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WO2019169179A1 - Augmentation de l'efficacité de traitements anticancéreux à l'aide de compositions à base de probiotiques - Google Patents

Augmentation de l'efficacité de traitements anticancéreux à l'aide de compositions à base de probiotiques Download PDF

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WO2019169179A1
WO2019169179A1 PCT/US2019/020121 US2019020121W WO2019169179A1 WO 2019169179 A1 WO2019169179 A1 WO 2019169179A1 US 2019020121 W US2019020121 W US 2019020121W WO 2019169179 A1 WO2019169179 A1 WO 2019169179A1
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cancer
lactobacillus
probiotic
formulation
probiotics
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Kim SHAFER
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
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    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
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    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
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    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4873—Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/54—Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A61K2035/115—Probiotics

Definitions

  • the invention pertains to the field of cancer therapy. Specifically, the invention pertains to methods and formulations of probiotics with digestive enzymes to increase efficacy of cancer therapies and/or for reducing the toxicity and adverse events associated with said cancer therapies.
  • chemotherapy-associated diarrhea occurs in 50-80% of cancer patients depending on the chemotherapy regimen that is administered [1, 2].
  • Some chemotherapy regimens for example, those utilizing irinotecan, fluorouracil, and leucovorin, can lead to potentially life-threatening gastrointestinal syndrome.
  • Adverse events include diarrhea (including Grades 3 and 4 severe diarrhea), nausea, vomiting, fatigue, malaise, leukopenia, and neutropenia can occur, to name a few. These adverse events can lead to dire medical consequences.
  • Diarrhea and nausea that are associated with cancer therapy can lead to dehydration, electrolyte imbalances, malnutrition, pain, and bleeding as a result of damge to the gastrointestinal tract.
  • patients have low immune function and inflammation.
  • Cancer treatments can therefore render patients more susceptible to various infections, which can themselves cause or exacerbate some of the abovementioned adverse events.
  • infections with Clostridium difficile are twice as common in hospitalized cancer patients as compared to other inpatients [3].
  • the antibiotics that are prescribed to treat these infections can themselves cause symptoms such as diarrhea; for example, for treating C. difficile, these antibodies may include vancomycin, fidaxomicin, or metronidazole.
  • the microbiome in the human gut is composed of 500-1000 distinct bacterial species and up to 10 14 total bacteria that are responsible for digestive health, including the assurance of nutrient and vitamin bioavailability and energy metabolism, and also have a significant impact on the immune system of a subject.
  • intestinal microorganisms may determine the outcome of cancer treatments and are also directly impacted by the treatments, often in a negative manner.
  • Gut dysbiosis whereby the composition of microorganisms is altered and often their diversity is reduced, predicted resistance to immunotherapeutic interventions such as checkpoint inhibitors in melanoma patients [5].
  • a low diversity of commensal microorganisms was also associated with immune suppression in cancer patients [6].
  • 5-fluoro uracil a first line agent for the treatment of metastatic colorectal agent, which is associated with severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. 5-FU diminishes bacterial richness and diversity in the gut, leading to reduced overall abundance of important phyla involved in normal microbial metabolism.
  • Aspect 1 A method of increasing efficacy of a cancer therapy comprising administration of a probiotic composition.
  • Aspect 2 The method of aspect 1, wherein said probiotic composition comprises one of more probiotics.
  • Aspect 3 The method of aspect 2, wherein said probiotic composition is comprised of one or more probiotics selected from a group comprising of: a)
  • Bifidobacterium infantis b) Bifidobacterium bifidum; c) Lactobacillus acidophilus; d) Lactobacillus salivarius; e) Lactobacillus plantarum; f) Lactobacillus rhamnosus; g) Bifidobacterium longum; h) Lactobacillus casei; and i) Lactobacillus paracasei.
  • Aspect 4 The method of aspect 1, wherein said probiotic composition comprises the addition of digestive enzymes to said probiotics
  • Aspect 5 The method of aspect 4, wherein said digestive enzymes are selected from a group comprising of: a) amylase; b) glucoamylase; c) lipase; d) bromelain; e) maltase; f) lactase; g) hemicellulose; h) xylanase; i) papain, and j) invertase.
  • Aspect 6 The method of aspect 1, wherein said cancer therapy is one or more therapies selected from a group comprising of: a) immunotherapy; b)
  • Aspect 7 The method of aspect 1, wherein augmentation of efficacy of said cancer therapy is reduction of toxicity associated with said cancer therapy.
  • Aspect 8 The method of aspect 1, wherein said probiotic composition is administered in a manner to augment immunogenic death of tumor cells.
  • Aspect 9. The method of aspect 8, wherein said immunogenic death of tumor cells is associated with release of HMGB-l from tumors.
  • Aspect 10 The method of aspect 8, wherein said immunogenic death of tumor cells is elicited by radiation therapy and augmented by treatment with said probiotic composition.
  • Aspect 11 The method of aspect 10, wherein said radiation therapy is capable of triggering an abscopal effect.
  • Aspect 12 The method of aspect 11, wherein said abscopal effect is amplified by administration of said probiotic composition.
  • Aspect 13 The method aspect 12, wherein said abscopal effect comprises one or more of the following biological events: a) recognition of non-viable cancer cells by antigen presenting cells; b) uptake of immunogenic agents from said non-viable cancer cells by said antigen presenting cells; c) presentation of peptides derived from said immunogenic agents by said antigen presenting cells to T cells; and d) activation of T cells capable of recognizing and killing identical or substantially similar cells to said non- viable cancer cells.
  • Aspect 14 The method of aspect 13, wherein said non-viable cancer cells are the result of exposure to radiation capable of inducing DNA damage.
  • Aspect 15 The method of aspect 13, wherein said non-viable cancer cells are the result of exposure to radiation capable of inducing ceramide signalling.
  • Aspect 16 The method of aspect 13, wherein said non-viable cancer cells are the result of exposure to radiation capable of inducing caspase activation.
  • Aspect 17 The method of aspect 13, wherein said non-viable cancer cells are the result of exposure to chemotherapy capable of inducing DNA damage.
  • Aspect 18 The method of aspect 13, wherein said non-viable cancer cells are the result of exposure to chemotherapy capable of inducing DNA damage.
  • Aspect 19 The method of aspect 13, wherein said antigen presenting cells are monocytes.
  • Aspect 20 The method of aspect 13, wherein said antigen presenting cells are macrophages.
  • Aspect 21 The method of aspect 13, wherein said antigen presenting cells are B cells.
  • Aspect 22 The method of aspect 13, wherein said antigen presenting cells are endothelial cells.
  • Aspect 23 The method of aspect 13, wherein said antigen presenting cells are dendritic cells.
  • Aspect 24 The method of aspect 13, wherein said dendritic cells are myeloid dendritic cells.
  • Aspect 25 The method of aspect 13, wherein said dendritic cells are lymphoid dendritic cells.
  • Aspect 26 The method of aspect 13, wherein said immunogenic agents are agents capable of acting as tumor antigens.
  • Aspect 27 The method of aspect 13, wherein said immunogenic agents are capable of stimulating a“danger signal” to the immune system.
  • Aspect 28 The method of aspect 27, wherein said danger signal comprises activation of a toll like receptor.
  • Aspect 29 The method of aspect 28, wherein said toll like receptor is selected from a group comprising of TLR 1-9.
  • Aspect 30 The method of aspect 13, wherein said presentation of peptides is accomplished by loading of peptides into MHC I or MHC II.
  • Aspect 31 The method of aspect 30, wherein said peptides presented on MHC I are involved in stimulation of CD8 T cells.
  • Aspect 32 The method of aspect 30, wherein said peptides presented on MHC I are involved in stimulation of CD4 T cells.
  • Aspect A method of preventing hematological toxicity of a cancer therapy comprising administration of a probiotic composition.
  • Aspect 34 The method of aspect 33, wherein said probiotic composition comprises one of more probiotics.
  • Aspect 35 The method of aspect 34, wherein said probiotic composition is comprised of one or more probiotics selected from a group comprising of: a)
  • Bifidobacterium infantis b) Bifidobacterium bifidum; c) Lactobacillus acidophilus; d) Lactobacillus salivarius; e) Lactobacillus plantarum; f) Lactobacillus rhamnosus; g) Bifidobacterium longum; h) Lactobacillus casei; and i) Lactobacillus paracasei.
  • Aspect 36 The method of aspect 33, wherein said probiotic composition comprises the addition of digestive enzymes to said probiotics
  • Aspect 37 The method of aspect 36, wherein said digestive enzymes are selected from a group comprising of: a) amylase; b) glucoamylase; c) lipase; d) bromelain; e) maltase; f) lactase; g) hemicellulose; h) xylanase; i) papain, and j) invertase.
  • said cancer therapy is selected from a group comprising of: a) radiotherapy; b) chemotherapy; c) immunotherapy; d) hyperthermia; and e) surgery.
  • Aspect 39 The method of aspect 33, wherein said hematopoietic toxicity is neutropenia.
  • Aspect 40 The method of aspect 33, wherein said hematopoietic toxicity is anemia.
  • Aspect 41 The method of aspect 33, wherein said hematopoietic toxicity is thrombocytopenia.
  • Aspect 42 The method of aspect 33, wherein said hematopoietic toxicity is pancytopenia.
  • Aspect 43 The method of aspect 33, wherein said hematopoietic toxicity is lymphopenia.
  • Aspect 44 The method of aspect 1 and 33, wherein said probiotic composition is a pharmaceutical composition comprising: a formulation of probiotics comprising: Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus casei, and Lactobacillus paracasei; and, a formulation of digestive enzymes comprising: amylase, glucoamylase, lipase, bromelain, maltase, lactase, hemicellulase, xylanase, papain, and invertase.
  • a formulation of probiotics comprising: Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus
  • Aspect 45 The method of aspect 44, wherein the form of composition is selected from the group consisting of a pharmaceutically acceptable: pill, a tablet, a caplet, a capsule, powder, a suspension, a gel, and a liquid.
  • Aspect 46 The method of aspect 45, wherein said probiotics are present in a total weight of 116.20 mg.
  • Aspect 47 The method of aspect 45, wherein said digestive enzymes are present in a total weight of 272.65 mg.
  • Aspect 48 The method of aspect 44, wherein said formulations of probiotics and digestive enzymes are contained in a plurality of capsules.
  • Aspect 49 The method of aspect 48, wherein said formulations of probiotics and digestive enzymes are present in the same, single, capsule.
  • Aspect 50 The method of aspect 44, wherein said probiotics are present in the following amounts: Bifidobacterium Infantis - between 5-7 billion cfu,
  • Aspect 51 The method of aspect 50, wherein said probiotics are present in the following amounts: Bifidobacterium Infantis - 6 billion cfu, Bifidobacterium Longum
  • Aspect 52 The method of Aspect 44, wherein said enzymes are present in the following amounts: hemicellulase - between 5-11 mg, xylanase - between 2-6 mg, amylase - between .5 - 2.5 mg, glucoamylase - between 30 - 70 mg, maltase - between 8
  • Aspect 53 The method of Aspect 52, wherein said enzymes are present in the following amounts: hemicellulase - 8 mg, xylanase - 3.9 mg, amylase - 1.33 mg, glucoamylase - 50 mg, maltase - 10 mg, papain - 1.7 mg, bromelain - 18 mg, lipase - 25 mg, invertase - 1.5 mg, and lactase - 9.5 mg.
  • Aspect 54 The method of aspects 1 and 33, wherein said probiotic composition is a pharmaceutical composition comprising: (a) probiotic formulation comprising Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus GG,
  • Bifidobacterium longum Lactobacillus casei, Lactobacillus paracasei, and (b) a formulation of digestive enzymes.
  • Aspect 55 The method of aspect 54, wherein said digestive enzymes are selected from the group consisting of: a) proteases; b) Carbohydrate-digesting enzymes; c) Fiber-digesting enzymes; and, d) lipases.
  • Aspect 56 The method of aspect 55, wherein said carbohydrate-digesting enzymes are selected from the group consisting of: a) Amylase; b) Glucoamylase; c) Lactase; d) Invertase; and, e) Maltase.
  • Aspect 57 The method of aspect 55, wherein said fiber-digesting enzymes are selected from the group consisting of: a) Xylanase; and b) Hemicellulase.
  • Aspect 58 The method of aspect 54, wherein the form of pharmaceutical composition is selected from the group consisting of: a pill, a tablet, a caplet, a capsule, powder, a suspension, a gel, and, a liquid.
  • Aspect 59 The method of aspect 54, wherein said formulations of probiotics and digestive enzymes are formulated in the same single formulation.
  • Aspect 60 The method of aspect 59, wherein said single formulation is a capsule.
  • Aspect 61 The method of aspect 55, wherein said formulation of digestive enzymes comprises at least two proteases.
  • a probiotic formulation having: Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius,
  • Lactobacillus plantarum Lactobacillus rhamnosus, Bifidobacterium longum,
  • Lactobacillus casei Lactobacillus paracasei; in conjunction with a formulation of digestive enzymes having: amylase, glucoamylase, lipase, bromelain, maltase, lactase, hemicellulase, xylanase, papain, and invertase that is useful in the preparation of a medicament for lowering cancer therapy associated toxicities in a subject in need.
  • Aspect 63 The probiotic formulation of aspect 62, wherein said formulation of probiotics and digestive enzymes are combined in capsules.
  • Aspect 64 The probiotic formulation of aspect 62, wherein said probiotics and digestive enzymes are formulated to be administered orally.
  • Aspect 65 The probiotic formulation of Aspect 62, wherein said probiotics are present in the following amounts: Bifidobacterium Infantis - between 5-7 billion cfu, Bifidobacterium Longum -between 750 million and 2 billion cfu, Bifidobacterium Bifidum -between 3-5 billion cfu, Lactobacillus Rhamnosus - between 5-7 billion cfu, Lactobacillus Acidophilus -between 1-3 billion cfu, Lactobacillus salivarius -between 1- 3 billion cfu, Lactobacillus plantarum - between 1-3 billion cfu, Lactobacillus Casei - between 750,000 million-2 billion cfu, Lactobacillus paracasei - between 1-3 billion cfu.
  • Aspect 66 The probiotic formulation of Aspect 65, wherein said probiotics are present in the following amounts: Bifidobacterium Infantis - 6 billion cfu, Bifidobacterium Longum - 1 billion cfu, Bifidobacterium Bifidum - 4 billion cfu, Lactobacillus Rhamnosus - 6 billion cfu, Lactobacillus Acidophilus - 2 billion cfu, Lactobacillus salivarius - 2 billion cfu, Lactobacillus plantarum - 2 billion cfu,
  • Aspect 67 The probiotic formulation of Aspect 66, wherein said enzymes are present in the following amounts: hemicellulase - between 5-11 mg, xylanase - between 2-6 mg, amylase - between .5 - 2.5 mg, glucoamylase - between 30 - 70 mg, maltase - between 8 - 12 mg, papain - between .5 - 3mg, portease, such as bromelain - between 13-23 mg, lipase - between 18- 32 mg, invertase - between .5-3 mg, lactase - between 8.0-11 mg.
  • Aspect 68 The probiotic formulation of Aspect 67, wherein said enzymes are present in the following amounts: hemicellulase - 8 mg, xylanase - 3.9 mg, amylase - 1.33 mg, glucoamylase - 50 mg, maltase - 10 mg, papain - 1.7 mg, bromelain - 18 mg, lipase - 25 mg, invertase - 1.5 mg, and lactase - 9.5 mg.
  • Aspect 69 The probiotic formulation of aspect 62, wherein said formulation is administered together with a chemotherapeutic agent.
  • Aspect 70 The probiotic formulation of aspect 69, wherein said
  • chemotherapeutic agent is capable of augmenting expression of immunogenic molecules on a cancer cell or plurality of cancer cells.
  • Aspect 71 The probiotic formulation of aspect 70, wherein said
  • chemotherapeutic agents are selected from a group comprising of: a) alkylating agents; b) plant alkaloids; c) antitumor antibiotics; d) antimetabolites; e) topoisomerase inhibitors; and f) ribonucleotide reductase inhibitors.
  • Aspect 72 The probiotic formulation of aspect 71, wherein said
  • chemotherapeutic agent is vinblastine at a concentration and duration sufficient to augment HLA I expression.
  • Aspect 73 The probiotic formulation of aspect 71, wherein said
  • chemotherapeutic agent is cyclophosphamide at a concentration and duration sufficient to augment HLA I expression.
  • Aspect 74 The probiotic formulation of aspect 71, wherein said
  • chemotherapeutic agent is topotecan at a concentration and duration sufficient to augment HLA I expression.
  • Aspect 75 The probiotic formulation of aspect 71, wherein said
  • chemotherapeutic agent is paclitaxel at a concentration and duration sufficient to augment HLA I expression.
  • Aspect 76 The probiotic formulation of aspect 62 wherein said formulation is administered to protect from toxicity effects of chemotherapy.
  • Aspect 77. The probiotic formulation of aspect 76, wherein said toxicity effect of chemotherapy is gastrointestinal toxicity.
  • Aspect 78 The probiotic formulation of aspect 76, wherein said toxicity effect of chemotherapy is hematological toxicity.
  • Aspect 79 The probiotic formulation of aspect 76, wherein said toxicity effect of chemotherapy is cardiac toxicity.
  • Aspect 80 The probiotic formulation of aspect 76, wherein said toxicity effect of chemotherapy is gastrointestinal toxicity.
  • Aspect 81 The probiotic formulation of aspect 76, wherein said toxicity effect of chemotherapy is vascular toxicity.
  • Aspect 82 The probiotic formulation of aspect 76, wherein said toxicity effect of chemotherapy is nephrotoxicity toxicity.
  • Aspect 83 The probiotic formulation of aspect 76, wherein said toxicity effect of chemotherapy is neurological toxicity.
  • Aspect 84 The probiotic formulation of aspect 76, wherein said toxicity effect of chemotherapy is alopecia.
  • Aspect 85 The probiotic formulation of aspect 76, wherein said toxicity is severity of grade 2 or higher diarrhea resulting from an anti-cancer chemotherapy in a subject in need thereof.
  • Aspect 86 The probiotic formulation of aspect 76, wherein said
  • chemotherapy comprises antibody therapy with or without small-molecule chemotherapy.
  • Aspect 87 The probiotic formulation of aspect 76, wherein said
  • chemotherapy comprises bevacizumab, cetuximab or panitumumab antibody therapy with or without small-molecule chemotherapy.
  • Aspect 88 The probiotic formulation of aspect 76, wherein said probiotic formulation is administered in a regimen comprising daily administration of said formulation for 2 to 10 days, and said chemotherapy cycle is 8 to 24 days.
  • chemotherapy comprises administration of one or more compounds selected from the group consisting of antimetabolites, alkylating agents, anticancer antibiotics, microtubule targeting agents, topoisomerase inhibitors, alkaloids, antibodies, pyrimidine analogs, purine analogs, folate antagonists, epidipodophyllotoxins, DNA damaging agents, antiplatelet agents, platinum coordination complexes, hormones, hormone analogs, aromatase inhibitors, anti-angiogenic compounds, growth factor inhibitors, angiotensin receptor blockers, nitric oxide donors, antisense oligonucleotides, cell cycle inhibitors, differentiation inducers, mTOR inhibitors, mitochondrial dysfunction inducers, chromatin disruptors.
  • compounds selected from the group consisting of antimetabolites, alkylating agents, anticancer antibiotics, microtubule targeting agents, topoisomerase inhibitors, alkaloids, antibodies, pyrimidine analogs, purine analogs, folate antagonists, epidipodophyllotoxins, DNA
  • Aspect 90 The probiotic formulation of aspect 76, wherein said
  • chemotherapy comprises administration of one or more compounds selected from the group consisting of 5-fluorouracil (5-FU), floxuridine, capecitabine, gemcitabine, cytarabine, irinotecan, doxorubicin (adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, mitoxantrone, topotecan, lapatinib, oxaliplatin, cisplatin, carboplatin, folinic acid, methothrexate, erlotinib, sorafenib, and lapatinib.
  • 5-FU 5-fluorouracil
  • floxuridine floxuridine
  • capecitabine gemcitabine
  • gemcitabine gemcitabine
  • cytarabine irinotecan
  • chemotherapy comprises administration of oxaliplatin or irinotecan.
  • chemotherapy comprises administration of oxaliplatin or irinotecan in combination with cetuximab, bevacizumab, and/or panitumumab.
  • chemotherapeutic agent(s) is administered at least during the first two consecutive days from the beginning of each chemotherapy cycle.
  • Aspect 94 The probiotic formulation of aspect 76, wherein said
  • chemotherapy is administered as FOLFOX or FOLFIRI chemotherapy regimen.
  • Aspect 95 The probiotic formulation of aspect 65, wherein said formulation is administered in 6 to 8 doses per day.
  • Aspect 96 The probiotic formulation of aspect 66, wherein said formulation is administered in 6 to 8 doses per day.
  • Aspect 97 The probiotic formulation of aspect 67, wherein said formulation is administered in 6 to 8 doses per day.
  • Aspect 98 Use of a probiotic formulation in the preparation of a medicament for improving the efficacy of a cancer therapy comprising in a subject with cancer scheduled to undergo or is undergoing treatment for cancer by administering to said subject said probiotic formulation in an amount sufficient to improve the efficacy of the cancer therapy.
  • Aspect 99 Use of a probiotic formulation in the preparation of a
  • Fig. 1A is a bar graph showing that as the reactors acidify during changes in microbial activity, base is added.
  • Fig. 1B is a bar graph showing that as the reactors acidify during changes in microbial activity, base is added.
  • Figure 2 depicts bar graphs showing analysis of acetate, propionate, and butyrate concentrations in the SHIME.
  • Figure 3 depicts bar graphs showing the effects of a curative (CUR) and preventive (PREV) administration of the probiotic with digestive enzymes supplement as compared to a control SHIME (CTRL) on luminal Lactobacillus and Bifidobacterium levels in the proximal (PC) and distal colon (DC).
  • CUR curative
  • PREV preventive
  • Figure 4 depicts bar graphs showing the effect of a curative (CUR) and preventive (PREV) administration of the probiotic with digestive enzymes supplement as compared to a control SHIME (CTRL) on luminal Bacteroidetes, and Finnicutes levels in the proximal (PC) and distal colon (DC).
  • CUR curative
  • PREV preventive
  • Figure 5 depicts a bar graph showing the differences in microbial compositions at the phylum level in the proximal and distal colons caused by the probiotic with digestive enzymes supplement.
  • Figure 6A depicts a bar graph showing modulation of IL-6 in an in vitro model of intestinal inflammation by metabolites from SHIME reactors treated with the probiotic with digestive enzymes supplement.
  • Figure 6B depicts a bar graph showing modulation of IL-10 in an in vitro model of intestinal inflammation by metabolites from SHIME reactors treated with the probiotic with digestive enzymes supplement.
  • This invention teaches methods and compositions for augmenting the efficacy of cancer therapeutic drugs using formulations comprising probiotic compositions combined with digestive enzymes. This invention also teaches methods and compositions for preventing, improving or alleviating adverse events that are associated with cancer therapeutic drugs in a subject in need of treatment.
  • probiotic (based) formulation and“probiotic (based) composition” may refer to a formulation comprising probiotics or to a formulation containing probiotics combined together with digestive enzymes.
  • formulation and “composition” encompass said probiotics or said probiotics with digestive enzyme ingredients that are mixed together into a delivery vehicle for administration to or consumption by a subject in need thereof.
  • administration or consumption of a probiotic based formulation by said subject may occur orally via swallowing of a capsule, tablet, or soft gel, orally via swallowing of a powder that may be dissolved or distributed in food or water, orally via gavage, sublingually via a troche, or rectally as a suppository.
  • each probiotic microorganism in said probiotic based formulation is measured by activity per gram(g), which is expressed as colony forming units (CFU).
  • each digestive enzymes in said probiotic based formulation is measured by enzyme activity per gram (g).
  • the activities of each digestive enzyme are measured using methods known in the art, as follows: Hemicellulase units (HU) for hemicellulase, Xylanase unit (XU) for xylanase, Alpha - amylase Dextrinizing units (DU) for amylase, amyloglucosidase (AGU) for glucoamylase, degrees Diastatic power (DP) for maltase, enzyme activity or units (TP) for papain, Gelatin Digestion units (GDU) for bromelain, Fungi Lipase-Intemational FIP standard (FIP) for lipase, Summer units (SU) for invertase, lactase units (ALU) for lactase.
  • HU Hemicellulase units
  • XU Xylanase unit
  • AGU amyloglucos
  • cancer therapeutic drug(s) “cancer therapeutic agent(s)”,“cancer drug(s)”,“cancer therapy”,“oncology drug(s)”,“treatment agent(s)”, and the like, are used synonymously to refer to the cancer treatment received by a subject in need thereof, as is recognized in the art.
  • these cancer treatments may include one or more of the following treatment categories: a) immunotherapy; b) chemotherapy; c) surgery; d) radiation therapy; e) hyperthermia; f) radiation; g) targeted therapy; h) hormone therapy; i) stem cell transplantation.
  • Use of these terms also signifies that one or more of the abovementioned treatment categories may be administered to said subject.
  • “subject” refers to a human (e.g. a subject with cancer and/or a subject taking one or more cancer therapeutic drugs and/or one or more antibiotics) and, more broadly speaking, may include any mammal. Accordingly, aspects of the present invention may be practiced in human clinical medicine as well as in veterinary medicine.
  • the phrase“augmentation of efficacy” or“improved efficacy” of a cancer therapeutic agent includes enhancement of one or more of the therapeutic effect(s) of said cancer drug.
  • the therapeutic effect of a cancer drug can refer to inhibition of tumor growth, induction of tumor regression, suppression of metastasis, inhibition of metastasis, suppression of proliferation, induction of programmed and/or non-programmed cell death.
  • cancer inhibiting drugs can be observed by one or more of the following clinical endpoints: a) Overall survival (OS); b) Progression-free survival (PFS); c) Time to progression (TTP); d) Time to treatment failure (TTF); c) Event- free survival; d) Objective response rate (ORR); e) Duration of response (DR); f) Improvement in immunoscore; and g) Decrease in cancer- associated biomarkers including but not limited to tumor-associated antigens (TAAs).
  • OS Overall survival
  • PFS Progression-free survival
  • TTP Time to progression
  • TTF Time to treatment failure
  • Event- free survival d
  • Objective response rate ORR
  • DR Duration of response
  • f Improvement in immunoscore
  • TAAs tumor-associated antigens
  • said subject may be afflicted with one or more types of cancer including but not limited to the following: brain, melanoma, bladder, breast, cervix, colon, rectal, head and neck, kidney, lung, non- small cell lung, mesothelioma, ovary, prostate, sarcoma, stomach, uterus, as well as carcinomas, including spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepid
  • Sarcomas include, chondrosarcoma, fibrosarcoma, lymphosarcoma, melano sarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilns' tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblast
  • One embodiment of the present invention teaches a method of improving the efficacy of a cancer therapy comprising the following: (a) Identifying a subject with cancer who plans to undergo or is undergoing treatment for cancer; (b) administering to said subject a formulation comprising a probiotic based formulation, which is preferably a formulation comprised of probiotics with digestive enzymes.
  • said formulation of probiotics with digestive enzymes comprises of one or more probiotics selected from a group comprising of: a) Bifidobacterium inf antis, b) Bifidobacterium bifidum, c) Lactobacillus acidophilus, d) Lactobacillus salivarius; e) Lactobacillus plantarum, f) Lactobacillus rhamnosus, g) Bifidobacterium longum, h) Lactobacillus casei; and i) Lactobacillus paracasei.
  • probiotics selected from a group comprising of: a) Bifidobacterium inf antis, b) Bifidobacterium bifidum, c) Lactobacillus acidophilus, d) Lactobacillus salivarius; e) Lactobacillus plantarum, f) Lactobacillus rhamnosus, g) Bifidobacterium longum,
  • Said formulation of probiotics with digestive enzymes may also be comprised of one or more digestive enzymes selected from a group comprising: a) amylase; b) glucoamylase; c) lipase; d) bromelain; e) maltase; f) lactase; g) hemicellulose; h) xylanase; i) papain, and j) invertase.
  • one or more digestive enzymes selected from a group comprising: a) amylase; b) glucoamylase; c) lipase; d) bromelain; e) maltase; f) lactase; g) hemicellulose; h) xylanase; i) papain, and j) invertase.
  • a preferred composition for improving the efficacy of cancer therapy in a subject comprises the following active ingredients: a) Bifidobacterium infantis; b) Bifidobacterium bifidum, c) Lactobacillus acidophilus, d) Lactobacillus salivarius; e) Lactobacillus plantarum; f) Lactobacillus rhamnosus; g) Bifidobacterium longum; h) Lactobacillus casei and i) Lactobacillus paracasei j) amylase; k) glucoamylase; 1) lipase; m) bromelain; n) maltase; o) lactase; p) hemicellulose; q) xylanase; r) papain, and s) invertase.
  • this compositon comprises between 100-500 mg by weight of digestive enzymes and between 50-250 mg by weight digestive enzymes per dose.
  • said formulation comprises 272.65 mg by weight of digestive enzymes and 116.20 mg of probiotics per dose.
  • this formulation is contained in capsules for oral administration.
  • treatment cycle is used herein to refer to a period of time between the initial administration of an anti-cancer agent and its repeat administration.
  • the cycle of the FOLFOX4 chemotherapy includes 14 days, wherein anti-cancer agents are administered only for the first 2 days of the cycle as follows: Day 1: oxaliplatin 85 mg/m.sup.2 IV infusion and leucovorin 200 mg/m.sup.2 IV infusion both given over 120 minutes at the same time in separate bags, followed by 5-FU 400 mg/m.sup.2 IV bolus given over 2-4 minutes, followed by 5-FU 600 mg/m.sup.2 IV infusion as a 22 -hour continuous infusion; Day 2: leucovorin 200 mg/m.sup.2 IV infusion, followed by 5-FU 400 mg/m.sup.2 IV bolus given over 2-4 minutes, followed by 5-FU 600 mg/m.sup.2 IV infusion as a 22-hour continuous infusion.
  • Day 1 oxaliplatin 85 mg/m.sup.2 IV infusion and leucovorin 200 mg/m.sup.2 IV infusion both given over 120 minutes at the
  • the cycle of the FOLFIRI chemotherapy includes 14 days, wherein anti-cancer agents are administered only for the first 2 days of the cycle as follows: irinotecan (180 mg/m.sup.2 IV over 90 minutes) concurrently with folinic acid (400 mg/m.sup.2 [or 2. times.250 mg/m.sup.2] IV over 120 minutes), followed by fluorouracil (400-500 mg/m.sup.2 IV bolus) then fluorouracil (2400-3000 mg/m.sup.2 intravenous infusion over 46 hours).
  • Bevacizumab is usually given intravenously every 14 days, although the frequency can be dose dependent (for example 5 mg/kg by intravenous infusion every two weeks or 7.5 mg/kg by intravenous infusion every three weeks).
  • it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatin or irinotecan.
  • 5-FU 5-fluorouracil
  • leucovorin oxaliplatin or irinotecan.
  • One recommended dose and schedule for cetuximab is 400 mg/m.sup.2 administered intravenously as a l20-minute infusion as an initial dose, followed by 250 mg/m.sup.2 infused over 30 minutes weekly, preferably in combination with FOLFIRI.
  • said probiotic based formulation for example, consisting of probiotics with digestive enzymes
  • said probiotic based formulation may be given for a duration that surpasses the therapeutic regimen that said subject undergoes.
  • administration of said probiotic based formulation may also be initiated during any of the treatment cycles with a given cancer therapeutic agent.
  • said probiotic based formulation will be administered on a daily basis thereafter.
  • the probiotic based formuations may be adminsiterd to a subject in need thereof a doses of 2-10 capsules per day and on a daily basis.
  • this formulation is administered in 6-8 doses per day and on a daily basis.
  • the probiotics based formuation is taken at a dose of 6 capsules per day; specifically, 2 capsules taken in the morning, 2 capsules at midday, and 2 capsules at night on days when cancer treatment agents are not being administered to said subject.
  • Eight capsules may be taken daily on each day that a cancer treatment agent is being administered to said subject; specifically, 2 capsules taken in the morning, 2 capsules at midday, 2 capsules at night, 1 additional capsule taken within 2 hours prior to the cancer treatment agent is administered, and 1 additional capsule taken within two hours after the cancer treatment agent has been administered.
  • This dosing regimen can be continued for the duration of cancer treatment cycles and irrespective of the specific cancer drug(s) being administered to said subject.
  • said probiotic based formulation contains said probiotics having the following activity/gram: between 25-150 billion colony forming units (cfu) for Bifidobacterium inf antis, between 50-150 billion cfu for Bifidobacterium longum, between 350-550 billion cfu for Bifidobacterium bifidum, between 100-300 billion cfu for Lactobacillus rhamnosus, between 100-300 billion cfu for Lactobacillus acidophilus, between 200-400 billion for Lactobacillus salivarius, between 300-500 billion cfu for Lactobacillus plantarum, between 200-400 billion cfu for Lactobacillus casei, and between 300-500 billion cfu Lactobacillus paracasei.
  • cfu colony forming units
  • said probiotic based formulation comprises digestive enzymes having the following activity/gram: between 300,000-500,000 HCU for hemicellulase, between 100,000-300,000 XU for xylanase, between 100,000-300,000 DU for amylase, between 900-1,100 AGU for glucoamylase, between 10,000-30,000 DP for maltase, between 900,000, 1,100,000 TU for papain, between 2,000-4,000 gdu for bromelain, between 150-300 FIP for lipase, between 100,000-300,000 SU for invertase, between 75,000-150,000 ALU for lactase.
  • digestive enzymes having the following activity/gram: between 300,000-500,000 HCU for hemicellulase, between 100,000-300,000 XU for xylanase, between 100,000-300,000 DU for amylase, between 900-1,100 AGU for glucoamylase, between 10,000-30,000 DP for maltas
  • the invention provides the ability to augment dosage of chemotherapy or other oncology drugs in order to achieve killing of tumor cells without achieving dose limiting toxicity.
  • the invention provides means of providing multiple therapies that would otherwise not be possible due to toxicities, in other embodiments the invention provides means of suppressing cytokine release syndrome associated with cancer therapies, particularly immunotherapies, in other embodiments the invention provides means of reducing adverse events associated with administration of checkpoint inhibitors through selectively enhancing tolerance towards self antigens while not suppressing or minimally suppressing antitumor immunity.
  • the invention teaches administration of probiotics and/or combinations of probiotics and digestive enzymes, collectively referred to herein as probiotic based compositions.
  • the present invention teaches methods for prevention or management of cancer treatment-related adverse events comprising the following: (a) Identifying a subject with cancer who has plans to undergo, is undergoing or has undergone treatment for cancer; (b) Identifying that said subject also exhibits symptoms of cancer treatment-related adverse events or is at-risk for experiencing cancer treatment-related adverse events (b) administering to said subject a formulation comprising probiotics with digestive enzymes.
  • “prevention” or“management” of said adverse event(s) may refer to initiation of administration of a probiotic based formulation prior to initiation or re-initiation of treatment with a cancer drug or at some time during the treatment with a cancer drug (i.e. whe treatment with the cancer drug has already commenced).
  • said cancer treatment-related adverse events may be identified as one or more of the following: a) Nausea; b) Vomiting; c) Diarrhea; d) Abdominal pain; e) Bloating; f) Ulcers in the gastrointestinal tract; g) Mucositis in the gastrointestinal tract; h) Esphagitis; i) Infusion-related reactions; j) Fatigue; k) Malaise; 1) Cytokine release syndrome; m) Serum sickness; n) Alopecia; o) Anemia; p) Leukocytosis; q) Viral infections; r) Bacterial infections; s) Yeast infections t) Acid reflux; u) Neutropenia; v) Lymphopenia; w) Thrombocytopenia; x) Leaky gut; y) Cardiomyopathy; and z) Neuropathy.
  • a preferred composition for prevention or management of cancer treatment-related adverse events in a subject comprises the following active ingredients: a) Bifidobacterium infantis b) Bifidobacterium bifidum c) Lactobacillus acidophilus ; d) Lactobacillus salivarius e) Lactobacillus plantarum f) Lactobacillus rhamnosus, g) Bifidobacterium longum h) Lactobacillus cased, and i) Lactobacillus paracasev, j) amylase; k) glucoamylase; 1) lipase; m) bromelain; n) maltase; o) lactase; p) hemicellulose; q) xylanase; r) papain, and s) in
  • this compositon comprises between 100-500 mg by weight of digestive enzymes and between 50-250 mg by weight digestive enzymes per dose.
  • said formulation comprises 272.65 mg of digestive enzymes and 116.20 mg of probiotics per dose.
  • this formulation is contained in capsules for oral administration.
  • dosing regimens for prevention or management of adverse event(s) in a subject may be similar or identifical to those used to improve the efficacy of cancer therapy in a subject as per the descriptions provided herein.
  • said probiotic based formulation(s) described herein can be used for reducing existing inflammation in a subject with cancer, wherein said inflammation may be caused by the cancer disease process and/or treatment agents used to treat cancer or infections.
  • said probiotic based formulation(s) described herein can be used for modulating the immune system in a subject with cancer, wherein said immune system may require modulation due to the cancer disease process and/or treatment agents used to treat cancer or infections.
  • said probiotic based formulation(s) described herein can be used for modulating the microbiome in the gut.
  • the microbiome refers to the microorganisms that are present in the gut, which can be assessed based on sequencing tehniques and analytical techniques that are known in the art.
  • the two main approaches for analyzing the microbiome 16S ribosomal RNA (rRNA) gene amplicons and shotgun metagenomics are widely practiced.
  • rRNA 16S ribosomal RNA
  • shotgun metagenomics are widely practiced.
  • these techniques may be performed using stool samples acquired before and after a specific treatment, which, in this case, may be before and after administration of a probiotics-based formulation to a subject in need thereof.
  • the probiotic based formulation(s) described herein are intended to treat, reverse, reduce or prevent dysbiosis of the gut microbiome. This may also be referred to generally as“modulating” the microbiome.
  • the term “dysbiosis” can refer to one or more of (i) an increase in the proportion of a first species (bacterial or archaeal species) or strain in the microbiota (eg, gut microbiota) (eg, Bacteriodes fragalis or thetaiotamicron ); (ii) an increase in the relative proportion of first and second species (eg, Bacteriodes fragalis versus Clostridium pere, or Streptococcus thermophilus verus Escherichia coli or Lactococcus lactis ), first and second strains of the same species, or first and second phyla which are different from each other (eg, Bacteriodetes versus Firmicutes); (iii) an addition of a first species (bacterial or archae
  • dysbiosis of the gut microbiome is treated, reversed, reduced and/or prevented by administering to a subject in need thereof a probiotic based composition
  • a probiotic based composition comprising the following: a) Bifidobacterium infantis, b) Bifidobacterium bifiidunv, c) Lactobacillus acidophilus, d) Lactobacillus salivarius; e) Lactobacillus plantarum, f) Lactobacillus rhamnosus, g) Bifidobacterium longum, h) Lactobacillus cased, and i) Lactobacillus paracasev, j) amylase; k) glucoamylase; 1) lipase; m) bromelain; n) maltase; o) lactase; p) hemicellulose; q) xylanase; r) papain, and s) invert
  • said formulation comprises 272.65 mg of digestive enzymes and 116.20 mg of probiotics per dose. In one embodiment, between 2-10 doses are administered daily. In a preferred embodiment, 6-8 doses are administered daily.
  • said formulation of probiotics with digestive enzymes is contained in capsules for oral administration to a subject in need thereof, wherein one dose is present in each capsule. In the context of the invention, said formulation is administered for a duration of a minimum of three weeks; preferably for at least three months.
  • said probiotic based composition comprising probiotics with digestive enzymes is administered to a subject in need thereof for modulating the ratios of Bacteroidetes to Firmicutes phyla in the gut of said subject.
  • This ratio is known in the art to have significance with regard to the health of the microbiome and the overall wellness of a subject.
  • modification of the presence of phyla can serve as confirmation of the bioactivity of the probiotics present in said formulation. Said modification can be measured by evaluating the composition of the microbiome from stool samples using methods known in the art, for example, 16S rRNA based sequencing methods, that may be performed before and after administration of said probiotic based composition.
  • changes in the genera and species within the Firmicutes and Bacteroidetes phyla can also be monitored.
  • Examples within the Firmicutes phylum include but are not limited to the following: Clostridium clusters IV and XlVa, the Veillonellaceae family, and Lactobacillus species.
  • Examples within Bacteroidetes phlyum including but are not limited to Bacteroides species.
  • other phyla, species and genera can also be evaluated in order to determine the effects of the probiotic based composition for modulating the gut microbiome; for example, Akkermansia muciniphila (phylum Verrucomicrobia).
  • modulation of the ratios and quantities of microorganisms belonging to the Firmicutes, Bacteroidetes or other phyla may also modulate the metabolic and fermentation activities in the gut, which may in turn modify the immune status, susceptibility to infections, manifestion of adverse events in response to cancer therapeutics, and/or the efficacy of cancer therapeutics.
  • said probiotic based composition comprising probiotics with digestive enzymes is administered to a subject in need thereof for increasing the presence of Lactobacillus and/or Bifidobacterium genera in the gut of said subject.
  • said probiotic based formulation is administered to a subject in need thereof prophylactically for modulating the gut microbiome.
  • prophylactically refers to initiation administration of said probiotic based formulation at a time prior to administration of one or more cancer therapeutic agents and/or an antibiotics. Administration of said probiotic based formulation may then continue throughout and following the administration of one or more cancer therapeutic agents and/or an antibiotics.
  • said probiotic based formulation will be administered for a total duration of at least three or six months.
  • said probiotic based formulation is administered to a subject in need thereof subsequent to administration of one or more cancer therapeutic agents or antibiotics for the purpose of modulating the gut microbiome. Administration of said probiotic based formulation may then continue throughout and following the administration of one or more cancer therapeutic agents and/or an antibiotics.
  • said probiotic based formulation will be administered for at least three or six months.
  • the probiotic based formulation may require testing for bioactivity of its active ingredients prior to administration to said subject.
  • Methods known in the art can be utilized for determining the activity of probiotic microorganisms.
  • he SHIME® model allows to culture the complex gut microbiota over a longer period under representative conditions of the different intestinal regions. Therefore, the SHIME® does not only allow to obtain detailed information about the fermentation profile of the test products, but importantly also about the localization of the intestinal fermentation activity.
  • the SHIME® allows for performance of mechanistic research as the gut microbiome is fully stable prior to treatment. This is achieved by applying a two- week stabilization period with strict control of the environmental conditions (e.g.
  • the human fecal inoculum evolves to a stable in vitro microbiota that is representative for the different colon regions of interest. This is crucial because a microbiota will inevitably alter after being transferred from an in vivo environment to a laboratory model.
  • the probiotic based composition may be added to the SHIME®.
  • the first two reactors are of the fill-and-draw principle to simulate different steps in food uptake and digestion, with peristaltic pumps adding a defined amount of SHIME feed (140 mL 3x/day) and pancreatic and bile liquid (60 mL 3x/day), respectively to the stomach and small intestine compartment and emptying the respective reactors after specified intervals.
  • the last three compartments simulate the large intestine.
  • These reactors are continuously stirred, they have a constant volume and pH control. Retention time and pH of the different vessels are chosen in order to resemble in vivo conditions in the different parts of the colon. Upon inoculation with fecal microbiota, these reactors simulate the ascending, transverse and descending colon. Inoculum preparation, retention time, pH, temperature settings and reactor feed composition were previously described by [11].
  • the probiotic based composition may be added to the SHIME® together with a chemotherapeutic agent and/or an antibiotic.
  • a chemotherapeutic agent and/or antibiotic can be added without the probiotic based composition.
  • the probiotic based composition can be added to the SHIME® reactors prior to addition of a chemotherapeutic agent and/or an antibiotic. Subsequently, activity in the SHIME® reactors can be measured based on acid/base consumption, concentrations of short-chain fatty acids in the reactors, concentration of lactate in the reactors, and the microbial community composition using quantitative PCR methods known in the art.
  • the SHIME® method can be used to assess the bioactivity of a probiotic based composition in the presence of a chemotherapeutic agent or an antibiotic. Additionaly, the SHIME® study can be utilized to gauge the optimum time for administration of the probiotic based composition for its microbiome modulating effects to occur (i.e. before or during chemotherapy and/or antibiotic administration).
  • probiotic based compositions or “probiotic based formulations” may refer to probiotics comprising two or more live microorganisms from the genera Lactobacillus or Bifidobacterium.
  • nine probiotic microorganisms from the genera Lactobacillus or Bifidobacterium are present in the composition
  • the following probiotic species are present in the composition: Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus casei, Lactobacillus paracasei
  • the terms“probiotic(s) based compositions” or“probiotic(s) based formulations” may also refer to two or more probiotics with two or more digestive enzymes.
  • said mixtures or blends of probiotics with digestive enzymes are prepared or manufactured in a manner that they are co-adminisetered to a subject in need thereof.
  • said digestive enzymes present in said formulation include enzymes that are have activity for digesting carbohydrates, proteins, and fats.
  • 10 digestive enzymes are present in the formulation.
  • the following digestive enzymes are present in the composition: a) amylase; b) glucoamylase; c) lipase; d) bromelain; e) maltase; f) lactase; g) hemicellulose; h) xylanase; i) papain, and j) invertase.
  • said probiotic based composition is contained in a capsule.
  • said capsule contains probiotics and digestive enzymes as active ingredients and inactive ingredients that include one or more of the following substances: a) Inulin; b) Rice extract; c) Hydroxypropyl methylcellulose.
  • said probiotic based composition is administered to a subject in need thereof by the oral route of administration.
  • said capsule may be broken open and the contents of said capsules may be mixed into applesauce for subjects who have difficulty swallowing intact capsules.
  • said probitioc based composition is adminsered to a subject with cancer who is taking antibotics or who may need antibiotics before, during or aftr the course of treatment with cancer drugs.
  • said subject may have an infection or be at-risk for an infection. It is known in the art, that infections in cancer patients often occr due to their immune suppressed status, which is due to their disease and/or secondary to certain cancer drug treatments.
  • Said antibiotics include but are not limited to the following: Aminocoumarins (such as Novobiocin, Albamycin, Coumermycin and Clorobiocin), Aminoglycosides (such as Amikacin, Apramycin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin and Spectinomycin), Ansamycins (such as Geldanamycin, Herbimycin, Rifaximin and Streptomycin), Carbapenems (such as Ertapenem, Daripenem, Cilastatin ('Imipenem') and Meropenem), Cephalosporins (such as Cefadroxil, Cefazolin, Cefalothin ('Cefalotin'), Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefoperazone, Cefotaxime, Ce
  • This invention teaches formulations of probiotics with digestive enzymes that can serve as anti-diarrhea agents in subjects with cancer for preventing or improving cancer drug-associated diarrhea.
  • Another embodiment of this invention pertains to formulations of probiotics with digestive enzymes that can serve to prevent or allevaite antibiotic-associated diarrhea in a subject with cancer in need thereof.
  • Another preferred embodiment of this invention pertains to formulations of probiotics with digestive enzymes that can serve as antiemetic agents in a subject with cancer for the purpose of preventing or improving cancer drug-associated nausea or vomiting.
  • Another embodiment of the invention pertains to formulations of probiotics with digestive enzymes that serve to prevent or treat antibiotic-associated nausea or vomiting in a subject with cancer.
  • Another embodiment of the invention pertains to formulations of probiotics with digestive enzymes that serve to prevent or treat alopecia in a subject with cancer.
  • Another embodiment of the invention pertains to a formulation of probiotics with digestive enzymes that serves to prevent or treat cardiotoxicity in a subject with cancer.
  • cardiotoxicity in said subject may include clinical syndromes including but not limited to reduced ejection fraction, dilated cardiomyopathy, and congestive heart failure.
  • Another embodiment of the invention pertains to a formulation of probiotics with digestive enzumes that serves to prevent or treat neurotoxicity in a subject with cancer.
  • neurotoxicity in a said subject may include clinical syndromes including but not limited to depression, encephalopathy, cerebellar ataxia, acute neuromuscular syndrome, thrombotic microangiopathy, blurred vision, dizziness, headaches, delayed progressive encephalopathy, optic neuropathy, Parkinsonism, leukocencephalopathy, and acute chemical meningitis.
  • immune suppression refers to reduction in numbers of immune cells.
  • immune suppression refers to activity of immune cells.
  • immune cells include neutrophils, eosinophils, basophils, natural killer cells, natural killer T cells, gamma delta T cells, monocytes, macrophages, dendritic cells, B cells, CD4 T cells, CD8 T cells, and innate lymphoid cells.
  • immune cell activities include cytokine production, phagocytosis, cytotoxic activity, and antigen presenting activity.
  • a formulation of probiotics with digestive enzymes is used for treating cytokine release syndrome, serum sickness, or sepsis in a subject with cancer. Said formulation may be used in conjunction with supportive care or other medications used to address said cytokine release syndrome, serum sickness or sepsis.
  • a subject receiving treatment with chimeric antigen receptor (CAR) T cells is administered a probiotic based formulation for several days prior to infusion of CAR T cells for the prevention of cytokine release syndrome.
  • CAR chimeric antigen receptor
  • compositions of probiotics with digestive enzymes for improving efficacy of cancer therapy, for reducing toxicities of cancer therapy, and/or for allowing for higher concentrations of cancer therapeutic agents to be used in a subject with cancer.
  • the invention also teaches compositions of probiotics with digestive enzymes administered to a subject with cancer in order to improve the subject’s tolerability to a cancer treatment for the purpose of allowing continued or extended administration of cancer therapeutic agents to said subject. For example, increased numbers of cycles of chemotherapy may be tolerated or additional cancer therapeutic agents may be administed to said subjects.
  • the specific probiotic based formulations when used in combination and administered to a subject can be utilized to improve the health of a subject undergoing cancer therapy; specifically, for subjects afflicted with toxicities associated with cancer therapy including hypotension, cardiovascular disease, disorders related to the vascular system, metabolic syndrome, disorders of the digestive tract, hematological toxicities, hepatotoxicities, and neural toxicities.
  • Said probiotics based formulation can also be administered to a subject as a to improve quality of life of said subject and of specific organ systems in said subject in the absence of any specific cancer therapy as a prophylactic.
  • the terms“overall wellness” or “quality of life’ may be used interchangeably in the context of the present invention.
  • Quality of life may be defined subjectively by said subject; for example, based on self- reporting of energy levels, presence or absence of malaise or other measures.
  • quality of life may be defined by a health care professional or clinical study personnel using a validated questionnaire.
  • One non-limiting example of a questionnaire is the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire.
  • EORTC European Organization for Research and Treatment of Cancer
  • efficacy of said probiotic based formulation for improving quality of life in a subject in need thereof is evaluated by a health care professional or clinical study personnel using Kamofsky Performance Status, an assessment tool for functional impairment that is known in the art.
  • An object of the invention is to provide a composition that relieves symptoms of chemotherapy induced toxicity.
  • An object of the invention is to provide a composition that relieves symptoms of radiotherapy induced toxicity.
  • An object of the invention is to provide a composition that relieves symptoms of immunotherapy induced toxicity.
  • An object of the invention is to provide a composition that relieves symptoms of hyperthermia induced toxicity.
  • An object of the invention is to provide a composition that relieves symptoms of surgery induced toxicity.
  • An object of the invention is to provide a probiotic based formulation that replaces and replenishes the bacteria that are beneficial to the human body in a subject in need thereof, after such bacteria are reduced or destroyed by intervention with a cancer therapy.
  • An object of the invention is to provide a probiotic based formulation to improve digestion and nutrient absorption in a subject with cancer.
  • An object of the invention is to provide the inventive composition in a form that has a long shelf life.
  • An object of the invention is to provide the inventive composition in pill form and to provide a pill that reaches the digestive tract prior to being absorbed.
  • An object of the invention is to provide a probiotic based formulation that allows a subject in need thereof to ingest foods that otherwise result in adverse reactions by the body (for example, any reaction related to food intolerance or allergic responses), subsequent to which the patient was treated with a cancer therapy or a plurality of cancer therapies.
  • Chemotherapeutic agents are well known in the art. Specific non-limiting examples of chemotherapeutic agents are provided throughout the specification and include, for example, FOLFOX (a chemotherapy regimen for treatment of colorectal cancer, which comprises administration of folinic acid (leucovorin), fluorouracil (5-FU), and oxaliplatin) and FOLFIRI (a chemotherapy regimen for treatment of colorectal cancer, which comprises administration of folinic acid (leucovorin), fluorouracil (5-FU), and irinotecan), as well as administration of targeted monoclonal antibody therapy (e.g., bevacizumab, cetuximab, or panitumumab) alone or in combination with chemotherapeutic agents.
  • FOLFOX a chemotherapy regimen for treatment of colorectal cancer, which comprises administration of folinic acid (leucovorin), fluorouracil (5-FU), and irinotecan
  • FOLFIRI a chemotherapy regimen for treatment of colorectal cancer
  • Bevacizumab (AVASTIN ® ) is a monoclonal antibody that targets a protein called VEGF that affects tumor blood vessel growth. It can cause debilitating side effects such as high blood pressure, bleeding, poor wound healing, blood clots, and kidney damage.
  • the probiotic based composition is used to enhance therapeutic efficacy of passively administered antibodies (such as Herceptin®, Rituximab®, and Cetuximab®), and/or augment cancer killing/inhibitor activity of endogenous antibodies in a subject.
  • passively administered antibodies such as Herceptin®, Rituximab®, and Cetuximab®
  • Antibodies exist in three formats; monoclonal (mAbs), oligo/polyclonal and antibody-drug conjugates.
  • mAbs represent an effective therapeutic modality and are important to the treatment paradigm of various diseases. Recent insights into the detailed mechanism of mAbs link their strong disease fighting potential to the immune system.
  • mAbs designed to inhibit specific checkpoints in the immune system have demonstrated strong immune responses and therapeutic benefit in patients.
  • Immune cells express proteins that are immune checkpoints that control and down-regulate the immune response. These are best defined in T lymphocytes and include PD-l, CTLA-4, TIM-3 and LAG3.
  • Tumor cells express the ligands to these receptors. When T cells bind the ligand to these proteins on the tumor cells, the T cell is turned off and does not attempt to attack the tumor cell.
  • These agents, typically mAbs, that block these proteins are known as checkpoint inhibitor drugs.
  • the degree of efficacy of these therapies is heavily reliant on the immune system of patients, many of whom are severely immuno-compromised.
  • checkpoint inhibitor drugs include the following: a) Inhibitors of Programmed Death 1 (PD-l, CD279), such as nivolumab (OPDIVO.RTM., BMS-936558, MDX1106, or MK-34775), and pembrolizumab (KEYTRODA.RTM., MK-3475, SCH-900475, lambrolizumab, CAS Reg. No. 1374853-91-4), as well as the PD-l blocking agents described in U.S. Pat. Nos.
  • PD-l Inhibitors of Programmed Death 1
  • CD279 Inhibitors of Programmed Death 1
  • nivolumab OPDIVO.RTM., BMS-936558, MDX1106, or MK-34775
  • pembrolizumab KEYTRODA.RTM., MK-3475, SCH-900475, lambrolizumab, CAS Reg. No. 1374853-91-4
  • WO 03042402 WO 2008156712, WO 2010089411, WO 2010036959, WO 2011066342, WO 2011159877, WO 2011082400, and WO 2011161699;
  • Inhibitors of Programmed Death— Ligand 1 include antibodies such as BMS-936559, MPDL3280A), MEDI4736, MSB0010718C, and MDX1105-01); also including: atezolizumab, durvalumab and avelumab;
  • Inhibitors of CTLA-4 such as ipilimumab (YERVOY.RTM., MDX-010, BMS-734016, and MDX-101), tremelimumab, antibody clone BNI3 (Abeam), RNA inhibitors, including those described in WO
  • the checkpoint inhibitor is an inhibitor of a checkpoint protein selected from the group of PD-l, PD-L1, and CTLA-4.
  • the checkpoint inhibitor is selected from the group of an anti-PD-l antibody, and anti-PD-Ll antibody, and an anti- CTLA-4 antibody.
  • the anti-PD-l antibody is selected from the group of nivolumab, pembrolizumab, and lambrolizumab.
  • the anti-PD-Ll antibody is selected from the group of as BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, and MDX1105-01.
  • the anti-PD-Ll antibody is selected from the group of durvalumab, atezolizumab, and avelumab.
  • the anti-CTLA-4 antibody is selected from the group of ipilimumab and tremelimumab.
  • the checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, MDX1105-01, durvalumab, atezolizumab, avelumab, ipilimumab, and tremelimumab.
  • the checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, durvalumab, atezolizumab, avelumab, ipilimumab, and tremelimumab. In some embodiment, In one embodiment, the checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab.
  • non-limiting examples of mAbs include the following: abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elot
  • the mAbs may be joined to another entity; for example, mAbs joined to a chemotherapy drug or to a radiolabeled particle, or they may be bispecific monoclonal antibodies that are made up of two different mAbs.
  • the probiotic based compositions disclosed herein can be administered to a subject in need thereof as a means of enhancing immune stimulatory efficacy of dendritic cell therapy.
  • the dendritic cell approach is designed to indirectly stimulate a patient’s T- cells by leveraging the role of dendritic cells in presenting antigens to T-cells.
  • Cancer vaccines are the most common application of dendritic cells.
  • the only FDA-approved dendritic cell therapy is PROVENGE, which entails collecting monocytes from the patient, maturing them into dendritic cells,“loading” ex vivo with the patient’s cancer antigens, and then re-infusing in the patient.
  • a probiotic based composition is is utilized to increase dendritic cell anticancer activity.
  • said probiotic mix is utilized to increase the number of dendritic cells infiltrating tumors.
  • the 5-year survival rate of patients with T-cell infiltration also was significantly better than that of patients without such infiltration (83% versus 61%; P ⁇ 0.05). Similar trends were observed in patients with adenocarcinoma; 5-year survival rates for patients with LC infiltration and those without LC infiltration were 49% and 25%, respectively (P ⁇ 0.025). The survival rates for patients with T-cell infiltration and those without were 50% and 33%, respectively (P ⁇ 0.1).
  • An analysis of patterns of failure of radiation therapy demonstrated that the favorable prognosis in LC infiltration was attributable mainly to improvement of local control rates, but that in T-cell infiltration was not. T-cells infiltrated into tumor specifically in the patients with LC infiltration in both cell types.
  • probiotic based compositions are administered to a subject with cancer for enhancing infiltration of immune cells, including antigen presenting cells, into tumors subsequent to radiation and/or chemotherapy.
  • patients treated with cancer therapy are administered a blend of probiotics; specifically, Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum,, Lactobacillus casei, Lactobacillus paracasei, in combination with a blend of digestive enzymes; specifically, amylase, glucoamylase, lipase, bromelain, maltase, lactase, hemicellulase, xylanase, papain, and invertase.
  • probiotics specifically, Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium
  • Identifying a patient in need can be done by any conventional detection method used in oncology practice, non-exclusively including blood tests, or identifying and assessing risk factors for cardiovascular disease, such as smoking, drinking, lack of exercise, weight of patient, age, family history, etc.
  • T cells recognize diseased cells by receptors engaging with antigens that are present on or inside the diseased cells.
  • CAR-T therapy entails genetically engineering T- cells to express synthetic CARs that direct T-cells to antigens on the surface of cancer cells.
  • TCR therapy modifies T-cells to express high-affinity tumor specific TCRs that recognize intra-cellular antigens that must be presented on the surface of target cells.
  • CAR-T and TCR therapies have demonstrated impressive anti-tumor activity in a narrow spectrum of hematologic cancers and garnered significant attention by research institutions and biopharmaceutical companies.
  • a probiotic based composition is administered to patients prior to CAR-T cell therapy for the purpose of off-setting probable toxicity caused by the treatment.
  • a probiotic with digestive enzymes formuaiton is administered to patients after CAR T cell therapy, either upon presentation of adverse events or before such adverse events are clinically manifested.
  • the probiotic based composition is used to reduce toxicity and augment efficacy of various cancer therapies, for example chemotherapeutic agents, radiotherapeutic agents, or drugs such as atovaquone, azacitidine, bexarotene, boceprevir, bosentan, bosutinib, brentuximab vedotin, carbidopa-levodopa, carglumic acid, decitabine, eribulin mesylate, foscarnet, metformin, ofatumumab, pomalidomide, prelatrexate solution, ropivacaine, rosiglitazone, sirolimus, temsirolimus, and valganciclovir.
  • the probiotic mixture and mixtures described in the invention mitigate or prevent the decrease in the production of red blood cells caused by the surgery or second drug.
  • the“probiotic composition” (which may also exist as a drug or pharmaceutical) may comprise at least two ingredients for administration to a subject with cancer.
  • the two ingredients may include at least one probiotic ingredient.
  • the composition may include at least two different probiotic ingredients or at least one probiotic ingredient and at least one digestive enzyme ingredient, or other ingredients in various combinations.
  • the composition may be substantially, if not completely, devoid of artificial flavors, colorings or preservatives.
  • the supplement may be developed for human or other animal consumption by swallowing or other ingestion technique. In a situation where the composition is developed for consumption by swallowing, the composition may be enclosed within a capsule or other form known to facilitate swallowing.
  • probiotics may be defined as live microorganisms thought to be healthy for the host organism; digestive enzymes may be defined as enzymes that break down polymeric macromolecules into their smaller building blocks in order to facilitate their absorption by the body; dietary supplements may be defined as a preparation intended to supplement the diet and provide nutrients that may be missing or may not be consumed in sufficient quantities in a human's diet.
  • the probiotic ingredients of the composition may be present in an effective dose.
  • the probiotic ingredients may total at least 6 x 1 Q9 colony forming units (cfu) and may include at least 13 x 1Q9 cfu of probiotics or more.
  • the probiotic ingredients total at least 13 x 1Q9 cfu of probiotics. In a more preferred aspect the probiotic ingredients total at least 14 x 1Q9 cfu of probiotics.
  • a colony forming unit (cfu) is generally accepted as a measure of viable bacterial or fungal numbers. Such quantity of probiotic ingredient may facilitate providing a consumer with an effective dose of probiotics at the time of ingestion, as the inventor has realized that probiotics may be destroyed during storage due to undesirable environments (e.g., temperature extremes) and other reasons.
  • the probiotic ingredients may comprise a probiotic blend including one or more of the following: Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus salivarius, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium bifidum.
  • the composition includes at least one probiotic from each of the strains listed above.
  • Each probiotic ingredient present in the probiotic based composition may be present in any desired quantity. In one aspect each probiotic ingredient of the composition may be present in an amount up to 1.5 x 10 9 cfu.
  • each probiotic ingredient of the probiotic based composition may be present in an amount equal to or greater than 1 x 10 9 cfu, and in a preferred aspect when combined the nine probiotic ingredients may total as much as, or more than, 13 x 10 9 cfu of probiotic ingredients. Preferably the amounts are equal to or are more than 14 x 10 9 cfu. In the example, these quantities may be measured at the time of manufacture.
  • GI gastrointestinal
  • Lactobacillis acidophilis is a prominent strain of probiotic for the small intestine
  • Bifidobacterium bifidum is a prominent strain of probiotic for the large intestine
  • those supplemental ingredients and other of the respective probiotic ingredients and the digestive enzymes
  • a blister pack for storing the capsule assists in preserving the potency of the ingredients such that the combination of the composition with the capsule in a protected blister package assists with appropriate and effective delivery (location and potency).
  • location and potency associated with appropriate and effective delivery
  • Digestive enzymes of the composition may be present in an effective dose to supplement existing quantities of enzymes and improve digestion of ingested food and absorption of the nutrients within the ingested food.
  • the digestive enzyme ingredients may comprise any enzyme that is useful in the digestion of ingested food.
  • inventors has developed a particularly effective probiotic based formulation also containing digestive enzymes comprising some or all of the following: amylase, glucoamylase, lipase, bromelain, maltase, lactase, hemicellulose, xylanase, papain, and invertase.
  • digestive enzymes comprising some or all of the following: amylase, glucoamylase, lipase, bromelain, maltase, lactase, hemicellulose, xylanase, papain, and invertase.
  • a capsule may enclose the probiotic based composition to facilitate increasing the shelf-life of the composition, swallowing of the composition, timing a release of the composition after ingestion and other considerations.
  • the capsule may be a gelatin capsule, vegetable- based (e.g., vegetable cellulose) capsule or other type of capsule. If the capsule is a vegetable-based capsule, the capsule may facilitate releasing the probiotics at a desirable location within the digestive tract. Preferably the capsule is a vegetable-based capsule.
  • An exemplary embodiment of the composition includes a probiotic blend and a digestive enzyme blend enclosed within a vegetable cellulose capsule.
  • capsules comprising the composition may be and are preferably stored in blister packs. That is, the blister packs may seal the capsule from a surrounding environment and thus, extend the life of the effective ingredients of the composition.
  • the method of using the composition may be used as desired by the subject in need thereof or as determined by the oncologist or other health practitioner who advises said subject.
  • the probiotics based composition is self-administered by said subject on a daily. Continuous daily use of the probiotic based composition may result in greater and sustained benefits for the subject.
  • the composition may include at least one of the probiotics of the Lactobacillus species and at least one probiotic of the Bifidobacterium species together with a digestive enzyme and contained in a vegetable-based capsule for at least 2 x 10 9 colony forming units.
  • the capsule is stored in a blister pack.
  • the blend includes at least some additional probiotic ingredients as noted above and at least 6 x 10 9 colony forming units assuming 1 billion cfu per probiotic at time of manufacture.
  • the composition may include, for instance, Lactobacillus acidophilus, Lactobacillus rhamnosus CG, Bifidobacterium infantis, and Bifidobacterium bifidum, together with a digestive enzyme and contained in a capsule.
  • the foregoing composition may include others from the above list of probiotics for at least 9 x 10 9 colony forming units, and stored in a blister pack or other sealed package.
  • the foregoing composition may include others from the above list of probiotics for at least 13 x 10 9 colony forming units, and stored in a blister pack or other sealed package.
  • the composition may include a greater amount of Lactobacillus probiotic as compared to Bifidobacterium probiotic.
  • said formulations of probiotics with digestive enzymes can contain said probiotics having the following activity/gram: between 25-150 billion colony forming units (cfu) for Bifidobacterium infantis, between 50-150 billion cfu for Bifidobacterium longum, between 350-550 billion cfu for Bifidobacterium bifidum, between 100-300 billion cfu for Lactobacillus rhamnosus, between 100-300 billion cfu for Lactobacillus acidophilus, between 200-400 billion for Lactobacillus salivarius, between 300-500 billion cfu for Lactobacillus plantarum, between 200-400 billion cfu for Lactobacillus casei, and between 300-500 billion cfu for Lactobacillus paracasei.
  • cfu colony forming units
  • said formulation of probiotics with digestive enzymes contains digestive enzymes having the following activity/gram: between 300,000-500,000 HCU for hemicellulase, between 100,000-300,000 XU for xylanase, between 100,000-300,000 DU for amylase, between 900-1,100 AGU for glucoamylase, between 10,000-30,000 DP for maltase, between 900,000, 1,100,000 TU for papain, between 2,000-4,000 GDU for bromelain, between 150-300 FIP for lipase, between 100,000-300,000 SU for invertase, between 75,000-150,000 ALU for lactase.
  • digestive enzymes having the following activity/gram: between 300,000-500,000 HCU for hemicellulase, between 100,000-300,000 XU for xylanase, between 100,000-300,000 DU for amylase, between 900-1,100 AGU for glucoamylase, between 10,000-30,000 DP for mal
  • a formulation comprising probiotics or probiotics with digestive enzymes may be utilized in subjects with cancer who are scheduled to undergo, are currently undergoing, and/or have undergone treatment with one or more types of chemotherapy. Selection of chemotherapy will depend on the subject to be treated, the type of cancer, and the intent of therapy. Selection of a subject for treatment with said probiotic based formulation may be performed prophylactically. Alternatively, the current invention may be practiced by selection of a subject for treatment with said probiotic based formulation during or after the course of chemoetherapy drug treatment.
  • chemotherapeutic agents that are known in the art and include but are not limited to: methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposides, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, and docetaxel, doxorubicin, epirubicin, 5-fluorouracil, taxanes such as docetaxel and paclitaxel, leucovorin, levamisole
  • imatinib mesylate herbimycin A, genistein, erbstatin, and lavendustin A.
  • the anti-cancer agent can be, but is not limited to, a drug listed: Alkylating agents Nitrogen mustards: Cyclophosphamide Ifosfamide Trofosfamide Chlorambucil Nitrosoureas: Carmustine (BCNU) Lomustine (CCNU) Alkylsulphonates: Busulfan Treosulfan Triazenes: dacarbazine Platinum containing Cisplatin compounds: Carboplatin Aroplatin Oxaliplatin Plant Alkaloids Vinca alkaloids: Vincristine Vinblastine Vindesine Vinorelbine Taxoids: Paclitaxel Docetaxel DNA Topoisomerase Inhibitors Epipodophyllins: Etoposide Teniposide Topotecan 9- aminocamptothecin Camptothecin Crisnatol mitomycins: Mitomycin C Anti-metabolites Anti-folates: DHFR inhibitors: Methotrexate Trimetrexate IMP dehydrogena
  • Angiostatin (plasminogen fragment) antiangiogenic antithrombin III Angiozyme ABT-627 Bay 12-9566 Benefin Bevacizumab BMS-275291 cartilage-derived inhibitor (CDI) CAI CD59 complement fragment CEP-7055 Col 3 Combretastatin A-4 Endostatin (collagen XVIII fragment) Fibronectin fragment Gro-beta Halofuginone Heparinases Heparin hexasaccharide fragment HMV833 Human chorionic gonadotropin (hCG) IM-862 Interferon alpha/beta/gamma Interferon inducible protein (IP- 10) Interleukin- 12 Kringle 5 (plasminogen fragment) Marimastat Metalloproteinase inhibitors (TIMPs) 2-Methoxyestradiol MMI 270 (CGS 27023A) MoAb IMC-1C11
  • Additional anti-cancer agents that may be used in the methods of the present invention include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; ce
  • the present invention is based on the discovery that the occurrence of chemotherapy-induced diarrhea is prevented or its severity is reduced upon administration of the probiotic with digestive enzyme compositions described herein.
  • the invention is based on the unexpected finding that the administration of said probiotic compositions provides a protective effect against chemotherapy-induced diarrhea that extends long after the composition is administered. The effect is especially pronounced for diarrhea of Grade II as determined by National Cancer Institute Common Toxicity Criteria for Diarrhea (CTCAE v.4.03).
  • the invention provides a method for preventing or reducing the occurrence of grade 2 or higher diarrhea resulting from an anti-cancer chemotherapy in a subject in need thereof, which method comprises administering to the subject an effective amount of a probiotic based composition. More generally speaking, the invention provides a method for treating gastrointestinal mucositis, or otherwise preventing or reducing gastrointestinal damage and/or dysfunction associated with an anti-cancer chemotherapy in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of probiotic based composition for a plurality of consecutive days, preferably commencing at the start of the chemotherapy cycle or prior to the chemotherapy cycle.
  • anti-cancer drugs that can be used include, but are not limited to: 20- epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-
  • the composition(s) of the invention including probiotics, and probiotics together with enzymes are administered in the form of a nutraceutical.
  • Nutraceuticals whether in the form of a liquid extract or dry composition, are edible and may be eaten directly by humans or mammals.
  • Said nutraceuticals are preferably provided to humans in the form of additives or nutritional supplements for example they may be administered in the form of tablets of the kind sold in health food stores, or as ingredients in edible solids, more preferably processed food products such as cereals, breads, tofu, cookies, ice cream, cakes, potato chips, pretzels, cheese, and in drinkable liquids such as beverages such as milk, soda, sports drinks, and fruit juices.
  • a method for enhancing the nutritional value of a food or beverage by intermixing the food or beverage with a nutraceutical in an amount that is effective to enhance the nutritional and probiotic or immune modulatory and/or cancer therapy augmentative value of the food or beverage.
  • a flavoring agent is added.
  • Preferred flavoring agents include sweeteners such as sugar, com syrup, fructose, dextrose, maltodextrose, cyclamates, saccharin, phenyl-alanine, xylitol, sorbitol, maltitol, and herbal sweeteners such as Stevia.
  • probiotics useful for the practice of the invention include soft drinks, a fruit juice or a beverage comprising whey protein, health teas, cocoa drinks, milk drinks and lactic acid bacteria drinks.
  • Probiotic bacteria may be administered together with agents known to enhance efficacy and retention of probiotics, including
  • various extracts and plant powders are incorporated into our compositions, depending on the desired properties according to the end use of said compositions.
  • compositions according to the present invention can be characterized in that in addition to the discussed prebiotics and phytosterols and lecithins the said further plant extracts or powders are one or more of those of Panax ginseng (red, Korean ginseng), Panax ginseng (white, Chinese ginseng), Rhodiola rosea (golden root), Panax quinquefolium (American ginseng), Eleutherococcus senticosus (Siberian ginseng), Cynara scolymus (artichoke), Uncaria tomentosa (Cat's claw), Lepidium meyenii (maca, Peruvian ginseng), Paullinia cupana (guarana), Croton lechleri (Sangre de Grado), Whitania somnifera (ashwagandha, Indian ginseng), Panax japonicus (Japanese ginseng), Panax vietnamensis (Vietnamese ginseng), Panax trifolius, Panax pseudo
  • plant extracts and plant powders are capable to potentiate the bioactivity of these compositions based on prebiotics, phytosterols, lecithins, vitamins and minerals. In given cases it also adds other prebiotics to the aforementioned prebiotic mixtures. These can result in more pronounced bioactivities as prebiotics and also in the chosen other bioactivity directions.
  • chemotherapy may be divided into the following classes: 1) Alkylating agents. These drugs kill cells that are not in cell cycle [13, 14], and include mustard gas derivatives such as Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan [15], and Ifosfamide. Ethylenimines such as Thiotepa and Hexamethylmelamine, Alkylsulfonates such as Busulfan, Hydrazines. Triazines such as Altretamine, Procarbazine, dacarbazine and Temozolomide. Nitrosureas such as Carmustine, Lomustine and Streptozocin.
  • mustard gas derivatives such as Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan [15], and Ifosfamide. Ethylenimines such as Thiotepa and Hexamethylmelamine, Alkylsulfonates such as Busulfan, Hydrazines. Triazines such
  • Alkylating agents are one of the original classes of chemotherapies that where historically developed [17, 18].
  • Plant Alkaloids These are chemotherapeutic drugs that are extracted from certain types of plants. The plant alkaloids are cell-cycle specific. This means they attack the cells during various phases of division.
  • the vinca alkaloids are made from the periwinkle plant (catharanthus rosea).
  • the taxanes are made from the bark of the Pacific Yew tree (taxus).
  • the vinca alkaloids and taxanes are also known as antimicrotubule agents.
  • the podophyllotoxins are derived from the May apple plant.
  • Camptothecan analogs are derived from the Asian "Happy Tree” (Camptotheca acuminata). Podophyllotoxins and camptothecan analogs are also known as topoisomerase inhibitors, which are used in certain types of chemotherapy. Vinca alkaloids include Vincristine, Vinblastine and Vinorelbine. Taxanes include Paclitaxel and Docetaxel. Podophyllotoxins include Etoposide and Tenisopide. Camptothecan analogs include Irinotecan and Topotecan. 3) Antitumor Antibiotics. This type of chemotherapy is generated from species of the soil fungus Streptomyces. These drugs act during multiple phases of the cell cycle and are considered cell-cycle specific.
  • Antitumor antibiotics include Anthracyclines such as Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, and Idarubicin.
  • Anthracyclines are generally a class of compounds that have the structural core of anthracene. They often are highly effective chemotherapeutics and therefore are used for the treatment of many cancers, including leukemias, lymphomas, breast, uterine, ovarian, bladder cancer, and lung cancers and are often used in childhood cancer treatment regimens.
  • Some anthracycline drugs include doxorubicin, daunorubicin, idarubicin, and epirubicin.
  • anthracyclines have been reported to work by inhibiting DNA and RNA synthesis; promoting free radical formation through redox cycling, with iron promoting the conversion of superoxide into hydroxyl radicals; inhibiting topoisomerases (e.g., topoisomerases Il.alpha. and/or Il.beta.); and evicting histones from open chromosomal areas.
  • Chromomycins such as Dactinomycin and Plicamycin. Additional antitumor antibiotics include Mitomycin and Bleomycin.
  • Antimetabolites This type of chemotherapy resembles normal substances within the cell. When the cells incorporate these substances into the cellular metabolism, they are unable to divide. Antimetabolites are cell-cycle specific.
  • Antimetabolites are classified according to the substances with which they interfere. Antimetabolites include the folic acid antagonist Methotrexate, the pyrimidine antagonists 5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, and Gemcitabine, the purine antagonists 6-Mercaptopurine and 6-Thioguanine, the adenosine deaminase inhibitors Cladribine, Fludarabine, Nelarabine and Pentostatin. 5) Topoisomerase Inhibitors. These chemotherapeutic agents that interfere with the action of topoisomerase enzymes (topoisomerase I and II).
  • topoisomerase enzymes control the manipulation of the structure of DNA necessary for replication. Ironotecan and topotecan are considered topoisomerase I inhibitors, whereas amsacrine, etoposide, etoposide phosphate, and teniposide are considered topoisomerase II inhibitors. 6) Alternative types of chemotherapy. Hydroxyurea is considered a ribonucleotide reductase inhibitor. Mitotane is considered an adrenocortical steroid inhibitor. Asparaginase and Pegaspargase are enzymatic types of chemotherapy. Estramustine is considered an antimicrotubule drug and members of the retinoid family of chemotherapies include Bexarotene, Isotretinoin, Tretinoin (ATRA).
  • the various probiotic, and probiotic/enzyme mixtures described herein are intended for human consumption and thus the processes for obtaining them are preferably conducted in accordance with Good Manufacturing Practices (GMP) and any applicable government regulations governing such processes. Especially preferred processes utilize only naturally derived solvents.
  • GMP Good Manufacturing Practices
  • the so-called “medical foods” are not meant to be used by the general public and are not available in stores or supermarkets. Medical foods are not those foods included within a healthy diet to decrease the risk of disease, such as reduced-fat foods or low-sodium foods, nor are they weight loss products.
  • a physician prescribes a medical food when a patient has special nutrient needs in order to manage a disease or health condition, and the patient is under the physician's ongoing care.
  • the label must clearly state that the product is intended to be used to manage a specific medical disorder or condition.
  • An example of a medical food is nutritionally diverse medical food designed to provide targeted nutritional support for patients with chronic inflammatory conditions. Active compounds of this product are for instance one or more of the compounds described herein.
  • the present invention thus relates to the use of an immuno-modulating properties of probiotics as related to prevention and/treatment of pregnancy complications.
  • said probiotics can be used in the preparation of a medicament, a vaginal suppository, medical food or nutraceutical to induce immune tolerance or immune modulation.
  • compositions according to the present invention comprise prebiotic components selected from fructose polymers GF.sub.n and F.sub.m, either containing a glucose (G) end-group, or without this glucose end-group and one or more component of a group of prebiotics consisting of modified or unmodified starch and partial hydrolysates thereof, partially hydrolysed inulin, natural oligofructoses, fructo- oligosaccharides (FOS), lactulose, galactomannan and suitable partial hydrolysates thereof, indigestible polydextrose, acemannan, various gums, indigestible dextrin and partial hydrolysates thereof, trans-galacto-oligosaccharides (GOS), xylo-oligosaccharides (XOS), beta-glucan and partial hydrolysates thereof, together if desired with phytosterol/phytostanol components and their suitable esters, and if desired other plant extracts, mineral components, vitamins
  • the fructose polymers of GF.sub.n or F.sub.m structures are linear fructose polymers having either a glucose (G) and -group, or being without this glucose and -group.
  • Oligofructoses are consisted of 3 to 10 carbohydrate units.
  • chicory inulin contains 10 to 60 carbohydrate units, typically with 27 carbohydrates (fructoses with our without one glucose end-group and a fructose chain).
  • Other plants may produce different fructans. These fructans are capable to increase the number of colonized and planktonic bacteria in the large intestine.
  • the local chemical carcinogenesis can also be the result of the formation of secondary bile acids.
  • These secondary bile acids are often formed upon the action of enzymes produced by resident Clostridia.
  • the chance of secondary bile acid formation can also be reduced. This can be demonstrated by measuring the faecal primary/secondary bile acid ratio.
  • prebiotics can be selected from a group of prebiotics consisting of various gums (guar gum, xanthan gum, locust been gum), carob seed flour, oat bran, rice bran, barley, modified or unmodified starch and suitable partial hydrolysates thereof, partially hydrolysed inulin, natural or synthetic/biosynthetic oligofructoses, fructo- oligosaccharides (FOS), lactulose, galactomannan and suitable hydrolysates thereof, indigestible polydextrose, indigestible dextrin and partial hydrolysates thereof, trans- galacto-oligosaccharides (GOS), xylo-oligosaccharides (XOS), acemannan, lentinan or beta-glucan and partial hydrolysates thereof, polysaccharides P and K (PSP, PSK), tagatose, various fungal oligosaccharides and polysaccharides, together with other components.
  • gums
  • probiotic compositions are utilized to enhance efficacy of immunotherapy.
  • Said immunotherapy may be utilized alone, or in combination with other types of cancer therapies such as chemotherapy, surgery, radiation therapy, or hyperthermia.
  • the basis of immunotherapy is activation of a competent T cell response. It is known that T cell responses are controlled in large part by activation of said T cells by antigen presenting cells.
  • probiotic compositions are utilized to augment efficacy of antigen presentation.
  • said probiotic compositions are utilized as in vivo activators of antigen presentation by stimulation of dendritic cell activity.
  • said probiotic compositions are administered after a patient is treated with dendritic cell therapy.
  • DCs dendritic cells
  • Numerous animal models have demonstrated that in the context of neoplasia dendritic cells (DCs) can bind to and engulf tumour antigens that are released from tumor cells, either alive or dying, and cross-present these antigens to T cells in tumour-draining lymph nodes. This results in the generation of tumour- specific immune responses that have been demonstrated to inhibit tumor growth or in some cases induced transferrable immunological memory.
  • DCs recognize tumors using the same molecular means that they would use to recognize apoptotic cells, or cells that are stressed.
  • One set of signals are molecules released from apoptotic cells, which are highly released by tumors, these include the nucleotides UTP and ATP, fractalkine, lipid lysophosphatidylcholine, and sphingosine 1- phosphate [19].
  • Signals from stressed cells, such as tumor cells include externalization of phosphatidylserine onto the outside of the cell membrane, calreticulin, avB5 integrin, CD36 and lactadherin.
  • dendritic cells actively promote tumor immunity in that patients with dendritic cell infiltration of tumors generally have a better prognosis [20-23].
  • Provenge is a cellular product derived from autologous peripheral blood mononuclear cell (PBMC) derived dendritic cells that have been grown using a chimeric protein comprised of GM-CSF and the prostate specific antigen, prostatic acid phosphatase [24, 25]. In the pivotal trial, this DC based therapeutic resulted in extension of survival by 4.1 months [25]. Prior to approval of Provenge, numerous clinical trials using DC were performed in prostate cancer, which will be discussed below.
  • PBMC peripheral blood mononuclear cell
  • probiotic compositions are performed with the intent of activating efficacy of dendritic cell therapy.
  • dendritic cell therapy in various types of cancers has previously been reported and incorporated by reference from the following publications melanoma [29-80], soft tissue sarcoma [81], thyroid [82-84], glioma [85-106], multiple myeloma ,[107-115], lymphoma [116-118], leukemia [119-126], as well as liver [127-132], lung [133-146], ovarian [147-150], and pancreatic cancer [151-153].
  • the probiotic with digestive enzymes formulation is used to enhance T cell immunity in a subject with cancer.
  • T cells are immune effectors against tumors, possessing ability to directly kill via CD8 cytotoxic cells [154- 156], or indirectly killing tumors by activation of macrophages through interferon gamma production [157-159]. Additionally, T cells have been shown to convert protumor M2 macrophages to Ml [160].
  • the probiotic with digestive enzymes formulation is used to enhance the functions of macrophages in a subject with cancer
  • Macrophages are key components of the innate immune system which play a principal role in the regulation of inflammation as well as physiological processes such as tissue remodeling [161, 162].
  • the diverse role of macrophages can be seen in conditions ranging from wound healing [163-166], to myocardial infarction [167-173], to renal failure [174- 177] and liver failure [178].
  • Ml macrophages are described as the pro-inflammatory sub-type of macrophages induced by IFN-. gamma and LPS. They produce effector molecules (e.g., reactive oxygen species) and pro- inflammatory cytokines (e.g., IL-12, TNF-. alpha and IL-6) and they trigger Thl polarized responses [181].
  • effector molecules e.g., reactive oxygen species
  • pro-inflammatory cytokines e.g., IL-12, TNF-. alpha and IL-6
  • manipulation of macrophages is performed using a probiotic with digestive enzyme formulation in combination with agents and approaches known to modulate macrophage activity.
  • Said macrophage activity may include pro-angiogenic activities or anti-angiogneic and cytotoxic activities.
  • Macrophages can play a tumor inhibitory, as well as a tumor stimulatory role. Initial studies supported the role of macrophages in mediating antibody dependent cellular cytotoxicity in tumors [182-189], and thus being associated with potentiation of antitumor immune responses.
  • Macrophages also possess the ability to directly recognize tumors by virtue of tumor expressed“eat-me” signals, which include the stress associated protein calreticulin [190, 191], which binds to the low-density lipoprotein receptor-related protein (LRP) on macrophages to induce phagocytosis [192].
  • Tumors protect themselves by expression of CD47, which binds to macrophage SIRP-l and transduces an inhibitory signal [193].
  • Blockade of CD47 using antibodies results in remission of cancers mediated by macrophage activation [194-198].
  • macrophages play an important role in induction of antitumor immunity.
  • the duality of macrophages in growth of tumors may be seen in studies of “inverse hormesis” in which low concentrations of antibodies targeting the tumor specific marker sialic acid N-glycolyl-neuraminic acid (Neu5Gc) actually leads to enhanced tumor growth in a macrophage dependent manner [212].
  • inverse hormesis in which low concentrations of antibodies targeting the tumor specific marker sialic acid N-glycolyl-neuraminic acid (Neu5Gc) actually leads to enhanced tumor growth in a macrophage dependent manner [212].
  • a probtioic with digestive enzyme formulation is used to generate Ml macrophages in a subject with cancer.
  • M2 macropahges are typically augmenters of tumor growth whereas Ml usually inhibit tumor growth [213, 214].
  • other agents may be used to modulate M2 to Ml transition of tumor associated macrophages including RRx-OOl [215], the bee venom derived peptide melittin [216], CpG DNA [217, 218], metformin [219], Chinese medicine derivative puerarin [220], rhubarb derivative emodin [221], dietary supplement chlorogenic acid [222], propranolol [223], poly ICLC [224], BCG [225], Agaricus blazei Murill mushroom extract [226], endotoxin [227], olive skin derivative maslinic acid [228], intravenous immunoglobulin [229], phosphotidylserine targeting antibodies [230], dimethyl sulfoxide [231], surfactant protein A [232], Zoledronic acid [233], bacteriophages [234]
  • a probtioic with digestive enzyme formulation is used to generate activated and/or tumor-cytotoxic T cells in a subject with cancer.
  • a probiotic with digestive enzyme formulation is used to reduce the prevalence of regulatory T (Treg) cells in a subject with cancer, as can be measured based on the presence of said cells in the peripheral blood of said subject with cancer using techniques that are known in the art.
  • Treg regulatory T
  • the importance of T cells in cancer is illustrated by positive correlation between tumor infiltrating lymphocytes and patient survival [235-239].
  • positive correlations between responses to various immunotherapies has been made with tumor infiltrating lymphocyte density [240, 241].
  • Increased T cell activity is associated with reduction in T regulatory (Treg) cells.
  • Treg cells have improved tumor control.
  • Agents that inhibit Treg cells include arsenic trioxide [242], cyclophosphamide [243-245], triptolide [244], gemcitabine [246], and artemether [247].
  • a probiotic with digestive enzyme formulation is utilized to augment the anticancer effects of metformin, and/or metformin together with chemotherapy.
  • metformin for the treatment of cancer and its activies is known in the art and includes macrophage Ml polarization and activation of CD8 T cells.
  • TAM tumor-associated macrophage
  • TAMs-conditioned medium and a coculture system were performed, which demonstrated an inhibitory effect of metformin on endothelial sprouting and tumour cell proliferation promoted by M2-polarized RAW264.7 macrophages [248] . From the CD8 perspective, Metformin enabled normal but not T-cell-deficient SCID mice to reject solid tumors.
  • CD8(+) tumor-infiltrating lymphocytes TILs
  • CD8(+) TILs capable of producing multiple cytokines were mainly PD-l(-)Tim-3(+), an effector memory subset responsible for tumor rejection.
  • metformin and cancer vaccine improved CD8(+) TIL multifunctionality.
  • Example 1 Clinical evaluation of a probiotic based formulation in patients with colorectal cancer.
  • the following example is a clinical study designed to evaluate the efficacy of a probiotic based formulation comprising a blend of probiotic and digestive enzymes contained in capsules.
  • This example teaches methods of use for a probiotic with digestive enzyme formulation disclosed in the present invention.
  • this example also teaches methods of using a probiotic with digestive enzyme formulation for improving the efficacy of a chemotherapy drug and/or for preventing and treating adverse events associated with chemotherapy drug treatment of a cancer patient.
  • the Investigation Product is a formulation comprising capsules that contain 9 probiotic microorganisms of the genera Lactobacillus and Bifidobacterium , as well as 10 digestive enzymes, and is being tested for its efficacy as part of a treatment regimen for patients with colon cancer.
  • DBR consists of capsules containing a proprietary blend of probiotics (116.20 mg total weight); specifically, Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus casei, Lactobacillus paracasei, and digestive enzymes (272.65 mg total weight); specifically, amylase, glucoamylase, lipase, bromelain, maltase, lactase, hemicellulose, xylanase, papain, and invertase.
  • the inactive ingredients are: inulin, rice extract, and hydroxypropyl methycellulose.
  • the Invesigational Product is manufactured in the United States under GMP conditions and is NSF certified. Placebo capsules will have the same packaging and labelling as the Investigational Product.
  • the capsules will be taken orally at 6 capsules daily (2 capsules in the morning, noon, and night) on days when chemotherapy is not administered. Eight capsules will be taken daily on each day of chemotherapy treatment (one additional capsule to be taken within two hours before chemotherapy and another additional capsule to be taken within two hours after the treatment session has been completed).
  • Cohort 2 Placebo supplementation for patients with stage IV colorectal cancer that are undergoing chemotherapy with FQLFQX .
  • Placebo capsules will be taken orally at 6 capsules daily on days when chemotherapy is not administered and 8 capsules daily on each day of scheduled chemotherapy treatment (one additional capsule to be taken within two hours before therapy and another additional capsule within two hours after the treatment session has been completed).
  • the capsules will be taken orally at 6 capsules daily on days when chemotherapy is not administered and 8 capsules daily on each day of scheduled chemotherapy treatment (one additional capsule to be taken within two hours before therapy and another additional capsule within two hours after the treatment session has been completed).
  • Placebo capsules will be taken orally at 6 capsules daily on days when chemotherapy is not administered and 8 capsules daily on each day of scheduled chemotherapy treatment (one additional capsule to be taken within two hours before therapy and another additional capsule within two hours after the treatment session has been completed).
  • CRP C-reactive protein
  • the duration of therapy with DBR for enrolled patients is 5 months.
  • Microbiome testing will demonstrate changes in the ratios of Firmicutes to Bacteroidetes that are associated with continued intake of the Investigational Product when analysis is performed at baseline (i.e. prior to Investigational Product administration, 3 months, and 5 months of the study).
  • Example 2 Evaluation of the bioactivity of a probiotic based formulation and its impact on a chemotherapeutic agent and an antibiotic
  • the following example is an in vitro study that was conducted to evaluate the activity of a probiotic based formulation comprising a blend of probiotic and digestive enzymes. This example validates the specific activity of a formulation disclosed in the present invention.
  • the supplement restored the Bacteroidetes to Firmicutes ratios in the colon reactors, increased the diversity of microbiota, and induced the production of microbial metabolites that elicited anti inflammatory cytokines in an in vitro model of intestinal inflammation.
  • preventative administration of the supplement resulted in full recovery of the gut microbial community after cessation of 5-FU and vancomycin treatment.
  • the probiotic with digestive enzymes supplement used herein comprises capsules is manufactured using proprietary methods and contains a blends of probiotics (116.20 mg total weight); specifically, Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus casei, Lactobacillus paracasei, and digestive enzymes (272.65 mg total weight); specifically, amylase, glucoamylase, lipase, bromelain, maltase, lactase, hemicellulose, xylanase, papain, and invertase.
  • the capsules used herein are the same formulation that would be administered in vivo.
  • the product was tested at an in vitro dose of 3 capsules/day before chemotherapy/antibiotic treatments, and 4 capsules/day during and after chemotherapy/antibiotic treatment (to be described below). This corresponds to an in vivo dosage of 6 capsules/day and 8 capsules/day before and after chemotherapy/antibiotic treatment, respectively.
  • the SHIME Set-un [00242] Briefly, the SHIME system consists of a series of double-jacketed vessels, simulating the digestive compartments that are initially inoculated with a fecal sample from a healthy adult donor using methods described previously [11].
  • the typical reactor setup consists of a succession of five reactors simulating the different parts of the human gastrointestinal tract.
  • the first two reactors simulate different steps in food uptake and digestion, with peristaltic pumps adding a defined amount of SHIME feed (140 mL 3x/day) and pancreatic and bile liquid (60 mL 3x/day), respectively to the stomach (VI) and small intestine (V2) compartment and emptying the respective reactors after specified intervals [11].
  • the last three compartments simulate the large intestine.
  • These reactors are continuously stirred, and they have a constant volume and pH control. Retention time and pH of the different vessels are chosen in order to resemble in vivo conditions in the different parts of the colon.
  • these reactors Upon inoculation with fecal microbiota, these reactors simulate the ascending (V3), transverse (V4) and descending (V5) colon.
  • Control Arm Chemotherapy and antibiotics; no supplement given.
  • Curative Arm Chemotherapy and antibiotics; probiotic with digestive enzymes supplement added at the same time as the other agents.
  • Preventative Arm Chemotherapy and antibiotics; probiotic with digestive enzymes supplement added prior to the other agents.
  • a two-week stabilization period allowed the microbial community to differentiate in the different reactors depending on the local environmental conditions.
  • the basic nutritional matrix was provided to the SHIME to support diversity of the gut microbiota originally present in the fecal inoculum.
  • the third arm of the SHIME setup (preventive arm; PREV), already received 3 capsules/day during the stabilization period (corresponding to an in vivo dose of 6 capsules/day).
  • lactate the precursor of SCFA
  • concentrations of lactate, the precursor of SCFA were also monitored using a d- lactate/l-lactate kit (R-Biopharm, Mannheim, Germany), according to the manufacturer's protocols.
  • SHIME experiments the following groups were quantified via quantitative PCR (qPCR; once/week): Bacteroidetes phylum, Firmicutes phylum, Lactobacillus spp. and Bifidobacterium spp. as previously reported [251].
  • 16S ribosomal RNA (rRNA) sequencing was used to analyze samples from the SHIME reactors to identify and compare the microorganisms using similar methods as published elsewhere [252].
  • the Illumina sequencing method was used to amplify microbial sequences until a saturation level was reached. Information on a broad spectrum of OTUs was obtained (>100 different of the most dominant OTUs), however, the results were presented as proportional values versus the total amount of sequences within each sample, thus providing semi-quantitative results.
  • the methodology used primers that span 2 hypervariable regions (V3-V4) of the 16S rDNA. Using a paired sequencing approach, sequencing of 2x250 bp resulted in 424 bp amplicons.
  • the Simpson reciprocal index was calculated as a measure of diversity and evenness of the microbiota as described previously [253].
  • An increase in the Simpson reciprocal index reflects a diversity increase, with 1 being the lowest possible number, and the number of bacterial species/OTUs present in the sample being the maximal number. The index will approach the maximal value when the OTU distribution is more even. The higher the index, the larger the diversity and the larger the evenness.
  • Caco-2 cells The co-culture experiment was performed as previously described [254] H3riefly, Caco-2 cells (HTB-37; American Type Culture Collection) were seeded in 24-well semi-permeable inserts (0.4 pm pore size) at a density of 1 x 10 5 cells/insert. Caco-2 monolayers were cultured for 14 days, with three medium changes/week, until a functional cell monolayer was obtained. Cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) containing 25 mM glucose and 4 mM glutamine and supplemented with 10 mM HEPES and 20% (v/v) heat-inactivated (HI) fetal bovine serum (FBS).
  • DMEM Dulbecco's Modified Eagle Medium
  • HI heat-inactivated
  • FBS heat-inactivated fetal bovine serum
  • THP-1 cells THP1 cells (InvivoGen) were maintained in Roswell Park Memorial Institute (RPMI) 1640 medium containing 11 mM glucose and 2 mM glutamine, supplemented with 10 mM HEPES, 1 mM sodium pyruvate and 10% (v/v) HI-FBS. THP1 cells were seeded in 24- well plates at a density of 5 x 10 5 cells/well and treated with 100 ng/mL of PMA for 48 hours (h). PMA induces the differentiation of the cells into macrophage-like cells.
  • RPMI Roswell Park Memorial Institute
  • Caco-2/THP-l co-cultures To mimic the interface between host immune cells and the fermentation products of the gut microbiome, in vitro experiments were conducted based on previous studies by Satsu and colleagues [255]. In this setup, the colonic suspensions collected from the SHIME are brought in contact with the apical side of the co-cultures (i.e. Caco-2 cells). The effects observed on the basolateral chamber where the THP-l cells reside are mediated indirectly by signals produced by the Caco-2 cells and/or by the transport of micro- and macro-molecules.
  • the apical compartment containing Caco-2 cells was filled with sterile- filtered (0.22 pm) colonic SHIME suspensions (diluted 1:5 (v/v) in Caco-2 complete medium). Cells were also treated apically with 12 mM Sodium butyrate (NaB) (Sigma- Aldrich) as a positive control in experiments establishing the system.
  • the basolateral compartment containing THP1 cells was filled with Caco-2 complete medium. Cells were also exposed to Caco-2 complete medium in both chambers in control experiments.
  • THP- 1 cells were stimulated with Caco-2 complete medium containing 500 ng/mL of ultrapure LPS (. Escherichia coli K12, InvivoGen). Cells were also stimulated at the basolateral side with LPS in combination with 1 pM hydrocortisone (HC) (Sigma-Aldrich) and medium without LPS (LPS-) in control experiments. Cultures were incubated at 37 degrees Celcius in a humidified atmosphere of air/C0 2 (95:5, v/v).
  • HC hydrocortisone
  • LPS- medium without LPS
  • the basolateral supernatants were collected for cytokine measurement (human IL-6 and IL-10) by Luminex. multiplex (Affymetrix-eBioscience) according to the manufacturers’ instructions. All treatments were done in triplicate.
  • the probiotic with digestive enzymes formulation increases fermentation activity in the simulated gut microenvironment:
  • the consumption of acid and base reflects the overall microbial activity in the SHIME reactors representing the proximal and distal colon. Generally speaking, there are distinct bacterial populations that are native to the proximal and distal colon regions, reflecting the different requirements for digestion in each segment. Ligures 1A and 1B depict the average weekly acid/base consumption during the control and treatment periods (i.e. before and after 5-LU/vancomycin treatment).
  • the treatment period consisted of one week of 5-LU/vancomycin followed by three weeks without these agents during which time recovery from 5-FU/vancomycin could be monitored and compared for the experimental treatment arms, as follows: 1) Control arm: receiving no supplement; 2) Preventative arm that had already been receiving the probiotic with digestive enzymes supplement all through the previous stabilization and control periods; and. 3; The curative arm that commenced supplementation with the probiotic with digestive enzymes supplement only at the start of 5-FU/vancomycin administration.
  • SCFA The abundant SCFA, acetate, propionate and butyrate, are generated by fermentation of dietary fibers by gut microbiota. SCFA have a plethora of health-promoting effects through their interactions with metabolite- sensing G protein-coupled receptors on the gut epithelium and on immune cells. In these experiments, we monitored the production of these three SCFA in the proximal and distal colon reactors, comparing pre- and post-5- FU/vancomycin treatments in the control (non-supplemented), curative, and preventative arms that were treated with the probiotic with digestive enzymes supplement.
  • Chemotherapy treatment resulted in a decrease in acetate levels in both the proximal and distal colon reactors. Although the recovery of acetate did not occur in the proximal colon, preventative treatment with the probiotic with digestive enzymes supplement increased acetate in both control and 5-FU/vancomycin treatment periods in the distal colon, suggesting that the pretreatment with the supplement offsets the adverse impact of the drugs on microbial metabolism.
  • Figure 2 also shows the results for butyrate production in the SHIME reactors, a primary product of Clostridium clusters IV and XlVa (phylum Firmicutes).
  • butyrate is largely metabolized by intestinal epithelial cells where it serves as an energy source as well as a homeostatic factor for normal colonic cell turnover and repair processes.
  • the expected result was obtained whereby 5-FU/vancomycin treatment strongly decreased butyrate levels in both the proximal and distal colon reactors.
  • Supplementation of the reactors with curative and preventative administration of the probiotic with digestive enzymes supplement resulted in improved butyrate production in the proximal and distal colon.
  • the differences between the curative and preventative arms were not statistically different in either of the reactors.
  • Figure 3 show the effects of a curative (CUR) and preventive (PREV) administration of the probiotic with digestive enzymes supplement as compared to a control SHIME (CTRF) on luminal Factobacillus (left panels) and Bifidobacterium (right panels) levels (16S rDNA copies/mF) in the proximal (PC; top panels) and distal colon (DC; bottom panels).
  • CUR curative
  • PREV preventive
  • CTRF control SHIME
  • the data are represented for the control weeks (Cl, C2)andtreatment weeks (TR1, TR2, TR3, and TR4. It should be noted that 5-FU/vancomycin was administered to the system in TR1 and discontinued in TR2- TR4.
  • Figure 4 shows the effect of a curative (CUR) and preventive (PREV) administration of the probiotic with digestive enzymes supplement as compared to a control SHIME (CTRL) on luminal Bacteroidetes, and Finnicutes levels (16S rDNA copies/mL) in the proximal (PC; top panels) and distal colon (DC; bottom panels).
  • CUR curative
  • PREV preventive
  • the data are represented for the control weeks (Cl, C2) and treatment weeks (TRI, TR2, TR3, and TR4. It should be noted that 5-FU/vancomycin was administered to the system in TRI and discontinued in TR2-TR4.
  • Preventative administration of the probiotic with digestive enzymes supplement was being administered throughout the control periods (Cl and C2), while curative supplementation of the probiotic with digestive enzymes formulation was initiated and maintained at TR1-TR4. () indicates statistically significant differences relative to the preceding period, while different letters indicate a statistical difference between different treatments; p ⁇ 0.05.
  • l6S-targeted Illumina sequencing was used whereby amplified 16S rRNA marker gene sequences are clustered into taxonomic units of bacteria.
  • the Simpson diversity index was calculated. The lowest possible value of the index is 1, representing a community consisting of only one Operational Taxonomic Unit (OTU). The highest possible value is the total number of OTUs, and the higher the index, the larger the diversity and the larger the evenness.
  • OTU Operational Taxonomic Unit
  • Table 1 shows the Simpson Diversity Index results to evaluate the impact of the probiotic with digestive enzymes supplement on diversity changes in the microbiota in the SHIME that are caused by 5-FU and vancomycin.
  • the supplement given preventatively had the most significant impact on increasing the microbial diversity.
  • the highest diversity was observed in the negative control (i.e. no supplement) following recovery from 5-FU and vancomycin (TR4).
  • Curative treatment with the supplement also increased the microbial diversity in both the proximal and distal colons.
  • FIG. 5 shows the abundance(%) of the dominant phyla in the lumen of the proximal (PC) and distal colon (DC) of the SHIME upon a curative (CUR) and preventive (PREV) administration of the probiotic with digestive enzymes supplement as compared to control (CTRL) the end of the control week 2 (C) and treatment week 4 (TR) period.
  • CUR curative
  • PREV preventive
  • preventative treatment prior to 5-FU/vancomycin treatment did not cause any major changes at the phylum level in the proximal colon.
  • preventative supplementation resulted in increases in abundance of Actinobacteria and reductions in Bacteroidetes and Proteobacteria.
  • the probiotic with digestive enzymes formulation modulates cytokine production in a model of intestinal inflammation:
  • THP-l cells derived from acute leukemia, differentiate into macrophages upon culture with phorbol l2-myristate l3-acetate (PMA), and can then be activated toward a highly pro-inflammatory phenotype upon treatment with lipopolysaccharide (LPS).
  • PMA phorbol l2-myristate l3-acetate
  • LPS lipopolysaccharide
  • Caco-2 cells were placed on top of PMA- treated THP-l cells, on the apical and basolateral sides of culture chambers, respectively.
  • Table 2 outlines the corresponding statistical analyses performed using two- way ANOVA with Dunnett's multiple comparisons test. Significance is depicted where (*), (**), (***) and (****) represent p ⁇ 0.05, p ⁇ 0.01, p ⁇ 0.001 and p ⁇ 0.0001, respectively.
  • Ns non- specific; PC: proximal colon; DC: distal colon.
  • a murine model will be implemented to evaluate the effect of a probiotic with digestive enzymes formulation on ovarian failure caused by chemotherapy.
  • C57BL6 mice Weight 20-25 g
  • Age 4-6 weeks will be allotted randomly to three different groups, and each had 6 mice; group 1; the control group (no chemotherapy; placebo supplement), group 2; the chemotherapy group (chemotherapy; placebo supplement), group 3 (treatment arm; the mice will be given chemotherapy and a probiotic with digestive enzymes supplement).
  • the supplement will be a formulation containing a proprietary blends of probiotic; specifically, Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus casei, Lactobacillus paracasei, and digestive enzymes; specifically, amylase, glucoamylase, lipase, bromelain, maltase, lactase, hemicellulose, xylanase, papain, and invertase.
  • probiotic specifically, Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus case
  • the probiotics with digestive enzymes formulation will be diluted at a concentration of (65 pg/mL) in the drinking water of the mice.
  • a placebo capsule will be diluted into the drinking water.
  • a combination chemotherapy (CTX) of busulfan (12 mg/kg) and cyclophosphamide (70 mg/kg) (Sigma Aldrich., St. Louis, MO, USA) will beadministered intra-peritoneal to mice in groups 2 and 3.
  • mice receiving chemotherapy will become infertile and posses enhanced levels of follicle stimulating hormone (FSH).
  • FSH follicle stimulating hormone
  • Mice that received the probiotic with digestive enzymes supplement will be compared in terms of the percentages of animals who developed ovarian failure vs. controls, as well as with respect to the blood concentrations of FSH. The results will show that fewer of the chemotherapy-treated mice that receive the probiotic with digestive enzyme formulation demonstrate an elevation of FSH levels and the FSH levels will be statistically lower in this group vs. the placebo group that will receive chemotherapy.
  • Lacy, M.Q., et al., Idiotype-pulsed antigen-presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival.
  • Hus, L, et al., Vaccination ofB-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response.

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Abstract

L'invention concerne des méthodes, des compositions et des protocoles visant à augmenter l'efficacité de traitements anticancéreux à l'aide de formulations comprenant des probiotiques et des enzymes digestives. Dans des modes de réalisation préférés, lesdites formulations de probiotiques associés à des enzymes digestives sont constituées d'un ou de plusieurs des éléments suivants : Bifidobacterium infantis, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus casei, Lactobacillus paracasei, et également d'un mélange d'enzymes digestives, comprenant, sans caractère limitatif, l'amylase, la glucoamylase, la lipase, la bromélaïne, la maltase, la lactase, l'hémicellulase, la xylanase, la papaïne et l'invertase.
PCT/US2019/020121 2018-02-28 2019-02-28 Augmentation de l'efficacité de traitements anticancéreux à l'aide de compositions à base de probiotiques Ceased WO2019169179A1 (fr)

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CN114053311A (zh) * 2020-07-29 2022-02-18 景岳生物科技股份有限公司 增加化疗药物吉西他滨抑制胰脏癌效果的益生菌组合物及其用途
CN114344342A (zh) * 2021-12-29 2022-04-15 广东南芯医疗科技有限公司 副干酪乳杆菌Lp.R3在制备预防或治疗肿瘤药物中的应用
CN114540227A (zh) * 2022-02-21 2022-05-27 南京医科大学 一种具有抑制肝癌肿瘤生长的副干酪乳杆菌l511及其用途
WO2022125805A1 (fr) * 2020-12-11 2022-06-16 Materia Therapeutics Inc. Traitement du cancer à l'aide de bosentan en combinaison avec un inhibiteur de point de contrôle
CN116144724A (zh) * 2023-04-23 2023-05-23 养系列(山东)生物科技有限公司 一种肿瘤患者康复用复合肽、喷雾剂及其制备方法
WO2023090903A1 (fr) * 2021-11-17 2023-05-25 씨제이바이오사이언스 주식회사 Composition pour la prévention ou le traitement du cancer ou d'une inflammation, comprenant une nouvelle souche de leuconostoc mesenteroides, et méthode de prévention ou de traitement du cancer ou d'une inflammation à l'aide de celle-ci
WO2023141119A1 (fr) * 2022-01-18 2023-07-27 The Regents Of The University Of California Compositions bactériennes et méthodes de traitement du cancer et de maladies immunitaires
CN116747227A (zh) * 2023-08-12 2023-09-15 杭州市第一人民医院 泊马度胺在制备抗细菌感染药物中的应用
CN117084410A (zh) * 2022-03-24 2023-11-21 景岳生物科技股份有限公司 一种包含副干酪乳杆菌的组合物、及其经由细胞焦亡、细胞周期停滞而抑制鼻咽癌的用途
EP4279131A1 (fr) * 2022-05-20 2023-11-22 Bioithas S.L. Compositions probiotiques pour le traitement de l'alopécie
CN118526523A (zh) * 2024-07-26 2024-08-23 山东大学齐鲁医院 一种治疗脑胶质母细胞瘤的药物组合物
EP4438050A1 (fr) 2023-03-31 2024-10-02 Igen Biolab Group AG Composition postbiotique pour administration orale pour le traitement des tumeurs solides
WO2024199728A1 (fr) * 2023-03-31 2024-10-03 Igen Biolab Group Ag Composition postbiotique d'administration orale comprenant des lysats bactériens pour le traitement de tumeurs solides
CN118806867A (zh) * 2024-09-14 2024-10-22 吉林天三奇药业有限公司 一种治疗肿瘤的中药发酵龙眼人参肽益生菌粉
US12156893B2 (en) 2016-12-15 2024-12-03 The Regents Of The University Of California Oral composition comprising lactic acid bacteria for regulating immune responses and methods related thereto
WO2024251031A1 (fr) * 2023-06-06 2024-12-12 四川厌氧生物科技有限责任公司 Composition probiotique pour la prévention et le traitement de la diarrhée liée au traitement antitumoral et son utilisation
EP4527398A1 (fr) * 2023-09-22 2025-03-26 Igen Biolab Group AG Utilisation thérapeutique d'une composition postbiotique dans le cancer du côlon et/ou du poumon

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US11969448B2 (en) 2020-07-29 2024-04-30 Genmont Biotech Inc. Method for improving an effect of chemotherapeutic drug of gemcitabine on inhibiting pancreatic cancer and improving side effect of chemotherapeutic drug of Gemcitabine
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WO2022125805A1 (fr) * 2020-12-11 2022-06-16 Materia Therapeutics Inc. Traitement du cancer à l'aide de bosentan en combinaison avec un inhibiteur de point de contrôle
CN112791106B (zh) * 2021-01-20 2022-03-08 北京科拓恒通生物技术股份有限公司 药物组合物及其治疗疾病的用途
CN112791106A (zh) * 2021-01-20 2021-05-14 北京科拓恒通生物技术股份有限公司 药物组合物及其治疗疾病的用途
WO2023090903A1 (fr) * 2021-11-17 2023-05-25 씨제이바이오사이언스 주식회사 Composition pour la prévention ou le traitement du cancer ou d'une inflammation, comprenant une nouvelle souche de leuconostoc mesenteroides, et méthode de prévention ou de traitement du cancer ou d'une inflammation à l'aide de celle-ci
CN114344342A (zh) * 2021-12-29 2022-04-15 广东南芯医疗科技有限公司 副干酪乳杆菌Lp.R3在制备预防或治疗肿瘤药物中的应用
WO2023141119A1 (fr) * 2022-01-18 2023-07-27 The Regents Of The University Of California Compositions bactériennes et méthodes de traitement du cancer et de maladies immunitaires
CN114540227A (zh) * 2022-02-21 2022-05-27 南京医科大学 一种具有抑制肝癌肿瘤生长的副干酪乳杆菌l511及其用途
CN117084410A (zh) * 2022-03-24 2023-11-21 景岳生物科技股份有限公司 一种包含副干酪乳杆菌的组合物、及其经由细胞焦亡、细胞周期停滞而抑制鼻咽癌的用途
EP4279131A1 (fr) * 2022-05-20 2023-11-22 Bioithas S.L. Compositions probiotiques pour le traitement de l'alopécie
EP4438050A1 (fr) 2023-03-31 2024-10-02 Igen Biolab Group AG Composition postbiotique pour administration orale pour le traitement des tumeurs solides
WO2024199728A1 (fr) * 2023-03-31 2024-10-03 Igen Biolab Group Ag Composition postbiotique d'administration orale comprenant des lysats bactériens pour le traitement de tumeurs solides
CN116144724B (zh) * 2023-04-23 2023-07-18 养系列(山东)生物科技有限公司 一种肿瘤患者康复用复合肽、喷雾剂及其制备方法
CN116144724A (zh) * 2023-04-23 2023-05-23 养系列(山东)生物科技有限公司 一种肿瘤患者康复用复合肽、喷雾剂及其制备方法
WO2024251031A1 (fr) * 2023-06-06 2024-12-12 四川厌氧生物科技有限责任公司 Composition probiotique pour la prévention et le traitement de la diarrhée liée au traitement antitumoral et son utilisation
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EP4527398A1 (fr) * 2023-09-22 2025-03-26 Igen Biolab Group AG Utilisation thérapeutique d'une composition postbiotique dans le cancer du côlon et/ou du poumon
CN118526523A (zh) * 2024-07-26 2024-08-23 山东大学齐鲁医院 一种治疗脑胶质母细胞瘤的药物组合物
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