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WO 2017/068349 Al 27 April 2017 (27.04.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/068349 Al 27 April 2017 (27.04.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/05 (2006.01) A61P 31/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/352 (2006.01) A61P 31/12 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 45/06 (2006.01) A61P 37/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, A61K 39/39 (2006.01) A61P 37/04 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, C07K 16/28 (2006.01) A61P 37/06 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, A61P 35/00 (2006.01) A61P 37/08 (2006.01) KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (21) International Application Number: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, PCT/GB20 16/053271 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (22) International Filing Date: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 20 October 2016 (20.10.201 6) ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (30) Priority Data: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 15 18805.5 23 October 2015 (23. 10.2015) GB TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 1609322. 1 26 May 2016 (26.05.2016) GB DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (71) Applicant: E-THERAPEUTICS PLC [GB/GB]; 17 Blen SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, heim Office Park, Long Hanborough OX29 8LN (GB). GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: FLORES, Maria Victoria; 17 Blenheim O f Published: fice Park, Long Hanborough Oxfordshire OX29 8LN (GB). — with international search report (Art. 21(3)) HYNES, Daniel Paul; 17 Blenheim Office Park, Long Hanborough Oxfordshire OX29 8LN (GB). — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (74) Agent: GILHOLM, Stephen Philip; The Smithy Office, amendments (Rule 48.2(h)) The Hawk Creative Business Park, Easingwold, York North Yorkshire Y061 3FE (GB). o © (54) Title: CANNABINOID FOR USE IN IMMUNOTHERAPY (57) Abstract: There is described the use of a therapeutically effective amount of a cannabinoid, or a derivative thereof, in the manu facture 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. 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 201 1). 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 a 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.
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