WO2017068349A1 - Cannabinoïde pour utilisation en immunothérapie - Google Patents

Cannabinoïde pour utilisation en immunothérapie Download PDF

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WO2017068349A1
WO2017068349A1 PCT/GB2016/053271 GB2016053271W WO2017068349A1 WO 2017068349 A1 WO2017068349 A1 WO 2017068349A1 GB 2016053271 W GB2016053271 W GB 2016053271W WO 2017068349 A1 WO2017068349 A1 WO 2017068349A1
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cannabinoid
treatment
derivative
pharmaceutical composition
csf
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Maria Victoria Flores
Daniel Paul HYNES
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E-Therapeutics Plc
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Priority claimed from GBGB1609322.1A external-priority patent/GB201609322D0/en
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Publication of WO2017068349A1 publication Critical patent/WO2017068349A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention provides medicaments and methods for reducing suppression of the immune system in animals, e.g. humans.
  • the invention provides the use of dexanabinol, or a derivative thereof, for the treatment of disorders by the modulation of cytokine release. More particularly the invention provides the use of dexanabinol, or a derivative thereof, for the treatment of disorders by reduction of IL-10 and/ or increase in GM- CSF. The invention also provides dexanabinol, or a derivative thereof, in combination with an immunotherapy, such as an immune checkpoint inhibitor.
  • Cytokines including interleukins and growth factors, are soluble proteins that mediate reactions between cells and influence cell growth and differentiation, as well as regulating growth and activation of immune cells. Cytokines exert their effects by binding to specific cell-surface receptors that leads to activation of cytokine- specific signal transduction pathways. These molecular messengers allow the cells of the immune system to coordinate and propagate the immune signalling to mount a quick response to target antigens (Lee & Margolin 2011). Cytokines are released in response to injury, infection, inflammation and cancer to control cellular stress and preserve cellular integrity. However, prolonged cytokine production can lead to altered cell growth and differentiation.
  • cytokines Important properties of cytokines are their redundancy in functionality, with more than one cytokine producing the same functional effect. Cytokines are able to stimulate immune effectors and enhance recognition of tumour cells. The anti-tumoral activity of cytokines has been demonstrated in animal models, and many of them (e.g. GM-CSF, IL-7, IL-12, IL-15, IL-18 and IL-21) have progressed as therapeutic proteins to clinical trials for the treatment of advanced carcinomas.
  • Interleukin-10 also known as human cytokine synthesis inhibitory factor (CSIF) is an anti-inflammatory cytokine.
  • IL-10 is encoded by the IL10 gene.
  • IL-10 signals through a receptor complex consisting of two IL-10 receptor- 1 and two IL-10 receptor 2 proteins; consequently, the functional receptor consists of four IL-10 receptor molecules.
  • IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively (Mosser et al, 2008).
  • IL-10 is a cytokine with immunosuppressive and anti-inflammatory properties.
  • IL-10 is a regulator of numerous myeloid and lymphoid cell activities and indirectly inhibits the production of various inflammatory cytokines by both T-cells and NK cells.
  • IL-10 is capable of inhibiting synthesis of pro-inflammatory cytokines such as IFN- ⁇ , IL-2, IL-3, T Fa and GM-CSF made by cells such as macrophages and regulatory T- cells. It also displays a potent ability to suppress the antigen-presentation capacity of antigen presenting cells. Therefore, a decrease in the levels of circulating IL-10 would generally be considered to have a pro-inflammatory effect or to reduce immunosuppression.
  • IL-10 down-regulates the production of pro-inflammatory cytokines and chemokines by activated macrophages, monocytes, polymorphonuclear leukocytes and eosinophils. Therefore, IL-10 is an anti-inflammatory cytokine that plays a role in suppressing immune and inflammatory responses. There is evidence that IL-10 can control both T helper 1 (Thl) type of responses and also Th2 mediated inflammatory processes.
  • Thl T helper 1
  • GM-CSF (Granulocyte-macrophage colony-stimulating factor) is a monomeric glycoprotein produced by macrophages, T cells, mast cells, NK cells, endothelial cells and fibroblasts. GM-CSF functions as a cytokine - it is a white blood cell growth factor.
  • GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells. Thus, it is part of the immune/inflammatory cascade, by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting infection, for tumour reduction, etc. Thus, GM-CSF facilitates development of the immune system and promotes defence against infections and cancers.
  • immune checkpoints are crucial for the maintenance of self-tolerance (i.e. prevention of autoimmunity) and also to protect tissues from damage when the immune system is responding to pathogenic infection.
  • the expression of immune-checkpoint proteins can be dysregulated by tumours as an important immune resistance mechanism.
  • T cells have been the major focus of efforts to therapeutically manipulate endogenous antitumor immunity owing to: their capacity for the selective recognition of peptides derived from proteins in all cellular compartments; their capacity to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells; also known as cytotoxic T lymphocytes (CTLs)); and their ability to orchestrate diverse immune responses (by CD4+ helper T cells), which integrates adaptive and innate effector mechanisms.
  • CTLs cytotoxic T lymphocytes
  • CD4+ helper T cells CD4+ helper T cells
  • T cell-mediated immunity includes multiple sequential steps involving the clonal selection of antigen-specific cells, their activation and proliferation in secondary lymphoid tissues, their trafficking to sites of antigen and inflammation, the execution of direct effector functions and the provision of help (through cytokines and membrane ligands) for a multitude of effector immune cells. Each of these steps is regulated by counterbalancing stimulatory and inhibitory signals that fine-tune the response. Although virtually all inhibitory signals in the immune response ultimately affect intracellular signalling pathways, many are initiated through membrane receptors, the ligands of which are either membrane-bound or soluble (cytokines).
  • co-stimulatory and inhibitory receptors and ligands that regulate T cell activation are not necessarily overexpressed in cancers relative to normal tissues, whereas inhibitory ligands and receptors that regulate T cell effector functions in tissues are commonly overexpressed on tumour cells or on non-transformed cells in the tumour microenvironment.
  • T-cell recognition of tumour cells requires the presentation of antigenic peptides by MHC molecules. These peptides are generated by proteasomal digestion and transported to the endoplasmic reticulum, where they are first loaded onto nascent MHC molecules, which ultimately transport them to the cell membrane.
  • CD28 is the master costimulatory receptor expressed on T cells and enhances T-cell activation upon antigen recognition when the antigen presenting cell (APC) expresses its ligands, B7-1 and B7-2. Tumour antigen must be processed and presented by the MHC complex to activate T cells.
  • CTLA-4 is rapidly expressed on T cells once antigen is recognized, and it binds the same ligands (B7.1/2) as CD28 but at higher affinity, thereby counterbalancing the costimulatory effects of CD28 on T-cell activation.
  • Tumour-specific T-cell activation leads to proliferations and effector function, but also the upregulation of PD-1.
  • PD-1+ T cells After trafficking to the tumour microenvironment, PD-1+ T cells might encounter PD-1 ligands, which can inhibit them from mediating their killing function.
  • the CTLA-4 and PD-1 pathways provide complementary mechanisms to regulate antitumor effector T cells, and blocking each one may prove to be synergistic.
  • CTLA-4 counterbalances the costimulatory signals delivered by CD28 during T-cell activation— both bind the B7 family ligands, B7.1 and B7.2.
  • PD-1 is also induced upon T-cell activation but seems to predominantly down modulate T-cell responses in tissues.
  • the PD-1 ligands, PD-L1 and PD-L2 are induced by distinct inflammatory cytokines— while PD-L1 expression can be induced on diverse epithelial and hematopoietic cell types, PD-L2 is predominantly expressed on dendritic cells and macrophages.
  • CTLA4 the first immune-checkpoint receptor to be clinically targeted, is expressed exclusively on T cells where it primarily regulates the amplitude of the early stages of T cell activation.
  • CTLA4 counteracts the activity of the T cell co- stimulatory receptor, CD28.
  • CD28 does not affect T cell activation unless the TCR is first engaged by cognate antigen. Once antigen recognition occurs, CD28 signalling strongly amplifies TCR signalling to activate T cells.
  • CD80 also known as B7.1
  • CD86 also known as B7.2.
  • CTLA4 also confers 'signalling-independent' T cell inhibition through the sequestration of CD80 and CD86 from CD28 engagement, as well as active removal of CD80 and CD86 from the antigen-presenting cell (APC) surface.
  • APC antigen-presenting cell
  • CTLA4 is expressed by activated CD8+ effector T cells
  • the major physiological role of CTLA4 seems to be through distinct effects on the two major subsets of CD4+ T cells: down-modulation of helper T cell activity and enhancement of regulatory T (TReg) cell immunosuppressive activity.
  • TReg regulatory T
  • Another immune-checkpoint receptor, PDl is emerging as a promising target, thus emphasizing the diversity of potential molecularly defined immune manipulations that are capable of inducing anti-tumour immune responses by the patient's own immune system.
  • PDl In contrast to CTLA4, the major role of PDl is to limit the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit). This translates into a major immune resistance mechanism within the tumour microenvironment. PDl expression is induced when T cells become activated. When engaged by one of its ligands, PDl inhibits kinases that are involved in T cell activation through the phosphatase SHP2, although additional signalling pathways are also probably induced. Also, because PDl engagement inhibits the TCR 'stop signal', this pathway could modify the duration of T cell-APC or T cell-target cell contact. Similarly to CTLA4, PDl is highly expressed on TReg cells, where it may enhance their proliferation in the presence of ligand. Because many tumours are highly infiltrated with TReg cells that probably further suppress effector immune responses, blockade of the PDl pathway may also enhance anti-tumour immune responses by diminishing the number and/or suppressive activity of intratumoural TReg cells.
  • the two ligands for PDl are PDl ligand 1 (PDL1 ; also known as B7-H1 and CD274) and PDL2 (also known as B7-DC and CD273). These ligands are induced by distinct inflammatory cytokines— while PD-L1 expression can be induced on diverse epithelial and hematopoietic cell types, PD-L2 is predominantly expressed on dendritic cells and macrophages.
  • PDl is more broadly expressed than CTLA4: it is induced on other activated non-T lymphocyte subsets, including B cells and natural killer (NK) cells, which limits their lytic activity. Therefore, although PDl blockade is typically viewed as enhancing the activity of effector T cells in tissues and in the tumour microenvironment, it also probably enhances NK cell activity in tumours and tissues and may also enhance antibody production either indirectly or through direct effects on PD1+ B cells.
  • T cells Various ligand-receptor interactions exist between T cells and antigen-presenting cells (APCs) that regulate the T cell response to antigen (which is mediated by peptide-major histocompatibility complex (MHC) molecule complexes that are recognized by the T cell receptor (TCR)).
  • APCs antigen-presenting cells
  • MHC peptide-major histocompatibility complex
  • TCR T cell receptor
  • T cells do not respond to these ligand-receptor interactions unless they first recognize their cognate antigen through the TCR.
  • Many of the ligands bind to multiple receptors, some of which deliver co-stimulatory signals and others deliver inhibitory signals.
  • ligands such as CD28 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)
  • CTL4 cytotoxic T-lymphocyte-associated antigen 4
  • Tumour necrosis factor (T F) family members that bind to cognate TNF receptor family molecules represent a second family of regulatory ligand- receptor pairs. These receptors predominantly deliver co-stimulatory signals when engaged by their cognate ligands. Another major category of signals that regulate the activation of T cells comes from soluble cytokines in the microenvironment. Communication between T cells and APCs is bidirectional. In some cases, this occurs when ligands themselves signal to the APC. In other cases, activated T cells upregulate ligands, such as CD40L, that engage cognate receptors on APCs.
  • ligands such as CD40L
  • IL-10 has a beneficial effect on a variety of acute and chronic inflammatory and autoimmune events including but not limited to rheumatoid arthritis, ischemia- reperfusion injury, atherosclerosis, psoriasis, pemphigus, allergic contact sensitivity reactions, uveitis, organ transplantation, injury, infection and sepsis, inflammatory bowel disease, acute pancreatitis, asthma, nephrotoxic nephritis and certain malignancies.
  • Dexanabinol (HU-211) is a synthetic cannabinoid derivative, known as (6aS, 10aS) 9-(hydroxymethyl)- 6,6-dimethyl- 3-(2-methyloctan-2-yl)- 6a,7, 10, 10a-tetrahydrobenzo [c]chromen-l-ol and is disclosed in U.S. Patent No. 4,876,276.
  • cannabinoids such as, dexanabinol
  • GM-CSF levels increase GM-CSF levels.
  • cannabinoids such as, dexanabinol
  • the present invention addresses the need for molecules useful in the treatment and/or prevention of inflammation, immune system under- or over-responses, cardiovascular and hematopoietic disorders and regulation of cellular proliferation by, inter alia, decreasing IL-10 expression and/ or increasing GM-CSF.
  • a therapeutically effective amount of a cannabinoid such as dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in immunotherapy.
  • a therapeutically effective amount of a cannabinoid such as dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in the treatment of one or more of, a proliferative disease, such as cancer, by promoting immune clearance of tumours; a persistent infection and/or a viral disorder; autoimmune disorders, including systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction.
  • the cannabinoid may be tetrahydrocannabinol (THC), cannabidiol, dexanabinol, or a derivative thereof, or combinations thereof.
  • THC tetrahydrocannabinol
  • cannabidiol cannabidiol
  • dexanabinol or a derivative thereof, or combinations thereof.
  • the cannabinoid is dexanabinol, or a derivative thereof.
  • the treatment of one or more of, cancer, by promoting immune clearance of tumours; a persistent infection and/or a viral disorder; autoimmune disorders, including systemic lupus erythematosus (SLE); immunodeficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction may be achieved by the reduction of IL-10.
  • the cannabinoid, or derivative thereof, such as dexanabinol may directly or indirectly reduce the effect of IL-10 effect.
  • the cannabinoid, or derivative thereof directly or indirectly reduce the effect of IL-10 by reduction of the expression of IL-10.
  • a cannabinoid, or a derivative thereof can enhance immune responses that by reducing the effect IL-10. Also, a cannabinoid, or a derivative thereof, can enhance immune responses by reducing the effect of IL-10, where IL-10 is up expressed, down-expressed or differentially expressed.
  • a cannabinoid, or a derivative thereof can reduce the IL-10 effect, inter alia, by enhancing the immune responses where the immune system is often compromised. This may be achieved locally or systemically where the immune system is compromised, and/ or where the immune system is compromised, downregulated or subverted by a tumour. Therefore, a cannabinoid, or a derivative thereof, can enhance immune responses to enhance the immune targeting of tumour cells by reducing the effect of IL-10.
  • the treatment of one or more of, cancer, by promoting immune clearance of tumours; a persistent infection and/or a viral disorder; autoimmune disorders, including systemic lupus erythematosus (SLE); immunodeficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction may be achieved by increasing GM-CSF.
  • the one or more of, cancer by promoting immune clearance of tumours; a persistent infection and/or a viral disorder; autoimmune disorders, including systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction, may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • autoimmune disorders including systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression
  • an allergy and/or hypersensitivity reaction may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • the immune system can detect a wide range of infectious organisms and prevent infections, and can also recognize, suppress and eliminate aberrant cells (a mechanism known as immunosurveillance).
  • tumour cells can create an inflammatory tumour environment that leads to suppression and modulation of the immune response (Alderton et al 2012).
  • Immunotherapies cover several different therapeutic approaches, such as cancer vaccines, monoclonal antibody therapies, check point inhibitors and cytokine modulation. All those therapies have different mode of action in the cancer context but a common aim: to restore and activate the immune system. However, most of these therapies are based on biologic modalities, with only a few small molecule approaches (e.g. inhibitors of amino acid metabolism, inhibitors of cyclooxygenases, inhibitors of cytokines, etc.).
  • Tumour cells in the tumour environment facilitate tumour growth and spread.
  • Tumour cells influence endothelial cells, macrophages, T cells, and fibroblasts to evade host defences, undergo angiogenesis, and produce factors that promote growth, survival, and metastases (Hanahan and Weinberg, 2000).
  • Tumours grow through signals elicited from cells in their microenvironment. For instance, some tumours downregulate immune surveillance molecules to avoid attack by T-cells and NK cells (Watson et al, 2006). Some tumours secrete growth factors that stimulate blood vessel formation (Demirkesen et al, 2006). Other tumours stop making molecules that maintain cell-cell interactions. Changes tumours impose on surrounding cells are called "tumour education" (Pollard, 2004), and often represent an inappropriate triggering of developmental programs within the tumour cells (Lotem and Sachs 2002).
  • GM-CSF has been shown to increase the immune response in animal tumour models as monotherapy (Disis et al 1996, Lee and Margolis 2011). In the clinic, systemic increase of GM-CSF confers clinical advantage in melanoma, prostate cancer and pulmonary metastases due to immune stimulation (Spitler et al 2000, Andersen 1999). Moreover, GM-CSF has been used in combination with immunotherapies, such as the monoclonal antibody CTL4 and has shown to promote an improvement in the survival of patients with metastatic melanoma (Hodi et al 2013, Hodi et al 2014). Combination of GM-CSF with rituximab in patients with follicular lymphoma has shown 36% of remission rate. As a single agent has shown anti-tumour activity when injected to metastatic melanoma lesions (Ridolfi et al 2001).
  • GM-CSF-stimulated monocytes exhibit anti-tumour behaviour.
  • GM-CSF enhances macrophage antigen presentation and immune responsiveness (Armstrong et al, 1996).
  • GM-CSF stimulates monocytes to secrete sVEGFR-1, which binds and inactivates VEGF and blocks angiogenesis (Eubank 2004).
  • Angiogenesis within the tumours is necessary for tumour progression, as tumours cannot grow beyond a few cubic millimetres without blood vessel formation to supply oxygen and nutrients.
  • sVEGFR-l in blocking cancer progression.
  • low intra-tumour sVEGFR-l and high total VEGF are associated with poor disease-free and overall survival.
  • Eubank et al (2009) show that intra-tumoural GM-CSF injections reversed some of the effects of tumour education and induced an anti-tumour phenotype in tumour-associated macrophages.
  • IL-10 is an immunosuppressive molecule secreted by tumours (or tumour-infiltrating immune cells) to allow malignant cells to escape from immune surveillance (Mapara et al 2005).
  • IL-10 inhibits tumour associated antigen (TAA) presentation by dendritic cells, potentially preventing T cells from mounting an effective immune response against malignant cells.
  • TAA tumour associated antigen
  • the secretion of IL-10 can be increased in the presence of anti-CTLA4 agents.
  • a cannabinoid such as, dexanabinol as herein described may act by decreasing IL-10, consequently changing the microenvironment away from immunosuppression.
  • a therapeutically effective amount of a cannabinoid such as, dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in the treatment of cancer, by promoting immune clearance of tumours.
  • a cannabinoid, or a derivative thereof can enhance immune responses that by reducing the effect of IL-10 to enhance the immune targeting of tumour cells, to induce inhibition of tumourigenesis, inhibition of cell proliferation, induction of cytotoxicity or induction of apoptosis.
  • the treatment of cancer, by promoting immune clearance of tumours may be achieved by the reduction of IL-10.
  • the treatment of cancer, by promoting immune clearance of tumours may be achieved by increasing GM-CSF.
  • the treatment of cancer by promoting immune clearance of tumours; by may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • Increased IL-10 results in Th2 related hypersensitivities e.g. allergic dermatitis and autoimmune disorders e.g. systemic lupus erythematosus (SLE). Increased IL-10 regulation has a negative impact on the biological system, specifically with the increased chance of cancer development, chronic infections and Lupus (Th2 dependent autoimmune disorder). Viral infections can become chronic due to IL- 10 upregulation.
  • Th2 related hypersensitivities e.g. allergic dermatitis and autoimmune disorders e.g. systemic lupus erythematosus (SLE).
  • SLE systemic lupus erythematosus
  • Increased IL-10 regulation has a negative impact on the biological system, specifically with the increased chance of cancer development, chronic infections and Lupus (Th2 dependent autoimmune disorder). Viral infections can become chronic due to IL- 10 upregulation.
  • a well developed immune system is required for proper clearance of pathogens, particularly ones that are adept at avoiding immune response: malaria causing Plasmodium, Hepatitis B and C Viruses (HBV, HCV), Epstein Barr Virus (HBV), Human papilloma virus (HPV), Human Immunodeficiency Virus (HIV) and others. While increased levels of IL-10 can result in severe immunosuppression, even normal levels of IL-10 can allow for chronic infection due to decreasing levels of proinflammatory cytokines and promoting effector T-cell anergy. Anti-viral medication has been shown to decrease levels of IL-10 thereby allowing the immune system to mount a stronger attack against the persistent viral infection.
  • Persistent infections are caused by malaria causing Plasmodium, Hepatitis B and C Viruses (HBV, HCV), Epstein Barr Virus (HBV), Human papilloma virus (HPV), Human Immunodeficiency Virus (HIV), Human T-Cell Leukaemia Viruses, Human Cytomegalovirus, Human Herpesviruses, Varicella-Zoster Virus, Measles Virus and Adenoviruses.
  • a cannabinoid, or derivative thereof can enhance immune responses where the immune system is compromised or downregulated or subverted by diseases or drugs, by reducing the effect of IL-10. Therefore, according to this aspect of the invention there is provided the use of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in the treatment of a persistent infection and/or a viral disorder.
  • the treatment of a persistent infection and/or a viral disorder may be achieved by the reduction of IL-10.
  • the treatment of a persistent infection and/or a viral disorder may be achieved by increasing GM-CSF.
  • the treatment of a persistent infection and/or a viral disorder may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • Increases in IL-10 can lead to a development of Th2 responses.
  • IL-10 activity promotes Th2 responses coordinated by an increase in IL-4, IL-5, IL-13 cytokines.
  • Prolonged exposure to increases in IL-10 can lead to Th2 related autoimmune responses. This is evident in the evaluation of cytokines profiles in systemic lupus erythematosus (SLE) patients and studies in animal models.
  • SLE is a categorized as a Th2 autoimmune disorder related to the production of autoreactive IgG antibodies.
  • the common SLE related self-antigens are nuclear self-antigens i.e. DNA binding histones and rheumatoid factor.
  • Studies linking IL-10 to SLE development have revealed that increased levels of IL-10 derived from NK cells and CD4+ cells with increased PD-1 are critical for the development of SLE in New Zealand Black (NZB) and New Zealand White (NZW) mixed strain. These NZB/NZW mice develop spontaneous SLE symptoms.
  • a therapeutically effective amount of a cannabinoid such as, dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in the treatment of autoimmune disorders, including systemic lupus erythematosus (SLE).
  • SLE systemic lupus erythematosus
  • the treatment of autoimmune disorders may be achieved by the reduction of IL-10.
  • the treatment of autoimmune disorders including systemic lupus erythematosus may be achieved by increasing GM-CSF.
  • the treatment of autoimmune disorders including systemic lupus erythematosus may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • Th2 allergic response may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • IL-10 may play a role in sensitization of Th2 related allergic response PBMCs (peripheral blood mononuclear cells) extracted from patients with severe allergic rhinitis and asthma, only patients exposed to allergens produced increased levels of IL-6, GM-CSF & T F- ⁇ , while the IL-10 increase was observed in these patients prior to and after exposure of allergen.
  • PBMCs peripheral blood mononuclear cells
  • IL-10 deficient mice demonstrated the absence of IL-10 levels reduces dermal lesions, eosinophilic infiltration into dermal and subcutaneous layers following cutaneous sensitization with ovalbumin (OVA) coated dermal strips. Additionally, when evaluating OVA stimulated T-cell responses from WBCs isolated from draining lymph nodes and spleen, there was a decrease in Th2 related cytokines in the IL-10-/- mice.
  • OVA ovalbumin
  • a therapeutically effective amount of a cannabinoid such as, dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in the treatment of an allergy and/or hypersensitivity reaction.
  • the treatment of an allergy and/or hypersensitivity reaction may be achieved by the reduction of IL-10.
  • the treatment of an allergy and/or hypersensitivity reaction may be achieved by increasing GM-CSF.
  • the treatment of an allergy and/or hypersensitivity reaction may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent.
  • An immuno deficiency disease may be one or more of, primary immuno deficiency disease, X-linked agammaglobulinemia, severe combined immunodeficiency (SCID disorders), common variable immunodeficiency, alymphocytosis ("boy in a bubble” disease), secondary immuno-deficiency disorders, AIDS, ataxia-telangiectasia, Chediak-Higashi syndrome, combined immunodeficiency disease, complement deficiencies, DiGeorge syndrome, hypogammaglobulinemia, Job syndrome, leukocyte adhesion defects, panhypogammaglobulinemia, Bruton's disease, congenital agammaglobulinemia, selective deficiency of IgA, and Wiskott-Aldrich syndrome.
  • a therapeutically effective amount of a cannabinoid such as, dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in the treatment of an immunodeficiency disease.
  • the treatment of an immunodeficiency disease may be achieved by the reduction of IL-10.
  • the treatment of an immunodeficiency disease may be achieved by increasing GM-CSF.
  • the treatment of an immunodeficiency disease may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • Non-deliberate immunosuppression can occur in, for example, malnutrition, aging, many types of cancer (such as leukaemia, lymphoma, multiple myeloma), and certain chronic infections such as Human Immunodeficiency virus (HIV).
  • HIV Human Immunodeficiency virus
  • the unwanted effect in non-deliberate immunosuppression is immunodeficiency that results in increased susceptibility to pathogens such as bacteria, viruses, or fungi. Immunosuppression can occur as a side effect or adverse effect of several therapeutic agents.
  • a therapeutically effective amount of a cannabinoid such as, dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in the treatment of undesired immunosuppression.
  • the treatment of undesired immunosuppression may be achieved by the reduction of IL-10.
  • the treatment of undesired immunosuppression may be achieved by increasing GM-CSF.
  • the treatment of undesired immunosuppression may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • the dosage of the cannabinoid, or a derivative thereof, administered to a patient may vary and may be an amount of from about 2mg/kg to about 50mg/kg, based on the weight of the patient.
  • the dosage of the cannabinoid, or a derivative thereof may vary depending upon, inter alia, nature of the disorder, the sex of the patient, i.e. male or female, etc. and may be about 1-lOmg/kg, about l l-20mg/kg, about 21-30mg/kg, about 31- 40mg/kg, about 41-50mg/kg, based on the weight of the patient.
  • the dosage of the cannabinoid, or a derivative thereof may vary depending upon, inter alia, the severity of the disorder, the nature of the disorder, the sex of the patient, i.e. male or female, etc. and may be about 21 ⁇ , about 25 ⁇ , about 30 ⁇ , about 35 ⁇ , about 40 ⁇ , about 45 ⁇ , about 50 ⁇ , about 55 ⁇ , about 60 ⁇ , about 65 ⁇ , about 70 ⁇ , about 75 ⁇ , about 80 ⁇ , about 85 ⁇ , about 90 ⁇ , about 95 ⁇ , or about ⁇ .
  • the dosage regime and the frequency of administration may be varied, depending upon, inter alia, the severity of the disorder, the nature of the disorder, the sex of the patient, i.e. male or female, etc. and may be for example, generally based on a dose regime of once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or every day; for one week in a 3 week cycle.
  • the dosage regime may be generally based on a dose regime of once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or every day; for two weeks in a 3 week cycle.
  • the dosage regime may be generally based on a dose regime of once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or every day; for 3 weeks in a 3 week cycle.
  • the dosage regime may be generally based on a dose regime of once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or every day; for one week in a 4 week cycle.
  • the dosage regime may be generally based on a dose regime of once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or every day; for two weeks in a 4 week cycle.
  • the dosage regime may be generally based on a dose regime of once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or every day; for 3 weeks in a 4 week cycle.
  • the dosage regime may be generally based on a dose regime of once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or every day; for 4 weeks in a 4 week cycle.
  • the duration of the infusion may vary.
  • the infusion may be administered as an intravenous infusion over a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, or 6 hours, each treatment day during a cycle.
  • the cancer may be selected from one or more of primary cancer, breast cancer, colon cancer, prostate cancer, non-small cell lung cancer, glioblastoma, lymphoma, melanoma, mesothelioma, liver cancer, intrahepatic bile duct cancer, oesophageal cancer, pancreatic cancer, stomach cancer, laryngeal cancer, brain cancer, ovarian cancer, testicular cancer, cervical cancer, oral cancer, pharyngeal cancer, renal cancer, thyroid cancer, uterine cancer, urinary bladder cancer, hepatocellular carcinoma, thyroid carcinoma, osteosarcoma, small cell lung cancer, leukaemia, myeloma, gastric carcinoma and metastatic cancers.
  • primary cancer breast cancer, colon cancer, prostate cancer, non-small cell lung cancer, glioblastoma, lymphoma, melanoma, mesothelioma, liver cancer, intrahepatic bile duct cancer, oesophageal cancer, pancreatic
  • the amount of a cannabinoid, such as, dexanabinol, or a derivative thereof, administered to a patient is sufficient to achieve a plasma concentration of the cannabinoid, such as, dexanabinol, from InM to 20 ⁇ .
  • a cannabinoid such as, dexanabinol, or a derivative thereof, sufficient to achieve a plasma concentration of at least 1 nM of therapeutic agent and is maintained for at least 2 hours in the patient.
  • a method of treatment comprising immunotherapy treatment wherein said method comprises the administration of a therapeutically effective amount of the cannabinoid, or a derivative thereof.
  • the method of treatment of one or more of, cancer, by promoting immune clearance of tumours; a persistent infection and/or a viral disorder; autoimmune disorders, including systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction may be achieved by the reduction of IL-10.
  • the method of treatment of one or more of, cancer, by promoting immune clearance of tumours; a persistent infection and/or a viral disorder; autoimmune disorders, including systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction may be achieved by increasing GM-CSF.
  • the method of treatment of one or more of, cancer by promoting immune clearance of tumours; a persistent infection and/or a viral disorder; autoimmune disorders, including systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction, may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • autoimmune disorders including systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression
  • an allergy and/or hypersensitivity reaction may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • a method of treatment of cancer by promoting immune clearance of tumours, which comprises the administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • a cannabinoid such as, dexanabinol
  • the method of treatment of cancer, by promoting immune clearance of tumours may be achieved by the reduction of IL-10.
  • the method of treatment of cancer, by promoting immune clearance of tumours may be achieved by increasing GM-CSF.
  • the method of treatment of cancer, by promoting immune clearance of tumours; by may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • a method of treatment of a persistent infection and/or a viral disorder which comprises the administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • a cannabinoid such as, dexanabinol
  • the method of treatment of a persistent infection and/or a viral disorder may be achieved by the reduction of IL-10.
  • the method of treatment of a persistent infection and/or a viral disorder may be achieved by increasing GM-CSF.
  • the method of treatment of a persistent infection and/or a viral disorder may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • a method of treatment of autoimmune disorders including systemic lupus erythematosus (SLE), which comprises the administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • SLE systemic lupus erythematosus
  • the method of treatment of autoimmune disorders may be achieved by the reduction of IL-10.
  • the method of treatment of autoimmune disorders may be achieved by increasing GM- CSF.
  • the method of treatment of autoimmune disorders may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF. Therefore in a further embodiment of the invention, there is provided a method of treatment of an allergy and/or hypersensitivity reaction which comprises administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • a cannabinoid such as, dexanabinol, or a derivative thereof.
  • the method of treatment of an allergy and/or hypersensitivity reaction may be achieved by the reduction of IL-10.
  • the method of treatment of an allergy and/or hypersensitivity reaction may be achieved by increasing GM-CSF.
  • the method of treatment of an allergy and/or hypersensitivity reaction may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • a method of treatment of immunodeficiency disease which comprises the administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • the method of treatment of immunodeficiency disease may be achieved by the reduction of IL-10.
  • the method of treatment of immunodeficiency disease may be achieved by increasing GM-CSF.
  • the method of treatment of immunodeficiency disease may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • a method of treatment of undesired immunosuppression which comprises the administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • the method of treatment of undesired immunosuppression may be achieved by the reduction of IL-10.
  • the method of treatment of undesired immunosuppression may be achieved by increasing GM-CSF.
  • the method of treatment of undesired immunosuppression may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.
  • the method comprises the apoptosis of the cancer, which comprises administering a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof, to a patient in need thereof, wherein the cancer is selected from one or more of primary cancer, breast cancer, colon cancer, prostate cancer, non-small cell lung cancer, glioblastoma, lymphoma, melanoma, mesothelioma, liver cancer, intrahepatic bile duct cancer, oesophageal cancer, pancreatic cancer, stomach cancer, laryngeal cancer, brain cancer, ovarian cancer, testicular cancer, cervical cancer, oral cancer, pharyngeal cancer, renal cancer, thyroid cancer, uterine cancer, urinary bladder cancer, hepatocellular carcinoma, thyroid carcinoma, osteosarcoma, small cell lung cancer, leukaemia, myeloma, gastric carcinoma and meta
  • a cannabinoid such as, dexanabinol
  • a method of treating cancer as hereinbefore described wherein the cancer is selected from one or more of pancreatic carcinoma, glioblastoma, gastric carcinoma, hepatocellular carcinoma, oesophageal carcinoma, ovarian carcinoma, renal carcinoma and thyroid carcinoma.
  • the cancer is selected from one or more of pancreatic carcinoma, glioblastoma, gastric carcinoma, hepatocellular carcinoma, oesophageal carcinoma, ovarian carcinoma, renal carcinoma and thyroid carcinoma.
  • a method of treating cancer as hereinbefore described primary cancer breast cancer, colon cancer, prostate cancer, non-small cell lung cancer, glioblastoma, lymphoma, and metastatic cancers.
  • the method according to this aspect of the invention comprises administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof, to a patient in need of such a therapy.
  • a cannabinoid such as, dexanabinol, or a derivative thereof
  • the method of the invention may comprise the administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof, sufficient to inhibit tumourigenesis of a cancer cell.
  • the method may comprise the administration of a therapeutically effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof, sufficient to induce cytotoxicity in the cancer cell.
  • the amount of therapeutic agent, e.g. a cannabinoid, such as, dexanabinol, which may be administered to a patient may vary depending upon, inter alia, the nature of the cancer, the severity of the cancer, etc.
  • the therapeutically effective amount of a cannabinoid, such as, dexanabinol administered to the patient may be sufficient to achieve a plasma concentration of the cannabinoid, such as, dexanabinol from lnM to 20 ⁇ .
  • the method may comprise the administration of an effective amount of a therapeutic agent, e.g. a cannabinoid, such as, dexanabinol, or a derivative thereof, sufficient to achieve a plasma concentration of at least 10 nM of therapeutic agent and is maintained for at least 2 hours in the patient.
  • a therapeutic agent e.g. a cannabinoid, such as, dexanabinol, or a derivative thereof
  • the method of the invention may comprise the administration of an effective amount of a cannabinoid, or a derivative thereof, such as, dexanabinol, in combination with a second therapeutic agent, such as an immunotherapeutic agent.
  • a cannabinoid or a derivative thereof, such as, dexanabinol
  • a second therapeutic agent such as an immunotherapeutic agent.
  • the immunotherapeutic agent may comprise one or more of CAR-T cells, vectors, vaccines, armed anti-bodies; an agent capable of enhancing use of the immune system to treat cancer; an agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer; an agent of the interferon class capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent may comprise one or more of CAR-T cells, vectors, vaccines and armed anti-bodies.
  • the immunotherapeutic agent consists of any agent capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent may consist of any agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic may consist of any agent of the interferon class capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent consists of any agent of the interleukin class capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent is a checkpoint inhibitor, such as, an agent which targets one or more of CTLA4, PD1, PDL1, PDL2, CD80, CD86, CD28, B7RP1, ICOS, B7-H3, B7-H4, HVEM, BTLA, MHC-Class 1, MHC-Class 2, KIR,TCR, LAG3, CD137L, CD 137, OX40L, OX40, CD70, CD27, CD40, CD40L, GAL9, TIM3, A2aR, CD52, CD20, CD274 and CD279.
  • the checkpoint inhibitor may be one or more of a CTLA4, PDl or PDLl inhibitor.
  • the checkpoint inhibitor when it is a CTLA4 inhibitor, it may be selected from one or more of ipilimumab, nivolumab, rituximab, pembrolizumab, ofatumumab, MS-936559, MedI-4736, MPDL-3280A, MSB0010718C, pidilizumab and MK-3475. Most preferably the checkpoint inhibitor is ipilimumab.
  • the checkpoint inhibitor when the checkpoint inhibitor is a PDl inhibitor, it may be selected from one or more of nivolumab, pidilizumab and MK-3475.
  • the checkpoint inhibitor when the checkpoint inhibitor is a PDLl inhibitor, it may be selected from one or more of BMS-936559, MedI-4736, MPDL-3280A and MSB0010718C.
  • the second therapeutic agent for example, an immunotherapeutic agent
  • a cannabinoid, or a derivative thereof e.g. dexanabinol, or a derivative thereof
  • the method of the invention comprises the administration of a cannabinoid, or a derivative thereof, in combination with an immunotherapeutic agent, wherein the cannabinoid, or a derivative thereof, suppresses the level of IL-10 or ILla secreted in response to the second therapeutic agent.
  • a pharmaceutical composition comprising a cannabinoid, or a derivative thereof, for use in a treatment comprising immunotherapy.
  • a pharmaceutical composition comprising a cannabinoid, such as, dexanabinol, or a derivative thereof, for use in the treatment of one or more of, a proliferative disease, such as cancer, by promoting immune clearance of tumours; a persistent infection and/or a viral disorder; autoimmune disorders, including systemic lupus erythematosus (SLE); immunodeficiency and/or immune suppression and an allergy and/or hypersensitivity reaction as herein described.
  • the pharmaceutical composition according to this aspect of the invention will generally comprise a cannabinoid, as herein described, such as, dexanabinol, or a derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a cannabinoid such as, dexanabinol, or a derivative thereof, for use in the treatment of cancer, by promoting immune clearance of tumours.
  • the invention also provides a pharmaceutical composition comprising a cannabinoid, such as, dexanabinol, or a derivative thereof, for use in the treatment of a persistent infection and/or a viral disorder.
  • a cannabinoid such as, dexanabinol, or a derivative thereof
  • the invention also provides a pharmaceutical composition comprising a cannabinoid, such as, dexanabinol, or a derivative thereof, for use in the treatment of autoimmune diseases, such as systemic lupus erythematosus (SLE).
  • a pharmaceutical composition comprising a cannabinoid, such as, dexanabinol, or a derivative thereof, for use in the treatment of immunodeficiency and/or immune suppression
  • the invention also provides a pharmaceutical composition comprising a cannabinoid, such as, dexanabinol, or a derivative thereof, for use in the treatment of an allergy and/or hypersensitivity.
  • a cannabinoid such as, dexanabinol, or a derivative thereof
  • the present invention contemplates that the cancer cells may be premalignant, malignant, primary, metastatic or multidrug-resistant.
  • the treatment of the cancer may comprise the inhibition of tumourigenesis of a cancer cell by contacting the cell with an effective amount of a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • a cannabinoid such as, dexanabinol, or a derivative thereof.
  • Inhibition of tumourigenesis may also include inducing cytotoxicity and/or apoptosis in the cancer cell.
  • the method of the invention is advantageous because, inter alia, it shows reduced toxicity, reduced side effects and/or reduced resistance when compared to currently employed chemotherapeutic agents.
  • a cannabinoid such as, dexanabinol or a derivative thereof, may be administered in combination with one or more further therapeutic agents. Such administration may be in any order, and may be simultaneously separately or sequentially.
  • the second therapeutic agent may comprise a chemotherapeutic agent, immunotherapeutic agent, gene therapy or radio therapeutic agent.
  • the second therapeutic agent may be administered with the cannabinoid, such as, dexanabinol, or a derivative thereof, separately, simultaneously or sequentially.
  • second or additional therapeutic agents may be used in conjunction with a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • the second or additional therapeutic agent may be selected from the group consisting of: a chemotherapeutic agent, an immunotherapeutic agent, a gene therapy agent, and a radiotherapeutic agent.
  • the second therapeutic agent may comprise: alemtuzumab, ipilimumab, nivolumab, ofatumumab, rituximab, actinomycin, azacitidine, azathioprin, carboplatin, capecitabin, cisplatin, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurin, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, sorafenib, teniposide, tioguanine, topotecan, valrubicin vinblastine, vincristine
  • the immunotherapeutic agent may consist of one or more of CAR-T cells, vectors, vaccines, armed anti-bodies; an agent capable of enhancing use of the immune system to treat cancer; an agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer; an agent of the interferon class capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent consists of one or more of CAR-T cells, vectors, vaccines, and armed anti-bodies.
  • the immunotherapeutic agent consists of any agent capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent consists of any agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer. In another aspect of the invention the immunotherapeutic agent consists of any agent of the interferon class capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent consists of any agent of the interleukin class capable of enhancing use of the immune system to treat cancer.
  • an immunotherapeutic agent may be checkpoint inhibitor as herein described, e.g. an agent which targets immune checkpoints, wherein immune checkpoints are those pathways within the system for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses.
  • the checkpoint inhibitor may be an agent which targets, i.e. inhibits, one or more of CTLA4, PD1, PDLl, PDL2, CD80, CD86, CD28, B7RP1, ICOS, B7-H3, B7-H4, HVEM, BTLA, MHC-Class 1, MHC-Class 2, KIR,TCR, LAG3, CD137L, CD137, OX40L, OX40, CD70, CD27, CD40, CD40L, GAL9, TIM3, A2aR, CD52, CD20, CD274 and CD279.
  • checkpoint inhibitor is one or more of a CTLA4, PD1 or PDLl inhibitor.
  • CTLA4 inhibitor examples include, but shall not be limited to,, one or more of ipilimumab, nivolumab, rituximab, pembrolizumab, ofatumumab, BMS-936559, MedI-4736, MPDL-3280A, MSB0010718C, pidihzumab and MK-3475.
  • a particular CTLA4 inhibitor which may be mentioned is ipilimumab.
  • Examples of PD1 inhibitor include, but shall not be limited to,, one or more of nivolumab, pidilizumab and MK-3475
  • PDLl inhibitor examples include, but shall not be limited to, one or more of BMS-936559, MedI-4736, MPDL-3280A and MSB0010718C.
  • the immunotherapeutic agent is a standard currently employed therapy
  • the dose of the immunotherapeutic given in combination with a cannabinoid, such as, dexanabinol, or a derivative thereof may be reduced compared to the standard dose given as a monotherapy.
  • the standard dose of the currently employed therapy would be recognised by a person skilled in the art as, for example, the dose recorded in the SPC (Summary of Product Characteristics), the dose approved by health authorities or a dose routinely given in medical practice in a given indication and patient population.
  • Such a reduction in dose could be performed in multiple ways; reducing actual dose, reducing dosing frequency, reducing overall number of doses, reducing duration of dosing.
  • Such a reduction in dose by the method of the invention is advantageous because, inter alia, it shows reduced toxicity, reduced side effects and/or reduced resistance when compared to currently employed immunotherapeutic agent standard dose.
  • the immunotherapeutic agent is a standard currently employed therapy, given in combination with a cannabinoid, such as, dexanabinol, or a derivative thereof
  • a cannabinoid such as, dexanabinol
  • the onset of efficacy of the immunotherapeutic is earlier compared to the standard currently employed therapy when given as a monotherapy.
  • the onset of efficacy would be understood by a person skilled in the art to be the time to complete response (CR), time to partial response (PR), or time to stabilisation of disease.
  • Such an earlier onset of efficacy by the method of the invention is advantageous, inter alia, because it can reduce the total duration of treatment required, resulting in reduced toxicity, reduced side effects and/or reduced resistance when compared to currently employed immunotherapeutic agent standard dose when given as a monotherapy.
  • the immunotherapeutic agent is a considered a standard currently employed therapy, given in combination with a cannabinoid, such as, dexanabinol, or a derivative thereof, frequency of responses in a given patient population is greater than for either agent administered individually in the same patient population.
  • the frequency of response would be understood by a person skilled in the art to be the number of patients in a given treatment population with complete responses (CR), partial responses (PR), or stabilisation of disease.
  • Standard currently employed therapies would be recognised by a person skilled in the art as those with market authorisations, approved by health authorities or routinely given in medical practice in a given indication and patient population.
  • standard currently employed therapies are not limited to use in indications approved by health authorities or routinely given in medical practice in a given indication and patient population. They may be considered as therapies in alternate indication and alternate doses as herein described.
  • a second therapeutic agent may be provided in combination with a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • the second therapeutic agent may comprise: an antibacterial agent, such as, sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine, nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin, isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid (calcium p- aminosalicylate
  • an antiviral drug such as, idoxuridine, acyclovir, vidarabine or gancyclovir;
  • an anti-HIV agent such as, zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate or ritonavir;
  • an antibiotic such as, tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor cephalexin, cefroxadine, cefadroxil, cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome,
  • a second therapeutic agent may be provided in combination with a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • the second therapeutic agent may comprise: an NSAID, such as, alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zalto
  • aminosalicylic acid preparation such as, sulfasalazine, mesalamine, olsalazine or balsalazide;
  • an antimalarial drug such as, chloroquine or artemisinin-based combination therapies
  • an immunosuppressant such as, methotrexate, cyclophosphamide, atiprimod dihydrochloride, rimexolone, cyclosporine, tacrolimus, gusperimus, azathiopurine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor interleukin or interferon;
  • a steroid such as, dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone dipropionate or estriol;
  • an antibacterial agent such as, sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine, nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin, isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid (calcium p- aminosalicylate), pyrazinamide, ethionamide, protionamide, rifampicin, streptomycin sulfate, kanamycin sulfate or cycloserine;
  • an antibacterial agent such as, sulf
  • an antiviral drug such as, idoxuridine, acyclovir, vidarabine, gancyclovir;
  • an anti-HIV agent such as, zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate or ritonavir
  • an antibiotic such as, tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor cephalexin, cefroxadine, cefadroxil, cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren
  • an antifungal agent such as, amphotericin B, nystatin, trichomycin, griseofulvin, pyrrolnitrin, flucytosine, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole, fluconazole, itraconazole, trinaphthol, metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride or quinine sulfate.
  • an antifungal agent such as, amphotericin B, nystatin, trichomycin, griseofulvin, pyrrolnitrin, flucytosine, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole, fluconazole, itraconazole, trinaphthol, metronidazole, tinidazole,
  • a second therapeutic agent may be provided in combination with a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • the second therapeutic agent may comprise an agent which has side effects of immune suppression.
  • Such agents which have side effects of immune suppression include irradiation, cytotoxic chemotherapeutics, glucocorticoids, methotrexate, cyclophosphamide, atiprimod dihydrochloride, rimexolone, cyclosporine, tacrolimus, gusperimus, azathiopurine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor interleukin and interferon.
  • a second therapeutic agent may be provided in combination with a cannabinoid, such as, dexanabinol, or a derivative thereof.
  • the second therapeutic agent may comprise an anti-inflammatory, bronchodilatory or antihistamine drug substances.
  • Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone; LTD4 antagonists such as montelukast and zafirlukast; dopamine receptor agonists such as cabergoline, bromocriptine, ropinirole; PDE4 inhibitors such as ariflos, roflumilast, and arofylline.
  • steroids in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone
  • LTD4 antagonists such as montelukast and zafirlukast
  • dopamine receptor agonists such as cabergoline, bromocriptine, ropinirole
  • PDE4 inhibitors such as ariflos, roflumilast, and arofylline.
  • Such bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide and tiotropium bromide, and beta-2 adrenoceptor agonists such as salbutamol, terbutaline, salmeterol and, especially, formoterol.
  • antihistamine drugs include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride.
  • drugs may include for example, antifungal agent, antiprotozoal agent, antibiotic, antitussive and expectorant drug, sedative, anaesthetic, antiulcer drug, antiarrhythmic agent, hypotensive diuretic drug, anticoagulant, tranquilizer, antipsychotic, antitumour drug, hypolipidemic drug, muscle relaxant, antiepileptic drug, antidepressant, antiallergic drug, cardiac stimulants, therapeutic drug for arrhythmia, vasodilator, vasoconstrictor, hypotensive diuretic, therapeutic drug for diabetes, antinarcotic, vitamin, vitamin derivative, antiasthmatic, therapeutic agent for pollakisuria/anischuria, antipruritic drug, therapeutic agent for atopic dermatitis, therapeutic agent for allergic rhinitis, hypertensor, endotoxin-antagonist or -antibody, signal transduction inhibitor, inhibitor of inflammatory mediator activity, antibody to inhibit inflammatory mediator activity, inhibitor of anti-inflammatory mediator activity, antibody to inhibit anti-inflammatory mediator
  • Administration in combination with one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order, and in any route of administration.
  • Treatment in accordance with the present invention may be symptomatic or prophylactic.
  • derivative used herein shall include any conventionally known derivatives of the cannabinoid, such as, dexanabinol, such as, inter alia, solvates. It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound described herein, which may be used in any one of the uses/methods described.
  • solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent.
  • the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc., depending on the number of water molecules present per molecule of substrate.
  • the term derivative shall especially include a salt.
  • Suitable salts of the cannabinoid, such as, dexanabinol are well known and are described in the prior art.
  • Salts of organic and inorganic acids and bases may be used to make pharmaceutically acceptable salts.
  • Such acids include, without limitation, hydrofluoric, hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric, phosphoric, citric, succinic, maleic, and palmitic acids.
  • the bases include such compounds as sodium and ammonium hydroxides.
  • quaternizing agents that can be used to make pharmaceutically acceptable quaternary ammonium derivatives of the cannabinoid, such as, dexanabinol. These include without limitation methyl and ethyl iodides and sulphates.
  • Dexanabinol and derivatives and/or combinations thereof are known per se and may be prepared using methods known to the person skilled in the art or may be obtained commercially. In particular, dexanabinol and methods for its preparation are disclosed in U.S. Patent No. 4,876,276.
  • the cannabinoid such as, dexanabinol, or a derivative thereof, may be administered in a variety of ways depending upon, inter alia, the nature of the cancer to be treated. Thus, the cannabinoid, such as, dexanabinol, or a derivative thereof, may be administered topically, transdermally, subcutaneously, intravenously, or orally.
  • composition of the invention of the compound may be put up as a tablet, capsule, dragee, suppository, suspension, solution, injection, e.g. intravenously, intramuscularly or intraperitoneally, implant, a topical, e.g. transdermal, preparation such as a gel, cream, ointment, aerosol or a polymer system, or an inhalation form, e.g. an aerosol or a powder formulation.
  • compositions suitable for oral administration include tablets, capsules, dragees, liquid suspensions, solutions and syrups.
  • Compositions suitable for topical administration to the skin include creams, e.g. oil- in-water emulsions, water-in-oil emulsions, ointments, gels, lotions, unguents, emollients, colloidal dispersions, suspensions, emulsions, oils, sprays, foams, mousses, and the like.
  • Compositions suitable for topical application may also include, for example, liposomal carriers made up of lipids or special detergents.
  • lubricants/glidants e.g. magnesium stearate and colloidal silicon dioxide
  • disintegrants e.g. sodium starch glycolate and sodium carboxymethylcellulose
  • for capsules - pregelatinised starch or lactose e.g. lactose, starch, microcrystalline cellulose, talc and stearic acid
  • lubricants/glidants e.g. magnesium stearate and colloidal silicon dioxide
  • disintegrants e.g. sodium starch glycolate and sodium carboxymethylcellulose
  • capsules - pregelatinised starch or lactose for capsules - pregelatinised starch or lactose
  • transdermal delivery device or a suitable vehicle or, e.g. in an ointment base, which may be incorporated into a patch for controlled delivery.
  • a transdermal delivery device or a suitable vehicle or, e.g. in an ointment base, which may be incorporated into a patch for controlled delivery.
  • Such devices are advantageous, as they may allow a prolonged period of treatment relative to, for example, an oral or intravenous medicament.
  • transdermal delivery devices may include, for example, a patch, dressing, bandage or plaster adapted to release a compound or substance through the skin of a patient.
  • a person of skill in the art would be familiar with the materials and techniques which may be used to transdermally deliver a compound or substance and exemplary transdermal delivery devices are provided by GB2185187, US3249109, US3,598, 122, US4, 144,317, US4,262,003 and US4,307,717.
  • the invention will now be illustrated by way of example only and with reference to the accompanying figures in which:
  • Figure 1 is a scheme of PBMCs treatment with dexanabinol and challenged with LPS
  • Figure 2 is a plot of IP- 10 (Interferon gamma-induced protein 10) release from healthy volunteers PBMCs treated with dexanabinol
  • Figure 3 is a plot of IP- 10 changes after dexanabinol and LPS challenge to healthy volunteers PBMCs;
  • Figure 4 is a plot of GM-CSF (A) and TNFa (B) changes after dexanabinol and LPS challenge to healthy volunteers PBMCs;
  • Figure 5 is a plot of the reduction of IL-10 (A) and IL- ⁇ (B) in healthy volunteers PBMCs pre- incubated with dexanabinol and challenged with LPS;
  • Figure 6 illustrates the same data as Figure 6 in a 'last observation carried forward' format (LOCF);
  • Figure 7 illustrates the number of partial and complete regressions of CT-26 tumours borne subcutaneously by immune-competent mice following administration of anti- mCTLA-4 in combination with dexanabinol;
  • Figure 8 illustrates the percent change in tumour volume from Baseline (best overall response) for groups 3-5.
  • Figure 9 illustrates the levels of IL-10 in terminal plasma samples in mice following administration of anti-mCTLA-4 in combination with dexanabinol;
  • Figure 10 illustrates the levels of IL-la in terminal plasma samples in mice following administration of anti-mCTLA-4 in combination with dexanabinol;
  • FIG. 11 illustrates mean tumour volume measurements
  • Figure 12 is a waterfall plot summarising maximum percentage change in CT-26 tumour burden (best overall response) across three studies at day 37 post- implantation; animals prematurely removed from study due to grade 3 ulceration have been removed from analysis.
  • Example 1
  • Dexanabinol has been tested for its capability to enhance and modulate cytokine response in PBMCs of healthy volunteers as described below. Part 1. Healthy volunteers PBMCs challenged with dexanabinol
  • PBMC peripheral blood mononuclear cells
  • the second series of experiments focused on the ability of Dexanabinol to alter the levels of cytokines released by PBMCs in response to 100 ng/ml LPS.
  • the experimental set up was as follows: Fresh peripheral blood mononuclear cells (PBMC) were prepared from healthy volunteers blood and incubated with dexanabinol (2.5, 5 and 10 ⁇ ) for 2 or 4 h prior to the addition of LPS (100 ng/ml). Cells were incubated for further 4h or overnight, and supernatants were used for cytokine analysis as described above.
  • PBMC peripheral blood mononuclear cells
  • Part 1 Data obtained from three donors (Part 1) suggested that exposure of healthy volunteers PBMCs to dexanabinol alone (at either 5 or 10 ⁇ ) did not alter cytokine/chemokine/growth factor production. An exception was IP- 10, where there was some evidence of upregulated production in direct response to dexanabinol. The levels of IP- 10 measured in the assay were relatively low and the response was variable across donors ( Figure 2). Following PBMC challenge with dexanabinol, a second set of experiments were carried out to test the ability of dexanabinol to alter the levels of cytokines released by PBMCs in response to LPS challenge (lOOng/ml).
  • LPS activates cells predominantly via TLR4, and therefore in this assay the response to dexanabinol will be primarily from monocytes as they are the responsive population in human peripheral blood.
  • B-cells are also highly responsive to LPS, but they typically represent a small fraction ( ⁇ 3%) of the total PBMC population.
  • T-cells are not directly responsive to LPS, however they may contribute to the production of some analytes if they are indirectly activated.
  • Table 2 below presents an overview of the general trend of the cytokines response in the experiment.
  • GM-CSF is a protein, produced by monocytes and T-cells, that stimulates the production of white blood cells (monocytes, neutrophils and basophils) and promotes the maturation of dendritic cells.
  • Recombinant GM-CSF has been approved by the FDA to help neutrophil recovery following chemotherapy in patients with leukaemia.
  • GM-CSF has been shown to increase the immune response in animal tumour models as monotherapy (Disis et al 1996, Lee and Margolis 2011). In the clinic, systemic increase of GM-CSF confers clinical advantage in melanoma, prostate cancer and pulmonary metastases due to immune stimulation (Spitler et al 2000, Andersen 1999). Moreover, GM-CSF has been used in combination with immunotherapies, such as the monoclonal antibody CTL4 and has shown to promote an improvement in the survival of patients with metastatic melanoma (Hodi et al 2013, Hodi et al 2014). Combination of GM-CSF with rituximab in patients with follicular lymphoma has shown 36% of remission rate. As a single agent has shown anti-tumour activity when injected to metastatic melanoma lesions (Ridolfi et al 2001).
  • cytokine modulation by dexanabinol has been observed under LPS challenge, it is possible that dexanabinol can also modulate cytokines in patients, as the tumour burden will generate an inflammatory response in cancer patients. Cytokine changes have been seen in cancer patient's serum. For example, IL-10 is frequently upregulated in various types of cancer, and an increase on IL-10 serum levels has been associated in general with cancer progression (Sato et al 2011, Stanilov et al 2010). It has been reported that IL-23 and IL-10 levels are significantly elevated in serum of colorectal cancer patients (Stanilov et al 2010).
  • IL-10 can promote growth of malignant B-cells (Beatty et al 1997), and has been shown to induce immune suppression by affecting the function of antigen-presenting cells and inhibiting the expression of MHC and co-stimulatory molecules (Sato et al 2011). Moreover, preclinical studies indicated that the anti-tumour activity achieved by CTL4 blockade may be mediated by a decrease in IL-10 secretion (Jovasevic et al 2004).
  • mice 5x10 s viable cells in 0.1ml PBS injected subcutaneously into the left flank of each mouse. Total of 120 mice implanted.
  • Plasma samples taken at termination were analysed by Luminex in order to quantitate levels ofIP-10, GM-CSF, IL-la, IL- ⁇ , TNFa, IL-10, IL-2, IL-15 andlFNy.
  • Figure 6 displays the mean tumour volume measurements per group same data in a 'last observation carried forward' format (LOCF).
  • the primary objective of this study was to assess the efficacy of dexanabinol in combination with the anti-CTLA4 monoclonal antibody on subcutaneous CT-26 allografts.
  • the dose levels of all test articles used in this study were well tolerated, with no loss of body weight or adverse effects relating to treatment were noted.
  • Anti-CTLA4 monotherapy exhibited a statistically significant reduction in tumour volume over the course of the study, but there was no effect with dexanabinol as a single agent.
  • Groups 1, 2 and 3 were terminated by day 28, so could not be used for terminal tumour weight comparison with the remaining groups (Groups 4 and 5).
  • Groups 4 and 5 When final tumour weights were assessed across groups 4 (Vehicle (dexanabinol) + a-mCTLA4) and 5 (dexanabinol + a-mCTLA4), no statistical significance at the level of p ⁇ 0.05 was recorded (p>0.05; unpaired t-test; PRISM 6; GraphPad Software, Inc.).
  • Anti-CTLA4 monotherapy and in combination with dexanabinol (Group 3, i.p. QD; Group 4 i.p. BiW) exhibited a statistically significant reduction in tumour volume over the course of the study when compared to the vehicle control group.
  • mice remaining in the test groups at the end of the dosing phase only the Group 3 mice went on to exhibit 100% tumour regression.
  • Group 3 mice also show an appreciable reduction in tumour volume after fewer days than other groups, Figure 11.
  • Example 3 Expanding on Example 3, a further study was conducted to assess the effect of dexanabinol in combination with anti-CTLA4 monoclonal antibody in a subcutaneous colorectal cancer model of CT-26 (results not shown). The response data from all 3 studies were combined and summarised below and in a waterfall plot, Figure 12. Combined experimental details
  • Anti-mCTLA-4 was administered as a monotherapy and in combination with ETS2101
  • Figure 12 is a waterfall plot summarising maximum percentage change in CT-26 tumour burden (best overall response) across three studies at day 37 post- implantation. Animals prematurely removed from study due to grade 3 ulceration have been removed from analysis
  • Tumour immunotherapy leukocytes take up the fight. Nature review immunology 12, 235 - 237.
  • Aerosol granulocyte macrophage-colony stimulating factor a low toxicity, lung specific biological therapy in patients with lung metastases. Clin. Cancer Res. 5, 2316-2323.
  • Granulocyte-macrophage colony-stimulating factor an effective adjuvant for protein and peptide-based vaccines.
  • GM-CSF induces expression of soluble VEGF receptor- 1 from human monocytes and inhibits angiogenesis in mice. Immunity. 2004;21 :831-842.
  • Pancreatic cancer The role of GM-CSF in pancreatic cancer unveiled. Nature Reviews Gastroenterology and Hepatology 9, 426.
  • Interleukin 10 in the tumor microenvironment a target for anticancer immunotherapy 51, 2, 170-182.
  • T cell-derived IL-10 promotes lung cancer growth by suppressing both T-cell and APC function. J Immunol 163, 5020-5028.

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Abstract

L'invention concerne l'utilisation d'une quantité thérapeutiquement efficace d'un cannabinoïde, ou d'un dérivé de celui-ci, dans la fabrication d'un médicament pour utilisation en immunothérapie. L'invention décrit notamment l'utilisation de dexanabinol ou d'un dérivé de celui-ci, dans la fabrication d'un médicament pour utilisation en immunothérapie.
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WO2020057486A1 (fr) * 2018-09-17 2020-03-26 中国科学院动物研究所 Lymphocyte t modifié, son procédé de préparation et son utilisation
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WO2021226206A3 (fr) * 2020-05-05 2021-12-16 Teon Therapeutics, Inc. Modulateurs de récepteur cannabinoïde de type 2 (cb2) et leurs utilisations
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