WO2017068349A1 - Cannabinoid for use in immunotherapy - Google Patents

Abstract

There is described the use of a therapeutically effective amount of a cannabinoid, or a derivative thereof, in the manufacture of a medicament for use in immunotherapy. There is especially described the use of dexanabinol, or a derivative thereof, in the manufacture of a medicament for use in immunotherapy.

Description

CANNABINOID FOR USE IN IM MUNOTHERAPY Field of the Invention

The present invention provides medicaments and methods for reducing suppression of the immune system in animals, e.g. humans.

More particularly 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. Background

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. 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.

IL-10

Interleukin-10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, 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-γ, 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.

GM-CSF

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.

Check point inhibitors

Under normal physiological conditions, 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. Thus, agonists of co-stimulatory receptors or antagonists of inhibitory signals, both of which result in the amplification of antigen-specific T cell responses, are the primary agents in current clinical testing (Table 1). Table 1

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). As a general rule, 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. It is the soluble and membrane-bound receptor-ligand immune checkpoints that are the most druggable using agonist antibodies (for co- stimulatory pathways) or antagonist antibodies (for inhibitory pathways). Therefore, in contrast to most currently approved antibodies for cancer therapy, antibodies that block immune checkpoints do not target tumour cells directly, instead they target lymphocyte receptors or their ligands in order to enhance endogenous antitumor activity. Direct 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. After trafficking to the tumour microenvironment, PD-1+ T cells might encounter PD-1 ligands, which can inhibit them from mediating their killing function. Thus, 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.

PDl and CTLA4 checkpoints seem to modulate very distinct components of T-cell immunity. 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

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. Primarily, 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. CD28 and CTLA4 share identical ligands: CD80 (also known as B7.1) and CD86 (also known as B7.2). The specific signalling pathways by which CTLA4 blocks T cell activation are still under investigation, although a number of studies suggest that activation of the protein phosphatases, SHP2 (also known as PTPN11) and PP2A, are important in counteracting kinase signals that are induced by TCR and CD28. However, 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.

Even though 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.

PDl

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.

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.

Although the major role of the PDl pathway is in limiting immune effector responses in tissues (and tumours), it can also shift the balance from T cell activation to tolerance at the early stages of T cell responses to antigens within secondary lymphoid tissues (that is, at a similar stage as CTLA4). Taken together, these findings imply a complex set of mechanisms of action for PD1 -pathway blockade.

Other

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)). These responses can occur at the initiation of T cell responses in lymph nodes (where the major APCs are dendritic cells) or in peripheral tissues or tumours (where effector responses are regulated). In general, 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. In general, pairs of co-stimulatory-inhibitory receptors that bind the same ligand or ligands— such as CD28 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)— display distinct kinetics of expression with the co-stimulatory receptor expressed on naive and resting T cells, but the inhibitory receptor is commonly upregulated after T cell activation. One important family of membrane-bound ligands that bind both co-stimulatory and inhibitory receptors is the B7 family. All of the B7 family members and their known ligands belong to the immunoglobulin superfamily. Many of the receptors for more recently identified B7 family members have not yet been identified. 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.

International Patent application No. WO 2003/077832 {Garzon & Avraham) describes that 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.

However, WO 2003/077832 {Garzon & Avraham) shows that dexanabinol increases the expression of IL-10. 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. The effect of dexanabinol and its analogues on IL-10 RNA levels in mice brains after 18 hours of MC Ao was tested by Garzon & Avraham; "Vehicle treated animals displayed a 35 fold increase in IL-10 gene expression versus sham operated animals. Treatment with dexanabinol and PRS-211,092 further increased this outcome by 4.4-fold and 2.3 -fold respectively, in comparison to the vehicle treated and the untreated groups". It has unexpectedly been identified that cannabinoids, such as, dexanabinol, decrease the amount of IL-10 in response to lipopolysaccharide (LPS) stimulus. It has additionally unexpectedly been identified that cannabinoids, such as, dexanabinol, decrease the amount of IL-10 when combined with anti-CTLA4 agents. This is contrary to the known state of the art.

Furthermore, it has also been identified that cannabinoids, such as, dexanabinol, increase GM-CSF levels.

Additionally it has unexpectedly been identified that cannabinoids, such as, dexanabinol, improve the efficacy of other immunotherapeutic agents when delivered in combination. The aforementioned findings lead to hitherto unknown novel therapies.

Summary of the Invention

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. According to a first 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 immunotherapy.

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 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. Preferably the cannabinoid is dexanabinol, or a derivative thereof.

According to this aspect of the invention, 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.

According to this aspect of the invention the cannabinoid, or derivative thereof, such as dexanabinol, may directly or indirectly reduce the effect of IL-10 effect. In one aspect of the invention 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.

In another aspect of the invention, 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.

In another aspect of the invention 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.

In another aspect of the invention there is provided the use as herein described which is achieved by increasing T Fa, RANTES, MIP-la, IP-10, IL-1RA, MCP-3 or GM- CSF and separately, simultaneously or sequentially decreasing IL-Ιβ, IL-la, IL-10, GRO or GCSF.

Immuno-oncology

In the past decades, significant efforts have been made to understand the role of the immune system in cancer, and how immunotherapies could be used for cancer treatment.

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). However, tumour cells can create an inflammatory tumour environment that leads to suppression and modulation of the immune response (Alderton et al 2012).

There are several strategies by which tumours can evade the immune response and some of them have already been exploited as immunotherapies. 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.).

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.

Recent studies illustrate the importance of sVEGFR-l in blocking cancer progression. For example, low intra-tumour sVEGFR-l and high total VEGF are associated with poor disease-free and overall survival (Bando et al, 2005). 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. The secretion of IL-10 can be increased in the presence of anti-CTLA4 agents. The use of a cannabinoid, such as, dexanabinol as herein described may act by decreasing IL-10, consequently changing the microenvironment away from immunosuppression.

According to a further 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 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.

According to this aspect of the invention the treatment of cancer, by promoting immune clearance of tumours, may be achieved by the reduction of IL-10.

In another aspect of the invention, the treatment of cancer, by promoting immune clearance of tumours; may be achieved by increasing GM-CSF.

In another aspect of the invention 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. Persistent infections and autoimmune disorders

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. 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.

In contrast to acute viral infections, persistent infections last for long periods, and occur when the primary infection is not cleared by the adaptive immune response. 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. According to this aspect of the invention, the treatment of a persistent infection and/or a viral disorder; may be achieved by the reduction of IL-10.

In another aspect of the invention, the treatment of a persistent infection and/or a viral disorder may be achieved by increasing GM-CSF.

In another aspect of the invention 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. As previously mentioned, 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.

Therefore, in a yet further 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 autoimmune disorders, including systemic lupus erythematosus (SLE).

According to this aspect of the invention, the treatment of autoimmune disorders, including systemic lupus erythematosus (SLE), may be achieved by the reduction of IL-10.

In another aspect of the invention, the treatment of autoimmune disorders including systemic lupus erythematosus (SLE) may be achieved by increasing GM-CSF.

In another aspect of the invention the treatment of autoimmune disorders including systemic lupus erythematosus (SLE) may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF. Th2 allergic response

Data indicate that 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-α, while the IL-10 increase was observed in these patients prior to and after exposure of allergen. Studies in 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.

Therefore in a further embodiment 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 an allergy and/or hypersensitivity reaction.

According to this aspect of the invention, the treatment of an allergy and/or hypersensitivity reaction, may be achieved by the reduction of IL-10.

In another aspect of the invention, the treatment of an allergy and/or hypersensitivity reaction, may be achieved by increasing GM-CSF. In another aspect of the invention 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.

Immuno-deficiency and immune suppression

Immunodeficiency (or immune deficiency) 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.

Therefore, in a further embodiment 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 an immunodeficiency disease.

According to this aspect of the invention, the treatment of an immunodeficiency disease, may be achieved by the reduction of IL-10. In another aspect of the invention, the treatment of an immunodeficiency disease, may be achieved by increasing GM-CSF. In another aspect of the invention 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). 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.

Therefore, in a further embodiment 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 undesired immunosuppression.

According to this aspect of the invention, the treatment of undesired immunosuppression, may be achieved by the reduction of IL-10.

In another aspect of the invention, the treatment of undesired immunosuppression, may be achieved by increasing GM-CSF. In another aspect of the invention 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. Thus, 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 21μΜ, about 25μΜ, about 30μΜ, about 35μΜ, about 40μΜ, about 45μΜ, about 50μΜ, about 55μΜ, about 60μΜ, about 65μΜ, about 70μΜ, about 75μΜ, about 80μΜ, about 85μΜ, about 90μΜ, about 95μΜ, or about ΙΟΟμΜ.

It will be understood by the person skilled in the art that 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. Alternatively, 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. Alternatively, 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. Alternatively, 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. Alternatively, 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. Alternatively, 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. Alternatively, 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. When the cannabinoid, or a derivative thereof, is administered by way of infusion, the duration of the infusion may vary. Thus, 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. When the use herein described comprises the treatment of cancer, 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.

According to this aspect of the invention we provide the use as herein described wherein 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 μΜ.

According to a further aspect of the invention we provide the use as herein described wherein the amount of 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.

According to another aspect of the invention there is provided 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. According to this aspect of the invention there is provided a method of 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; which comprises the administration of a therapeutically effective amount of the cannabinoid, such as, dexanabinol, or a derivative thereof.

According to this aspect of the invention, 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.

In another aspect of the invention, 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.

In another aspect of the invention 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.

According to a further aspect of the invention there is provided 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.

According to this aspect of the invention the method of treatment of cancer, by promoting immune clearance of tumours, may be achieved by the reduction of IL-10.

In another aspect of the invention, the method of treatment of cancer, by promoting immune clearance of tumours; may be achieved by increasing GM-CSF. In another aspect of the invention 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.

Therefore, according to this aspect of the invention there is provided 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.

According to this aspect of the invention, the method of treatment of a persistent infection and/or a viral disorder; may be achieved by the reduction of IL-10. In another aspect of the invention, the method of treatment of a persistent infection and/or a viral disorder may be achieved by increasing GM-CSF.

In another aspect of the invention 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.

Therefore, in a yet further aspect of the invention there is provided 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.

According to this aspect of the invention, the method of treatment of autoimmune disorders, including systemic lupus erythematosus (SLE), may be achieved by the reduction of IL-10.

In another aspect of the invention, the method of treatment of autoimmune disorders, including systemic lupus erythematosus (SLE), may be achieved by increasing GM- CSF.

In another aspect of the invention the method of treatment of autoimmune disorders, including systemic lupus erythematosus (SLE), 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.

According to this aspect of the invention, the method of treatment of an allergy and/or hypersensitivity reaction, may be achieved by the reduction of IL-10.

In another aspect of the invention, the method of treatment of an allergy and/or hypersensitivity reaction, may be achieved by increasing GM-CSF.

In another aspect of the invention 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.

Therefore, in a yet further aspect of the invention there is provided 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.

According to this aspect of the invention, the method of treatment of immunodeficiency disease may be achieved by the reduction of IL-10.

In another aspect of the invention, the method of treatment of immunodeficiency disease may be achieved by increasing GM-CSF. In another aspect of the invention the method of treatment of immunodeficiency disease may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

Therefore, in a yet further aspect of the invention there is provided 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.

According to this aspect of the invention, the method of treatment of undesired immunosuppression may be achieved by the reduction of IL-10.

In another aspect of the invention, the method of treatment of undesired immunosuppression may be achieved by increasing GM-CSF.

In another aspect of the invention the method of treatment of undesired immunosuppression may be achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

According to a yet further aspect of the invention we provide a method of treating cancer wherein 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 metastatic cancers.

In one preferred embodiment of the invention there is provided 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. In another preferred embodiment of the invention there is provided 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.

More specifically, 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.

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. Alternatively or in addition 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. Thus, for example, 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 μΜ.

More specifically, 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.

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.

According to this aspect of the invention 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.

In a particular aspect of the invention 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. In addition, 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. Preferably, the checkpoint inhibitor may be one or more of a CTLA4, PDl or PDLl inhibitor. When the checkpoint inhibitor 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.

When the checkpoint inhibitor is a PDl inhibitor, it may be selected from one or more of nivolumab, pidilizumab and MK-3475. 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.

In some instances the second therapeutic agent, for example, an immunotherapeutic agent, may cause IL-10 or ILla to be secreted in response to that second therapeutic agent. The use of a cannabinoid, or a derivative thereof, e.g. dexanabinol, or a derivative thereof, may suppress the level IL-10 or ILla secreted in response to the second therapeutic agent. Thus, according to a further aspect of the invention 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.

According to a yet further aspect of the invention there is provided a pharmaceutical composition comprising a cannabinoid, or a derivative thereof, for use in a treatment comprising immunotherapy. According to a this aspect of the invention there is provided 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. Thus, this aspect of the invention provides a pharmaceutical composition comprising 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.

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). The invention also provides 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.

The present invention contemplates that the cancer cells may be premalignant, malignant, primary, metastatic or multidrug-resistant.

Alternatively, 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. Inhibition of tumourigenesis may also include inducing cytotoxicity and/or apoptosis in the cancer cell.

Furthermore 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.

In the use and/ or method of the invention 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.

When the use or method comprises the treatment of cancer, the second therapeutic agent may comprise a chemotherapeutic agent, immunotherapeutic agent, gene therapy or radio therapeutic agent. When a second therapeutic agent is included in the treatment according to the invention, the second therapeutic agent may be administered with the cannabinoid, such as, dexanabinol, or a derivative thereof, separately, simultaneously or sequentially.

Although a variety of second or additional therapeutic agents may be used in conjunction with a cannabinoid, such as, dexanabinol, or a derivative thereof. However, preferably, 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, vindesine or vinorelbine. In one aspect of the invention the additional therapeutic agent may be an immunotherapeutic agent.

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. In one aspect of the invention the immunotherapeutic agent consists of one or more of CAR-T cells, vectors, vaccines, and armed anti-bodies.

In another aspect of the invention the immunotherapeutic agent consists of any agent 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 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.

In another aspect of the invention the immunotherapeutic agent consists of any agent of the interleukin class capable of enhancing use of the immune system to treat cancer. Such 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.

According to this aspect of the invention 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.

In a preferred aspect of the invention checkpoint inhibitor is one or more of a CTLA4, PD1 or PDLl inhibitor.

Examples of CTLA4 inhibitor, 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

Examples of PDLl inhibitor, include, but shall not be limited to, one or more of BMS-936559, MedI-4736, MPDL-3280A and MSB0010718C. In another aspect of this invention, where 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.

In another aspect of this invention, where the immunotherapeutic agent is a standard currently employed therapy, given in combination with a cannabinoid, such as, dexanabinol, or a derivative thereof, 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.

In another aspect of this invention, where 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. For the purposes of the invention, 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.

When the use or method comprises the treatment of a persistent infection and/or a viral disorder, 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), pyrazinamide, ethionamide, protionamide, rifampicin, streptomycin sulfate, kanamycin sulfate or cycloserine;

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, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt a salt thereof, griseofulvin, lankacidin- group [Journal of Antibiotics (J. Antibiotics), 38, 877-885 (1985)], azole compound [2-[( lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy- 1 -methyl-3 -( 1H- 1 ,2,4-triazol- 1 - yl)propyl] -4- [4-(2,2, 3 , 3 -tetrafluoropropoxyl)phenyl] -3 (2H,4H)- 1 ,2,4-triazolone, fluconazole or itraconazole;

When the use or method comprises the treatment of autoimmune disorders, including systemic lupus erythematosus (SLE), 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, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium aurothiomalate, hyaluronate sodium, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol or oxymorphone; a COX-1 or a COX-2 inhibitor, such as, salicylic acid derivatives (e.g., celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin or loxoprofen;

a penicillamine;

an 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 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 pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt a salt thereof, griseofulvin, lankacidin- group [Journal of Antibiotics (J. Antibiotics), 38, 877-885 (1985)], azole compound [2-[( lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy- 1 -methyl-3 -( 1H- 1 ,2,4-triazol- 1 - yl)propyl] -4- [4-(2,2, 3 , 3 -tetrafluoropropoxyl)phenyl] -3 (2H,4H)- 1 ,2,4-triazolone, fluconazole or itraconazole;

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. When the use or method comprises the treatment of immuno-deficiency and/or immune suppression, 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.

When the use or method comprises the treatment of allergies and/or hypersensitivity reactions, 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.

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. Such antihistamine drugs include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride. Other 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 activity and the like.

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. The term "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. The term solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, 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. Those skilled in the art are familiar with 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.

Thus, in the use, method and/or 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.

Examples of other adjuvants, diluents or carriers are:

for tablets and dragees - fillers, 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; for capsules - pregelatinised starch or lactose;

for oral or injectable solutions or enemas - water, glycols, alcohols, glycerine, vegetable oils;

for suppositories - natural or hardened oils or waxes.

It may be possible to administer the compound or derivatives and/or combination thereof or any combined regime as described above, transdermally via, for example, 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.

Examples of 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-Ιβ (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;

Figure 11 illustrates mean tumour volume measurements; and

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

The first series of experiments focused on determining the effect of dexanabinol in eliciting cytokine response. Fresh peripheral blood mononuclear cells (PBMC) were prepared from healthy volunteer's blood. Cells from three donors were exposed to either lipopolysaccharide from Gram negative bacteria (LPS, 100 ng/ml) or dexanabinol (5 and 10 μΜ). Cells were incubated at 37°C and 5% C02 for 4, 6 and 24h. Supernatants were used for cytokine and chemokine analysis using a Luminex array. The analyses included VEGF, sCD40L, EGF, Eotaxin, FGF-2, Flt3, Fractalkine, G-CSF, GM-CSF, GRO, IFN-a2, IFNy, IL-la, IL-Ιβ, IL-ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL- 17, IP- 10, MCP-1, MCP-3, MDC (CCL22), ΜΙΡ-Ια, ΜΙΡ-Ιβ, PDGF-AA, PDGF- AB/BB, RANTES, TGFa, T Fa, T Fp.

Part 2. Healthy volunteers PBMCs pre-treated with dexanabinol and subsequently challenged with LPS or vehicle control

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 μΜ) 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. A scheme of the experimental set up is shown in Figure 1.

Results

Data obtained from three donors (Part 1) suggested that exposure of healthy volunteers PBMCs to dexanabinol alone (at either 5 or 10μΜ) 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).

It is worth noting that 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.

Table 2. Summary of the effects of dexanabinol on the analytes tested

In concordance with the results from PBMCs challenged with dexanabinol only (Part 1), an increase in IP-10 is also seen after LPS challenge (Figure 3A). Interestingly, after LPS challenge, changes in the concentration of a range of other cytokines were also observed. Some of the cytokines upregulated by dexanabinol over LPS are positive regulators of inflammation and immune function. Examples of these cytokines are granulocyte-macrophage-colony stimulating factor (GM-CSF), and tumour necrosis factor alpha TNFa (Figure 4). 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).

Dexanabinol-driven down-regulation of other pro-inflammatory and immune regulatory cytokines has been observed {e.g. IL-la, IL-Ιβ and IL-10). The down- regulation of IL-10 can be seen in Figure 5 (Note: Changes in concentration levels of IL-10 (Fig 5A) and IL-Ιβ (Fig 5B). Groups are defined in Figure 1).

Although 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).

Taken together, the observed inhibition of IL-10 and the increase of GM-CSF by dexanabinol in the context of PBMCs challenged with LPS, strongly suggest that dexanabinol could enhance immunity in cancer patients either as a single agent or in combination with other immune therapies.

Example 2

Dexanabinol combined with anti-CTLA mAb

Study Objective

To assess the effect of dexanabinol and its combination with anti-CTLA4 monoclonal antibody in a subcutaneous colorectal cancer model of CT-26. STUDY METHODS

Species: Mus musculus

Strain: BALB/cAnNCrl

Gender: female

Implantation: s.c (left flank)

Cell line: CT26

5x10^s viable cells in 0.1ml PBS injected subcutaneously into the left flank of each mouse. Total of 120 mice implanted.

Mice randomly allocated to treatment groups. Treatment commenced when tumours reached a mean volume of ~100mm3; mice allocated to their treatment groups with uniform mean tumour volume between groups. Treatment continued for 3 weeks. Groups 4 and 5 dosed for 4 weeks in total.

Plasma samples taken at termination were analysed by Luminex in order to quantitate levels ofIP-10, GM-CSF, IL-la, IL-Ιβ, TNFa, IL-10, IL-2, IL-15 andlFNy.

DOSING

Results

Loss of mice due to early terminations affected the mean tumour volume from day 16 onward. Figure 6 displays the mean tumour volume measurements per group same data in a 'last observation carried forward' format (LOCF).

Increased levels of IL-10 and IL-la were observed following mCTLA-4 treatment compared to mCTLA-4 vehicle (Figures 9 and 10 respectively) and mCTLA-4 + Dexanabinol treatment reduced levels of these cytokines compared to mCTLA-4 treatment alone.

Summary

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.

Although there was no additive effect, in terms of tumour growth inhibition, for group 5 (dexanabinol + a-mCTLA4) when compared to group 4 (Vehicle (dexanabinol) + a-mCTLA4); there was an observed difference in the number of mice exhibiting a partial/complete regression in tumour volume for group 5 (42% versus 5%) (Figure 8).

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). 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.).

Example 3

Dexanabinol combined with anti-CTLA mAb (Part 2)

A further study to assess the effect of dexanabinol and its combination with anti- CTLA4 monoclonal antibody in a subcutaneous colorectal cancer model of CT-26 was conducted using the same treatment methods as Example 2 with the following dosing groups:

The mean tumour volume measurements per group are presented in Figure 11. Combination treatment exhibited a statistically significant reduction in tumour volume over the course of the study when compared to antibody monotherapy group up to Day 28 (p<0.0006; Bonferroni's multiple comparisons).

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.

An additive effect, in terms of tumour growth inhibition, was noted for Group 3 (Dexanabinol i.p. QD + a-mCTLA4 i.p. BiW) when compared to Group 2 (Vehicle (Dexanabinol) + a-mCTLA4) from study Day 25 onwards.

Of the 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 4

Dexanabinol combined with anti-CTLA mAb (Part 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

• CT-26 colon carcinoma tumour line was implanted s.c. into immune- competent mice

• Anti-mCTLA-4 was administered as a monotherapy and in combination with ETS2101

• Anti-mCTLA-4 administered at 10 mg/kg i.p. BiW

• ETS2101 administered at 200 mg/kg QD

• Animals prematurely removed from study due to grade 3 ulceration have been removed from analysis

There was an observed difference in the number of mice exhibiting a partial/complete regression in tumour volume for the combination arm versus the antibody monotherapy arm: Antibody monotherapy resulted in at least partial regression in 44% of tumours and complete regression in 7%. Combination treatment resulted in at least partial regression in 74% of tumours and complete regression in 36%.

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

0493P.WO.Spec(2) References

Alderton et al 2012. Tumour immunotherapy— leukocytes take up the fight. Nature review immunology 12, 235 - 237.

Anderson et al. 1999. Aerosol granulocyte macrophage-colony stimulating factor: a low toxicity, lung specific biological therapy in patients with lung metastases. Clin. Cancer Res. 5, 2316-2323.

Armstrong CA, Botella R, Galloway TH, Murray N, Kramp JM, Song IS, Ansel JC. Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells. Cancer Res. 1996; 56:2191-2198. Bando H, Weich HA, Brokelmann M, Horiguchi S, Funata N, Ogawa T, Toi M. Association between intratumoral free and total VEGF, soluble VEGFR-l, VEGFR-2 and prognosis in breast cancer. Br J Cancer. 2005;92:553-561.

Beatty et al 1997. Involvement of IL-10 in the autonomous growth of EBV- transformed B cell lines. J. Immunol. 158, 4045-4051.

Demirkesen C, Buyukpinarbasjli N, Ramazanoglu R, Oguz O, Mandel M, Kaner G. The correlation of angiogenesis with metastasis in primary cutaneous melanoma: a comparative analysis of microvessel density, expression of vascular endothelial growth factor and basic fibroblastic growth factor. Pathology. 2006;38: 132-137.

Disis ML et al 1996. Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood 88, 202-210. Eubank TD, Roberts R, Galloway M, Wang Y, Cohn DE, Marsh CB. GM-CSF induces expression of soluble VEGF receptor- 1 from human monocytes and inhibits angiogenesis in mice. Immunity. 2004;21 :831-842.

Eubank TD, Roberts RD, Khan M, et al. GM-CSF Inhibits Breast Cancer Growth And Metastasis By Invoking An Anti- Angiogenic Program In Tumor-Educated Macrophages. Cancer research. 2009;69(5):2133-2140. doi: 10.1158/0008-5472.CAN- 08-1405.

Fujii et al 2001. Interleukin-10 promotes the maintenance of antitumor CD8(p) T-cell effector function in situ. Blood 98, 2143-2151.

Greenhill 2012. Pancreatic cancer: The role of GM-CSF in pancreatic cancer unveiled. Nature Reviews Gastroenterology and Hepatology 9, 426.

Hagenbaugh et al 1997. Altered immune responses in interleukin 10 transgenic mice. J Exp Med 185, 2101-2110.

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.

Hodi et al 2013 Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: ASCO 2013. E1608. Hodi e al 2014. Sargramostim plus Ipilimumab vs Ipilimumab Alone for Treatment of Metastatic Melanoma: A Randomized Clinical Trial. JAMA 5, 1744 -1753.

Jovasevic et al 2004. Importance of IL-10 for CTLA-4-mediated inhibition of tumor- eradicating immunity. J. Immunol. 172, 1449-1454.

Lee & Margolis 2011. Cytokines in Cancer Immunotherapy. Cancers 3, 3856-3893.

Lotem J, Sachs L. Cytokine control of developmental programs in normal hematopoiesis and leukemia. Oncogene. 2002;21 :3284-3294.

Mapara, M. Y., Sykes, M. (2004) Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance J. Clin. Oncol. 22, 1136-1151. Martinez et al 2008. Macrophage activation and polarization. Front Biosci. 13, 453- 61.

Mosser DM, Zhang X (Dec 2008). "Interleukin-10: new perspectives on an old cytokine". Immunological Reviews 226 (1): 205-18.

Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71-78.

Ridolfi et al 2011. Intralesional granulocyte-monocyte colony- stimulating factor followed by subcutaneous interleukin-2 in metastatic melanoma: A pilot study in elderly patients. J. Eur. Acad. Dermatol. Venereol. 15, 218-223.

Sato et al 2011. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy 51, 2, 170-182.

Sharma et al 1999. T cell-derived IL-10 promotes lung cancer growth by suppressing both T-cell and APC function. J Immunol 163, 5020-5028.

Spitler et al. 2000. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony- stimulating factor. J Clin. Oncol. 18, 1614-1621.

Stanilov et al 2010. Advanced Colorectal Cancer Is Associated With Enhanced IL-23 and IL-10 Serum Levels. Science 41. Sun et al 2015. IL10 and PD-1 Cooperate to Limit the Activity of Tumor- Specific CD8p T Cells Cancer Res 15, 1635 - 1644.

Watson NF, Ramage JM, Madjd Z, Spendlove I, Ellis IO, Scholefield JH, Durrant LG. Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int J Cancer. 2006;118:6-10.

0493P.WO.Spec(3)

Claims

Claims

1. The use of a therapeutically effective amount of a cannabinoid, or a derivative thereof, in the manufacture of a medicament for use in immunotherapy.

2. The use according to claim 1 which comprises the use of a therapeutically effective amount of a cannabinoid, 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; an autoimmune disorder, such as, systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction.

3. The use according to claims 1 or 2 which is achieved by the reduction of IL- 10.

4. The use according to claims 1 or 2 which is achieved by increasing GM-CSF.

5. The use according to any one of the preceding claims which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM- CSF.

6. The use according to claims 1 or 2 which is achieved by increasing T Fa, RANTES, MIP-la, IP- 10, IL-1RA, MCP-3 or GM-CSF and separately, simultaneously or sequentially decreasing IL-Ιβ, IL-la, IL-10, GRO or GCSF.

7. The use of a therapeutically effective amount of a cannabinoid, or a derivative thereof, in the manufacture of a medicament for use in the treatment of a proliferative disease, such as cancer, by promoting immune clearance of tumours.

8. The use according to claim 7 which is achieved by the reduction of IL-10.

9. The use according to claim 7 which is achieved by increasing GM-CSF.

10. The use according to claim 7 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

11. The use of a therapeutically effective amount of cannabinoid, or a derivative thereof, in the manufacture of a medicament for use in the treatment of a persistent infection and/or a viral disorder.

12. The use according to claim 11 which is achieved by the reduction of IL-10.

13. The use according to claim 11 which is achieved by increasing GM-CSF.

14. The use according to claim 11 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

15. The use of a therapeutically effective amount of a cannabinoid, or a derivative thereof, in the manufacture of a medicament for use in the treatment of an autoimmune disorder, such as, systemic lupus erythematosus (SLE).

16. The use according to claim 15 which is achieved by the reduction of IL-10.

17. The use according to claim 15 which is achieved by increasing GM-CSF.

18. The use according to claim 15 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

19. The use of a therapeutically effective amount of a cannabinoid, or a derivative thereof, in the manufacture of a medicament for use in the treatment of an allergy and/or hypersensitivity reaction.

20. The use according to claim 19 which is achieved by the reduction of IL-10.

21. The use according to claim 19 which is achieved by increasing GM-CSF.

22. The use according to claim 19 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

23. The use of a therapeutically effective amount of a cannabinoid, or a derivative thereof, in the manufacture of a medicament for use in the treatment of an immunodeficiency disease.

24. The use according to claim 23 which is achieved by the reduction of IL-10.

25. The use according to claim 23 which is achieved by increasing GM-CSF.

26. The use according to claim 23 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

27. The use of a therapeutically effective amount of a cannabinoid, or a derivative thereof, in the manufacture of a medicament for use in the treatment of undesired immunosuppression.

28. The use according to claim 27 which is achieved by the reduction of IL-10.

29. The use according to claim 27 which is achieved by increasing GM-CSF.

30. The use according to claim 27 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

31. The use according to any one of the preceding claims wherein the amount of a cannabinoid, or a derivative thereof, administered to a patient is sufficient to achieve a plasma concentration of the cannabinoid from InM to 20 μΜ.

32. The use according to any one of claims 1 to 30 wherein the amount of a cannabinoid, 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.

33. The use according to any one of the preceding claims wherein the cannabinoid is selected from tetrahydrocannabinol (THC), cannabidiol or dexanabinol, or a derivative thereof, or combinations thereof.

34. The use according to any one of the preceding claims wherein the cannabinoid is dexanabinol, or a derivative thereof.

35. The use according to claim 33 wherein the cannabinoid is tetrahydrocannabinol (THC), or a derivative thereof.

36. The use according to claim 33 wherein the cannabinoid is cannabidiol, or a derivative thereof.

37. The use according to any one of the preceding claims wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent.

38. The use according to claim 37 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent suitable for the treatment of a proliferative disease, such as cancer.

39. The use according to claim 37 wherein the cannabinoid, or a derivative thereof is in combination with a second therapeutic agent suitable for the treatment of a persistent infection and/or a viral disorder.

40. The use according to claim 37 wherein the cannabinoid, or a derivative thereof is in combination with a second therapeutic agent suitable for the treatment of an autoimmune disorder, such as, systemic lupus erythematosus (SLE).

41. The use according to claim 37 wherein the cannabinoid, or a derivative thereof is in combination with a second therapeutic agent suitable for the treatment of an allergy and/or hypersensitivity reaction.

42. The use according to claim 37 wherein the cannabinoid, or a derivative thereof is in combination with a second therapeutic agent suitable for the treatment of an immunodeficiency disease.

43. The use according to claim 37 wherein the cannabinoid, or a derivative thereof is in combination with another therapeutic agent suitable for the treatment of undesired immunosuppression.

44. The use according to claim 37 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent, wherein the second therapeutic agent is an immunotherapeutic agent.

45. The use according to claim 44 wherein the immunotherapeutic agent is 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.

46. The use according to claim 44 wherein the immunotherapeutic agent is one or more of CAR-T cells, vectors, vaccines, and armed anti-bodies.

47. The use according to claim 44 wherein the immunotherapeutic agent consists of any agent capable of enhancing use of the immune system to treat cancer.

48. The use according to claim 47 wherein the immunotherapeutic agent consists of any agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer.

49. The use according to claim 47 wherein the immunotherapeutic consists of any agent of the interferon class capable of enhancing use of the immune system to treat cancer.

50. The use according to claim 47 wherein the immunotherapeutic agent consists of any agent of the interleukin class capable of enhancing use of the immune system to treat cancer.

51. The use according to any one of claims 44 to 50 wherein the immunotherapeutic agent is a checkpoint inhibitor.

52. The use according to claim 51 wherein the checkpoint inhibitor is an agent which targets one or more of CTLA4, PDl, 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.

53. The use according to claims 51 or 52 wherein the checkpoint inhibitor is one or more of a CTLA4, PDl or PDLl inhibitor.

54. The use according to any one of claims 51 to 53 wherein the checkpoint inhibitor is a CTLA4 inhibitor, selected from one or more of ipilimumab, nivolumab, rituximab, pembrolizumab, ofatumumab, BMS-936559, MedI-4736, MPDL-3280A, MSB0010718C, pidilizumab and MK-3475.

55. The use according to any one of claims 51 to 54 wherein the checkpoint inhibitor is ipilimumab.

56. The use according to any one of claims 51 to 53 wherein the checkpoint inhibitor is a PDl inhibitor selected from one or more of nivolumab, pidilizumab and MK-3475.

57. The use according to any one of claims 51 to 53 wherein the checkpoint inhibitor is a PDLl inhibitor, selected from one or more of BMS-936559, MedI-4736, MPDL-3280A and MSB0010718C.

58. 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.

59. A method of treatment according to claim 58 which comprises 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; an autoimmune disorder, such as, systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction; which comprises the administration of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

60. The method of treatment according to claims 58 or 59 which is achieved by the reduction of IL-10.

61. The method of treatment according to claim 58 or 59 which is achieved by increasing GM-CSF.

62. The method of treatment according to claim 58 or 59 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM- CSF.

63. The method of treatment according to claim 58 or 59 which is achieved by increasing T Fa, RANTES, MIP-la, IP- 10, IL-1RA, MCP-3 or GM-CSF and separately, simultaneously or sequentially decreasing IL-Ιβ, IL-la, IL-10, GRO or GCSF.

64. The method of treatment according to claim 59 which comprises the treatment of a proliferative disease, such as cancer in a patient, by promoting immune clearance of tumours, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

65. The method of treatment according to claim 64 which is achieved by the reduction of IL-10.

66. The method of treatment according to claim 64 which is achieved by increasing GM-CSF.

67. The method of treatment according to claim 64 which is achieved the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM- CSF.

68. The method of treatment according to claim 59 which comprises the treatment of a persistent infection and/or a viral disorder, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

69. The method of treatment according to claim 68 which is achieved by the reduction of IL-10.

70. The method of treatment according to claim 68 which is achieved by increasing GM-CSF.

71. The method of treatment according to claim 68 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM- CSF.

72. The method of treatment according to claim 59 which comprises the treatment of an autoimmune disorder, such as, systemic lupus erythematosus (SLE), by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

73. The method of treatment according to claim 72 which is achieved by the reduction of IL-10.

74. The method of treatment according to claim 72 which is achieved by increasing GM-CSF.

75. The method of treatment according to claim 72 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM- CSF.

76. The method of treatment according to claim 59 which comprises the treatment of an allergy and/or hypersensitivity reaction, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

77. The method of treatment according to claim 76 which is achieved by the reduction of IL-10.

78. The method of treatment according to claim 76 which is achieved by increasing GM-CSF.

79. The method of treatment according to claim 76 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM- CSF.

80. The method of treatment according to claim 59 which comprises the treatment of an immunodeficiency disease, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

81. The method according to claim 80 which is achieved by the reduction of IL- 10.

82. The method according to claim 80 which is achieved by increasing GM-CSF.

83. The method according to claim 80 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

84. The method of treatment according to claim 59 which comprises the treatment of undesired immunosuppression, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

85. The method according to claim 84 which is achieved by the reduction of IL- 10.

86. The method according to claim 84 which is achieved by increasing GM-CSF.

87. The method according to claim 84 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

88. The method according to any one of claims 58 to 87 wherein the amount of the cannabinoid, or a derivative thereof, administered to a patient is sufficient to achieve a plasma concentration of the cannabinoid from 10 to 20 μΜ.

89. The method according to any one of claims 58 to 87 wherein the amount of the cannabinoid, or a derivative thereof, sufficient to achieve a plasma concentration of at least 10 μΜ of therapeutic agent and is maintained for at least 2 hours in the patient.

90. The method according to any one of claims 58 to 87 wherein the cannabinoid is selected from tetrahydrocannabinol (THC), cannabidiol or dexanabinol, or a derivative thereof, or combinations thereof.

91. The method according to claim 90 wherein the cannabinoid is dexanabinol, or a derivative thereof.

92. The method according to claim 90 wherein the cannabinoid is tetrahydrocannabinol (THC), or a derivative thereof.

93. The method according to claim 90 wherein the cannabinoid is cannabidiol, or a derivative thereof.

94. The method according to any one of claims 58 to 93 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent.

95. The method according to claim 94 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent suitable for the treatment of a proliferative disease, such as cancer.

96. The method according to claim 94 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent suitable for the treatment of a persistent infection and/or a viral disorder.

97. The method according to claim 94 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent suitable for the treatment of an autoimmune disorder, such as, systemic lupus erythematosus (SLE).

98. The method according to claim 94 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent suitable for the treatment of an allergy and/or hypersensitivity reaction.

99. The method according to claim 94 wherein the cannabinoid, or a derivative thereof is in combination with a second therapeutic agent suitable for the treatment of an immunodeficiency disease.

100. The method according to claim 94 wherein the cannabinoid, or a derivative thereof is in combination with a second therapeutic agent suitable for the treatment of undesired immunosuppression.

101. The method according to claim 94 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent, wherein the second therapeutic agent is an immunotherapeutic agent.

102. The method according to claim 101 wherein the cannabinoid, or a derivative thereof, suppresses the level of IL-10 or ILla secreted in response to the second therapeutic agent.

103. The method according to claim 101 wherein the immunotherapeutic agent is 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.

104. The method according to claims 101 to 103 wherein the immunotherapeutic agent is one or more of CAR-T cells, vectors, vaccines, and armed anti-bodies.

105. The method according to claim 101 wherein the immunotherapeutic agent consists of any agent capable of enhancing use of the immune system to treat cancer.

106. The method according to claim 105 wherein the immunotherapeutic agent consists of any agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer.

107. The method according to claim 105 wherein the immunotherapeutic consists of any agent of the interferon class capable of enhancing use of the immune system to treat cancer.

108. The method according to claim 105 wherein the immunotherapeutic agent consists of any agent of the interleukin class capable of enhancing use of the immune system to treat cancer.

109. The method according to any one of claims 101 to 108 wherein the immunotherapeutic agent is a checkpoint inhibitor.

110. The method according to claim 109 wherein the checkpoint inhibitor is an agent which targets one or more of CTLA4, PDl, 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.

111. The method according to claims 109 or 110 wherein the checkpoint inhibitor is one or more of a CTLA4, PDl or PDLl inhibitor.

112. The method according to any one of claims 109 to 111 wherein the checkpoint inhibitor is a CTLA4 inhibitor, selected from one or more of ipilimumab, nivolumab, rituximab, pembrolizumab, ofatumumab, BMS-936559, MedI-4736, MPDL-3280A, MSB0010718C, pidilizumab and MK-3475.

113. The method according to claim any one of claims 109 to 111 wherein the checkpoint inhibitor is ipilimumab.

114. The method according to claims 110 or 111 wherein the checkpoint inhibitor is a PDl inhibitor selected from one or more of nivolumab, pidilizumab and MK- 3475.

115. The method according to claims 110 or 111 wherein the checkpoint inhibitor is a PDLl inhibitor, selected from one or more of BMS-936559, MedI-4736, MPDL- 3280A and MSB0010718C.

116. A pharmaceutical composition comprising a cannabinoid, or a derivative thereof, for use in a treatment comprising immunotherapy.

117. A pharmaceutical composition according to claim 126 comprising a cannabinoid, 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; an autoimmune disorder, such as, systemic lupus erythematosus (SLE); immuno-deficiency and/or immune suppression; and an allergy and/or hypersensitivity reaction as herein described.

118. The pharmaceutical composition according to claim 117 which is achieved by the reduction of IL-10.

119. The pharmaceutical composition according to claim 117 which is achieved by increasing GM-CSF.

120. The pharmaceutical composition according to claim 117 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

121. The pharmaceutical composition according to claim 117 which comprises the treatment of a proliferative disease, such as cancer in a patient, by promoting immune clearance of tumours, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

122. The pharmaceutical composition according to claim 121 which is achieved by the reduction of IL-10.

123. The pharmaceutical composition according to claim 121 which is achieved by increasing GM-CSF.

124. The pharmaceutical composition according to claim 121 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

125. The pharmaceutical composition according to claim 117 which is achieved by increasing T Fa, RANTES, MIP-la, IP- 10, IL-1RA, MCP-3 or GM-CSF and separately, simultaneously or sequentially decreasing IL-Ιβ, IL-la, IL-10, GRO or GCSF.

126. The pharmaceutical composition according to claim 117 which comprises the treatment of a persistent infection and/or a viral disorder, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

127. The pharmaceutical composition according to claim 126 which is achieved by the reduction of IL-10.

128. The pharmaceutical composition according to claim 126 which is achieved by increasing GM-CSF.

129. The pharmaceutical composition according to claim 126 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

130. The pharmaceutical composition according to claim 117 which comprises the treatment of an autoimmune disorder, such as, systemic lupus erythematosus (SLE), by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

131. The pharmaceutical composition according to claim 130 which is achieved by the reduction of IL-10.

132. The pharmaceutical composition according to claim 130 which is achieved by increasing GM-CSF.

133. The pharmaceutical composition according to claim 130 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

134. The pharmaceutical composition according to claim 117 which comprises the treatment of an allergy and/or hypersensitivity reaction, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

135. The pharmaceutical composition according to claim 132 which is achieved by the reduction of IL-10.

136. The pharmaceutical composition according to claim 134 which is achieved by increasing GM-CSF.

137. The pharmaceutical composition according to claim 134 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

138. The pharmaceutical composition according to claim 117 which comprises the treatment of an immunodeficiency disease, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

139. The pharmaceutical composition according to claim 138 which is achieved by the reduction of IL-10.

140. The pharmaceutical composition according to claim 138 which is achieved by increasing GM-CSF.

141. The pharmaceutical composition according to claim 138 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

142. The pharmaceutical composition according to claim 117 which comprises the treatment of undesired immunosuppression, by administering to the patient of a therapeutically effective amount of the cannabinoid, or a derivative thereof.

143. The pharmaceutical composition according to claim 142 which is achieved by the reduction of IL-10.

144. The pharmaceutical composition according to claim 142 which is achieved by increasing GM-CSF.

145. The pharmaceutical composition according to claim 142 which is achieved by the reduction of IL-10 and, separately, simultaneously or sequentially, increasing GM-CSF.

146. The pharmaceutical composition according to any one of claims 116 to 145 wherein the amount of the cannabinoid, or a derivative thereof, administered to a patient is sufficient to achieve a plasma concentration of the cannabinoid from InM to 20 μΜ.

147. The pharmaceutical composition according to any one of claims 116 to 145 wherein the amount of the cannabinoid, 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.

148. The pharmaceutical composition according to any one of claims 116 to 145 wherein the cannabinoid is selected from tetrahydrocannabinol (THC), cannabidiol or dexanabinol, or a derivative thereof or combinations thereof.

149. The pharmaceutical composition according to claim 148 wherein the cannabinoid is dexanabinol, or a derivative thereof.

150. The pharmaceutical composition according to claim 148 wherein the cannabinoid is tetrahydrocannabinol (THC), or a derivative thereof.

151. The pharmaceutical composition according to claim 148 wherein the cannabinoid is cannabidiol, or a derivative thereof.

152. The pharmaceutical composition according to any one of claims 116 to 151 wherein the cannabinoid, or a derivative thereof is in combination with a second therapeutic agent.

153. The pharmaceutical composition according to claim 152 wherein the second therapeutic agent is an immunotherapeutic agent for use in immunotherapy.

154. The pharmaceutical composition according to claim 152 wherein the second therapeutic agent is suitable for the treatment of a proliferative disease, such as cancer.

155. The pharmaceutical composition according to claim 152 wherein the second therapeutic agent is suitable for the treatment of a persistent infection and/or a viral disorder.

156. The pharmaceutical composition according to claim 152 wherein the second therapeutic agent is suitable for the treatment of an autoimmune disorder, such as, systemic lupus erythematosus (SLE).

157. The pharmaceutical composition according to claim 152 wherein the second therapeutic agent is suitable for the treatment of an allergy and/or hypersensitivity reaction.

158. The pharmaceutical composition according to claim 152 wherein the second therapeutic agent is suitable for the treatment of an immunodeficiency disease.

159. The pharmaceutical composition according to claim 152 wherein the second therapeutic agent is suitable for the treatment of undesired immunosuppression.

160. The pharmaceutical composition according to claim 152 wherein the cannabinoid, or a derivative thereof, is in combination with a second therapeutic agent, wherein the second therapeutic agent is an immunotherapeutic agent.

161. The pharmaceutical composition according to claim 160 wherein the immunotherapeutic agent is 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.

162. The pharmaceutical composition according to claims 160 or 161 wherein the immunotherapeutic agent is one or more of CAR-T cells, vectors, vaccines, and armed anti-bodies.

163. The pharmaceutical composition according to claims 160 or 161 wherein the immunotherapeutic agent consists of any agent capable of enhancing use of the immune system to treat cancer.

164. The pharmaceutical composition according to claims 160 or 161 wherein the immunotherapeutic agent consists of any agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer.

165. The pharmaceutical composition according to claims 160 or 161 wherein the immunotherapeutic consists of any agent of the interferon class capable of enhancing use of the immune system to treat cancer.

166. The pharmaceutical composition according to claims 160 or 161 wherein the immunotherapeutic agent consists of any agent of the interleukin class capable of enhancing use of the immune system to treat cancer.

167. The pharmaceutical composition according to any one of claims 160 to 166 wherein the immunotherapeutic agent is a checkpoint inhibitor.

168. The pharmaceutical composition according to claim 167 wherein the checkpoint inhibitor is an agent which targets one or more of CTLA4, PDl, 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.

169. The pharmaceutical composition according to claims 167 or 168 wherein the checkpoint inhibitor is one or more of a CTLA4, PDl or PDLl inhibitor.

170. The pharmaceutical composition according to any one of claims 167 to 169 wherein the checkpoint inhibitor is a CTLA4 inhibitor, selected from one or more of ipilimumab, nivolumab, rituximab, pembrolizumab, ofatumumab, BMS-936559, MedI-4736, MPDL-3280A, MSB0010718C, pidilizumab and MK-3475.

171. The pharmaceutical composition according to any one of claims 167 to 170 wherein the checkpoint inhibitor is ipilimumab.

172. The pharmaceutical composition according to any one of claims 167 to 169 wherein the checkpoint inhibitor is a PDl inhibitor selected from one or more of nivolumab, pidilizumab and MK-3475.

173. The pharmaceutical composition according to any one of claims 167 to 169 wherein the checkpoint inhibitor is a PDLl inhibitor, selected from one or more of BMS-936559, MedI-4736, MPDL-3280A and MSB0010718C.

174. A use, method, composition or the use substantially as hereinbefore described with reference to the accompanying examples.