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WO2021245677A1 - Compositions et méthodes pour le traitement d'affections néoplasiques à un stade précoce et dysplasiques - Google Patents

Compositions et méthodes pour le traitement d'affections néoplasiques à un stade précoce et dysplasiques Download PDF

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Publication number
WO2021245677A1
WO2021245677A1 PCT/IL2021/050668 IL2021050668W WO2021245677A1 WO 2021245677 A1 WO2021245677 A1 WO 2021245677A1 IL 2021050668 W IL2021050668 W IL 2021050668W WO 2021245677 A1 WO2021245677 A1 WO 2021245677A1
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Prior art keywords
dysplastic
pharmaceutical composition
early
tissue
cannabinoid
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Ceased
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PCT/IL2021/050668
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English (en)
Inventor
Gabriel Adam YARIV
Eitan SCAPA
Eyal Ballan
Eyal BARAD
Ilan HOCHMAN
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Digestix Bioscience Inc
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Digestix Bioscience Inc
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Publication of WO2021245677A1 publication Critical patent/WO2021245677A1/fr
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/348—Cannabaceae
    • A61K36/3482—Cannabis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0031—Rectum, anus
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods and compositions for inhibiting cancer progression of dysplastic or early-stage neoplastic conditions.
  • Polyps are referred to as abnormal tissue growth projecting from the inner most epithelial cell layer (a.k.a the "mucosal layer"). Most polyps are small and less than 5 mm wide, but larger polyps also exist. Colorectal polyps are the most common in the gastrointestinal tract, but polyps can also develop in other tissues where there are mucous membranes (e.g., ear canal, cervix, esophagus, stomach, small intestine, nasal cavity, uterus, oropharynx, and nasopharynx). Most polyps are benign. Nevertheless, due to their abnormal cell growth nature, polyps can progress and become malignant.
  • mucous membranes e.g., ear canal, cervix, esophagus, stomach, small intestine, nasal cavity, uterus, oropharynx, and nasopharynx.
  • Most polyps are benign. Nevertheless, due to their abnormal cell growth nature
  • LSTs lateral spreading tumors
  • EMR endoscopic mucosal resection
  • CBG cannabigerol
  • R. Nallathambi et ah demonstrated that C. sativa compounds interact synergistically, exhibiting cytotoxic activity against colon cancer cells and induce cell cycle arrest, apoptotic cell death, and distinct gene expression.
  • Cannabinoid extracts of C. sativa compounds were also found to be active on adenomatous polyps (R. Nallathambi et ah, Cannabis and Cannabinoid Research; Volume 3.1, 2018).
  • WO/2011/110866 discloses the use of the phytocannabinoids Tetrahydrocannabinol (THC), Tetrahydrocannabinolic acid (THCA), Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabigerol (CBG) and Cannabichromene (CBC), in an isolated form or THC, THCA, CBD, CBDA, CBG and CBC in the form of a botanical drug substance (BDS) in the treatment of cancer.
  • THC Tetrahydrocannabinol
  • THCA Tetrahydrocannabinolic acid
  • CBD Cannabidiol
  • CBDA Cannabigerol
  • CBD Cannabichromene
  • BDS botanical drug substance
  • the present invention provides methods and compositions for treating a tissue bearing a dysplastic or early-stage neoplastic condition.
  • the invention is particularly useful in treating pre-cancerous or early-stage neoplastic conditions, especially in inhibiting/decreasing recurrence of dysplastic or early-stage neoplastic polyps or lesions.
  • the invention pertains to inventive methods of treating subjects afflicted with a dysplastic or early-stage neoplastic lesion and includes applying pharmaceutically active compositions to a tissue proximate the dysplastic or early-stage neoplastic lesion and removing the dysplastic or early-stage neoplastic lesion.
  • an aspect of the invention provides a method of treating a dysplastic or early-stage neoplastic lesion in a target tissue of a subject, the method comprising: providing a pharmaceutical composition comprising a therapeutic effective amount of one or more agents having a malignant/cancer progression inhibitory effect on dysplastic or early-stage neoplastic cells; introducing a device configured to deliver the pharmaceutical composition to a tissue afflicted with/bearing the dysplastic or early-stage neoplastic lesion; applying the pharmaceutical composition to the tissue proximate the dysplastic or early- stage neoplastic lesion; introducing to the target tissue a tissue resection device; and removing the dysplastic or early-stage neoplastic lesion from the target tissue using the tissue resection device, thereby treating the dysplastic or early-stage neoplastic lesion in the subject.
  • the dysplastic or early-stage neoplastic lesion is characterized by one or more of: an in- situ neoplasm (i.e., did not spread to other organs), lacks lymphovascular invasion, exhibits a depth of invasion of less than 1.5 mm into the submucosa, lacks high-grade tumor budding, and exhibits tumor-free lateral and deep margins of the excised lesion.
  • the dysplastic or early-stage neoplastic lesion is characterized by one or more of: an in-situ neoplasm, lack of lymphovascular invasion, exhibits a depth of invasion of less than 1 mm into the submucosa, and lacks high-grade tumor budding.
  • the one or more agent having a malignant/cancer progression inhibitory effect on cells derived from a dysplastic or early-stage neoplastic polyp or lesion is selected from a cannabis derived compound, an anti-malignant agent other than a cannabis derived compound, or a combination thereof.
  • the pharmaceutical composition is applied into the mucosa and/or submucosal tissue proximate the dysplastic or early stage neoplastic lesion.
  • the pharmaceutical composition is applied into the mucosa and/or submucosal tissue, under the dysplastic or early-stage neoplastic lesion. In one or more embodiments, the pharmaceutical composition is applied into the mucosa and/or submucosal tissue, at the periphery of the dysplastic or early-stage neoplastic lesion. In one or more embodiments, the pharmaceutical composition is applied into the mucosa and/or submucosal tissue, at the periphery of and below the dysplastic or early-stage neoplastic lesion. In one or more embodiments, the pharmaceutical composition is not applied into the dysplastic or early- stage neoplastic lesion. In one or more embodiments, the pharmaceutical composition is applied on top of the tissue, at the periphery of the dysplastic or early-stage neoplastic lesion.
  • the periphery of the dysplastic or early-stage neoplastic lesion is a perimeter of less than 20 mm.
  • the device configured to deliver the composition is a catheter connected at a proximal end thereof to a syringe and at a distal end thereof to a needle and the composition is applied into the submucosal tissue by injection.
  • the device configured to deliver the composition includes at a distal end thereof a sprayer and the composition is applied onto the mucosal/submucosal tissue by spraying. In one or more embodiments, the device configured to deliver the composition includes at a distal end thereof a dropper and the composition is applied onto the mucosal/submucosal tissue by dripping. In one or more embodiments, the device configured to deliver the composition includes at a distal end thereof an applicator for delivering the composition onto the mucosal/submucosal tissue by spreading.
  • the target tissue is a tissue bearing a dysplastic or early- stage neoplastic lesion.
  • the tissue afflicted with/bearing a dysplastic or early-stage neoplastic lesion is a tissue having a mucous membrane.
  • the tissue having a mucous membrane is selected from the group consisting of colon, ear canal (external acoustic meatus), cervix, esophagus, stomach, small intestine, nasal cavity, uterus, urethra, anus, oral cavity, oropharynx, and nasopharynx.
  • the tissue afflicted with/bearing a dysplastic or early-stage neoplastic lesion is selected from the group consisting of: colon, uterine, skin, breast, cervix, bladder, stomach, oral cavity, esophagus, liver, pancreas, small intestine and prostate.
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colorectal carcinoma, endometrial cancer, gastro intestinal cancer, head and neck squamous cell carcinoma, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, cancer of the external auditory canal, cervical cancer, esophagus cancer, nasal and paranasal sinus cancer, urethral cancer, oral cavity cancer, oropharyngeal cancer, nasopharyngeal cancer, and thyroid cancer.
  • the target tissue is colon tissue and the dysplastic or early- stage neoplastic lesion is Lateral Spreading Tumor (LST).
  • the Lateral Spreading Tumor is selected from a sessile, flat, flat-elevated, depressed LST or combinations thereof.
  • the step of removing the dysplastic or early-stage neoplastic lesion is conducted following the step of delivering/applying the pharmaceutical composition. In one or more embodiments, the step of removing the dysplastic or early-stage neoplastic lesion is conducted prior to the step of applying the pharmaceutical composition. In one or more embodiments, the step of applying the pharmaceutical composition is conducted prior to and following the step of removing the dysplastic or early-stage neoplastic lesion.
  • one or more of a cannabis derived compound is a cannabinoid selected from the group consisting of: one or more of a purified cannabinoid, one or more of a cannabis plant extract or fraction, one or more of a synthetic cannabinoid, a cannabis plant extract enriched with one or more cannabinoid, and a combination thereof.
  • the one or more of cannabinoid is selected from the group consisting of: Tetrahydrocannabinol (THC), delta-8-Tetrahydrocannabinol (THC-A8), (-)- trans-A 9 -tetrahydrocannabinol (THC-A9), cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabinolic acid (THCA), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabinol (CBN) cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabielso
  • THC Tetra
  • the one or more of cannabinoid is selected from the group consisting of: THC-A8, THC-A9, CBC, CBN, CBDV, CBD, THCV, CBL, CBG, THCA, CBDA, CBDVA, CBNA, CBCA, CBGA.
  • the cannabinoid is a combination of at least two cannabinoids selected from the group consisting of CBCA, CBDV, THCV, CBGA, CBDVA.
  • the cannabinoid is a combination of no more than two cannabinoids selected from the group consisting of CBCA and CBDV, CBCA and THCV, CBCA and CBGA, CBDV and CBGA, CBDV and CBDVA, CBGA and CBDVA, and THCV and CBGA.
  • the agent is a cannabis derived compound and wherein the pharmaceutical composition comprises one or more of terpene and/or terpenoid.
  • the anti-malignant agent is selected from the group consisting of: a cytotoxic agent, a hormone, an antibody, an alkylating agent, an antimetabolite agent, an antibiotic, a non-steroidal anti-inflammatory (NSAID) drug, an organic solvent with an anti-malignant effect (e.g., DMSO and ethanol), a biological agent, and a combination thereof.
  • the NSAID is aspirin.
  • the biological agent is a small inhibitory RNA (i.e., SiRNA) that targets cellular RNA sequences associated with cancer development/progression/infiltration.
  • the pharmaceutical composition is delivered to the tissue by injection, spraying, dripping, spreading, patching or a combination thereof.
  • the pharmaceutical composition is provided within a patch, a scaffold, a viscous carrier, a liquid carrier or a combination thereof.
  • the viscous carrier is selected from hydroxyethyl starch and sodium hyaluronate.
  • the pharmaceutical composition comprises one or more of an oily liquid, micelles, liposomes, a surfactant and a combination thereof.
  • the method further comprises providing a biological sample of the dysplastic or early-stage neoplastic lesion, analyzing efficacy of one or more anti-malignant malignant agents on the sample; and identifying the agents effective in inhibiting malignancy of the biological sample.
  • the method further comprises providing a biological sample of the dysplastic or early-stage neoplastic polyp or lesion, conducting a histological evaluation of the sample to thereby determine suitability and responsiveness to one or more anti-malignant agents.
  • the method further comprises applying a pharmaceutical composition comprising the agents effective in inhibiting malignancy of the biological sample in subsequent treatment or monitoring procedures.
  • the method further comprises administering orally or rectally a pharmaceutical composition comprising one or more malignant inhibitory agents prior to and/or after the target tissue treatment.
  • application of the pharmaceutical composition inhibits dysplastic or early-stage neoplastic lesion recurrence in the target tissue following removal thereof.
  • the present invention provides a method of treating a dysplastic or early-stage neoplastic condition in a target tissue, the method comprising introducing into the target tissue a tissue resection device; removing a dysplastic or early-stage neoplastic lesion from the target tissue; providing a biological sample of the dysplastic or early-stage neoplastic lesion; analyzing efficacy of one or more anti-malignant agents on the biological sample; identifying the one or more agents exhibiting malignant inhibitory effect on the sample; and applying a pharmaceutical composition comprising the one or more agents effective in inhibiting malignancy of the biological sample in subsequent treatment or monitoring procedures.
  • the step of analyzing efficacy comprises contacting cells derived from the biological sample with a plurality of the anti-malignant agents and detecting a signal indicative of an anti-malignant effect relative to a control.
  • subsequent tissue treatment procedures include administering orally or rectally the pharmaceutical composition.
  • subsequent tissue treatment or monitoring procedures include treating a recurrent dysplastic or early-stage neoplastic lesion comprising introducing a device configured to deliver the pharmaceutical composition to a tissue proximate a dysplastic or early-stage neoplastic lesion; applying the pharmaceutical composition to the tissue proximate the dysplastic or early- stage neoplastic lesion; introducing to the target tissue a tissue resection device; and removing the dysplastic or early-stage neoplastic or lesion from the target tissue using the tissue resection device.
  • the composition is applied into the submucosal tissue proximate the dysplastic or early-stage neoplastic lesion.
  • the device for application of the composition is a syringe connected to a catheter needle and the composition is applied into the submucosal tissue by injection.
  • the target tissue is any tissue bearing a dysplastic or early- stage neoplastic or lesion and is optionally selected from the group consisting of: colon, uterine, skin, breast, cervix, bladder, stomach, oral cavity, esophagus, liver, pancreas, small intestine and prostate.
  • the target tissue is colon tissue and the dysplastic or early-stage neoplastic lesion is Lateral Spreading Tumor (LST).
  • the Lateral Spreading Tumor is selected from a sessile, flat, flat-elevated, depressed LST or combinations thereof.
  • the agent is selected from a cannabis derived compound, an anti-malignant agent other than a cannabis derived compound, and a combination thereof.
  • the one or more of a cannabis derived compound is a cannabinoid selected from the group consisting of: one or more of a purified cannabinoid, one or more of a cannabis plant extract or fraction thereof, one or more of a synthetic cannabinoid, a cannabis plant extract enriched with one or more cannabinoid, and a combination thereof.
  • the one or more of cannabinoid is selected from the group consisting of: Tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabinolic acid (THCA), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabinol (CBN) cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabielsoin (CBE), cannabicitran (CBT), cannabidivarinic acid (CBDVA), cannabinolic acid (CBNA), cannabichromenic acid
  • THC Tetra
  • the agent is a cannabis derived compound
  • the pharmaceutical composition comprises one or more of terpene and/or terpenoid.
  • the anti-malignant agent is selected from the group consisting of: a cytotoxic agent, a hormone, an antibody, an alkylating agent, an antimetabolite agent, an antibiotic, a non-steroidal anti-inflammatory (NSAID) drug, an organic solvent selected from DMSO and ethanol, a biological agent, and a combination thereof.
  • the pharmaceutical composition is applied to the tissue by injection, spraying, dripping, spreading, patching or a combination thereof.
  • the pharmaceutical composition is provided within a patch, a scaffold, a viscous carrier, a liquid carrier or a combination thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more agents having a malignant inhibitory effect on dysplastic or early-stage neoplastic cells, and a pharmaceutically acceptable carrier for use in the treatment of a target tissue afflicted with a dysplastic or early- stage neoplastic lesion, wherein the pharmaceutical composition is suitable for use by application thereof to a site proximate the dysplastic or early-stage neoplastic lesion in the target tissue.
  • the pharmaceutical composition is prescribed for administration following and/or before removal of the dysplastic or early-stage neoplastic lesion. In one or more embodiments, the pharmaceutical composition is prescribed for application to the tissue by injection, spraying, dripping, spreading, patching or a combination thereof.
  • the target tissue is any tissue bearing a dysplastic or early- stage neoplastic lesion and is optionally selected from the group consisting of: colon, uterine, skin, breast, cervix, bladder, stomach, oral cavity, esophagus, liver, pancreas, small intestine and prostate.
  • the target tissue is colon tissue and wherein the dysplastic or early-stage neoplastic lesion is Lateral Spreading Tumor (LST).
  • the Lateral Spreading Tumor is selected from a sessile, flat, flat-elevated, depressed LST or combinations thereof.
  • the agent is selected from a cannabis derived compound, an anti-malignant agent other than a cannabis derived compound, and a combination thereof.
  • the one or more of a cannabis derived compound is a cannabinoid selected from the group consisting of: one or more of a purified cannabinoid, one or more of a cannabis plant extract or fraction thereof, one or more of a synthetic cannabinoid, a cannabis plant extract enriched with one or more cannabinoid, and a combination thereof.
  • the one or more of cannabinoid is selected from the group consisting of: Tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabinolic acid (THCA), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabinol (CBN) cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabielsoin (CBE), cannabicitran (CBT), cannabidivarinic acid (CBDVA), cannabinolic acid (CBNA), cannabichromenic acid
  • THC Tetra
  • the cannabinoid is selected from the group consisting of: THC-A8, THC-A9, CBC, CBN, CBDV, CBD, THCV, CBL, CBG, THCA, CBDA, CBDVA, CBNA, CBCA, CBGA and a combination thereof.
  • the cannabinoid is a combination of at least two cannabinoids selected from the group consisting of CBCA, CBDV, THCV, CBGA, CBDVA.
  • the cannabinoid is a combination of no more than two cannabinoids selected from the group consisting of a combination of CBCA and CBDV, a combination of CBCA and THCV, a combination of CBCA and CBGA, a combination of CBDV and CBGA, a combination of CBDV and CBDVA, a combination of CBGA and CBDVA, and a combination of THCV and CBGA.
  • the agent is a cannabis derived compound and the pharmaceutical composition comprises one or more of terpene and/or terpenoid.
  • the anti-malignant agent is selected from the group consisting of: a cytotoxic agent, a hormone, an antibody, an alkylating agent, an anti metabolite agent, an antibiotic, a non-steroidal anti-inflammatory (NSAID) drug, an organic solvent selected from DMSO and ethanol, a biological agent, and a combination thereof.
  • a cytotoxic agent a hormone, an antibody, an alkylating agent, an anti metabolite agent, an antibiotic, a non-steroidal anti-inflammatory (NSAID) drug, an organic solvent selected from DMSO and ethanol, a biological agent, and a combination thereof.
  • the pharmaceutical composition is provided within a patch, a scaffold, a viscous carrier, a liquid carrier or a combination thereof.
  • the viscous carrier comprises hydroxyethyl starch and sodium hyaluronate.
  • the pharmaceutical composition further comprises one or more of epinephrine, a dye, a complex sugar, a polymeric agent (e.g., a polymer having an inverse temperature - viscosity correlation), and a combination thereof.
  • FIG. 1 is a bar graph illustrating the viability of cells (% of viable cells) derived from a polyp vs. cells derived from a normal tissue adjacent the polyp taken from a patient, following treatment with cannabidiol (CBD) or vehicle (non-treated (NT)+DMSO).
  • CBD cannabidiol
  • NT non-treated
  • FIG. 2 is a bar graph illustrating the viability and synergistic effect of CBCA (at XI concentration - 14.5 m M; or X2 concentration - 29 mM) and CBDV (at XI concentration -
  • FIG. 3 is a bar graph illustrating the viability and synergistic effect of CBCA (at XI concentration - 14.5 mM; or X2 concentration - 29 mM) and THCV (at XI concentration - 20 mM; or X2 concentration - 40 mM) on polyp-derived colon cells.
  • FIG. 4 is a bar graph illustrating the viability and synergistic effect of CBCA (at XI concentration - 14.5 mM; or X2 concentration - 29 mM) and CBGA (at XI concentration -
  • FIG. 5 is a bar graph illustrating the viability effect of CBCA (at XI concentration -
  • FIG. 6 is a bar graph illustrating the viability and synergistic effect of CBDV (at XI concentration - 23.5 mM; or X2 concentration - 47 mM) and CBGA (at XI concentration -
  • FIG. 7 is a bar graph illustrating the viability and synergistic effect of CBDV (at XI concentration - 23.5 mM; or X2 concentration - 47 mM) and CBDVA (at XI concentration -
  • FIG. 8 is a bar graph illustrating the viability of CBDV (at XI concentration - 23.5 mM; or X2 concentration - 47 mM) and THCV (at XI concentration - 24 mM; or X2 concentration - 48 mM) on polyp-derived colon cells.
  • FIG. 9 is a bar graph illustrating the viability and synergistic effect of CBGA (at XI concentration - 25.6 mM; or X2 concentration - 51.2 mM) and CBDVA (at XI concentration - 25.6 mM; or X2 concentration - 51.2 mM) on polyp-derived colon cells.
  • FIG. 10 is a bar graph illustrating the viability and synergistic effect of THCV (at XI concentration - 20 mM; or X2 concentration - 40 mM) and CBGA (at XI concentration - 25.6 mM; or X2 concentration - 51.2 mM) on polyp-derived colon cells.
  • FIG. 11 is a bar graph illustrating the viability and additive effect of THCV (at XI concentration - 20 mM; or X2 concentration - 40 mM) and CBDVA (at XI concentration - 25.6 mM; or X2 concentration - 51.2 mM) on polyp-derived colon cells.
  • the present invention is directed to methods and compositions for treating subjects afflicted with early-stage neoplastic or dysplastic condition by application of agents, capable of inhibiting tumor progression, to tissue surrounding and/or tissue underlying the early-stage neoplastic or dysplastic lesion and by removing the early-stage neoplastic or dysplastic lesion.
  • agents capable of inhibiting tumor progression
  • tissue surrounding and/or tissue underlying the early-stage neoplastic or dysplastic lesion and by removing the early-stage neoplastic or dysplastic lesion.
  • the methods and compositions of the invention are applicable for various solid early- stage neoplastic or dysplastic polyps or lesions, particularly, but not necessarily for the treatment and recurrence prevention of neoplastic or dysplastic colorectal polyps, such as Lateral Spreading Tumor (LST).
  • LST Lateral Spreading Tumor
  • LST Lateral spreading tumors
  • EMR endoscopic mucosal resection
  • ESD endoscopic submucosal dissection
  • EMR electrospray recurrence recurrence recurrence recurrence .
  • ESD instead allows dissection of larger lesions in one piece, although the procedure is technically more difficult, much more time-consuming, mandates multiday hospital admission and has an increased risk of colon perforation.
  • the herein invention thus provides methods and compositions that are dedicated for reducing the recurrence rate of LTS or other neoplastic or dysplastic lesions by applying specific agents capable of eliminating residual cells with malignancy potential, thus inhibiting or preventing the recurrence of such lesions.
  • the early-stage neoplastic or dysplastic lesion is a Lateral Spreading Tumor (LST). In one or more embodiments, the early-stage neoplastic or dysplastic lesion does not include early-stage neoplastic or dysplastic conditions other than a Lateral Spreading Tumor (LST).
  • LST Lateral Spreading Tumor
  • an aspect of the invention pertains to a method of treating a dysplastic or early- stage neoplastic lesion in a target tissue of a subject, the method comprising: providing a pharmaceutical composition comprising a therapeutic effective amount of one or more agents having a malignant inhibitory effect on cells derived from a dysplastic or early-stage neoplastic lesion; introducing a device for application/administration/delivery of the pharmaceutical composition to a tissue proximate the dysplastic or neoplastic polyp or lesion; applying/administering/delivering the pharmaceutical composition to the tissue proximate the dysplastic or early-stage neoplastic lesion; introducing to the target tissue a tissue resection device; and removing the dysplastic or neoplastic lesion from the target tissue using the tissue resection device, thereby treating the dysplastic or early-stage neoplastic lesion in the subject.
  • Another aspect of the herein invention pertains to a method of treating a dysplastic or early-stage neoplastic condition in a target tissue, the method comprising introducing into the target tissue a tissue resection device; removing a dysplastic or early-stage neoplastic lesion from the target tissue; providing a biological sample of the dysplastic or early-stage neoplastic lesion; analyzing efficacy of one or more anti-malignant agents on the biological sample; identifying the one or more agents exhibiting malignant inhibitory effect on the sample; and applying a pharmaceutical composition comprising the one or more agents effective in inhibiting malignancy of the biological sample in subsequent tissue treatments or monitoring procedures.
  • the herein methods of the invention are applicable for use along with, but not necessitate, minimal invasive devices such as endoscopes, laparoscopes or other imaging guided non-invasive devices.
  • tissue resection device refers to any medical device and particularly to devices capable of removing a dysplastic or early-stage neoplastic tissue.
  • Non limited examples include, endoscopic snares (cold or hot), forceps, scalpels, electrosurgical knifes and the alike.
  • the technique of EMR may involve the injection of a lifting agent solution into the submucosa just below the location of the polyp. This lifts the polyp up above the bowel wall on a cushion and allows safely snaring off either in one or in many pieces, until it has been completely removed.
  • the solution is made up of a volume expanding type of medical grade solution (e.g., Gelofusine® mixed with blue dye (methylene blue) to highlight the polyp tissue) and optionally a tiny amount of adrenaline to prevent bleeding.
  • the solution can be injected using an injection needle. EMR is performed with a snare to capture the target tissue.
  • the snare includes a wire loop electrode that is advanced beyond a catheter to encircle the target tissue and transect thereof via mechanical and electrosurgical cutting as the loop is withdrawn into the catheter.
  • An electrosurgical current may be used to transect the tissue that has been grasped. If the lesion is larger than 15 to 20 mm, it typically has to be removed in piecemeal fashion.
  • the main use of EMR is to remove dysplastic polyps that are larger than 10 mm.
  • ESD also involves injecting fluid into the submucosa and elevating it. ESD further involves creating an incision (using an endoscopic knife) around the perimeter of the lesion, and then carefully dissecting the lesion from the deeper layers. ESD is used for removing lesions that have a high likelihood of cancer invading the superficial submucosa and for lesions that cannot be removed by EMR due to fibrosis in the submucosal space or post-EMR recurrences.
  • One exemplary use of the herein invention involves application of a composition comprising one or more agents having a malignant/cancer progression inhibitory effect into the mucosa and/or submucosa tissue of a target organ proximate (below and/or around) the location of a dysplastic or early-stage neoplastic lesion. Nevertheless, application on top of a mucosa layer is also applicable and herein contemplated.
  • proximate the location of a dysplastic or early-stage neoplastic lesion it is meant to refer to administration of the herein composition, on top, below and/or at the perimeter of the lesion.
  • administration may be effected by injection, into the submucosa and optionally the mucosa below a dysplastic or early-stage neoplastic lesion.
  • administration of the herein composition may be conducted after removal of the dysplastic or early-stage neoplastic lesion and at a location where the lesion was located and/or at the periphery thereof.
  • administration of the herein composition for example, by injection into the mucosa and/or submucosa and/or by spraying, onto the mucosa includes administration at the periphery, of a dysplastic or early-stage neoplastic lesion, for example, at a perimeter of about 10 mm, 20 mm, or 30 mm, optionally up to about 40 mm, up to 30 mm, or up to 20 mm, or at margins within a range of 10 mm - 20 mm.
  • a dysplastic or early-stage neoplastic lesion for example, at a perimeter of about 10 mm, 20 mm, or 30 mm, optionally up to about 40 mm, up to 30 mm, or up to 20 mm, or at margins within a range of 10 mm - 20 mm.
  • compositions comprising the one or more agents having a malignant inhibitory effect, may be injected to the mucosa and/or submucosa, prior to the removal of the lesion, and this would enable a dual beneficial effect of both lifting the polyp up and allowing treatment against any residual cells derived from the lesion that may be left in the tissue following removal thereof.
  • the herein disclosed compositions may also be applied into or on top of a tissue following removal of the lesion. In such cases, the dysplastic or neoplastic lesion is firstly removed and then the composition with the one or more active pharmaceutical agents can be applied.
  • the device configured to deliver the composition and used for application thereof may be a syringe, for example, a syringe or any other container connected to a catheter with a needle at the distal tip (e.g., an endoscopic injection needle) and the composition is applied into the tissue by injection.
  • the device configured to deliver the composition may include a sprayer or dropper or any other means to apply the composition on top of the tissue.
  • compositions are applied on top of a tissue, for example, following the resection of a polyp or lesion.
  • Topical applications may include spraying, application using a patch or a scaffold, application by dripping, or by smearing, and any of the alike.
  • malignant inhibitory effect used interchangeably with the terms “malignant inhibitory agent” “anti-malignant agent”
  • anti-neoplastic agent and “anti-cancer agent” are contemplated. Such agents are capable of inhibiting transformation of early-stage neoplastic or dysplastic lesions into cancerous/malignant tumors or inhibiting tumor progression thereof. . Suitable agents may be effective in inhibiting processes associated with tumor progression and development. For example, the agents may inhibit cells proliferation, migration, invasion, or capability to induce tumor vasculature (e.g., angiogenesis).
  • tumor vasculature e.g., angiogenesis
  • Exemplary suitable agents include without limitation cannabinoids, and anti-malignant agents other than cannabinoids.
  • a combination of anti-malignant agents is applicable.
  • the agents having a malignant-progression inhibitory effect selectively target the dysplastic or neoplastic lesions. Namely, those agents exert their malignant inhibitory effect on dysplastic or neoplastic lesions and do not substantially affect normal healthy tissues or have a lesser effect on normal healthy tissue. In some cases, malignant inhibitory effect depends on the concentrations of the active agents.
  • the effective amount used for treating may be an amount that predominantly affects the dysplastic or neoplastic lesions and not healthy tissues.
  • the cannabinoid may be a cannabinoid purified/isolated from a cannabis plant.
  • the cannabinoid may be a synthetic compound or a derivative thereof.
  • synthetic cannabinoid refers to a chemical man-made compound functionally and structurally similar to its corresponding natural cannabinoid compound.
  • Synthetic cannabinoids are not derived from cannabis.
  • Synthetic cannabinoid molecules typically bind to same receptors to which the natural corresponding cannabinoids from cannabis plants attach. These synthetic analogs often, but not necessarily, have greater binding affinity and greater potency to the cannabinoid receptor.
  • isolated and purified are interchangeable and refer to a cannabinoid compound which is separated from at least some of the components with which it is usually associated in nature or in in vitro conditions, and/or prepared or purified by a process that involves the hand of a man.
  • isolated can be taken to mean that no substantial or essential amounts of components with which the cannabinoid is usually associated in nature or in in vitro conditions other than the specific cannabinoid and optionally its carrier or solvent is detectable by high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the isolated cannabinoid is substantially free of any compounds other than the specific cannabinoid and optionally its carrier or solvent. In one or more embodiment, the isolated cannabinoid is essentially free of any compounds other than the specific cannabinoid and optionally its carrier or solvent. In one or more embodiment, the isolated cannabinoid is free of compounds other than the specific cannabinoid and optionally its carrier or solvent.
  • substantially free refers to a compound or composition comprising less than about 0.5%, or less than about 0.4%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1%, or any percentage in between of a particular compound.
  • the term “essentially free” refers to a compound or composition comprising less than about 0.05%, or less than about 0.04%, or less than about 0.03%, or less than about 0.02%, or less than about 0.01%, or less than about 0.005%, or any percentage in between, or having only trace amounts of a particular compound or of other compounds.
  • the cannabis derived compound may be a cannabis plant extract or fraction.
  • the cannabis derived compound may be a cannabis plant extract or fraction which may be enriched with one or more cannabinoid.
  • cannabisbis extract or “cannabis fraction” refers hereinafter to any extract or concentrate derived from the cannabis plant which contains at least one cannabinoid.
  • the cannabis extract or fraction may contain 10, 20, 30, 40, 50, 60 or 70 or more different cannabinoids.
  • the cannabinoids may be extracted from the cannabis plant using any one of the many known extraction methods, such as nonhydrocarbons extraction methods (e.g., carbon dioxide extraction) and hydrocarbons extraction methods (e.g., butane, propane or alcohol extractions). It further refers to cannabis extract treated by separation or purification or fractionation processes. More particularly it refers to purified or partially purified cannabis extract containing cannabinoids.
  • the cannabinoid extract or fraction may be enriched with one or more cannabinoids, namely, the specific (principal) cannabinoid with which the extract is enriched is present in an amount that is higher than that of the other cannabinoids.
  • the principal cannabinoid is present in an amount greater than 40% (w/w) of the total extract.
  • the principal cannabinoid is present in an amount greater than 50% (w/w), greater than 60% (w/w), greater than 75% (w/w), greater than 85% (w/w), or greater than 95% (w/w) of the cannabinoid- containing fraction or extract.
  • the cannabis derived compounds may be any one or more of a cannabinoid.
  • suitable cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabinolic acid (THCA), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabinol (CBN) cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabielsoin (CBE), cannabicitran (CBT), cannabidivarinic acid (CBDVA), cannabin
  • THC cannabidio
  • THC or a derivative thereof may be selected from THC, THCV, THCA, THCVA, Delta- 9-tetrahydrocannabinol (A9-THC) and delta-8- tetrahydrocannabinol (A8-THC) and any combination thereof.
  • composition especially composition comprising a cannabis derived molecule includes one or more of terpene and/or terpenoid.
  • the terpene/terpenoid may be provided within a cannabis extract or fraction.
  • a composition comprising a cannabis derived molecule does not include terpene(s) and/or terpenoid(s).
  • Terpenes or “terpenoids” as used herein refers to a class of hydrocarbon molecules, which often provide a unique smell. Terpenes are derived from units of isoprene, which is an unsaturated alkenyl that has the molecular formula C5H8. The basic molecular formula of terpenes are multiples of the isoprene unit, i.e. (C5Hs) n where n is the number of linked isoprene units. Terpenoids are terpene compounds that have been further metabolized in the plant, typically through an oxidative process, and therefore usually contain at least one oxygen atom.
  • the cannabinoid is a combination of two or more, or only two cannabinoids selected from cannabichromenic acid (CBCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA).
  • cannabichromenic acid CBCA
  • CBDV cannabidivarin
  • CBDVA cannabidivarinic acid
  • THCV cannabigerolic acid
  • combinations of the cannabinoids CBCA, CBDV, CBDVA, THCV and CBGA exhibit a synergistic anti-proliferative effect on cells derived from colon polyps.
  • combinations of CBCA, CBDV, CBDVA, THCV and CBGA exhibit cells viability inhibitory effect being profoundly higher than the effect exhibited by the individual cannabinoids.
  • Cannabidivarin As used herein by Cannabidivarin (CBDV) it is meant to refer to the phytocannabinoid molecule 2-(( 1 S , 6S)-3 -methyl-6-(prop- 1 -en-2-yl)cyclohex-2-enyl)-5 -propylbenzene- 1 , 3-diol, having the CAS number 24274-48-4.
  • Cannabigerolic acid As used herein by Cannabigerolic acid (CBGA) it is meant to refer to the acidic form (COOH) of cannabigerolic acid (3-[(2E)-3,7-dimethylocta-2,6-dienyl]-2,4-dihydroxy-6- pentylbenzoic acid) or its corresponding salts, having the CAS number 25555-57-1.
  • Cannabichromenic acid it is meant to refer to a precursor of cannabichromen (CBC) biosynthesis, a non-psychoactive cannabinoid of Cannabis, having the formal name: 5 -hydroxy-2-methyl-2-(4-methyl-3 -pen ten- 1 -yl)-7 -pentyl-2H- 1 -benzopyran-6- carboxylic acid and having the CAS number 185505-15-1.
  • CBDV A is having the CAS number 31932-13-5
  • Tetrahydrocannabivarin As used herein by Tetrahydrocannabivarin (THCV) it is meant to refer to 6aR,7,8,10aR- tetrahydro-6,6,9-trimethyl-3-propyl-6H-dibenzo [b, d] pyran-l-ol, having the CAS number 31262-37-0.
  • the scope of the invention also includes all different geometrical isomers (including cis, trans) of CBCA, CBDV, CBDVA, THCV and CBGA.
  • the "anti-malignant agents other than cannabis derived compounds” may be chemotherapeutic agents, or biological agents (a.k.a. biological therapy) such as immunotherapeutic agents.
  • the "anti-malignant agents other than cannabis derived compounds” may be nucleotide sequences (e.g., small interfering RNA; siRNA) that interfere with the expression of specific genes, causing degradation of mRNA molecules, preventing translation thereof.
  • the siRNA may target specific genes known to be associated with progression of adenoma to carcinoma.
  • Suitable chemotherapeutic agents include, but are not limited to, antimetabolite drugs, DNA alkylating agents, platinum compounds, enzyme inhibitors (e.g., topoisomerase inhibitors, tyrosine kinase inhibitors), vincalkaloids, taxanes, receptor antagonists, and antibiotics.
  • the invention also pertains to non-steroidal anti-inflammatory (NSAID) drugs (e.g., aspirin), and cytotoxic organic solvents having anti-malignant efficacy (e.g., DMSO and ethanol).
  • NSAID non-steroidal anti-inflammatory
  • cytotoxic organic solvents having anti-malignant efficacy e.g., DMSO and ethanol
  • the invention also pertains to chemotherapeutic combination therapies, including by not limited to the combinations FOLFOX (folinic acid (leucovorin), fluorouracil (5-FU) and Oxaliplatin) and FOLFIRI (folinic acid (leucovorin), fluorouracil (5-FU) and irinotecan).
  • FOLFOX folinic acid (leucovorin), fluorouracil (5-FU) and Oxaliplatin
  • FOLFIRI folinic acid (leucovorin), fluorouracil (5-FU) and irinotecan
  • a "DNA alkylating agent” is an agent which attaches an alkyl group to DNA and thereby prevents its replication.
  • Non-limited examples of DNA alkylating agents are Nitrogen mustards, such as Cyclophosphamide, Mechlorethamine, Uramustine, Melphalan, Chlorambucil, Ifosfamide, Bendamustine; Nitrosoureas, such as Carmustine, Lomustine, Streptozocin; Alkyl sulfonates, such as Busulfan; and ThioTEPA.
  • Platinum compounds are a subclass of the DNA alkylating agents. Non-limited examples of such compounds include Cisplatin, Carboplatin, Nedaplatin, Oxaliplatin, Satraplatin, and Triplatin tetranitrate.
  • Topoisomerase inhibitors are agents that interfere with the action of topoisomerase enzymes (topoisomerase I and II).
  • Topoisomerase I inhibitors include CPT-ll/Irinotecan, topotecan, camptothecin, and lamellarin D.
  • Topoisomerase II inhibitors include, but are not limited to, Etoposide, Teniposide, Anthracyclines (e.g., Doxorubicin, Daunorubicin), Mitoxantrone, amsacrine, aurintricarboxylic acid, ellipticines and HU-331 a quinolone synthesized from cannabidinol.
  • TKIs Tumorin kinase inhibitors
  • Non limited examples of TKI chemotherapeutic agents include: Imatinib (brand name: Gleevac), gefinitib (Iressa) Erlotinib (Tarceva), Lapatinib (Tykerb), Sunitinib (Sutent), Sorafenib (Nexavar), Nilotinib (Tasinga), Bosutinib, Neratinib, and Vatalanib.
  • Antimetabolite drugs include pyrimidine antagonists, purine antagonists and folic acid analogues.
  • Non limited examples of pyrimidine antagonists include: 5-fluoruracil (5-FU, 5FU), arabinosylcytosine (cytarabine), capecitabine (an oral 5-FU pro-drug), gemcitabine and decitabine.
  • Suitable immunotherapeutic agents according to the invention include but are not limited to immunomodulatory agents including for example, therapeutic antibodies, immune checkpoints inhibitors, cytokines (e.g., IL-2 or interferon alpha.), T cell modulators, tumor infiltrating lymphocytes (TIL), and therapeutic or preventive cancer vaccines.
  • immunomodulatory agents including for example, therapeutic antibodies, immune checkpoints inhibitors, cytokines (e.g., IL-2 or interferon alpha.), T cell modulators, tumor infiltrating lymphocytes (TIL), and therapeutic or preventive cancer vaccines.
  • Exemplary "Therapeutic antibodies” may include monoclonal antibodies that are used in cancer treatment. Such antibodies are directed against tumor markers or antigens and exert their activity either by inducing antibody-dependent cell cytotoxicity (ADCC), or by association with a toxic agent.
  • Non limited example of therapeutic antibodies include Anti- CD52 (Alemtuzumab, Campath.RTM.), Anti-HER2/neu (erbB2) receptor (Trastuzumab, Herceptin.RTM.), anti-HERl/EGFR (Cetuximab, Panitumumab); Anti-VEGF-A (Bevacizumab); Anti-CD20 (Rituximab, Tositumomab, Ibritumomab); and Anti-CD33 (Gemtuzumab).
  • the therapeutic antibodies may also include immune checkpoint blocking antibodies such as anti-CTLA4 (e.g., Ipilimumab), anti-PD-1 (e.g., lambrolizumab) and anti- PD-L1 (the ligand of PD1) (e.g., MPDL3280A).
  • anti-CTLA4 e.g., Ipilimumab
  • anti-PD-1 e.g., lambrolizumab
  • anti- PD-L1 the ligand of PD1
  • immune checkpoints inhibitors it is meant to refer to compounds that interfere in pathways that regulate the immune status of a patient.
  • immune checkpoints are CTLA-4 and PD-1.
  • therapeutic effective amount of agents having a malignant inhibitory effect is an amount sufficient to effect beneficial or desired results, i.e., an amount sufficient to prevent recurrence, treat, ameliorate, alleviate, stabilize disease, or prevent cancer progression or development of polyps or lesions, or transformation of dysplastic cells into cancerous cells, or prevent tumor progression of neoplastic lesions.
  • the target tissue is a tissue bearing/afflicted with a dysplastic or early-stage neoplastic lesion.
  • the tissue bearing a dysplastic or early-stage neoplastic lesion is selected from the group consisting of: colon, uterine, skin, breast, cervix, bladder, stomach, oral cavity, esophagus, oropharynx, liver, pancreas, ear canal, small intestine, nasal cavity, nasopharynx, and prostate.
  • the tissue afflicted with/bearing a dysplastic or early-stage neoplastic lesion is a tissue having a mucous membrane.
  • Exemplary suitable tissues having a mucous membrane include colon, rectum, ear canal, cervix, esophagus, stomach, small intestine, nasal cavity, uterus, urethra, anus, oropharynx, nasopharynx, oral cavity, and throat.
  • polyps or other lesions in tissues having a mucous membrane are treated with endoscopic procedures whereby the endoscope is inserted within the tissue's cavity and visualizes the tissue, treats the tissue with the herein agents having a malignant inhibitory effect, and removes the polyp.
  • Other tissues such as breast, prostate etc., with no cavities, can be visualized using other non-invasive means (e.g., ultrasound, fluoroscopy) and at the same time be treated with the herein agents which can be injected around and/or below the lesion. The removal of the lesion in such tissues can be thereafter conducted utilizing typical surgical procedures.
  • the term “lesion” refers to an abnormal change in tissue. By “lesion” it is meant to encompass “polyps”. As used herein the term “polyp” refers to an abnormal growth of tissue projecting from a mucous membrane. Some polyps are neoplastic, and others are non neoplastic, for example hyperplastic or dysplastic.
  • hypoplastic refers to polyps having no malignant potential.
  • displastic lesion it is meant to refer to a tissue that appears abnormal under a microscope, or other means of magnification, but is not cancerous, namely it is pre- cancerous. It is known that before cancer cells evolve in tissues of the body, the cells go through abnormal changes called dysplasia that potentially, culminate in neoplasia.
  • the term a "dysplastic lesion” encompasses a “dysplastic polyp”.
  • neoplastic lesion it is meant to refer to a tissue that has completed its transformation to being malignant/cancerous, and if left untreated will progress through excepted stages of cancer progression such as locoregional growth and spread, and distant metastasis.
  • the neoplastic lesion can be referred to "an early stage neoplastic lesion", namely, it is an in situ neoplasm (i.e., did not spread to other organs), and/or lacks lymphovascular spread, and/or exhibits a depth of invasion of less than 1 mm into the submucosa, and/or lacks high-grade tumor budding and/or exhibits tumor-free lateral and deep margins of the excised polyp/lesion.
  • an early stage neoplastic lesion namely, it is an in situ neoplasm (i.e., did not spread to other organs), and/or lacks lymphovascular spread, and/or exhibits a depth of invasion of less than 1 mm into the submucosa, and/or lacks high-grade tumor budding and/or exhibits tumor-free lateral and deep margins of the excised polyp/lesion.
  • the early-stage neoplastic lesion exhibits a depth of submucosal invasion of less than 1.5 mm, less than 1.4 mm, less than 1.3 mm, less than 1.2 mm, less than 1.1 mm, less than 1 mm, less than 0.9 mm, less than 0.8 mm, less than 0.7 mm, less than 0.5 mm, or less than 0.2 mm into the submucosa.
  • Endoscopic therapy in the gastrointestinal tract, whereby polyp lesions are removed is typically indicated for lesions that are confined to the mucosal layer, or at most the more superficial submucosa, under strict pathological criteria that determine the chances that such therapy will eliminate further spread (e.g., depth of invasion of less the 1 mm into the submucosa in the colon, lack of lymphovascular spread, lack of high-grade tumor budding etc.).
  • carcinoma In the lower Gastrointestinal (GI) tract, carcinoma first starts with mucosal infiltration.
  • the “dysplastic polyp or lesion” cannot be referred to as carcinoma, i.e., the polyp/lesion is limited to the epithelial cell layer (a.k.a high-grade dysplasia or low-grade dysplasia).
  • certain "neoplastic polyps or lesion" can be completely removed by endoscopic means if they adhere to predetermined well known conditions, as described above, under which further cancerous spread is extremely low.
  • the method pertains to therapies directed at lesions that are targeted for removal by endoscopic means, with an effort to reduce/prevent their local recurrence.
  • the dysplastic or early-stage neoplastic lesion exhibits a depth of invasion of less than 1.5 mm into the submucosa, lacks lymphovascular spread, lacks high-grade tumor budding and/or exhibits tumor-free lateral and deep margins of the excised polyp/lesion.
  • the depth of invasion of the polyp/lesion depends on the organ bearing the polyp/lesion. For example, in the esophagus, the depth of submucosal invasion of the polyps/lesion is less than 200 pm. In the stomach, the depth of invasion is typically less than 500 pm, whereas in the colon it is less than 1500 pm, or less than 1000 pm.
  • the Paris classification is a method that was developed to classify polyps by their size and morphology. Superficial or early neoplasms in the entire GI tract are primarily assessed on the basis of their endoscopic appearance. In the Paris classification, mucosal lesions are characterized as polypoid (pedunculated (Ip), and sessile (Is)), nonpolypoid (slightly elevated [Ila], flat [lib], depressed [He]), or excavated/ulcerated (III).
  • LST laterally spreading tumors
  • the dysplastic/neoplastic lesion is any one of a lesion in the GI selected from a pedunculated (Ip), a sessile (Is), a slightly elevated [Ila], a flat [lib], a depressed [He], an excavated/ulcerated (III) or a combination thereof.
  • the dysplastic/neoplastic lesion is any one of a mucosal lesion in the GI selected from a pedunculated (Ip), a sessile (Is), a slightly elevated [Ila], a flat [lib], a depressed [He], and a combination thereof.
  • the dysplastic/neoplastic lesion is any one of a mucosal lesion in the GI selected from a sessile (Is), a slightly elevated [Ila], a flat [lib], a depressed [He], and a combination thereof.
  • a sessile (Is) a slightly elevated [Ila]
  • a flat [lib] a flat [lib]
  • a depressed [He] a combination thereof.
  • the target tissue is colon tissue and the dysplastic or neoplastic lesion is Lateral Spreading Tumor (LST) (i.e., polyps >10 mm, which is sessile or flat (Paris Is or II)).
  • LST Lateral Spreading Tumor
  • the polyp is a protruded lesion, for example having a size of 10 mm, 15 mm or 20 mm and above.
  • the Lateral Spreading Tumor may be selected from a sessile, a flat, a flat-elevated, or a depressed LST.
  • the Lateral Spreading Tumor may have a surface morphology which is granular (LST-G) or non-granular (LST-NG).
  • the invention pertains to two prominent surgical steps, i.e., a step of removing the dysplastic or neoplastic polyp or lesion; and a step of applying the pharmaceutical composition which comprises one or more anti-malignant active agents.
  • a step of removing the dysplastic or neoplastic polyp or lesion a step of removing the dysplastic or neoplastic polyp or lesion
  • the pharmaceutical composition which comprises one or more anti-malignant active agents.
  • the submucosal tissue located below the lesion may be injected with a lifting agent to thereby lift the lesion and allow the removal feasible.
  • the herein active pharmaceutical composition comprising one or more agents having a malignant inhibitory effect is injected prior to the step of removing the lesion and optionally, but not necessarily, along with a lifting agent.
  • the step of removing the dysplastic or neoplastic lesion may be conducted prior to the step of applying the pharmaceutical composition. Namely, the lesion is firstly removed and thereafter the tissue proximate (surrounding, or below) the lesion is being treated with the active pharmaceutical composition.
  • Application of the pharmaceutical composition may be applied to the tissue by various procedures, including, but not limited to injection, spraying, dripping, spreading, patching or a combination thereof.
  • the pharmaceutical composition may be provided within a patch, a scaffold, a viscous carrier, a liquid carrier or a combination thereof.
  • the active agents may be formulated within a solution, that comprises a lifting agent.
  • the solution or carrier may be a viscous carrier.
  • suitable solutions or carriers include solutions or carriers comprising hydroxyethyl starch and/or sodium hyaluronate.
  • Volume expanders are further contemplated, and may include, for example, one or more of dextrans (e.g., 50% dextrose), gelatin or derivatives thereof, hydroxy ethyl starch, glycerol, dilute hyaluronic acid, methylcellulose, fibrinogen and human albumin.
  • a volume expander includes Gelofusine® which includes a 4% w/v solution of succinylated gelatin, sodium chloride, and sodium hydroxide.
  • the volume expander may include biocompatible polymers.
  • Exemplary polymers include, without limitation, polyethylene glycol (PEG) (a.k.a., polyethylene oxide (PEO)), Polypropylene glycol (PPG), or a combination thereof.
  • Exemplary commercially available volume expanders which may be used as carriers of the herein active pharmaceutical agents include ELEVIEW® and ORISETM.
  • the composition may be a fluid solution such as saline.
  • the solution may include epinephrine for hemostasis and an inert dye (e.g., methylene blue, or indigo carmine) for demarcation of the polyp margins.
  • the pharmaceutical composition may include oils (e.g., mineral oils, essential oils), micelles, liposomes, surfactants, slow-release carriers (e.g., polymeric carrier, or micelles, nanostructures, and the alike), and a combination thereof.
  • the slow-release carrier is selected from a monoglyceride, a diglyceride, a carrageenan and any mixture thereof.
  • the carrageenan is selected from the group consisting of lambda-carrageenan, kappa-carrageenan, iota-carrageenan and any mixture of the carrageenan.
  • the sustained release formulation further comprises an edible oil such as coconut oil, wheat sprout oil, olive oil, sprouted wheat oil, sesame oil, peanut oil, grape seed oil, palm oil, papaya seed oil or any combination thereof.
  • the solution is comprised of medium-chain triglycerides as the oily phase, poloxamer 188 as the bulking/cushioning agent, polyoxyl-15-hydroxystearate as the surfactant, sodium chloride as the osmotic agent, and methylene blue as the dye. Additional optional steps applicable in the herein methods include providing a biological sample of the dysplastic or neoplastic lesion, and analyzing efficacy of various active agents, optionally using personalized medicine (PM) techniques.
  • PM personalized medicine
  • the biological sample of a patient may be dissociated to thereby obtain a cell culture, and an efficacy analysis of one or more malignant inhibitory agents on the cells obtained from the sample may be conducted. Additional optional steps applicable in the herein methods include providing a biological sample of the dysplastic or neoplastic lesion, dissociating the sample to thereby obtain a cell culture, and analyzing efficacy of one or more malignant inhibitory agents on the cells obtained from the sample. After identifying the agents effective in inhibiting malignancy of the cells obtained from the biological sample, same active agents may be used in subsequent treatment or monitoring procedures.
  • the agents determined to be active in inhibiting tumor progression may be applied to a tissue proximate the recurrent lesion/polyp.
  • Alternative or additional subsequent treatment or monitoring procedures may include parenteral administration (e.g., rectal, or intravenous), or oral administration of those agents found active in inhibiting tumor progression.
  • the step of analyzing efficacy comprises contacting cells, or tissue derived from the biological sample with a plurality of malignant inhibitory agents and detecting a signal indicative of an anti-malignant effect relative to a control.
  • the effect can be measured by reading a signal or combination of signals using a microplate reader.
  • the measurement can be of an optic, luminescent, fluorescent, immunological, radioactive, non radioactive isotopic or electrical signal, cell count, or any combination thereof.
  • the measurement and detection of the signal can be carried out by any high throughput screening (HTS) system known in the art.
  • HTS high throughput screening
  • the step of analyzing efficacy comprises conducting a histopathological examination whereby cells from a histological section are stained to evaluate expression of certain proteins that when expressed, indicate suitability to certain anti-malignant therapeutic agents.
  • the signal indicative of an anti-malignant effect may be any biological assay associated with cancerous condition evaluation and particularly assays illustrating cancer inhibitory effects of active agents.
  • Non -limited examples include, viability assay, cellular apoptosis assay, cellular invasion assay, cellular migration assay, cellular proliferation assay, cellular necrosis assay, cell cycle assay, cellular differentiation assay and the alike.
  • the control in such assays may be same cells, specimen, or same histological section not treated with any of the tested agent or treated with only the vehicle of the tested agent.
  • the control in such assays may alternatively or additionally by standard values (for example depicting non-cancerous conditions).
  • subsequent tissue treatment or monitoring procedures may include: introducing a device for application of the pharmaceutical composition to a tissue proximate a recurrent dysplastic or neoplastic lesion; delivering the pharmaceutical composition to the tissue proximate the recurrent dysplastic or neoplastic lesion; introducing to the target tissue a tissue resection device; and removing the recurrent dysplastic or neoplastic lesion from the target tissue using the tissue resection device.
  • the present invention further provides a pharmaceutical composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA, and a pharmaceutical acceptable carrier.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA, and a pharmaceutical acceptable carrier for use in the treatment of a dysplastic or early-stage neoplastic lesions.
  • the present invention further provides a method of treatment of a dysplastic or an early- stage neoplastic lesion comprising administering to the subject a pharmaceutical composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA, and a pharmaceutical acceptable carrier.
  • the present invention further provides a method of treatment of a dysplastic or an early- stage neoplastic lesion comprising administering to the subject, proximate the position of the lesion a pharmaceutical composition comprising at least two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV and CBGA, and a pharmaceutical acceptable carrier.
  • the composition comprises at least three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition comprises at least four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition comprises CBCA, CBDV, CBDVA, THCV, and CBGA.
  • the composition comprises two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition comprises three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition comprises four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition comprises CBCA, CBDV, CBDVA, THCV, and CBGA.
  • the composition consists essentially of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition consists essentially of three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition consists essentially of four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition consists essentially of CBCA, CBDV, CBDVA, THCV, and CBGA.
  • the composition consists of two cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition consists of three cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition consists of four cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA. In some embodiments, the composition consists of CBCA, CBDV, CBDVA, THCV, and CBGA.
  • the composition comprises CBCA, and CBDV. In some embodiments, the composition comprises CBCA and CBDVA. In some embodiments, the composition comprises, CBCA, and THCV. In some embodiments, the composition comprises CBCA, and CBGA. In some embodiments, the composition comprises CBDV and CBDVA. In some embodiments, the composition comprises CBDV and THCV. In some embodiments, the composition comprises CBDV and CBGA. In some embodiments, the composition comprises CBDVA, and THCV. In some embodiments, the composition comprises CBDVA, and CBGA. In some embodiments, the composition comprises THCV, and CBGA. In some embodiments, the composition comprises THCV, and CBGA. In some embodiments, the composition comprises THCV, and CBGA. In some embodiments, the composition comprises THCV, and CBGA. In some embodiments, the composition comprises THCV, and CBGA.
  • compositions comprising, consisting essentially of, or consisting of at least one cannabinoid selected from the group consisting of (THC-A8), tetrahydrocannabinol (THC-A9), cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabinolic acid (THCA), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabinol (CBN) cannabichromene (CBC), cannabicyclol (CBL), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabinolic acid (CBNA), and cannabichromenic acid (CBCA).
  • THC-A8 tetrahydrocannabinol
  • CBD cannabigerol
  • THCA cannabigerolic acid
  • CBDA canna
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one cannabinoid selected from the group consisting of: tetrahydrocannabinol (THC-A8), tetrahydrocannabinol (THC-A9), cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabinolic acid (THCA), cannabigerolic acid (CBGA), cannabidiolic acid
  • CBDA cannabinol
  • CBN cannabichromene
  • CBL cannabicyclol
  • THCV cannabidivarin
  • CBDV cannabidivarinic acid
  • CBDVA cannabinolic acid
  • CBDA cannabichromenic acid
  • CBCA cannabichromenic acid
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one cannabinoid selected from the group consisting of: tetrahydrocannabinol (THC-A8), tetrahydrocannabinol (THC-A9), cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabinolic acid (THCA), cannabigerolic acid (CBGA), cannabidiolic acid
  • CBDA cannabinol
  • CBN cannabichromene
  • CBL cannabicyclol
  • THCV cannabidivarin
  • CBDV cannabidivarinic acid
  • CBDA cannabinolic acid
  • CBCA cannabichromenic acid
  • the invention pertains to methods of treating early-stage neoplastic or dysplastic lesions comprising administering a pharmaceutical composition comprising, consisting essentially of, or consisting of at least one cannabinoid selected from the group consisting of THC-A8, THC-A9, CBD, CBG, THCA, CBGA, CBDA, CBN, CBC, CBL, THCV, CBDV, CBDVA, CBNA, CBCA.
  • a pharmaceutical composition comprising, consisting essentially of, or consisting of at least one cannabinoid selected from the group consisting of THC-A8, THC-A9, CBD, CBG, THCA, CBGA, CBDA, CBN, CBC, CBL, THCV, CBDV, CBDVA, CBNA, CBCA.
  • the composition includes a cannabinoid that effects toxicity only toward cells of the dysplastic or neoplastic lesion, such as CBD which when provided at a concentration of 15 m M is selectively toxic to the dysplastic or neoplastic lesion.
  • a cannabinoid that effects toxicity only toward cells of the dysplastic or neoplastic lesion, such as CBD which when provided at a concentration of 15 m M is selectively toxic to the dysplastic or neoplastic lesion.
  • the herein composition includes CBD at a concentration of about 15 mM, or below about 30 mM.
  • CBD is present in the composition as a sole cannabinoid component.
  • the herein composition is substantially free, or essentially free, or entirely free of any other cannabinoid except for the one, two, or more of the cannabinoids selected from the group consisting of CBCA, CBDV, CBDVA, THCV, and CBGA.
  • the composition is substantially free, or essentially free, or entirely free of any cannabinoids other than the one or two or more cannabinoids selected from the group listed above.
  • the composition is substantially free, or essentially free, or entirely free of CBG.
  • the composition is substantially free, or essentially free, or entirely free of CBGA.
  • the composition is substantially free, or essentially free, or entirely free of THCA.
  • the weight to weight ratio between the two cannabinoids may be between 1:99 to 99:1.
  • the weight ratio is between 1:90 to 90:1, between 1:80 to 80:1, between 1:70 to 70:1, between 1:60 to 60:1, between 1:50 to 50:1, between 1:40 to 40:1, between 1:30, to 30:1, between 1:20 to 20:1, between 1:10 to 10:1, between 10:90 to 90:10, between 1:8 to 8:1, between 1:7 to 7:1, between 1:6 to 6:1, between 1:5 to 5:1, between 1:4 to 4:1, between 1:3 to 3:1, between 1:2 to 2:1, or between 1:1.5 to 1.5:1.
  • the weight ratio is between 20:80 to 80:20, in some embodiments between 30:70 to 70:30 and in some embodiments between 40:60 to 60:40, respectively.
  • the weight-to- weight ratio between the two cannabinoid ingredients is 1:1 to 1:10, or 1:1 to 1:9, or 1:1 to 1:8, or 1:1 to 1:7, or 1:1 to 1:6, or 1:1 to 1:5, or 1:1 to 1:4, or 1:1 to 1:3, or 1:1 to 1:2, or any value in between.
  • the weight-to-weight ratio between the two cannabinoid ingredients is 1:1.
  • the molar ratio between the two cannabinoids that are selected from CBCA, CBDV, CBDVA, THCV and CBGA may be between 1:99 to 99:1.
  • the molar ratio is between 1:90 to 90:1, between 1:80 to 80:1, between 1:70 to 70:1, between 1:60 to 60:1, between 1:50 to 50:1, between 1:40 to 40:1, between 1:30, to 30:1, between 1:20 to 20:1, between 1:10 to 10:1, between 10:90 to 90:10, between 1:8 to 8:1, between 1:7 to 7:1, between 1:6 to 6:1, between 1:5 to 5:1, between 1:4 to 4:1, between 1:3 to 3:1, between 1:2 to 2:1, or between 1:1.5 to 1.5:1, or any value in between.
  • the molar ratio is between 20:80 to 80:20, in some embodiments between 30:70 to 70:30 and in some embodiments between 40:60 to 60:40, respectively.
  • the molar ratio between the two cannabinoid ingredients is 1:1 to 1:10, or 1:1 to 1:9, or 1:1 to 1:8, or 1:1 to 1:7, or 1:1 to 1:6, or 1:1 to 1:5, or 1:1 to 1:4, or 1:1 to 1:3, or 1:1 to 1:2, or any value in between.
  • molar ratio between the two cannabinoid ingredients is 1:1.
  • the cannabinoid is present in the composition at a concentration of up to about 1000 m M.
  • a concentration of up to about 1000 m M for example, up to about 500 mM, up to about 400 mM, up to about 300 mM, up to about 200 mM, or up to about 100 mM.
  • the cannabinoid may be present in the composition at a concentration of between about 2 mM and about 100 mM, between about 5 mM and about 100 mM, between about 5 mM and about 90 mM, between 5 mM and 80 mM, between 5 mM and 70 mM, between about 5 mM and about 60 mM, between about 20 mM and about 55 mM, or between 10 mM and about 55 mM, or any value in between.
  • the cannabinoid is present in the composition at a concentration of between about 5mM and about 1000 mM, between about 5mM and about 500 mM. between about 5mM and about 100 mM. For example, between about 5mM and about 50 mM, between 5mM and 40 mM, between 5mM and about 30mM, between about 5mM and about 20 mM, or between 10 mM and about 20mM, or any value in between, or any value in between.
  • the weight to volume of each cannabinoid in the composition is between 1% w/v to 80% w/v.
  • the weight to volume of each cannabinoid is 10% w/v.
  • the total amount of cannabinoids selected from CBCA, CBDV, CBDVA, THCV and CBGA in a dosage unit form can be up to about 2000 mg, For example, between about 10 mg and about 2000 mg.
  • the total amount can be about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1500 mg, or 2000 mg.
  • the total amount of cannabinoids can be between about 10 mg and 1500 mg, between about 10 mg and 1000 mg, between about 10 mg and about 800 mg, between about 10 mg and 500 mg, between about 100 mg and 800 mg, or between about 100 mg and 500 mg, or any value in between.
  • the composition exhibits a synergistic effect of the two or more cannabinoids selected from the list provided above.
  • compositions refers to compositions comprising at least one active pharmaceutical agent, i.e., agents having a malignant inhibitory effect on cells of dysplastic or early-stage neoplastic lesions (e.g., a cannabinoid) as herein disclosed, and at least one other substance, such as a carrier, excipient, or diluent.
  • active pharmaceutical agent i.e., agents having a malignant inhibitory effect on cells of dysplastic or early-stage neoplastic lesions (e.g., a cannabinoid) as herein disclosed
  • other substance such as a carrier, excipient, or diluent.
  • pharmaceutically acceptable carrier applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which the herein agents (e.g., cannabinoid compound) is administered.
  • the carrier refers to an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • carrier it is meant to refer to any substance suitable as a vehicle for delivering of the herein active agent of the present invention to a suitable biological site or tissue.
  • carriers can act as a pharmaceutically acceptable excipient of the pharmaceutical composition of the present invention.
  • Carriers of the present invention may include: (1) excipients or formularies that transport, but do not specifically target a molecule to a cell (referred to herein as non-targeting carriers); and (2) excipients or formularies that deliver a molecule to a specific site in a subject or a specific cell (i.e., targeting carriers).
  • non-targeting carriers examples include, but are not limited to water, phosphate buffered saline, Ringer’s solution, dextrose solution, serum-containing solutions, Hank’s solution, other aqueous physiologically balanced solutions, oils, esters and glycols.
  • Aqueous carriers can contain suitable auxiliary substances required to approximate the physiological conditions of the recipient, for example, by enhancing chemical stability and isotonicity.
  • phytocannabinoids are cannabinoids that originate from nature and can be found in the cannabis plant.
  • the phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
  • Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
  • composition may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition.
  • the term “subject” means any human or non-human animal in need of medical treatment. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • the term “synergistic” refers to e.g., an observed effect which is higher in the presence of the cannabinoids together than the sum of the individual effects of each cannabinoid when administered separately.
  • the observed combined effect of the cannabinoids is significantly higher than the sum of the individual effects.
  • the term significant means that the statistical p value observed is less than 0.05, i.e., p ⁇ 0.05. It is contemplated that the therapeutic effects achieved as a result of the combination of two or more cannabinoids selected from CBCA, CBDV, CBDVA, THCV and CBGA are significantly better than the expected additive therapeutic effects. Thus, the doses of each of the agents can be reduced.
  • the synergistic effect can be calculated according to the cells mortality experimental results according to the Bliss equation as follows:
  • M designates mortality; wherein MAB- is a calculation of mortality, e.g., of cells exposed to a combination of cannabinoid A and cannabinoid B; MA is the mortality of cells exposed to cannabinoid A only; MB is the mortality of cells exposed to cannabinoid B only. MAB designates the observed mortality of cells exposed to the combination of cannabinoid A and cannabinoid B.
  • the synergistic effect can be calculated according to the cells survival experimental results according to the Bliss equation as follows:
  • S designates survival; wherein SAB (Cal)- is a calculation of survival, e.g., of cells exposed to a combination of cannabinoid A and cannabinoid B; SA is the survival of cells exposed to cannabinoid A only; SB is the survival of cells exposed to cannabinoid B only. SAB (Exp) designates the observed survival of cells exposed to the combination of cannabinoid A and cannabinoid B.
  • Cannabinoids - the cannabinoids used in the experiments were either synthetic cannabinoids obtained from Restek Corporation USA, or plant derived purified cannabinoids.
  • Cannabinoid solutions were prepared by dissolving the cannabinoid in dimthylsulphoxide (DMSO) at the desired concentration.
  • DMSO dimthylsulphoxide
  • Polyp derived cells - polyps from several different patients were obtained following surgical resection.
  • the polyp tissues were dissociated, and about 4,000 cells were plated into each well in a well plate. Cells were incubated for 48 hours at 37 °C with various purified cannabinoids at different concentrations.
  • Cell viability - cell viability was performed by CellTiter-Glo (CTG) Luminescent Cell Viability Assay.
  • Synergistic calculation - synergism was calculated according to the Bliss equation defined supra.
  • Example 1 evaluation of the efficacy of cannabinoids on the viability of cells derived from colon polyps of patients.
  • Polyps from several different patients were obtained following surgical resection.
  • the polyp tissues were dissociated, and about 4,000 cells were plated into each well in a well plate. Cells were incubated for 48 hours at 37°C with various purified cannabinoids at a concentration of 20 mM.
  • Cannabinoid's vehicle i.e., DMSO
  • the cannabinoids effect on the viability of the polyp-derived cells was evaluated and is presented in table 1.
  • Table 1 - toxicity of cannabinoids on colon polyp-derived cells P004-P010 designate the various patients' polyps
  • isolated cannabinoids illustrate different effects on the viability of cells derived from patients' polyps.
  • THC-d8 and THC-d9 were most toxic and exhibited persistent toxicity in all polyps tested.
  • CBCA and CBGA were the least toxic.
  • some cannabinoids exhibited a broad variability in their capacity to elicit toxicity between different origins of polyps. Thus, it may be advantageous to allow personal evaluation regarding the toxicity of the antitumor agent that should be used for the prevention of polyp recurrence.
  • Example 2 - evaluation of the efficacy of cannabidiol (CBD) on the viability of cells derived from patient’s colon polyp and adjacent normal cells.
  • CBD cannabidiol
  • Tissues were dissociated, and about 5,000 cells were plated into each well in a well plate. Cells were incubated for 36 hours at 37°C with purified CBD at a concentration of 15 m M and at a concentration of 30 mM. Medium and DMSO were used as control.
  • CBD at 15 mM was found more toxic to polyp derived cells than to normal tissue cells, higher concentrations of CBD (30mM) were toxic to both polyp and normal tissues.
  • a composition comprising CBD at a concentration of about 15 mM or at a concentration of below about 30 mM is administered to a patient onto a mucosa layer, or by injection into the mucosa and/or submucosa layers during a treatment procedure for polyp removal.
  • it may be advantageous to administer a treatment that is more toxic even if toxic to normal tissue as well (e.g., CBD at concentrations of 30 mM or even higher), to reduce the chances of subsequent lesion recurrence.
  • Example 3- combinations of the cannabinoids CBDV, THCV, CBDVA, CBCA, and CBGA exhibit a synergistic inhibitory effect on the viability of cells derived from colon polyps of patients.
  • cancerous cells may develop resistance to anti-cancer drugs.
  • cannabinoids may be of particular interest in the treatment of cancer in general and also for inhibiting pre-cancerous lesions and avoiding recurrence following removal thereof.
  • Various cannabinoids were evaluated for synergistic interaction in inhibiting colon polyp-derived cells' viability. As can be seen in table 2 below and in FIGs.
  • the cannabinoid combinations: CBCA+CBDV, CBCA+THCV, CBCA+CBGA, CBDV+CBGA, CBDV+CBDVA, CBGA+CBDVA, and THCV+CBGA presented a synergistic effect according to Bliss equation calculation.
  • the cannabinoids CBCA and CBGA that when administered as single active compounds (shown in table 1 above) exhibited weak toxicity, significantly became more toxic when combined with other cannabinoids.
  • Example 4 an endoscopic procedure for removing and treating with CBD a pre- cancerous lesion in the colon.
  • An endoscopic procedure in the colon is performed by inserting an endoscope to colon of a patient.
  • a non-pedunculated lesion is identified under white light by visual means.
  • 30 mL of a solution comprising hydroxyl ethyl starch and 15 m M CBD (0.47 % W/V out of the total volume of the composition) is injected to the submucosa tissue under the sessile polyp as follows: a small amount of solution is injected in the first phase followed by rapid large- volume injection while maneuvering the syringe after insertion to the submucosal tissue.
  • a stiff snare is used to capture the lesion, the lumen is insufflated with carbon dioxide (CO2) to stretch the wall, and the snare is lifted up while the snare is slightly loosened to release any entrapped muscularis propria. The snare is then closed entirely, and the lesion is transected using microprocessor-controlled cautery.
  • Example 5 an endoscopic procedure for removing and treating with combinations of cannabinoids a pre-cancerous lesion in the colon.
  • An endoscopic procedure in the colon is performed by inserting an endoscope to colon of a patient.
  • a non-pedunculated lesion is identified under white light by visual means.
  • 30 mL of a solution comprising hydroxyl ethyl starch and an anti-malignant agent comprising a cannabinoid combination comprising two or more of CBCA (at m M 14 - 30 m M), CBDV (at 23 mM - 47 mM), CBDVA (at 25 mM - 52 mM), THCV (at 20 mM - 48 mM), and CBGA (at 26 mM - 52 mM) is injected to the submucosa tissue under the sessile polyp as follows: a small amount of solution is injected in the first phase followed by rapid large-volume injection while maneuvering the syringe after insertion to the submucosal tissue.
  • a stiff snare is used to capture the lesion, the lumen is insufflated with carbon dioxide (CO2) to stretch the wall, and the snare is lifted up while the snare is slightly loosened to release any entrapped muscularis propria. The snare is then closed entirely, and the lesion is transected using microprocessor-controlled cautery.
  • CO2 carbon dioxide
  • Example 6 an endoscopic procedure for removing and treating with combinations of cannabinoids in subsequent procedures a pre-cancerous lesion in the colon.
  • An endoscopic procedure in the colon is performed by inserting an endoscope to colon of a patient.
  • a non-pedunculated lesion is identified under white light by visual means.
  • 30 mL of a solution comprising hydroxyl ethyl starch (with or without an anti- malignant agent) is injected to the submucosa tissue under the sessile polyp as follows: a small amount of solution is injected in the first phase followed by rapid large-volume injection while maneuvering the syringe after insertion to the submucosal tissue.
  • a stiff snare is used to capture the lesion, the lumen is insufflated with carbon dioxide (CO2) to stretch the wall, and the snare is lifted up while the snare is slightly loosened to release any entrapped muscularis propria. The snare is then closed entirely, and the lesion is transected using microprocessor-controlled cautery.
  • CO2 carbon dioxide
  • the lesion is then dissociated, and cells are plated onto each well in a well plate.
  • Cells are incubated for several (e.g., 36 hours at 37°C) with various anti-malignant agents to identify and select the agents that are most effective in inhibiting viability of the lesion's cells.
  • Those toxic agents are then prescribed for subsequent treatments by applying a pharmaceutical composition comprising the one or more agents effective in inhibiting malignancy of the resected tissue in subsequent tissue treatment or monitoring procedures (e.g., by oral or rectal administration of the anti-malignant agents, or by subsequent invasive procedures for removal of any recurrent lesion and injection of the active anti-tumor agents).

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Abstract

La présente invention concerne des méthodes et des compositions destinées à inhiber la progression du cancer d'affections néoplasiques à un stade précoce ou dysplasiques. Certains modes de réalisation de l'invention concernent une méthode de traitement d'une affection néoplasique à un stade précoce ou dysplasique dans un tissu cible d'un sujet, la méthode consistant à fournir une composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un ou de plusieurs agents ayant un effet inhibiteur de malignité sur des cellules néoplasiques à un stade précoce ou dysplasiques ; à introduire un dispositif configuré pour administrer la composition pharmaceutique à un tissu atteint de la lésion néoplasique à un stade précoce ou dysplasique ; à appliquer la composition pharmaceutique au tissu à proximité de la lésion néoplasique à un stade précoce ou dysplasique ; à introduire un dispositif de résection tissulaire dans le tissu cible ; et à éliminer la lésion néoplasique à un stade précoce ou dysplasique du tissu cible à l'aide du dispositif de résection de tissu, ce qui permet de traiter l'affection néoplasique à un stade précoce ou dysplasique chez le sujet.
PCT/IL2021/050668 2020-06-05 2021-06-03 Compositions et méthodes pour le traitement d'affections néoplasiques à un stade précoce et dysplasiques Ceased WO2021245677A1 (fr)

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