the area of ​​removal as much as possible (reduced surgery), as well as laparoscopic surgery using an endoscope (small camera) and thoracic surgery have also been developed, and these are also included in surgical therapy.

[0046] Chemotherapy is a treatment method that mainly uses anticancer drugs to kill cancer cells or suppress their growth. Anticancer drugs can be administered by infusion, injection, or orally. Because they circulate throughout the body through the blood, they are effective against even the smallest cancer tissues that have metastasized. Hormone therapy (endocrine therapy) is also included in this type of chemotherapy.

[0047] Radiation therapy is a localized treatment that kills cancer cells by irradiating the cancerous lesion with radiation. Advances in pre-treatment testing technology and irradiation methods have made it possible to accurately measure the size and location of the cancer and then irradiate only that area in a concentrated manner. In addition to "external irradiation," which irradiates the body from outside, there are other types of treatments, such as "brachytherapy," in which needles or capsules sealed with a radioactive substance are inserted into the lesion, and "internal radioisotope therapy," in which radioactive substances are administered by injection or orally. X-rays are often used as the radiation source for radiation therapy, but proton therapy and heavy particle (carbon ion) therapy, which use particle beams, can also be used.

[0048] Subjects to which the composition of the present invention can be administered include any mammal, such as rodents such as mice, rats, hamsters, and guinea pigs; lagomorphs such as rabbits; ungulates such as pigs, cows, goats, horses, and sheep; carnivores such as dogs and cats; and primates such as humans, monkeys, rhesus monkeys, cynomolgus monkeys, marmosets, orangutans, and chimpanzees. Mammals are preferably primates or rodents (such as mice), more preferably primates, and even more preferably humans.

[0049] The frequency of intake of the composition of the present invention is usually three divided doses per day, but it is understood that it may also be twice or once a day, or conversely, four or five times a day. Preferably, different formulations are used for the induction phase (usually the first week), transition phase (usually two weeks to three months), and maintenance phase (usually after three months), and therefore the intake method or administration method may be changed as appropriate or may be the same.

[0050] The present invention may also relate to a combination for cancer treatment comprising an inflammatory cytokine suppressor and a ketogenic diet composition. The combination is a combination of an inflammatory cytokine suppressor and a ketogenic diet composition. The present invention includes a combined use of an inflammatory cytokine suppressor and a ketogenic diet composition. The present invention also includes a mixture of an inflammatory cytokine suppressor and a ketogenic diet composition. The present invention also includes a kit of an inflammatory cytokine suppressor and a ketogenic diet composition.

[0051] The present application includes an invention relating to a composition for cancer treatment containing an inflammatory cytokine suppressor, which is used in combination with a ketogenic diet composition. The composition containing an inflammatory cytokine suppressor may contain the inflammatory cytokine suppressor and other ingredients, such as other active ingredients, excipients, stabilizers, etc.

[0052] The present application includes an invention relating to a composition for enhancing the anti-cancer effect of ketogenic diet therapy, which comprises an inflammatory cytokine inhibitor. The composition has the effect of enhancing the anti-tumor effect of ketogenic diet therapy. The composition for enhancing the anti-cancer effect, which comprises an inflammatory cytokine inhibitor, may comprise the inflammatory cytokine inhibitor and other ingredients, such as other active ingredients, excipients, stabilizers, etc.

[0053] This application includes an invention relating to a method of treating cancer that involves administering a pro-inflammatory cytokine inhibitor and a ketogenic diet.

[0054] A method for treating cancer comprising administering an inflammatory cytokine inhibitor and a ketogenic diet is a method for treating cancer that combines administration of an inflammatory cytokine inhibitor and a ketogenic diet, and includes a method for treating cancer using a ketogenic diet in combination with administration of an inflammatory cytokine inhibitor.

[0055] In the ketogenic diet of the present invention, the lower limit of the daily lipid intake, based on a body weight of 50 kg, can be 80 g, 90 g, 100 g, 110 g, 115 g, 120 g, 125 g, 130 g, 135 g, 140 g, 145 g, or 150 g. The upper limit can be 180 g, 170 g, 160 g, 150 g, or 140 g. These lower and upper limits can be combined in any manner. In the ketogenic diet, based on a body weight of 50 kg, the daily lipid intake can be 80 g to 180 g, 90 g to 170 g, 100 g to 160 g, 110 g to 150 g, or 120 g to approximately 140 g.

[0056] In the ketogenic diet of the present invention, carbohydrate intake is restricted. Based on a body weight of 50 kg, the upper limit of the amount of carbohydrates per day can be 90 g, 80 g, 70 g, 60 g, 50 g, 40 g, 35 g, 30 g, 25 g, 20 g, 15 g, or 10 g, and the lower limit can be 5 g, 10 g, 15 g, 20 g, or 25 g. These lower and upper limits can be combined in any manner, and in the ketogenic diet, based on a body weight of 50 kg, the daily carbohydrate intake can be 5 g to 90 g, 10 g to 50 g, or 10 g to 30 g.

[0057] In a preferred embodiment of ketogenic diet therapy, carbohydrate intake may be severely restricted during the initiation phase, for example, to 20 g / day or less, or even 10 g / day or less. Strict carbohydrate restriction during the initiation phase allows for rapid induction of blood ketone bodies (acetoacetate, β-hydroxybutyrate), thereby improving the prognosis of cancer patients. However, because the nutritional intake during the initial phase differs from conventional eating habits, it can be difficult to maintain. Gradually reducing the carbohydrate restriction can enable continuation of a carbohydrate-restricted, high-fat diet and achieve therapeutic benefits. Therefore, it is preferable to gradually reduce the carbohydrate restriction (carbohydrate intake) from a strict initial level (e.g., 10 g / day or less). For example, the initial initiation level can be approximately 5 to approximately 15 g / day, maintained at approximately 15 to approximately 25 g / day in the second phase, and continued at approximately 25 to approximately 35 g / day in the final phase.

[0058] A method for treating cancer using a ketogenic diet may include the following steps. The steps below are described assuming a body weight of 50 kg. (1) Induction phase (usually the first approximately one week, but this can be extended or shortened as needed, and may last from several days to several weeks): The subject is provided with nutritional intake of approximately 1500±500 kcal per day, approximately 110-170 g of fat, approximately 35-85 g of protein, approximately 5-40 g of carbohydrates (preferably 5 g-15 g), and a ketone ratio of 2±1. Other nutrients may be consumed without restriction, and trace elements and vitamins may be appropriately ingested using supplements, etc., if necessary. (2) Transition phase (usually from the second week to the third month, but this can be adjusted as needed, with a delay of several weeks acceptable): The subject is provided with nutritional intake targeting approximately 1200 to approximately 2000 kcal per day, approximately 90 to 170 g of fat, approximately 45 to 95 g of protein, approximately 10 to 40 g of carbohydrates (preferably 10 to 30 g), and a ketone ratio of 1 to 2. Preferably, the subject is instructed to maintain a blood acetoacetate concentration of 400 μmol / L or less and a blood β-hydroxybutyrate concentration of 800 μmol / L or more, with the goal of 800 μmol / L or more of acetoacetate and 1600 μmol / L or more of β-hydroxybutyrate. Preferably, the subject is provided with nutritional intake using medium-chain fatty acid oils and the ketogenic dietary composition of the present invention. More preferably, the subject is provided with nutritional intake using medium-chain fatty acid oils and a ketone formula or a modified composition thereof. Administration of an inflammatory cytokine inhibitor is initiated once blood ketone body concentrations have stabilized. (3) Maintenance phase (after the transition phase, usually from the third month onward): The subject is provided with nutrition in the same manner as in (2) above, with a single carbohydrate intake of approximately 30 g or less (preferably 5 g to 15 g) and a daily intake of approximately 50 g or less, preferably 30 g or less. Administration of the inflammatory cytokine inhibitor is continued.

[0059] As used herein, "tumor" and "cancer" have the same meaning. For example, "anti-tumor effect" has the same meaning as "anti-cancer effect."

[0060] In this specification, "mass" is a value calculated as solid content unless otherwise specified. Furthermore, in this specification, "solid content" means components excluding water.

[0061] The daily intake of grams of lipids, carbohydrates, or proteins described herein is based on a real body weight of 50 kg. As used herein, "real body weight" refers to actual body weight. Those skilled in the art will understand that the daily intake in grams may vary depending on the real body weight. For example, if the real body weight is 80 kg, it will be understood that the intake will be 1.6 times the intake based on a real body weight of 50 kg.

[0062] In this specification, the range "X to Y" means "X or more, Y or less." Furthermore, unless otherwise specified, a numerical value followed by "about" indicates the significant digits. Furthermore, a numerical value indicated as a "lower limit" includes both a value "greater than" that numerical value and a value "greater than" that numerical value. Furthermore, a numerical value indicated as an "upper limit" includes both a value "less than" that numerical value and a value "below" that numerical value.

[0063] The present invention will be explained in more detail below, but the present invention is not limited to these examples.

[0064] The ketogenic diet is explained to cancer patients undergoing standard treatment (surgery, chemotherapy, radiation therapy, etc.) and is initiated after obtaining their consent. The following steps are described assuming an actual body weight of 50 kg.

[0065] (a) During the first week, calorie intake will be 30 kcal / kg based on actual body weight, with carbohydrate intake targeted at 10 g or less per day. Specifically, assuming a body weight of 50 kg, the daily calorie intake will be 1500 kcal, with a ratio of 140 g fat, 60 g protein, and 10 g carbohydrate. The target ketone ratio will be 2, with unlimited intake of other nutrients. Necessary trace elements and vitamins will be provided as appropriate using supplements, etc. When introducing the ketogenic diet, the patient will consume meals according to a menu created by a nutritionist.

[0066] (b) From week 2 to month 3, blood ketone levels were used as a guide to adjust carbohydrate intake and medium-chain fatty acid intake via Ketone Formula and MCT oil. Blood ketone levels were instructed to maintain acetoacetate and beta-hydroxybutyrate levels above 500 μmol / L and above 1000 μmol / L, respectively, with the goal of achieving acetoacetate and beta-hydroxybutyrate levels above 1000 μmol / L and above 2000 μmol / L. Daily carbohydrate intake was limited to 20 g or less, with a daily calorie intake of 1400-1600 kcal, with a ratio of 120-140 g fat, 70 g protein, and 20 g carbohydrate. Ketone Formula (817-B, Meiji Co., Ltd.) and medium-chain fatty acid oil (MCT oil, Nisshin Oillio Group, Inc.) were used to adjust blood ketone levels and provide calories. The composition of Ketone Formula (817-B) is shown in Table 1. Once the blood ketone body concentration has stabilized, administration of an inflammatory cytokine inhibitor will begin.

[0067]

[0068] In addition to the main ingredients listed above, Ketone Formula (817-B) contains vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, pantothenic acid, niacin, folic acid, calcium, magnesium, sodium, potassium, phosphorus, chlorine, iron, copper, and zinc, and its composition is shown in Table 2.

[0069]

[0070] (c) From the third month onwards, carbohydrate intake should be limited to 5-15g per meal and 30g or less per day, with other restrictions as in (b). Administration of inflammatory cytokine inhibitors should be continued.

[0071] <Test Example 1> Antitumor effect of ketogenic diet therapy in cancer-implanted mice

[0072] The antitumor effect of the ketogenic diet was evaluated using tumor-bearing mice subcutaneously implanted with mouse colon cancer Colon-26 cells. Cisplatin (CDDP) was used as a positive control, and the antitumor effect of the combination of the ketogenic diet and CDDP was also evaluated.

[0073] Mouse colon cancer Colon-26 cells were subcutaneously transplanted (5 × 10) into the abdominal cavity of a mouse CD2F1 / Slc (8-week-old, male, Japan SLC). ４ Seven days after transplantation (Day 0), the mice were divided into 5 groups of 12 mice each. A high-dose CDDP group was used as a positive control.

[0074]

[0075] The mice were given Ketone Formula (817-B, Meiji Co., Ltd.) as a ketogenic diet and AIN93G (EPS Ekishin Co., Ltd.) as a normal diet ad libitum starting on the day of group assignment (Day 0). On Days 0, 7, and 14 (Days 0, 7, and 14) after group assignment, CDDP was administered intravenously at the doses shown in Table 3 to the ketogenic diet-CDDP combination group, the CDDP administration group, and the high-dose CDDP administration group, while the control group received vehicle alone. The study period was 21 days (until Day 21). Tumor volumes were measured using digital calipers (model: CD-15AX, Mitutoyo Corporation) on Days 2, 6, 9, 13, 16, and 21. The results are shown in Figure 1. From Day 13 onwards, the tumor volume in the ketogenic diet-CDDP combination group was shown to be significantly lower than that in the CDDP administration group. On Day 21, tumors were excised and tumor weight in each group was measured using an electronic balance (model: GX-2000, A&D Co., Ltd.). The tumor weight in the ketogenic diet-CDDP combination group was shown to be significantly lower than that in the CDDP administration group (Figure 2). It was revealed that the combination of CDDP administration and a ketogenic diet suppressed tumor growth more than CDDP administration alone.

[0076] Test Example 2 Histopathological evaluation

[0077] To confirm the involvement of the ketogenic diet in cell death, histopathological evaluation was performed. Tumors from each group on Day 21 of Test Example 1 were collected and stained for Cleavage Caspase-3 using Rabbit Polyclonal Cleavage Caspase-3 antibody (abcam). Five randomly taken images of tumor cells were taken at 400x magnification, and the stained apoptotic cells were counted and separated into 1 mm sections. ２The average value per 1000 cells was calculated. The results are shown in Figure 3. Apoptosis was suppressed by high-dose CDDP administration (5.0 mg / kg), but the suppression of apoptosis was alleviated by ketogenic diet intervention. The ketogenic diet demonstrated an apoptosis-inducing effect.

[0078] <Test Example 3> Comprehensive genetic analysis of cancer-implanted mice

[0079] Blood, liver, cancer tissue, and muscle tissue were extracted from 59 mice from each group that survived on Day 21 of Test Example 1, and comprehensive genetic analysis was performed. RNA-Seq analysis was performed at Takara Bio Inc. Sample quality was confirmed by electrophoresis, and full-length double-stranded DNA derived from total RNA was synthesized using the SMART method. The amplified double-stranded cDNA was fragmented and adapter sequences were added to both ends by a tagmentation reaction using a transposon to create a DNA library that served as a sequencing template. RNA amplification was performed using the SMART-Seq v4 Ultra Low Input RNA Kit for Sequencing. The Nextera XT DNA Sample Preparation Kit was used to prepare the DNA library. Using the NovaSeq system (Illumina), 150-base double-end analysis (equivalent to 4 billion reads / 600 Gb per sample) was performed. Sequencing was performed using an Illumina sequencer, and the base sequence (read sequence) was obtained using the software provided with the sequencer. The base sequence (read sequence) was classified based on the tag sequence. Cancer tissue data was extracted from the delivered data, normalized, and expression levels were analyzed.

[0080] Gene expression levels in cancer tissues from the control group and those from the high-dose CDDP group were compared, and 508 genes whose expression was altered by CDDP administration (FC (Fold Change) < 0.5 or FC > 2, 364 genes with increased expression and 144 genes with decreased expression) were extracted.

[0081] Next, the gene expression levels of the cancer tissues from the CDDP-administered group were compared with those from the ketogenic diet-CDDP combination group, and 106 genes (FC<0.5 or FC>2, 95 genes with increased expression and 11 genes with decreased expression) were extracted from the 508 identified genes whose expression changed with the ketogenic diet and were expected to have antitumor effects.

[0082] Furthermore, analysis of the signaling pathways involving the extracted 106 genes using Wikipathways suggested that the ketogenic diet is involved in cytokine and chemokine signaling (Table 4).

[0083]

[0084] Furthermore, the results of pathway analysis for "Mm_Type_II_interferon_signaling_(IFNG)_WP1253_71753" in Table 4 are shown in Figures 4 and 5. Figure 4 shows the expression status of each gene in the pathway in the CDDP-administered group. Figure 5 shows the expression status of each gene in the pathway in the ketogenic diet-CDDP combined group. In Figures 4 and 5, a change in color from yellow to red indicates a higher level of expression. In the grayscale, darker gray indicates a higher level of expression. A comparison of Figures 4 and 5 revealed that the expression levels of genes marked with an * were increased by a ketogenic diet. The genes whose expression levels were increased were Irf9 (Interferon Regulatory Factor 9), Cxcl10 (C-X-C motif chemokine ligand 10, also known as Interferon gamma-induced protein 10 (IP-10)), Il1b (Interleukin-1β), Cybb (Cytochrome B-245, Beta Polypeptide), and Isg15 (Interferon-stimulated gene 15). It has been shown that a ketogenic diet enhances the activity of interferon signals.

[0085] Furthermore, the results of pathway analysis for "Mm_Apoptosis_WP1254_89986" in Table 4 are shown in Figures 6 and 7. Figure 6 shows the expression status of each gene in the pathway in the CDDP-administered group. Figure 7 shows the expression status of each gene in the pathway in the ketogenic diet-CDDP combined group. A change in color from yellow to red indicates a higher level of expression. In the grayscale, darker gray indicates a higher level of expression. A comparison of Figures 6 and 7 revealed that the expression levels of genes marked with an * were increased by a ketogenic diet. The genes whose expression levels were increased were Gzmb (Granzyme B), Prf1 (Perforin 1), and Irf7 (Interferon Regulatory Factor 7). It was shown that a ketogenic diet activates signals to caspase 3.

[0086] Test Example 4 Comprehensive functional analysis using human peripheral blood mononuclear cells (PBMC)

[0087] To elucidate the mechanism of the antitumor effect of a ketogenic diet, we performed comprehensive genetic analysis of peripheral blood mononuclear cells (PBMCs) from cancer patients before and three months after the introduction of a ketogenic diet. Cancer patients consented to the ketogenic diet and underwent blood sampling. PBMCs were isolated from blood samples taken from 50 patients undergoing the ketogenic diet before and three months after the introduction of the ketogenic diet. Of the 37 clinically evaluable cases, 31 remaining evaluable specimens were used for analysis (1 case of endometrial cancer, 1 case of peritoneal cancer, 7 cases of colorectal cancer, 5 cases of breast cancer, 2 cases of otolaryngological cancer, 2 cases of sarcoma, 3 cases of lung cancer, 1 case of ovarian cancer, 1 case of brain tumor, 1 case of uterine leiomyosarcoma, 4 cases of pancreatic cancer, 1 case of bile duct cancer, 1 case of gastric cancer, and 1 case of prostate cancer; all stage 4 cancers). The therapeutic effect three months after the introduction of the ketogenic diet was assessed by RECIST (Response Evaluation Criteria in Solid Tumors), with one patient achieving a complete response (CR), eight a partial response (PR), 12 stable disease (SD), and 10 progressive disease (PD). Patients were divided into three groups based on their therapeutic effect: the response group (nine patients with complete response (CR) and partial response (PR)), the stable group (12 stable disease (SD)), and the progress group (10 progressive disease (PD)).

[0088] From the RNA-Seq analysis data of mice in Test Example 3, genes whose expression was altered by high-dose CDDP administration were re-extracted by changing the fold change (FC), and 1,462 genes were extracted. Genes whose expression was altered by a ketogenic diet were further extracted in the same manner as in Test Example 3, and 181 genes (177 genes by gene symbol) were extracted. 168 genes (gene symbols) that correspond to the 177 genes (gene symbols) and are expected to have antitumor effects were analyzed.

[0089] We analyzed the expression changes of these 168 genes in PBMCs from patients before and 3 months after the introduction of a ketogenic diet using RNA-Seq. 12 genes were identified by extraction with a fold change (FC) of >1.25. The identified genes were CD9 (CD9 Molecule), IFIT3 (Interferon-Induced Protein With Tetratricopeptide Repeats 3), IFIT1 (Interferon-Induced Protein With Tetratricopeptide Repeats 1), IRF7 (Interferon Regulatory Factor 7), CXCL10 (CXC Motif Chemokine Ligand 10), IL1b (Interleukin 1 Beta), PTGS2 (Prostaglandin-Endoperoxide Synthase 2), RALGDS (Ral Guanine Nucleotide Dissociation Stimulator), PLAUR (Plasminogen Activator, Urokinase Receptor), MORF4L2 (Mortality Factor 4 Like 2), SPON2 (Spondin 2), and TRAPPC1 (Trafficking Protein Particle Complex Subunit 1).

[0090] Clustering based on these gene expressions showed that improved patients (Response group) were present in a different cluster from non-improved patients, and that improved patients had a unique gene expression pattern.

[0091] Furthermore, analysis of the signal transduction pathways involving the extracted 12 genes using Wikipathways suggested that the ketogenic diet was involved in cytokine signaling (Table 5).

[0092]

[0093] Furthermore, NLP analysis of the 12 extracted genes suggested that the ketogenic diet is involved in the immune response via PTGS2-IL1b-CXCL10 and cytokine signaling via IL1b-CXCL10-IFIT1, and that 8 of the 12 identified genes were related to PTGS2 (Figure 8).

[0094] The time course of expression of these eight genes was analyzed in three patient groups (Response group, Stable group, and Progress group). The results are shown in Figure 9. CXCL10, which is downstream of PTGS2, showed increased expression in the Response group (improved patient group), behaving differently from the other non-improved patients. These results suggest that the PTGS2-to-IL1b change is a unique change during ketogenic diet therapy for cancer.

[0095] Test Example 4: Inhibition of tumor growth by IL-1β inhibition

[0096] Mouse colon cancer Colon-26 cells were subcutaneously transplanted (5 × 10) into the abdominal cavity of a mouse CD2F1 / Slc (8-week-old, male, Japan SLC). ５ Seven days after transplantation, the mice were divided into four groups of 12 mice each.

[0097]

[0098] Anti-IL-1β antibody (anti-IL-1β, IL-1F2 antibody, affinity-purified (goat), R&D Systems) and control antibody (normal goat IgG, AB-108-C, R&D Systems) were intraperitoneally administered at 50 μg / body on Day 3 after group assignment. AIN93G (EPS Ekishin Co., Ltd.) was given as a normal diet, and Ketone Formula 817-B (Meiji Co., Ltd.) was given as a ketogenic diet ad libitum from the day of group assignment. The study period was 17 days. Tumor volume was measured using a digital caliper (model: CD-15AX, Mitutoyo Corporation) on Days 3, 7, 10, 14, and 17. The results are shown in Figure 10. Fourteen days after the start of the ketogenic diet, the ketogenic diet + anti-IL-1β antibody group was shown to have significantly lower tumor volume than the normal diet + control antibody group and the normal diet + anti-IL-1β antibody group.

[0099] Tumor weight on Day 17 was measured using an electronic balance (model: GX-2000, A&D Co., Ltd.). The results are shown in Figure 11. The ketogenic diet + anti-IL-1β antibody administration group showed significantly lower tumor weight than the normal diet + anti-IL-1β antibody administration group. This demonstrates that tumor growth can be suppressed by combining a ketogenic diet with an anti-IL-1β antibody.

[0100] The molecular mechanism of synergistic expression of CRP, an acute inflammatory protein, by the combination of the inflammatory cytokines IL-1β and IL-6 has been elucidated, and the JAK-STAT system, downstream of IL-6, is essential for this synergistic expression (Nishikawa T et al., J Immunol 2008). High CRP levels are known to be associated with poor prognosis in patients on a ketogenic diet (Patent Document 2). Therefore, inhibition of IL-6 and inhibition of the JAK-STAT system are expected to have similar effects to those of IL-1β inhibition.

[0101] It is expected that this invention will lead to improvements in the quality of life and survival rates of many cancer patients.

Claims

1. A composition for cancer treatment comprising a ketogenic dietary composition used in combination with an inflammatory cytokine inhibitor.

2. The composition of claim 1 , wherein the ketogenic dietary composition contains lipids.

3. The composition according to claim 2, wherein the lipid content relative to the total solid content of the ketogenic dietary composition is 55% by mass or more.

4. The composition according to claim 3, wherein the carbohydrate content of the total solid content contained in the ketogenic diet composition is 0 to 15% by mass.

5. The composition of claim 2 , wherein the lipid comprises a medium-chain fatty acid oil.

6. The composition according to any one of claims 1 to 5, wherein the proinflammatory cytokine inhibitor is an IL-1 inhibitor, an IL-6 inhibitor, or a TNF-α inhibitor.

7. The composition according to any one of claims 1 to 5, wherein the proinflammatory cytokine inhibitor is an IL-1β inhibitor.

8. The composition of claim 7, wherein the IL-1β inhibitor is an anti-IL-1β antibody.

9. The composition according to any one of claims 1 to 5, which is a pharmaceutical composition.

10. A combination for the treatment of cancer comprising an inflammatory cytokine suppressor and a ketogenic dietary composition.

11. A composition for cancer treatment comprising an inflammatory cytokine inhibitor used in combination with a ketogenic dietary composition.

12. A composition for enhancing the anti-cancer effect of a ketogenic diet, comprising an inflammatory cytokine inhibitor.