WO2021021543A1 - Compositions and methods for attenuating side effects of immune checkpoint inhibitor therapy - Google Patents

Abstract

Disclosed in certain embodiments are compositions and methods for treating side- effects of immune check point inhibitors with a cannabinoid type 2 receptor modulator.

Description

COMPOSITIONS AND METHODS FOR ATTENTUATING SIDE EFFECTS OF

IMMUNE CHECKPOINT INHIBITOR THERAPY

RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application No. 62/878,866, filed on July 26, 2019, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present disclosure is directed to pharmaceutical compositions and methods directed to the treatment of side effects associated with immune checkpoint inhibitor therapy.

BACKGROUND OF THE INVENTION

[0003] There has recently been a growth of innovative therapeutic modalities for patients with cancer such as therapies based on the inhibition of“immune checkpoints” (negative immune regulatory mechanisms), which has been recognized by the 2018 Nobel Prize in Physiology or Medicine.

[0004] Although the development of immune checkpoint therapy has proven to be revolutionary and life-saving in many instances, it is associated with immune-related adverse events affecting skin, gut, liver, kidneys, heart, lungs, endocrine glands, and peripheral and central nervous systems.

[0005] The FDA issued relevant guidelines that recommend using various regimens of typical immunosuppressive drugs, such as systemic corticosteroids (e.g., prednisone), TNF inhibitors (e.g., infliximab) and agents such as mycophenolate mofetil for managing immune-related adverse events. These drug are known to elicit side effects of their own. [0006] There exists a need in the art for new therapies for the treatment of immune-related adverse events (e.g., immune-related inflammation) associated with immune checkpoint inhibitor therapy.

OBJECTS AND SUMMARY OF THE INVENTION

[0007]It is an object of certain embodiments of the present invention to provide pharmaceutical compositions for the treatment or prevention of immune-related adverse events (e.g., immune- related inflammation) induced by immune checkpoint inhibitor therapy.

[0008]It is an object of certain embodiments of the present invention to provide methods for the treatment or prevention of immune-related adverse events (e.g., immune-related inflammation) induced by immune checkpoint inhibitor therapy.

[0009] The above objects and others are met by the present invention which in certain embodiments is directed to a method of treating cancer comprising administering to a patient in need thereof an immune checkpoint inhibitor and a cannabinoid type 2 receptor modulator.

[0010] In other embodiments, the invention is directed to a method of treating immune-related adverse events associated with immune checkpoint inhibitor therapy comprising administering to a patient in need thereof a cannabinoid type 2 receptor modulator.

[0011] In further embodiments, the invention is directed to a pharmaceutical composition comprising an immune check point inhibitor and a cannabinoid type 2 receptor modulator.

DEFINITIONS

[0012] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a drug" includes a single drug as well as a mixture of two or more different drugs; and reference to a“an immune check point inhibitor” includes a single immune check point inhibitor as well as a mixture of two or more different immune check point inhibitors, and the like.

[0013] As used herein, the term“about” in connection with a measured quantity, refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment. In certain embodiments, the term “about” includes the recited number ±10%, such that“about 10” would include from 9 to 11.

[0014] As used herein, a "patient" refers to a subject, particularly a human (but could also encompass a non-human), who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated prophylactically for a condition, or who has been diagnosed with a condition to be treated.

[0015] The term“subject” encompasses the definition of the term“patient” and does not exclude individuals who are otherwise healthy.

[0016] The terms“treatment of’ and“treating” include the administration of a drug with the intent to lessen the severity of or prevent a condition and is not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, the present invention also contemplates treatment that merely reduces symptoms, improves (to some degree) and/or delays disease progression. It is not intended that the present invention be limited to instances wherein a disease or affliction is cured. It is sufficient that symptoms are reduced.

[0017] The terms“prevention of’ and“preventing” include (1) inhibiting or avoiding the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.

[0018] The term“condition” or“conditions” refers to those medical conditions, such as cancer, that can be treated, mitigated or prevented by administration to a subject of an effective amount of a drug.

[0019] An "effective amount" refers to the amount of an active agent that is sufficient to produce a beneficial or desired effect at a level that is readily detectable by a method commonly used for detection of such an effect. In some embodiments, such an effect results in a change of at least 10% from the value of a basal level where the active agent is not administered. In other embodiments, the change is at least 20%, 50%, 80%, or an even higher percentage from the basal level. As will be described below, the effective amount of an active agent may vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, the particular active agent administered and the like. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation.

[0020] As used herein, the terms "active agent" refer to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose.

[0021] The term“alkyl” when used without the“substituted” modifier refers to a non-aromatic monovalent group with a saturated carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups,— CEE (Me),— CH2CH3 (Et),— CH2CH2CH3 (n-Pr), — CH(CH )₂ (iso-Pr or i-Pr), — CH(CH₂)₂ (cyclopropyl), — CH2CH2CH2CH3 (n-Bu), — CH(CH3)CH2CH3 (sec-butyl or sec-Bu),— CH2CH(CH3)2 (iso-butyl or i-Bu),— 0(O¾)3 (tert- butyl or t-Bu), — CH₂C(CH₃)₃ (neo-pentyl), cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl are non-limiting examples of alkyl groups. The term“substituted alkyl” refers to a non-aromatic monovalent group with a saturated carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The following groups are non-limiting examples of substituted alkyl groups: — CH₂OH, — CH₂C1, — CH₂Br, — CH₂SH, — CF , — CH₂CN, — CH₂C(0)H, — CH₂C(0)0H,— CH₂C(0)0CH ,— CH₂C(0)NH₂,— CH₂C(0)NHCH ,— CH₂C(0)CH ,— CH2OCH3,— CH2OCH2CF3,— CH₂0C(0)CH ,— CH2NH2,— CH2NHCH3, CH₂N(CH )2, CH2CH2CI,— CH2CH2OH,— CH2CF3,— CH₂CH₂0C(0)CH3,— CH₂CH₂NHC0₂C(CH3)3, and— CH₂Si(CH3)₃.

[0022] The term“alkanol” refers to any of a class of organic compounds containing the hydroxyl (— OH) functional group except those in which the OH group is attached to an aromatic ring (phenols).

[0023] In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and ¹⁴C. Similarly, it is contemplated that one or more carbon atom(s) of a compound of the present invention may be replaced by a silicon atom(s). Furthermore, it is contemplated that one or more oxygen atom(s) of a compound of the present invention may be replaced by a sulfur or selenium atom(s).

[0024] In structures wherein stereochemistry is not explicitly indicated, it is assumed that either stereochemistry is considered and both isomers claimed. [0025] Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to the atom.

[0026] An“isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.

[0027] The term“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. In a specific embodiment, the term“pharmaceutically acceptable” means approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0028]“Pharmaceutically acceptable salts” or“salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as, but not limited to, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic, acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Suitable pharmaceutically-acceptable base addition salts include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N- ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of the invention. Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002) [1]

[0029] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein, is intended merely to illuminate certain materials and methods and does not pose a limitation on scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods

DETAILED DESCRIPTION

[0030] In certain embodiments, the present invention is directed to pharmaceutical compositions and methods for the treatment of cancer comprising administering to a patient in need thereof an immune check point inhibitor and a cannabinoid type 2 receptor modulator.

[0031] In other embodiments, the present invention is directed to a method of treating immune- related adverse events associated with immune checkpoint inhibitor therapy comprising administering to a patient in need thereof a cannabinoid type 2 receptor modulator.

[0032] In certain embodiments, the cannabinoid type 2 receptor modulator may be administered prophylactically before a patient experiences immune-related adverse events associated with immune checkpoint inhibitor therapy. For instance, the cannabinoid type 2 receptor modulator may be administered about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, or about 0.5 hours before the onset of immune-related adverse events or before first administration of an immune checkpoint inhibitor.

[0033] In other embodiments, the cannabinoid type 2 receptor modulator may be administered in response to immune-related adverse events associated with immune checkpoint inhibitor therapy. For instance, the cannabinoid type 2 receptor inhibitor may be administered about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, or about 48 hours after the onset of immune-related adverse events or after first administration of an immune checkpoint inhibitor.

[0034] The cannabinoid type 2 receptor modulator can be permeable to the blood brain barrier such that a central effect is provided or impermeable to the blood brain barrier such that a central effect is not provided. In certain embodiments, the cannabinoid can be partially permeable to the blood brain barrier such that a central effect is not provided.

[0035] In certain embodiments, the cannabinoid type 2 receptor modulator is administered in an effective amount to reduce one or more immune-related adverse events. The immune related adverse events may be one or more of, e.g., cardiac, dermatologic, gastrointestinal, renal, hepatic, endocrine, exocrine, neurological (including peripheral and central nervous systems), ocular, pulmonary, or rheumatologic adverse events. In other embodiments, the immune- related adverse events are inflammatory conditions.

[0036] An example of a pulmonary adverse is pneumonitis which could present itself in an asymptomatic manner on imaging, or with symptoms such as cough, mild dyspnea, or severe shortness of breath with life threatening hypoxia. Pneumonitis symptoms may present themselves as early as two weeks up to as late as 11.5 months (and possibly longer) after treatment initiation with an immune check point inhibitor. About 1% to 10% of patients treated with one or more immune check point inhibitors may experience pulmonary adverse events of various grades.

[0037] Current treatment of pneumonitis depends on the grade. Grade I pneumonitis, in which patients are asymptomatic and pulmonary inflammation is detected by imaging or on clinical exam can be managed, e.g., by withholding the immune checkpoint inhibitor. Grade II pneumonitis may be symptomatic and current treatment may warrant steroid treatment (e.g., a dose of 1 mg/kg/day of methylprednisolone or its oral equivalent) as well as a bronchoscopy with lavage. Grade III and IV pneumonitis under current treatment warrant urgent hospitalization, discontinuation of the checkpoint inhibitor, steroid treatment (e.g., a dose of 2- 4 mg/kg/day of methylprednisolone), and possibly immunosuppression therapy (e.g., with infliximab, mycophenolate mofetil, or cyclophosphamide) as patients are symptomatic and often hypoxic.

[0038] Another example of a pulmonary adverse event is sarcoidosis. It may be diagnosed through imaging findings including hilar lymphadenopathy and/or a transbronchial biopsy showing non-caseating granulomas. Patients experiencing this pulmonary adverse event may be examined and monitored using pulmonary function tests, CT, 6-minute walk test, resting O2 saturation, electrocardiogram (EKG), eye exam, or a combination thereof. Patients with hypercalcemia, progressive symptoms, declining lung function, or evolving radiographic changes should all initiate treatment of the adverse effects.

[0039] Thus, in some embodiments, the instant disclosure may be directed to a method for treating a pulmonary adverse event associated with immune checkpoint inhibitor therapy comprising administering to a patient experiencing a pulmonary adverse event a cannabinoid type 2 receptor modulator. The pulmonary adverse event may be pneumonitis, sarcoidosis, or symptoms thereof. Administration of the cannabinoid type 2 receptor modulator may reduce the pulmonary adverse event grade experienced by the patient (e.g., from grade 2 to grade 1 pneumonitis). In certain embodiments, the immune checkpoint inhibitor therapy may be withheld until treatment of the pulmonary adverse event is concluded and/or until the pulmonary adverse event is treated. In other embodiments, the immune checkpoint inhibitor therapy may be discontinued. In other embodiments, the immune checkpoint inhibitor therapy is continued while the pulmonary adverse event is treated by the cannabinoid type 2 receptor modulator. The method may further comprise detecting and/or monitoring the pulmonary adverse event (prior to, during, or after administration of the cannabinoid type 2 receptor modulator) with one or more of imaging, clinical exam, bronchoscopy, transbronchial biopsy, pulmonary function tests, CT, 6-minute walk test, resting O2 saturation, electrocardiogram (EKG), eye exam, or a combination thereof.

[0040] An example of gastrointestinal adverse events include diarrhea, severe bowel inflammation, colitis, abdominal pain, hematochezia, ileus, hepatitis, elevated transaminases, and could be life threatening.

[0041] Various grades of diarrhea may occur in about 1% to about 15% of patients treated with one or more immune checkpoint inhibitors. Grade 1 diarrhea (<4 bowl movements/day) under current treatments can typically be managed as an outpatient with anti-motility agents (e.g., loperamide, diphenoxylate/atropine, tincture of opium) as well as increasing fiber intake. Grade 2 diarrhea (4-6 bowel movements/day with or without abdominal pain or bloody stools) under current treatments may warrant steroid treatment (e.g., a dose of 1-2 mg/kg/day of prednisone or its equivalent for up to about 4-6 weeks as long as improvement is seen) and withholding the immune checkpoint inhibitor therapy until treatment of the gastrointestinal adverse event is concluded and/or until the gastrointestinal adverse event is treated. Grade 3 or 4 diarrhea under current treatments may warrant hospitalization and an endoscopic evaluation of the enteric tract. With grade 3 or 4 diarrhea, the offending checkpoint inhibitor under current treatments should be permanently discontinued. It is also recommended under current treatments to permanently discontinue the offending checkpoint inhibitor with lower grade diarrhea if the patient is unable to taper steroids to the equivalent of <10 mg of prednisone/day.

[0042] Evidence of liver inflammation (e.g., hepatitis) may occur in about 1% to about 30% of patients treated with one or more immune checkpoint inhibitors. Accordingly, liver function testing, monitoring AST or ALT levels, monitoring bilirubin levels, and/or a biopsy are recommended to detect and/or monitor development of hepatitis. If the immune checkpoint inhibitor therapy is identified as the cause for the liver inflammation (as opposed to another infectious or malignant cause), current treatments may warrant steroids initiated at about 0.5-1 mg/kg (or higher doses if more severe transaminitis or hyperbilirubinemia is present).

[0043] Thus, in some embodiments, the instant disclosure may be directed to a method for treating a gastrointestinal adverse event associated with immune checkpoint inhibitor therapy comprising administering to a patient experiencing a gastrointestinal adverse event a cannabinoid type 2 receptor modulator. The gastrointestinal adverse event may be diarrhea, severe bowel inflammation, colitis, abdominal pain, hematochezia, ileus, hepatitis, elevated transaminases, or symptoms thereof. Administration of the cannabinoid type 2 receptor modulator may reduce the gastrointestinal adverse event grade experienced by the patient (e.g., from grade 2 to grade 1 diarrhea). In certain embodiments, the immune checkpoint inhibitor therapy may be withheld until treatment of the gastrointestinal adverse event is concluded and/or until the gastrointestinal adverse event is treated. In other embodiments, the immune checkpoint inhibitor therapy may be discontinued. In other embodiments, the immune checkpoint inhibitor therapy is continued while the gastrointestinal adverse event is treated by the cannabinoid type 2 receptor modulator. The method may further comprise detecting and/or monitoring the gastrointestinal adverse event (prior to, during, or after administration of the cannabinoid type 2 receptor modulator) with one or more of endoscopic evaluation of the enteric tract, clinical exam, liver function testing, monitoring AST or ALT levels, monitoring bilirubin levels, and/or a biopsy, or a combination thereof.

[0044] Examples of cardiac adverse events may range from asymptomatic dilated cardiomyopathy to symptomatic heart failure with reduced systolic function on echocardiogram, myocardial fibrosis, takotsubo cardiomyopathy with apical ballooning, pericarditis, myocarditis, tachyarrhyth ias including ventricular fibrillation and cardiac arrest, bradyarrhythmias including first, second, and third-degree heart block, acute coronary syndrome, moderate-severe decompensated heart failure, severe arrythmias. Cardiac adverse events may occur in <1% of patients treated with one or more immune checkpoint inhibitors.

[0045] With grade I or II cardiac adverse events as defined by the Common Terminology Criteria for Adverse Events (CTCAE 4.0), such as asymptomatic arrhythmias or structural heart failure without symptoms, initiating routine cardiac monitoring with clinical exam, serial EKGs, left ventricular ejection fractions or cardiac cell death (troponin-I, CK-MB), troponins, and echocardiograms may be appropriate under current treatments. If the cardia adverse events are symptomatic, the immune checkpoint inhibitor therapy may be withheld under current treatments until the symptoms are stabilized. With grade III or IV adverse events, including acute coronary syndrome, moderate-severe decompensated heart failure, or severe arrhythmias, the offending immune checkpoint inhibitor should be permanently discontinued under current treatments.

[0046] Thus, in some embodiments, the instant disclosure may be directed to a method for treating a cardiac adverse event associated with immune checkpoint inhibitor therapy comprising administering to a patient experiencing a cardiac adverse event a cannabinoid type 2 receptor modulator. The cardiac adverse event may be one or more of asymptomatic dilated cardiomyopathy, symptomatic heart failure with reduced systolic function on echocardiogram, myocardial fibrosis, takotsubo cardiomyopathy with apical ballooning, pericarditis, myocarditis, tachyarrhythmias including ventricular fibrillation and cardiac arrest, bradyarrhythmias including first, second, and third-degree heart block, acute coronary syndrome, moderate-severe decompensated heart failure, severe arrhythmias, or symptoms thereof. Administration of the cannabinoid type 2 receptor modulator may reduce the cardiac adverse event grade experienced by the patient (e.g., from grade 2 to grade 1 cardiac adverse event). In certain embodiments, the immune checkpoint inhibitor therapy may be withheld until treatment of the cardiac adverse event is concluded and/or until the cardiac adverse event is treated and/or until the symptoms of the cardiac adverse event are stabilized. In other embodiments, the immune checkpoint inhibitor therapy may be discontinued. In other embodiments, the immune checkpoint inhibitor therapy is continued while the cardiac adverse event is treated by the cannabinoid type 2 receptor modulator. The method may further comprise detecting and/or monitoring the cardiac adverse event (prior to, during, or after administration of the cannabinoid type 2 receptor modulator) by monitoring one or more of serial EKGs, left ventricular ejection fractions or cardiac cell death (troponin-I, CK-MB), troponins, echocardiograms, or a combination thereof.

[0047] Examples of rheumatologic adverse events include arthralgias, myalgias, myositis, lupus nephritis, and vasculitis. Rheumatologic adverse events may be seen in about 2-12% of patients treated with one or more immune checkpoint inhibitors. Grade I musculoskeletal pain may be managed under current treatments with nonsteroidal anti-inflammatory drugs (NSAIDS) with escalation to steroids if no improvement is observed. For more severe joint pain and swelling that limit a patient’s activities of daily living, a more thorough work-up may be performed including inflammatory and rheumatologic tests such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-nuclear antibody (ANA), cyclic citrullinated peptide antibody (anti-CCP), imaging of affected joints, or a combination thereof. [0048] Thus, in some embodiments, the instant disclosure may be directed to a method for treating a rheumatologic adverse event associated with immune checkpoint inhibitor therapy comprising administering to a patient experiencing a rheumatologic adverse event a cannabinoid type 2 receptor modulator. The rheumatologic adverse event may be one or more of arthralgias, myalgias, myositis, lupus nephritis, vasculitis or symptoms thereof. Administration of the cannabinoid type 2 receptor modulator may reduce the rheumatologic adverse event grade experienced by the patient (e.g., from grade 2 to grade 1 rheumatologic adverse event). In certain embodiments, the immune checkpoint inhibitor therapy may be withheld until treatment of the rheumatologic adverse event is concluded and/or until the rheumatologic adverse event is treated and/or until the symptoms of the rheumatologic adverse event are stabilized. In other embodiments, the immune checkpoint inhibitor therapy may be discontinued. In other embodiments, the immune checkpoint inhibitor therapy is continued while the rheumatologic adverse event is treated by the cannabinoid type 2 receptor modulator. The method may further comprise detecting and/or monitoring the rheumatologic adverse event (prior to, during, or after administration of the cannabinoid type 2 receptor modulator) by clinical exam, performing inflammatory and rheumatologic tests such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-nuclear antibody (ANA), cyclic citrullinated peptide antibody (anti-CCP), imaging of affected joints, or a combination thereof.

[0049] Examples of renal adverse events include elevated creatinine levels, hematuria, edema, decreased urine output, kidney failure, metabolic derangements, or a combination thereof. Renal adverse events may occur in about 2% to about 5% of patients treated with one or more immune checkpoint inhibitors and may occur between about 3 months to about 10 months after initiating immune checkpoint inhibitor therapy. Renal adverse events may be detected and/or monitored by clinical exam, routine lab work, monitoring serum renal indices, serum creatinine levels, urine and serum studies, imaging, nephrology consult, renal biopsy, or a combination thereof. Renal adverse events under current treatments may warrant corticosteroid treatment in addition to stopping the offending immune checkpoint inhibitor therapy either permanently or temporarily.

[0050] Thus, in some embodiments, the instant disclosure may be directed to a method for treating a renal adverse event associated with immune checkpoint inhibitor therapy comprising administering to a patient experiencing a renal adverse event a cannabinoid type 2 receptor modulator. The renal adverse event may be one or more of elevated creatinine levels, hematuria, edema, decreased urine output, kidney failure, metabolic derangements, or symptoms thereof. Administration of the cannabinoid type 2 receptor modulator may reduce the renal adverse event grade experienced by the patient (e.g., from grade 2 to grade 1 renal adverse event). In certain embodiments, the immune checkpoint inhibitor therapy may be withheld until treatment of the renal adverse event is concluded and/or until the renal adverse event is treated and/or until the symptoms of the renal adverse event are stabilized. In other embodiments, the immune checkpoint inhibitor therapy may be discontinued. In other embodiments, the immune checkpoint inhibitor therapy is continued while the renal adverse event is treated by the cannabinoid type 2 receptor modulator. The method may further comprise detecting and/or monitoring the renal adverse event (prior to, during, or after administration of the cannabinoid type 2 receptor modulator) by clinical exam, routine lab work, monitoring serum renal indices, serum creatinine levels, urine and serum studies, imaging, nephrology consult, renal biopsy, or a combination thereof.

[0051] Examples of endocrine and exocrine adverse events include one or more of thyroid disease, hypothyroidism, hyperthyroid state, thyrotoxicosis, hypophysitis, central adrenal insufficiency, life threatening electrolyte abnormalities, hypoglycemia, dehydration, hypotension, adrenal crisis, elevated serum amylase and lipase values, autoimmune diabetes, insulin dependence, diabetic ketoacidosis, hyperglycemia, fatigue, hair loss, cold intolerance, constipation, poor mood, and symptoms thereof. Endocrine and exocrine adverse events may occur in about 0.6% to about 13 % of patients treated with one or more immune checkpoint inhibitors. These adverse events may be detected and/or monitored by clinical examination, serum thyroid tests, lab tests for thyroid stimulating hormone (TSH) and free T4, titration of levothyroxine, imaging, brain MRI with special attention to the sella turcica region to evaluate swelling and enhancement of the pituitary gland, endocrinology consult, glucose level, a basic or comprehensive metabolic panel, or a combination thereof.

[0052] Thus, in some embodiments, the instant disclosure may be directed to a method for treating endocrine and exocrine adverse events associated with immune checkpoint inhibitor therapy comprising administering to a patient experiencing endocrine and exocrine adverse event a cannabinoid type 2 receptor modulator. The endocrine and exocrine adverse event may be one or more of thyroid disease, hypothyroidism, hyperthyroid state, thyrotoxicosis, hypophysitis, central adrenal insufficiency, life threatening electrolyte abnormalities, hypoglycemia, dehydration, hypotension, adrenal crisis, elevated serum amylase and lipase values, autoimmune diabetes, insulin dependence, diabetic ketoacidosis, hyperglycemia, fatigue, hair loss, cold intolerance, constipation, poor mood, and symptoms thereof. Administration of the cannabinoid type 2 receptor modulator may reduce the endocrine and exocrine adverse event grade experienced by the patient (e.g., from grade 2 to grade 1 endocrine and exocrine adverse event). In certain embodiments, the immune checkpoint inhibitor therapy may be withheld until treatment of the endocrine and exocrine adverse event is concluded and/or until the endocrine and exocrine adverse event is treated and/or until the symptoms of the endocrine and exocrine adverse event are stabilized. In other embodiments, the immune checkpoint inhibitor therapy may be discontinued. In other embodiments, the immune checkpoint inhibitor therapy is continued while the endocrine or exocrine adverse event is treated by the cannabinoid type 2 receptor modulator. The method may further comprise detecting and/or monitoring the endocrine and exocrine adverse event (prior to, during, or after administration of the cannabinoid type 2 receptor modulator) by clinical examination, serum thyroid tests, lab tests for thyroid stimulating hormone (TSH) and free T4, titration of levothyroxine, imaging, brain MRI with special attention to the sella turcica region to evaluate swelling and enhancement of the pituitary gland, endocrinology consult, glucose level, a basic or comprehensive metabolic panel, or a combination thereof.

[0053] Examples of neurologic and ocular adverse events include one or more of peripheral neuropathies (e.g., motor or sensory dysfunction, Guillain-Barre Syndrome, myasthenia gravis, fluctuating or progressive muscle weakness, ocular changes such as diplopia or ptosis), central neurological adverse events (e.g., immune mediated encephalitis, aseptic meningitis, posterior reversible encephalopathy syndrome), ocular adverse events (e.g., episcleritis, uveitis, conjunctivitis), altered mental status, headaches, fevers, confusion, receptive and expressive aphasia, motor and sensory changes, ocular pain, dryness, photophobia, vision changes, or symptoms thereof. Neurologic and ocular adverse events may occur in about 1% to about 12% of patients treated with one or more immune checkpoint inhibitors. These adverse events may be detected and/or monitored by clinical exam, lumbar puncture to look for elevated protein levels, nerve conduction studies, PFTs, physical exam that assesses for proximal muscle fatigue and ocular muscle dysfunction, laboratory tests that include acetylcholine receptor and anti- MuSK antibodies, neurology consult, central nervous system imaging, ophthalmology consult, or a combination thereof.

[0054] Thus, in some embodiments, the instant disclosure may be directed to a method for treating neurologic and/or ocular adverse events associated with immune checkpoint inhibitor therapy comprising administering to a patient experiencing neurologic and/or ocular adverse event a cannabinoid type 2 receptor modulator. The neurologic and/or ocular adverse event may be one or more peripheral neuropathies (e.g., motor or sensory dysfunction, Guillain-Barre Syndrome, myasthenia gravis, fluctuating or progressive muscle weakness, ocular changes such as diplopia or ptosis), central neurological adverse events (e.g., immune mediated encephalitis, aseptic meningitis, posterior reversible encephalopathy syndrome), ocular adverse events (e.g., episcleritis, uveitis, conjunctivitis), altered mental status, headaches, fevers, confusion, receptive and expressive aphasia, motor and sensory changes, ocular pain, dryness, photophobia, vision changes, or symptoms thereof. Administration of the cannabinoid type 2 receptor modulator may reduce the neurologic and/or ocular adverse event grade experienced by the patient (e.g., from grade 2 to grade 1 neurologic and ocular adverse event). In certain embodiments, the immune checkpoint inhibitor therapy may be withheld until treatment of the neurologic and/or ocular adverse event is concluded and/or until the neurologic and/or ocular adverse event is treated and/or until the symptoms of the neurologic and/or ocular adverse event are stabilized. In other embodiments, the immune checkpoint inhibitor therapy may be discontinued. In other embodiments, the immune checkpoint inhibitor therapy is continued while the neurologic and/or ocular adverse event is treated by the cannabinoid type 2 receptor modulator. The method may further comprise detecting and/or monitoring the neurologic and/or ocular adverse event (prior to, during, or after administration of the cannabinoid type 2 receptor modulator) by clinical exam, lumbar puncture to look for elevated protein levels, nerve conduction studies, PFTs, physical exam that assesses for proximal muscle fatigue and ocular muscle dysfunction, laboratory tests that include acetylcholine receptor and anti-MuSK antibodies, neurology consult, central nervous system imaging, ophthalmology consult, or a combination thereof.

[0055] Examples of dermatologic adverse events include one or more of rashes (such as morbilliform or maculopapular and pruritic), toxic epidermal necrolysis, and symptoms thereof. Dermatologic adverse events may occur in about 2% to about 24% of patients treated with one or more immune checkpoint inhibitors. Under current treatments, grade 1-2 rashes with mild pruritus may be treated with topical steroids and oral antihistamines if needed and the immunotherapy agent need not necessarily be discontinued. Grade 3 skin reactions under current treatments may require systemic high-dose steroids with temporary withholding of the offending immunotherapy agent. Grade 4 reactions under current treatments may require permanent discontinuation of the immunotherapy agent and high-dose systemic steroids.

[0056] Thus, in some embodiments, the instant disclosure may be directed to a method for treating dermatologic adverse events associated with immune checkpoint inhibitor therapy comprising administering to a patient experiencing dermatologic adverse event a cannabinoid type 2 receptor modulator. The dermatologic adverse event may be one or more rashes (such as morbilliform or maculopapular and pruritic), toxic epidermal necrolysis, and symptoms thereof. Administration of the cannabinoid type 2 receptor modulator may reduce the dermatologic adverse event grade experienced by the patient (e.g., from grade 2 to grade 1 rash). In certain embodiments, the immune checkpoint inhibitor therapy may be withheld until treatment of the dermatologic adverse event is concluded and/or until the dermatologic adverse event is treated and/or until the symptoms of the dermatologic adverse event are stabilized. In other embodiments, the immune checkpoint inhibitor therapy may be discontinued. In other embodiments, the immune checkpoint inhibitor therapy is continued while the dermatologic adverse event is treated by the cannabinoid type 2 receptor modulator. The method may further comprise detecting and/or monitoring the dermatologic adverse event (prior to, during, or after administration of the cannabinoid type 2 receptor modulator) by clinical exam.

[0057] In certain embodiments, the cannabinoid type 2 receptor modulator exhibits a higher affinity for the CB2 receptor than the CB 1 receptor. The cannabinoid type 2 receptor modulator can exhibit an affinity for the CB2 receptor, e.g., ranging from about 2 times to about 1000 times, from about 5 times to about 900 times, from about 10 times to about 800 times, from about 15 times to about 700 times, from about 20 times to about 600 times, from about 25 times to about 500 times, from about 30 times to about 400 times, from about 40 times to about 300 times, from about 50 times to about 250 times, from about 60 times to about 200 times, from about 70 times to about 150 times, from about 80 times to about 100 times, or from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 to about 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, or 1000 greater than its affinity for the CB 1 receptor.

[0058] In certain embodiments, the immune check point inhibitor and the cannabinoid type 2 receptor modulator can be administered at the same time. The agents can be combined in the same dosage form or be in separate dosage forms. When in separate dosage forms the agents can be administered by the same route of administration (e.g., oral) or by different routes of administration (e.g., parenteral and oral).

[0059] In certain embodiments, the immune check point inhibitor and the cannabinoid type 2 receptor modulator can be administered simultaneously or sequentially. In certain embodiments, the two agents are administered sequentially such that there is an overlap of the therapeutic interval provided by each agent. With sequential administration, the agents are in separate dosage forms and can be administered by the same route of administration (e.g., oral) or by different routes of administration (e.g., parenteral and oral).

[0060] The term “simultaneously” as used herein means that a dose of one agent is administered at the same time as another agent, regardless of whether the agents are administered separately via the same or different routes of administration or in a single pharmaceutical composition or dosage form. For example, a dose of a cannabinoid type 2 receptor modulator may be administered at the same time as a dose of an immune check point inhibitor. [0061] The term“sequentially” as used herein means that a dose of one agent is administered first and thereafter a dose of another agent is administered second. For example, a dose of an immune check point inhibitor may be administered and thereafter a dose of a cannabinoid type 2 receptor modulator may be administered. The subsequent administration of the other agent may be inside or outside the dosing interval of agent that was administered first.

[0062] The route of administration for the compositions and methods of the present invention can be independently selected from oral, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal route. In certain embodiments, the immune check point inhibitor is administered parenterally and the cannabinoid type 2 receptor modulator is administered orally.

[0063] In certain embodiments, the immune checkpoint inhibitor utilized in the present invention may be a CTLA-4 inhibitor (e.g., ipilimunab), a PD-1 inhibitor (e.g., pembrolizumab, nivolumab, cemiplimab-rwlc, or a combination thereof), a PD-Ll inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a combination thereof) or a combination thereof.

[0064] In certain embodiments, the cannabinoid type 2 receptor modulator utilized in the present invention may be ajulemic acid having a purity greater than about 95% (w/w), about 96% (w/w), about 97% (w/w), about 98% (w/w), about 99% (w/w), about 99.5% (w/w), or about 99.8% (w/w), based on weight of all cannabinoids. In other embodiments, the ajulemic acid has less than about 5% (w/w), about 4% (w/w), about 3% (w/w), about 2% (w/w), about 1% (w/w), about 0.5% (w/w), or about 0.2% (w/w) of 1 l-hydroxy-(6aR,10aR)-3-(l ',l '- di methyl heptyl)-A8-tetrahydrocannabinol (HU-210) or other highly CB1 active compounds, based on weight of all cannabinoids.

[0065] In certain embodiments, the cannabinoid type 2 receptor modulator may be administered in a daily dose, e.g., of about 0.5 mg to about 1 g, about 1 mg to about 900 mg, about 5 mg to about 800 mg, about 10 mg to about 750 mg, about 50 mg to about 500 mg, or about 100 mg to about 250 mg, about 5 mg, and/or about 20 mg.

[0066] In certain embodiments the weight ratio (w/w) of the cannabinoid type 2 receptor modulator to the immune checkpoint inhibitor, per unit dose, may range, e.g., from about 100: 1 to about 1 : 100, from about 80: 1 to about 1 :80, from about 50: 1 to about 1 :50, from about 30: 1 to about 1 :30, from about 15: 1 to about 1 : 15, from about 10: 1 to about 1 : 10, from about 8: 1 to about 1 :8, from about 5: 1 to about 1 :5, from about 3 : 1 to about 1 :3, or from about 2: 1 to about 1 :2. The disclosed weight ratios can be when the agents are combined in the same dosage form or when administered in separate dosage forms.

[0067] In certain embodiments, the patient is on a previous regimen of an immunosuppressive agent (e.g., glucocorticosteroids, TNF inhibitors, my cophenol ate, or mycophenolate mofetil, salts thereof, or a combination thereof) and the cannabinoid type 2 receptor modulator replaces the immunosuppressive agent (i.e., the immunosuppressive agent is discontinued). In other embodiments, the patient is on a previous regimen of an immunosuppressive agent and the cannabinoid type 2 receptor modulator is added to the dosing regimen. In further embodiments, the patient is not on a previous regimen or a concurrent regimen of an immunosuppressive agent upon the initiation and duration of the cannabinoid type 2 receptor modulator therapy. The term“concurrent,” as used herein, refers to an overlap in the therapeutic window of the immunosuppressive agent and the cannabinoid type 2 receptor modulator therapy. The active agent(s) that are part of the cannabinoid type 2 receptor modulator therapy can be administered simultaneously with the immunosuppressive agent, but simultaneous administration is not required.

[0068] The cancer that is treated by the compositions and methods of the invention may be one or more of, e.g., melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, Hodgkin lymphoma, non-small cell lung cancer, or Merkel cell carcinoma.

Cannabinoid type 2 receptor modulator

[0069] In certain embodiments, the cannabinoid type 2 receptor modulator is a (3R,4R)-A8- tetrahydrocannabinol-11-oic acid of the formula (I):

[0070] wherein R¹ is hydrogen, COCH3 or COCH2CH3; R² is a branched C5-C12 alkyl group which may optionally have a terminal aromatic ring, or optionally a branched OCHCH3(CH2)_m alkyl group which may have a terminal aromatic ring, wherein m is 0 to 7; and R³ is hydrogen, a Ci-₈ alkyl or a Ci-₈ alkanol group; and Y is nil or a bridging group of NH or oxygen; provided that where Y is oxygen and R² is a branched C5-C12 alkyl, R³ is not CHCH3. In one embodiment, the composition comprises a pharmaceutically acceptable salt, ester, or solvate of (3R,4R)-A8- tetrahydrocannabinol-11-oic acid. In one embodiment, R¹ is hydrogen and R² is 1 ', 1 dimethylheptyl. In one embodiment, said composition has the structure:

[0071] In one embodiment, R² is a branched OCHCH3(CH2)_m alkyl group terminated with a phenyl ring, wherein m is 0 to 7, and R³ is CHCH3. In one embodiment, said composition has the structure:

[0072] In a further embodiment, the cannabinoid type 2 receptor modulator is a (3R,4R)-A8- tetrahydrocannabinol-l l-oic acid and is a (6aR,10aR)-4-(l,l-dimethylheptyl)-A8-tetrahydro- cannabinol-9-carboxylic acid of the formula (II):

[0073] wherein R¹ is hydrogen, COCH3 or COCH2CH3; and R² is a branched C5-C12 alkyl group which may optionally have a terminal aromatic ring, or optionally a branched OCHCH3(CH₂)_m alkyl group which may have a terminal aromatic ring, wherein m is 0 to 7. In one embodiment, said composition comprises a pharmaceutically acceptable salt, ester, or solvate of (3R,4R)-A8-tetrahydrocannabinol-l 1-oic acid that is (6aR, 10aR)-4-( 1,1- dim ethyl heptyl)-A8-tetrahydro-cannabinol -9-carboxyl ic

_{n one} embodiment, R¹ is hydrogen and R² is 1 ', 1 '-dimethylheptyl. In one embodiment, R² is a branched OCHCH3(CH2)_m alkyl group terminated with a phenyl ring, wherein m is 0 to 7, and R³ is CHCH3. [0074] In alternative embodiments, the cannabinoid type 2 receptor modulator is a tetracycline (e.g., minocycline); echinacea purpurea; beta-caryophyllene (BCP); [(lR,2R,5R)-2-[2,6- dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4- -bicyclo[3.1.1]hept-3- enyl] methanol (HU-308); an aminoalkylindole (e.g., (l-(methylpiperidin-2-ylmethyl)-3-(2- iodo-5-nitrobenzoyl)indole (AM01241)); a naphthoylindole (e.g., JWH-015); JWH-133; ([(lR,2R,5R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7, 7-dimethyl -4- bicyclo[3.1. l]hept-3-enyl]methanol (HU-308)); GW-405,833; L-759,633; L-759,656; 6- iodopravadoline (AM-630); indomethacin morpholinylamide (BML-190); JTE-907 and SR- 144,528.

Immune Checkpoint Inhibitors

[0075] With respect to the present disclosure, an immune checkpoint molecule means a molecule that exhibits an immunosuppression function by delivering an inhibitory co-signal. Examples of known immune checkpoint molecules include CTLA-4, PD-1, PD-L1 (programmed cell death-ligand 1), PD-L2 (programmed cell death-ligand 2), LAG-3 (Lymphocyte activation gene 3), TIM3 (T cell immunoglobulin and mucin-3), BTLA (B and T lympho-cyte attenuator), B7H3, B7H4, 2B4, CD 160, A2aR (adenosine A2a receptor), KIR (killer inhibitory receptor), VISTA (V-domain Ig-containing suppressor of T cell activation), TIGIT (T cell immunoglobulin and ITIM domain), and the like (see, Nature Reviews Cancer, 12, pp. 252-264, 2012, Cancer Cell, 27, pp. 450-461, 2015). The immune checkpoint molecule is not particularly limited as described above.

[0076] An immune checkpoint inhibitor used in the combination of the present invention is a substance that inhibits the function of an immune checkpoint molecule. The immune checkpoint inhibitor is not particularly limited as long as it can inhibit the function (signal) of the immune checkpoint molecule. [0077] The immune checkpoint inhibitor is preferably an inhibitor of a human immune checkpoint molecule.

[0078] Examples of the immune checkpoint inhibitor include an inhibitor against an immune checkpoint molecule such as, without limitations, CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, 2B4, CD 160, A2aR, KIR, VISTA, TIGIT, or a combination thereof. The followings are examples of the immune checkpoint inhibitors, but the immune checkpoint inhibitor is not necessarily limited to these examples.

[0079] Examples of immune checkpoint inhibitors include an anti-CTLA-4 antibody (for example, Ipilimumab (YERVOY®), Tremelimumab, AGEN-1884), anti-PD-1 antibody (for example, nivolumab (OPDIVO®), REGN-2810, Pembrolizumab (KEYTRUDA®), PDR-001, BGB-A317, AMP-514 (MEDI0680), BCD-100, IBI-308, JS-001, PF-06801591, and TSR- 042), an anti-PD-Ll antibody (for example, Atezolizumab (RG7446 and MPDL3280A), Avelumab (PF-06834635 and MSB0010718C), Durvalumab (MEDI4736), BMS-936559, CA- 170, and LY-3300054), anti-PD-L2 antibody (for example, rHIgM12B7), PD-L1 fusion protein, PD-L2 fusion protein (for example, AMP -224), an anti-Tim-3 antibody (for example, MBG453), an anti -LAG-3 antibody (for example, BMS-986016, and LAG525), and an anti- KIR antibody (for example, Lirilumab). Furthermore, antibodies including heavy chain and light chain complementarity determining regions (CDRs) or variable region (VR) of the above- mentioned known antibodies are also one embodiment of the immune checkpoint inhibitor.

[0080] In certain embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 therapy selected from the group consisting of ipilimumab, tremelimumab, and combinations thereof. In a specific embodiment, the immune checkpoint inhibitor is ipilimumab. In another embodiment, the immune checkpoint inhibitor is an anti-PD-1 therapy selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, MEDI0680, and combinations thereof. Examples of further embodiments of the anti-PD-1 antibody include an antibody including heavy chain and light chain complementarity determining regions (CDRs) or variable region (VR) of nivolumab.

[0081] In still another embodiment, the immune checkpoint inhibitor is an anti-PD-Ll therapy selected from the group consisting of atezolizumab, BMS-936559, MEDI4736, MSB0010718C, and combinations thereof.

[0082] In still another embodiment, the CB2 modulator is administered with one or more immune checkpoint inhibitors selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, pidilizumab, urelumab, MEDI0680, atezolizumab, BMS-936559, MEDI4736, MSB0010718C, and combinations thereof.

[0083] In certain embodiments, the CB2 modulator is administered along with a nivolumab treatment plan for a condition such as lung cancer, kidney cancer, liver cancer, colorectal cancer, melanoma, head and neck squamous cell cancer, bladder cancer, classical Hodgkin lymphoma, or a combination thereof. In one embodiment, the nivolumab treatment plan may comprise administering 240 mg of nivolumab every two weeks. In another embodiment, the nivolumab treatment plan may comprise administering intravenously 480 mg of nivolumab for a duration of 30 minutes every four weeks.

[0084] In certain embodiments, the CB2 modulator is administered along with a pembrolizumab treatment plan for a condition such as non-small cell lung cancer, urothelial bladder cancer, mediastinal b-cell lymphoma, melanoma, kidney cancer, gastric cancer, hepatocellular carcinoma, head and neck squamous cell cancer, microsatellite instability, cervical cancer, merkel cell carcinoma, or a combination thereof. In one embodiment, the pembrolizumab treatment plan may comprise administering intravenously 200 mg of pembrolizumab for a duration of 30 minutes every three weeks.

[0085] In certain embodiments, the CB2 modulator is administered along with an ipilimumab treatment plan for a condition such as melanoma (e.g., stage III melanoma, metastatic melanoma, or a combination thereof). In one embodiment, the ipilimumab treatment plan may comprise administering intravenously 10 mg/kg of ipilimumab for a duration of 90 minutes every three weeks for four doses followed by 10 mg/kg of ipilimumab every 12 weeks for up to three years. In one embodiment, the ipilimumab treatment plan further comprises administering 240mg of involumab every two weeks or administering intravenously 480mg of involumab every four weeks for a duration of 30 minutes.

[0086] In certain embodiments, the CB2 modulator is administered along with an atezolizumab treatment plan for a condition such as non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, bladder cancer, or a combination thereof. In one embodiment, the atezolizumab treatment plan may comprise administering intravenously 1200 mg of atezolizumab for a duration of 60 minutes every three weeks.

[0087] In certain embodiments, the CB2 modulator is administered along with a durvalumab treatment plan for a condition such as non-small cell lung cancer, urothelial carcinoma, or a combination thereof. In one embodiment, the durvalumab treatment plan may comprise administering intravenously 10 mg/kg of durvalumab for a duration of 60 minutes every two weeks.

[0088] In certain embodiments, the CB2 modulator is administered along with an avelumab treatment plan for a condition such as merkel cell carcinoma, urothelial carcinoma, or a combination thereof. In one embodiment, the avelumab treatment plan may comprise administering intravenously 10 mg/kg of durvalumab for a duration of 60 minutes every two weeks.

[0089] In certain embodiments, the CB2 modulator is administered along with a cemiplimab- rwlc treatment plan for a condition such as cutaneous squamous cell carcinoma. In one embodiment, the cemiplimab-rwlc treatment plan may comprise administering intravenously 350 mg of cemiplimab-rwlc for a duration of 30 minutes every three weeks. Pharmaceutical Compositions

[0090] The present compositions may be administered one or more times daily (e.g., once daily, twice daily, or three times daily) and may optionally be administered just before or with a meal (e.g., in a fed or fasted state).

[0091] A pharmaceutical composition of this invention can be administered, e.g., parenterally, orally, nasally, rectally, topically, buccally, by ophthalmic administration, or by inhalation. The term "parenteral" as used herein refers, e.g., to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.

[0092] In some embodiments, the dosage form of the immune check point inhibitor and/or the cannabinoid type 2 receptor modulator may be suitable for oral administration such as a pressed tablet, capsule (gelatin capsules, HPMC, hard shell, soft shell, or any other suitable capsule), enteric coated tablet, osmotic release tablet or capsule, unique combination of excipients, a chewable gum, lozenge, candy, or an edible form. In some embodiments, the immune check point inhibitor and/or the cannabinoid type 2 receptor modulator may be formulated in a manner suitable for parenteral administration, such as a solution, a suspension (e.g., an aqueous suspension), a dispersion, an emulsion, or a powder. In some embodiments, the immune check point inhibitor and/or the cannabinoid type 2 receptor modulator may be formulated in a manner suitable for topical administration, such as solutions, ointments, creams, suspensions, lotions, powders, pastes, gels, sprays, aerosols, or oils, a patch, or a dressing. In some embodiments, the immune check point inhibitor and/or the cannabinoid type 2 receptor modulator may be formulated in a manner suitable for administration by inhalation, such as through a nebulizer, vaping, smoking, and the like. In some embodiments, the immune check point inhibitor and/or the cannabinoid type 2 receptor modulator may be formulated in a manner suitable for intranasal administration, such as drops, an aerosol, or spray.

[0093] In certain embodiments, the dosage forms disclosed herein may be formulated as a matrix encompassing the active agent(s), optionally along with one or more pharmaceutically acceptable excipients. In other embodiments, the dosage forms disclosed herein may be formulated in a layered manner where the active agent(s), optionally with one or more pharmaceutically acceptable excipients, may be in one or more layers, and one or more additional pharmaceutically acceptable excipient(s) and/or one or more additional active agent(s) may be in another layer. In yet other embodiments, the dosage forms disclosed herein may be formulated as particles (e.g., microspheres, micelles, granules, extrudates). The particles themselves could be dispersed in a matrix and/or contain layers.

[0094] In some embodiments, the dosage form and the pharmaceutically acceptable excipients therein are selected to control the release rate of the dosage form. The active agent(s) in the dosage form may have an immediate release profile, an extended release profile, a delayed release profile, or a combination thereof (e.g., where one of the active agents is released according to one release profile and another active agent is released according to a different release profile).

[0095]“Immediate release,” as used herein, refers to a pharmaceutical composition that releases at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the active agent(s) within about 15 minutes, within about 30 minutes, within about 45 minutes, or within about 60 minutes.

[0096]“Extended or sustained release,” as used herein, refers to an active agent that is released over a period of time, e.g., over about a 2 hour period, over about a 6 hour period, over about a 12 hour period, over about a 24 hour period, or over about a 48 hour period. [0097]“Delayed release,” as used herein, refers to a pharmaceutical composition that released the active agent(s) after a triggering event, e.g., by formulating with an enteric coating. A triggering event may be, for example, change in pH, or any other comparable event as understood by one of ordinary skill in the art.

[0098] The pharmaceutical compositions of the invention additionally include a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to any inert ingredient in a composition is combined with an active agent in a formulation. A pharmaceutically acceptable excipient can include, but is not limited to, carbohydrates (such as glucose, sucrose, dextrans, maltose, galactose, rhamnose, lactose, dextrose, sugar alcohols (e.g., mannitol, xylitol, sorbitol), and combinations thereof), antioxidants (such as ascorbic acid or glutathione), chelating agents, low-molecular weight proteins, high-molecular weight polymers, gel-forming agents or other stabilizers and additives, solvents, diluents, or other liquid vehicle, adjuvants, dispersion or suspension aids or surfactants, surface active agents, isotonic agents, wetting agents, thickening (also viscosity enhancing agent) or emulsifying agents, preservatives, binders, lubricants, disintegrants, osmotic agents, pore formers, hygroscopic polymer, hydrophilic polymers, rate-controlling polymer, materials for forming semi-permeable layers, biocompatible polymers, pH adjusting agents, sweeteners, flavorants, colorants, releasing agents, coating agents, perfuming agents, preservatives, antioxidants, stabilizers, lubricants, and auxiliary agents as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro (Mack Publishing Co., Easton, Pa., 1990) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional excipient medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.

[0099] Some examples of materials which can serve as pharmaceutically acceptable excipients include, but are not limited to:

[00100] Solvents and/or diluents and/or liquid vehicles such as, without limitations, ethyl acetate, triacetin, dimethyl sulfoxide (DIV1 SO), propylene carbonate, N-methylpyrrolidone (NMP), ethyl alcohol, benzyl alcohol, glycofurol, alpha-tocopherol, Miglyol 81 0, isopropyl alcohol, diethyl phthalate, polyethylene glycol 400 (PEG 400), tri ethyl citrate, benzyl benzoate, sucrose acetate isobutyrate (SA1 B), cellulose acetate butyrate (CAB) 381 -20, 1,3-butanediol, Ringer's solution, water and oils (including those of petroleum, animal, vegetable or synthetic origin, such as cocoa butter, suppository waxes, peanut oil, cottonseed oil, safflower oil, olive oil, castor oil, com oil, soybean oil, mineral oil, sesame oil, polyoxyethylated versions thereof, and the like), saline, glycerol solution, gum acacia, gelatin, starch paste (e.g., corn starch and potato starch), talc, keratin, colloidal silica, urea, the like, and combinations thereof;

[00101] Dispersion or suspension aid or surfactants, such as, without limitations, Tweens, other similar polymeric delivery matrices, synthetic mono- or diglycerides, fatty acids, such as, but not limited to, oleic acid and its glyceride derivatives, carboxymethylcellulose, Spans, and combinations thereof.

[00102] Thickening (also viscosity enhancing agent(s)) or emulsifying agents, such as, without limitations, caprylic/capric triglyceride (Migliol 810), isopropyl myristate (IPM), ethyl oleate, triethyl citrate, dimethyl phthalate, benzyl benzoate, various grades of polyethylene oxide, and combinations thereof;

[00103] Preservatives, such as, without limitations, phenol, ascorbic acid, and combinations thereof; [00104] Binders, such as, without limitations, hydroxyalkylcellulose, a hydroxyalkylalkylcellulose, a polyvinylpyrrolidone, and combinations thereof;

[00105]Disintegrants, such as, without limitations, croscarmellose sodium, crospovidone, sodium alginate, similar excipients, and combinations thereof;

[00106] Osmotic agents, such as, without limitations, sorbitol, mannitol, sodium chloride, other salts, and combinations thereof.

[00107] Hygroscopic polymer, such as, without limitations, polyethylene oxide (e.g., Polyox. RTM. with MWs from 4,000,000 to 10,000,000), cellulose hydroxymethyl cellulose, hydroxyethyl-cellulose, crosslinked polyacrylic acids, xantham gum, and combinations thereof;

[00108] Rate-controlling polymer, such as, without limitations, polymeric acrylate, methacrylatelacquer or mixtures thereof, polymeric acrylate lacquer, methacrylate lacquer, an acrylic resin including a copolymer of acrylic and methacrylic acid esters or an ammonium methacrylate lacquer with a plasticizer, and combinations thereof.

[00109] Biocompatible polymers, such as, without limitations, poly(hydroxyl acids), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyelkylenes, polyelkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polysiloxanes, polyvinyl alcohols), poly (vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, synthetic celluloses, polyacrylic acids, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone), ethylene vinyl acetate, copolymers and blends thereof;

Materials for forming semi-permeable layers, such as, without limitations, cellulosic polymers such as cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose diacetate, cellulose triacetate or any mixtures thereof; ethylene vinyl acetate copolymers, polyethylene, copolymers of ethylene, polyolefins including ethylene oxide copolymers (e.g., Engage. RTM.-Dupont Dow Elastomers), polyamides, cellulosic materials, polyurethanes, polyether blocked amides, copolymers (e.g., PEBAX.RTM., cellulosic acetate butyrate and polyvinyl acetate), and combinations thereof; pH adjusting agents, such as, without limitations, acids (e.g., hydrochloric acid, citric acid), bases (e.g., sodium hydroxide), or buffers (e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate) to enhance the stability of the formulated compound or its delivery form; auxiliary agents, such, without limitations, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, dried skim milk, propylene glycol, ethanol, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-E-tocopherol polyethylene-glycol 1 000 succinate, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts; or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, zinc salts, ethyl laurate, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoyl lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, diastearoyl phosphatidylethanolamine (DSPE) and its pegylated esters, such as DSPE-PEG750 and, DSPE- PEG2000, phosphatidic acid, phosphatidyl glycerol and phosphatidyl serine, powdered tragacanth, hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, polyethylene glycol, sodium carboxmethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha, beta and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- beta cyclodextrins, or other solubilized derivatives may also be used to enhance delivery of compound(s) of the formulations disclosed herein that can be used in the methods of the invention.

Kits

[00110] Any of the dosage forms described herein may be provided in a kit. The kit includes (a) the compounds used in a method described herein (in the same or separate dosage forms), and, optionally (b) informational material. The informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the dosage form for the methods described herein.

[00111] The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the compound(s), molecular weight of the compound(s), concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to methods for administering the compound(s).

[00112] In one embodiment, the informational material can include instructions to use the compound(s) or composition(s) described herein in a suitable manner to perform the methods described herein.

[00113] In many cases, the informational material, e.g., instructions, is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet. However, the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording. In another embodiment, the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about a compound described herein and/or its use in the methods described herein. Of course, the informational material can also be provided in any combination of formats.

[00114] In addition to dosage form(s) described herein, the composition of the kit can include other ingredients, such as a solvent or buffer, a stabilizer, a preservative, a flavoring agent (e.g., a bitter antagonist or a sweetener), a fragrance, a dye or coloring agent, for example, to tint or color one or more components in the kit, or other cosmetic ingredient, and/or a second agent for treating a condition or disorder described herein. Alternatively, the other ingredients can be included in the kit, but in different compositions or containers than the compound(s) described herein. In such embodiments, the kit can include instructions for admixing the compound(s) described herein and the other ingredients, or for using the compound(s) described herein together with the other ingredients.

[00115] In some embodiments, the components of the kit are stored under inert conditions (e.g., under nitrogen or another inert gas such as Argon). In some embodiments, the components of the kit are stored under anhydrous conditions (e.g., with a desiccant). In some embodiments, the components are stored in a light blocking container such as an amber vial.

[00116] The dosage form(s) described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that the compound(s) described herein be substantially pure and/or sterile. When the compound(s) described herein is provided in a liquid solution, the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred. When the compound(s) described herein is provided as a dried form, reconstitution generally is by the addition of a suitable solvent. The solvent, e.g., sterile water or buffer, can optionally be provided in the kit.

[00117] The kit can include one or more containers for the composition(s) containing a dosage form described herein. In some embodiments, the kit contains separate containers, dividers or compartments for the composition(s) and informational material. For example, the composition(s) can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the dosage form(s) is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label. In some embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of the compound(s) described herein. For example, the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of the dosage form(s) described herein.

[00118] The containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.

[00119] The kit optionally includes a device suitable for use of the dosage form(s), e.g., a syringe, pipette, forceps, measured spoon, swab (e.g., a cotton swab or wooden swab), or any such device.

[00120] The kits of the invention can include dosage forms of varying strengths to provide a subject with doses suitable for one or more of the initiation phase regimens, induction phase regimens, or maintenance phase regimens described herein. Alternatively, the kit can include a scored tablet(s) to allow the user to administered divided doses, as needed.

[00121] In further embodiments, the dosage form includes an additional agent or is provided together with a second dosage form, which includes the additional agent. Exemplary additional agents include an analgesic agent such as an NS AID or opiate, an anti-inflammatory agent or a natural agent such as a triglyceride containing unsaturated fatty acid, or isolated pure fatty acids such as eicosapentaenoic acid (EPA), dihomogamma linolenic acid (DGLA), docosahexaenoic acid (DHA) and others. Cancer Therapy

[00122] The compositions disclosed herein, in any of the forms disclosed herein, can be used for treating cancer or a side effect of immune checkpoint inhibitor therapy, or any other disease or condition disclosed herein. An effective amount refers to the amount of an active compound/agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the desired outcome, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.

[00123] The cancers treated by the present invention include, but are not limited to, any solid tumor or liquid cancers, including urogenital cancers (such as prostate cancer, renal cell cancers, bladder cancers), gynecological cancers (such as ovarian cancers, cervical cancers, endometrial cancers), lung cancer, gastrointestinal cancers (such as non-metastatic or metastatic colorectal cancers, pancreatic cancer, gastric cancer, oesophageal cancers, hepatocellular cancers, cholangiocellular cancers), head and neck cancer (e.g. head and neck squamous cell cancer), malignant glioblastoma, malignant mesothelioma, non-metastatic or metastatic breast cancer (e.g. hormone refractory metastatic breast cancer), malignant melanoma, Merkel Cell Carcinoma or bone and soft tissue sarcomas, and haematologic neoplasias, such as multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia, and combinations thereof. In certain embodiments, the disease is non-small cell lung cancer (NSCLC), breast cancer (e.g. hormone refractory metastatic breast cancer), head and neck cancer (e.g. head and neck squamous cell cancer), metastatic colorectal cancers, hormone sensitive or hormone refractory prostate cancer, colorectal cancer, ovarian cancer, hepatocellular cancer, renal cell cancer, soft tissue sarcoma, small cell lung cancer, and combinations thereof. [00124] The cancers can also be any neoplasm, malignant carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous; adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; and roblastoma, malignant; Sertoli cell carcinoma; Leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocyto a, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocyto a; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; hairy cell leukemia; and combinations thereof.

EXAMPLES [00125] The following prophetic examples and/or studies are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of any or all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in therapeutic design, are to be considered to fall within the scope of the invention incorporated herein.

[00126] Referring to the table below, patients experiencing one or more of the listed conditions are prescribed a treatment regime encompassing a cannabinoid type 2 receptor modulator in the listed dosages to ameliorate the listed adverse events associated with one or more of the listed immune checkpoint inhibitors having been administered according to the listed doses.

[00127] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the disclosure.

[00128] All patents, patent publications and publications mentioned herein are incorporated herein by reference in their entirety to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Claims

CLAIMS What is claimed is:

1. A method of treating immune related-adverse events associated with immune

checkpoint inhibitor therapy comprising administering to a patient in need thereof a cannabinoid type 2 receptor modulator.

2. The method of claim 1, wherein the cannabinoid type 2 receptor modulator is

permeable to the blood brain barrier.

3. The method of claim 1, wherein the cannabinoid type 2 receptor modulator is

impermeable to the blood brain barrier.

4. The method of any of claims 1-3, wherein the immune related adverse events are cardiac, dermatologic, gastrointestinal, renal, hepatic, endocrine, neurological, pulmonary adverse events, or a combination thereof.

5. The method of any of claims 1-4, where immune-related adverse events are

inflammatory conditions.

6. The method of any of claims 1-5, wherein the cannabinoid type 2 receptor modulator exhibits a higher affinity for the CB2 receptor than the CB 1 receptor.

7. The method of claim 6, wherein the cannabinoid type 2 receptor modulator exhibits affinity for the CB2 receptor ranging from about 2 times to about 1000 times greater than its affinity for the CB 1 receptor.

8. The method of any of claims 1-7, wherein the immune checkpoint inhibitor is administered parenterally.

9. The method of claims 8, wherein the immune checkpoint inhibitor is a CTLA-4

inhibitor, a PD-1 inhibitor, a PD-Ll inhibitor, a PD-L2 inhibitor, a LAG-3 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a B7H3 inhibitor, a B7H4 inhibitor, a 2B4 inhibitor, a CD 160 inhibitor, a A2aR inhibitor, a KIR inhibitor, a VISTA inhibitor, a TIGIT inhibitor, or a combination thereof.

10. The method of claim 9, wherein the CTLA-4 inhibitor is ipilimunab.

11. The method of claim 9, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, cemiplimab-rwlc, or a combination thereof.

12. The method of claim 9, wherein the PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, or a combination thereof.

13. The method of any of claims 1-12, wherein the cancer is melanoma of the skin, non small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers,

Hodgkin lymphoma, non-small cell lung cancer, Merkel cell carcinoma, or a combination thereof.

14. The method of any of claims 1-13, wherein the cannabinoid type 2 receptor modulator is ajulemic acid having a purity greater than about 97% (w/w) based on total weight of cannabinoids.

15. The method of claim 14, wherein the ajulemic acid has less than about 1% (w/w) of

1 l-hydroxy-(6aR, 10aR)-3-(T, 1 '-dim ethyl heptyl)-A8-tetrahydrocannabinol (HU-210) or other highly CB1 active compounds, based on total weight of cannabinoids.

16. The method of any of claims 1-15, wherein the cannabinoid type 2 receptor modulator is administered by a route selected from oral, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal route.

17. The method of claim 16, wherein the cannabinoid type 2 receptor modulator is

administered orally.

18. The method of claim 17, wherein the cannabinoid type 2 receptor modulator is

administered in a daily dose of about 0.5 mg to about 1 g.

19. The method of any of claims 1-18, wherein the patient is on a previous regimen of an immunosuppressive agent and the cannabinoid type 2 receptor modulator replaces the immunosuppressive agent.

20. The method of any of claims 1-18, wherein the patient is not concurrently

administered an immunosuppressive agent.

21. The method of claim 20, wherein the patient is not concurrently administered an immunosuppressive agent that is a glucocorticosteroid, TNF inhibitor,

my cophenol ate, mycophenolate mofetil, salts thereof, or a combination thereof.

22. The method of any of claims 1-18, wherein the patient is concurrently administered an immunosuppressive agent.

23. The method of claim 19 or 22, wherein the immunosuppressive agent is a

glucocorticosteroid, a TNF inhibitor, a mycophenolate, mycophenolate mofetil, salts thereof, or a combination thereof.

24. A method of treating cancer comprising administering to a patient in need thereof an immune check point inhibitor and a cannabinoid type 2 receptor modulator.

25. The method of claim 24, wherein the cannabinoid type 2 receptor modulator is

administered in an effective amount to reduce one or more immune-related adverse events.

26. The method of claim 24 or 25, wherein the cannabinoid type 2 receptor modulator is permeable to the blood brain barrier.

27. The method of claim 24 or 25, wherein the cannabinoid type 2 receptor modulator is impermeable to the blood brain barrier

28. The method of claim 25, wherein the immune related adverse events are cardiac, dermatologic, gastrointestinal, endocrine, renal, hepatic, neurological, pulmonary adverse events, or a combination thereof.

29. The method of claim 25, wherein the immune-related adverse events are

inflammatory conditions.

30. The method of any of claims 24-29, wherein the cannabinoid type 2 receptor

modulator exhibits a higher affinity for the CB2 receptor than the CB1 receptor.

31. The method of claim 30, wherein the cannabinoid type 2 receptor modulator exhibits affinity for the CB2 receptor ranging from about 2 times to about 1000 times greater than its affinity for the CB 1 receptor.

32. The method of any of claims 24-31, wherein the immune check point inhibitor and the cannabinoid type 2 receptor modulator are administered simultaneously or sequentially.

33. The method of claim 32, wherein the immune check point inhibitor and the

cannabinoid type 2 receptor modulator are administered by the same route of administration.

34. The method of claim 32, wherein the immune check point inhibitor and the

cannabinoid type 2 receptor modulator are administered by different routes of administration.

35. The method of any of claims 32-33, wherein the immune check point inhibitor and the cannabinoid type 2 receptor modulator are administered in the same pharmaceutical composition.

36. The method of any of claims 32-33, wherein the immune check point inhibitor and the cannabinoid type 2 receptor modulator are administered in different pharmaceutical compositions.

37. The method of any of claims 24-36, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a LAG-3 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a B7H3 inhibitor, a B7H4 inhibitor, a 2B4 inhibitor, a CD 160 inhibitor, a A2aR inhibitor, a KIR inhibitor, a VISTA inhibitor, a TIGIT inhibitor, or a combination thereof.

38. The method of claim 37, wherein the CTLA-4 inhibitor is ipilimunab.

39. The method of claim 37, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, cemiplimab-rwlc, or a combination thereof.

40. The method of claim 37, wherein the PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, or a combination thereof.

41. The method of any of claims 24 to 40, wherein the cancer is melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, Hodgkin lymphoma, non-small cell lung cancer, Merkel cell carcinoma, or a combination thereof.

42. The method of any of claims 24-41, wherein the cannabinoid type 2 receptor

modulator is ajulemic acid having a purity greater than about 97% (w/w), based on total weight of cannabinoids.

43. The method of claim 42, wherein the ajulemic acid has less than about 1% (w/w) (w/w) of H-hydroxy-(6aR,10aR)-3-(r,r-dimethylheptyl)-A8-tetrahydrocannabinol (HU-210) or other highly CB1 active compounds, based on total weight of cannabinoids.

44. The method of claim 33, wherein the route is selected from oral, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal route.

45. The method of claim 34, wherein the route is independently selected from oral, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal route.

46. The method of claim 34, wherein the immune check point inhibitor is administered parenterally and the cannabinoid type 2 receptor modulator is administered orally.

47. The method of claim 46, wherein the cannabinoid type 2 receptor modulator is administered in a daily dose of about 0.5 mg to about 1 g.

48. The method of any of claims 24-47, wherein the patient is on a previous regimen of an immunosuppressive agent and the cannabinoid type 2 receptor modulator replaces the immunosuppressive agent.

49. The method of any of claims 24-47, wherein the patient is not concurrently

administered an immunosuppressive agent.

50. The method of claim 49, wherein the patient is not concurrently administered an immunosuppressive agent that is a glucocorticosteroid, a TNF inhibitor,

mycophenolate, mycophenolate mofetil, salts thereof, or a combination thereof.

51. The method of any of claims 24-47, wherein the patient is concurrently administered an immunosuppressive agent.

52. The method of claim 48 or 51, wherein the immunosuppressive agent is a

glucocorticosteroid, a TNF inhibitors, a mycophenolate, mycophenolate mofetil, salts thereof, or a combination thereof.

53. A pharmaceutical composition comprising an immune check point inhibitor and a cannabinoid type 2 receptor modulator.

54. The pharmaceutical composition of claim 53, wherein the cannabinoid type 2 receptor modulator is in an effective amount to reduce one or more immune-related adverse events.

55. The pharmaceutical composition of claim 53 or 54, wherein the cannabinoid type 2 receptor modulator is permeable to the blood brain barrier.

56. The pharmaceutical composition of claim 53 or 54, wherein the cannabinoid type 2 receptor modulator is impermeable to the blood brain barrier.

57. The pharmaceutical composition of claim 54, wherein the immune-related adverse events are cardiac, dermatologic, gastrointestinal, renal, hepatic, endocrine, neurological, pulmonary adverse events, or a combination thereof.

58. The pharmaceutical composition of claim 54, where immune-related adverse events are inflammatory conditions.

59. The pharmaceutical composition of any of claims 53-58, wherein the cannabinoid type 2 receptor modulator exhibits a higher affinity for the CB2 receptor than the CB1 receptor.

60. The pharmaceutical composition of claim 59, wherein the cannabinoid type 2 receptor modulator exhibits affinity for the CB2 receptor ranging from about 2 times to about 1000 times greater than its affinity for the CB1 receptor.

61. The pharmaceutical composition of any of claims 53-60, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PD- L2 inhibitor, a LAG-3 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a B7H3 inhibitor, a B7H4 inhibitor, a 2B4 inhibitor, a CD 160 inhibitor, a A2aR inhibitor, a KIR inhibitor, a VISTA inhibitor, a TIGIT inhibitor, or a combination thereof.

62. The pharmaceutical composition of claim 61, wherein the CTLA-4 inhibitor is

ipilimunab.

63. The pharmaceutical composition of claim 61, wherein the PD-1 inhibitor is

pembrolizumab, nivolumab, cemiplimab-rwlc, or a combination thereof.

64. The pharmaceutical composition of claim 61, wherein the PD-L1 inhibitor is

atezolizumab, avelumab, durvalumab, or a combination thereof.

65. The pharmaceutical composition of any of claims 53-64, wherein the cannabinoid type 2 receptor modulator is ajulemic acid having a purity greater than about 97% (w/w), based on total weight of cannabinoids.

66. The pharmaceutical composition of claim 65, wherein the ajulemic acid has less than about 1% (w/w) of H-hydroxy-(6aR,10aR)-3-(l ',l '-dimethylheptyl)-A8- tetrahydrocannabinol (HU-210) or other highly CB1 active compounds, based on total weight of cannabinoids.

67. The pharmaceutical composition of any of claims 53-66, formulated for

administration by a route selected from oral, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal.

68. The pharmaceutical composition of any of claims 53-67 comprising about 0.5 mg to about 1 g of the cannabinoid type 2 receptor modulator.

69. A method for treating a pulmonary adverse event associated with immune checkpoint inhibitor therapy, comprising administering to a patient experiencing a pulmonary adverse event a cannabinoid type 2 receptor modulator.

70. The method of claim 69, wherein the pulmonary adverse event is pneumonitis,

sarcoidosis, or symptoms thereof.

71. The method of claim 70, wherein symptoms thereof comprise one or more of cough, mild dyspnea, severe shortness of breath with life threatening hypoxia,

hypercalcemia, progressive symptoms, declining lung function, evolving radiographic changes, or a combination thereof.

72. The method of any of claims 70-71, wherein the pulmonary adverse event grade is reduced.

73. The method of any of claims 69-72, wherein the immune checkpoint inhibitor therapy is withheld until treatment of the pulmonary adverse event is concluded and/or until the pulmonary adverse event is treated.

74. The method of any of claims 69-72, wherein the immune checkpoint inhibitor therapy is discontinued.

75. The method of any of claims 69-74, further comprising detecting and/or monitoring the pulmonary adverse event with one or more of imaging, clinical exam,

bronchoscopy, transbronchial biopsy, pulmonary function tests, CT, 6-minute walk test, resting O2 saturation, electrocardiogram (EKG), eye exam, or a combination thereof.

76. A method for treating a gastrointestinal adverse event associated with immune

checkpoint inhibitor therapy, comprising administering to a patient experiencing a gastrointestinal adverse event a cannabinoid type 2 receptor modulator.

77. The method of claim 76, wherein the gastrointestinal adverse event is diarrhea, severe bowel inflammation, colitis, abdominal pain, hematochezia, ileus, hepatitis, elevated transaminases, or symptoms thereof.

78. The method of any of claims 76-77, wherein the gastrointestinal adverse event grade is reduced.

79. The method of any of claims 76-78, wherein the immune checkpoint inhibitor therapy is withheld until treatment of the gastrointestinal adverse event is concluded and/or until the gastrointestinal adverse event is treated.

80. The method of any of claims 76-78, wherein the immune checkpoint inhibitor therapy is discontinued.

81. The method of any of claims 76-80, further comprising detecting and/or monitoring the gastrointestinal adverse event with one or more of endoscopic evaluation of the enteric tract, clinical exam, liver function testing, monitoring AST or ALT levels, monitoring bilirubin levels, and/or a biopsy, or a combination thereof.

82. A method for treating a cardiac adverse event associated with immune checkpoint inhibitor therapy, comprising administering to a patient experiencing a cardiac adverse event a cannabinoid type 2 receptor modulator.

83. The method of claim 82, wherein the cardiac adverse event is one or more of

asymptomatic dilated cardiomyopathy, symptomatic heart failure with reduced systolic function on echocardiogram, myocardial fibrosis, takotsubo cardiomyopathy with apical ballooning, pericarditis, myocarditis, tachyarrhythmias including ventricular fibrillation and cardiac arrest, bradyarrhythmias including first, second, and third-degree heart block, acute coronary syndrome, moderate-severe

decompensated heart failure, severe arrhythmias, or symptoms thereof.

84. The method of any of claims 82-83, wherein the cardiac adverse event grade is

reduced.

85. The method of any of claims 82-84, wherein the immune checkpoint inhibitor therapy is withheld until treatment of the cardiac adverse event is concluded and/or until the cardiac adverse event is treated and/or until symptoms of the cardiac adverse event are stabilized.

86. The method of any of claims 82-84, wherein the immune checkpoint inhibitor therapy is discontinued.

87. The method of any of claims 82-86, further comprising detecting and/or monitoring the cardiac adverse event by clinical exam, monitoring one or more of serial EKGs, left ventricular ejection fractions or cardiac cell death (troponin-I, CK-MB), troponins, echocardiograms, or a combination thereof.

88. A method for treating a rheumatologic adverse event associated with immune

checkpoint inhibitor therapy, comprising administering to a patient experiencing a rheumatologic adverse event a cannabinoid type 2 receptor modulator.

89. The method of claim 88, wherein the rheumatologic adverse event is one or more of arthralgias, myalgias, myositis, lupus nephritis, vasculitis or symptoms thereof..

90. The method of any of claims 88-89, wherein the rheumatologic adverse event grade is reduced.

91. The method of any of claims 88-90, wherein the immune checkpoint inhibitor therapy is withheld until treatment of the rheumatologic adverse event is concluded and/or until the rheumatologic adverse event is treated and/or until symptoms of the rheumatologic adverse event are stabilized.

92. The method of any of claims 88-90, wherein the immune checkpoint inhibitor therapy is discontinued.

93. The method of any of claims 88-92, further comprising detecting and/or monitoring the rheumatologic adverse event by performing a clinical exam inflammatory and rheumatologic tests such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-nuclear antibody (ANA), cyclic citrullinated peptide antibody (anti-CCP), imaging of affected joints, or a combination thereof.

94. A method for treating a renal adverse event associated with immune checkpoint

inhibitor therapy, comprising administering to a patient experiencing a renal adverse event a cannabinoid type 2 receptor modulator.

95. The method of claim 94, wherein the renal adverse event is one or more of elevated creatinine levels, hematuria, edema, decreased urine output, kidney failure, metabolic derangements, or symptoms thereof.

96. The method of any of claims 94-95, wherein the renal adverse event grade is reduced.

97. The method of any of claims 94-96, wherein the immune checkpoint inhibitor therapy is withheld until treatment of the renal adverse event is concluded and/or until the renal adverse event is treated and/or until symptoms of the renal adverse event are stabilized.

98. The method of any of claims 94-96, wherein the immune checkpoint inhibitor therapy is discontinued.

99. The method of any of claims 94-98, further comprising detecting and/or monitoring the renal adverse event by clinical exam, routine lab work, monitoring serum renal indices, serum creatinine levels, urine and serum studies, imaging, nephrology consult, renal biopsy, or a combination thereof.

100. A method for treating an endocrine and/or exocrine adverse event associated with immune checkpoint inhibitor therapy, comprising administering to a patient experiencing the endocrine and/or exocrine adverse event a cannabinoid type 2 receptor modulator.

101. The method of claim 100, wherein the endocrine and/or exocrine adverse event is one or more of thyroid disease, hypothyroidism, hyperthyroid state, thyrotoxicosis, hypophysitis, central adrenal insufficiency, life threatening electrolyte abnormalities, hypoglycemia, dehydration, hypotension, adrenal crisis, elevated serum amylase and lipase values, autoimmune diabetes, insulin dependence, diabetic ketoacidosis, hyperglycemia, fatigue, hair loss, cold intolerance, constipation, poor mood, and symptoms thereof.

102. The method of any of claims 100-101, wherein the endocrine and/or exocrine

adverse event grade is reduced.

103. The method of any of claims 100-102, wherein the immune checkpoint inhibitor therapy is withheld until treatment of the endocrine and/or exocrine adverse event is concluded and/or until the endocrine and/or exocrine adverse event is treated and/or until symptoms of the endocrine and/or exocrine adverse event is stabilized.

104. The method of any of claims 100-102, wherein the immune checkpoint inhibitor therapy is discontinued.

105. The method of any of claims 100-104, further comprising detecting and/or monitoring the endocrine and/or exocrine adverse event by clinical examination, serum thyroid tests, lab tests for thyroid stimulating hormone (TSH) and free T4, titration of levothyroxine, imaging, brain MRI with special attention to the sella turcica region to evaluate swelling and enhancement of the pituitary gland, endocrinology consult, glucose level, a basic or comprehensive metabolic panel, or a combination thereof.

106. A method for treating a neurologic and/or ocular adverse event associated with

immune checkpoint inhibitor therapy, comprising administering to a patient experiencing the neurologic and/or ocular adverse event a cannabinoid type 2 receptor modulator.

107. The method of claim 106, wherein the neurologic and/or ocular adverse event is one or more of peripheral neuropathies (e.g., motor or sensory dysfunction, Guillain-Barre Syndrome, myasthenia gravis, fluctuating or progressive muscle weakness, ocular changes such as diplopia or ptosis), central neurological adverse events (e.g., immune mediated encephalitis, aseptic meningitis, posterior reversible encephalopathy syndrome), ocular adverse events (e.g., episcleritis, uveitis, conjunctivitis), altered mental status, headaches, fevers, confusion, receptive and expressive aphasia, motor and sensory changes, ocular pain, dryness, photophobia, vision changes, or symptoms thereof.

108. The method of any of claims 106-107, wherein the neurologic and/or ocular adverse event grade is reduced.

109. The method of any of claims 106-108, wherein the immune checkpoint inhibitor therapy is withheld until treatment of the neurologic and/or ocular adverse event is concluded and/or until the neurologic and/or ocular adverse event is treated and/or until symptoms of the neurologic and/or ocular adverse event is stabilized.

110. The method of any of claims 106-108, wherein the immune checkpoint inhibitor therapy is discontinued.

111. The method of any of claims 106-110, further comprising detecting and/or

monitoring the endocrine and/or exocrine adverse event by clinical exam, lumbar puncture to look for elevated protein levels, nerve conduction studies, PFTs, physical exam that assesses for proximal muscle fatigue and ocular muscle dysfunction, laboratory tests that include acetylcholine receptor and anti-MuSK antibodies, neurology consult, central nervous system imaging, ophthalmology consult, or a combination thereof.

112. A method for treating a dermatologic adverse event associated with immune

checkpoint inhibitor therapy, comprising administering to a patient experiencing the dermatologic adverse event a cannabinoid type 2 receptor modulator.

113. The method of claim 112, wherein the dermatologic adverse event is one or more of rashes (such as morbilliform or maculopapular and pruritic), toxic epidermal necrolysis, and symptoms thereof.

114. The method of any of claims 112-113, wherein the dermatologic adverse event grade is reduced.

115. The method of any of claims 112-114, wherein the immune checkpoint inhibitor therapy is withheld until treatment of the dermatologic adverse event is concluded and/or until the dermatologic adverse event is treated and/or until symptoms of the dermatologic adverse event is stabilized.

116. The method of any of claims 112-114, wherein the immune checkpoint inhibitor therapy is discontinued.