Combination therapy and uses thereof

Abstract

This disclosure relates to combinations of BH-3 mimetics and STING agonists, and their use in combination therapies for the treatment of cancer.

Description

COMBINATION THERAPY AND USES THEREOF

[0001] This application claims priority to Australian provisional patent application 2023902434 (filed 1 August 2023) and 2023903793 (filed 24 October 2023), the entire contents of each of which is incorporated herein by reference. Field of the invention

[0002] The disclosure herein relates to combination therapies and methods of using same in medicine. More particularly, the disclosure herein relates to therapies comprising a combination of a BH3-mimetic drug and a STING agonist that are suitable for the treatment and management of proliferative diseases, such as cancer, and methods of medical treatment using same. Background

[0003] Survival rates for many cancers have improved significantly over the last decade as a result of improvements in molecular profiling and novel therapeutic approaches to tackle these malignancies. However, tumour suppressor gene TP53 (also called TRP53 in mice or p53 generally) mutant disease remains a major clinical challenge for treatment of cancer. TP53 is the most commonly mutated gene across all cancer types, but TP53 mutant cancers are particularly resistant to cytotoxic drugs that depend on causing DNA damage to trigger cancer cell death. TP53 mutant cancer cells frequently also harbour defects in a broad range of pathways, including metabolism, genome stability and autophagy, conferring reduced sensitivity to diverse anti-cancer agents. For blood cancers, such as lymphoma and leukaemia, patient sub-groups bearing TP53 mutations in their malignant cells are generally considered to have adverse risk and inferior survival outcomes. TP53 mutations are found in 5-15% of acute myeloid leukemias (AML) (up to 25% in elderly patients), 25% of Non-Hodgkin lymphomas (NHL), and up to 60% of natural killer / T (NKT) cell lymphoma cases in some populations. Effective treatment approaches for TP53 mutated cancers, and especially for TP53 mutated blood cancers, therefore, currently represents an urgent and inadequately addressed clinical need.

[0004] TP53 is activated in response to oncogene activation, DNA-damaging cytotoxic drugs, and g-radiation, amongst other stresses, where it transcriptionally upregulates expression of the genes encoding the pro-apoptotic BH3-only proteins (e.g. 1005442107NOXA, PUMA, BIM) and thereby initiates the intrinsic apoptosis pathway. Intrinsic apoptotic signalling is governed by the balance between pro- and anti-apoptotic members of the BCL-2 family. Pro-apoptotic BH3-only proteins bind and sequester pro- survival proteins (e.g. MCL-1, BCL-2, BCL-XL), promoting activation of the pro-apoptotic effectors BAK and BAX. Activated BAK and BAX cause mitochondrial outer membrane permeabilization (MOMP), which releases apoptogenic factors into the cytoplasm catalysing activation of the caspase cascade and cell demolition.

[0005] BH3-mimetic drugs are small molecule inhibitors which directly bind and inhibit select pro-survival members of the BCL-2 family. The identification of the functions of the different BCL-2 family members, complemented by emerging insights into the structural interactions between pro-apoptotic and pro-survival family members, engendered the concept of killing cancer cells by targeting the pro-survival members with small molecules that mimic the function of the BH3-only proteins, now termed BH3- mimetic drugs.

[0006] The development of BH3-mimetic drugs was seen as a major milestone towards developing a cancer therapy that was TP53-agnostic, as their use would allow for activation of apoptosis downstream of TP53. Unfortunately, although patients may initially respond well to treatment with BH3-mimetics, emerging clinical data suggest that most will relapse. A range of mechanisms propagating resistance to BH3-mimetics have been identified, with perhaps the most surprising being that functional TP53 is required for maximal BH3-mimetic drug induced apoptosis of leukaemic cells. While the mechanisms underlying this TP53-mediated response to BH3-mimetic drugs are thus far unclear, recent evidence shows that patients with TP53-defective blood cancers, such as chronic lymphocytic leukaemia (CLL) or AML, have poorer outcomes after treatment with the BCL-2 specific BH3 mimetic drug venetoclax.

[0007] Treatments for cancer that address one or more of the above problems or at least provide a useful alternative are therefore desirable. In particular, improved methods of treating or inhibiting the progression of cancer by killing malignant cells independent of their TP53 status (mutant or wild-type) are desirable.

[0008] The invention described herein provides a new combination therapy that overcomes the TP53 mutation status driven impediment to successful treatment of otherwise vulnerable cancers by BH3 mimetic drugs and possibly also other anti-cancer 1005442107agents. In particular, the disclosure herei describes a combination of a BH3-mimetic drug with a STING agonist that synergistically enhances killing of cancer cells in a TP53-independent manner. This combination offers a new treatment regime that targets wild type and mutant TP53 cancer cells and may thereby avoid creation of a therapy-resistant refractory TP53 mutant cell subpopulation and / or a TP53 mutant cell subpopulation capable of triggering disease relapse. The combinations described herein are therefore suitable for use against refractory or relapsed cancers, including cancers previously treated with a TP53-sensitive compound, such as a DNA damage inducing chemotherapeutic agents or a BH3-mimetic drug, as well as induction therapy for newly diagnosed disease.

[0009] A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that the document or matter was known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims. Definitions

[0010] C3-6Cycloalkyl: The term “C3-6cycloalkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic hydrocarbon compound having from 3 to 6 carbon atoms. Examples of C3-6cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5) and cyclohexyl (C6).

[0011] C3-7Heterocyclyl: The term “ C3-7heterocyclyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a monocyclic heterocyclic compound, which moiety has from 3 to 7 ring atoms; of which from 1 to 2 atoms are heteroatoms, chosen from oxygen, sulfur or nitrogen. The C3-7heterocyclyl groups may be non-aromatic or aromatic ring systems. Aromatic C3-7heterocyclyl groups may be referred to as C3-7heteroaryl groups.

[0012] In this context, the prefixes (e.g. C3-7) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. Thus a prefix may in some instances be interchanged with an alternative prefix defining the number of ring member atoms, for example the prefix “C3-7” may be interchanged with the prefix “3- to 7-membered”. In some embodiments, the C3-7heterocyclyl moieties in the 1005442107compounds of the invention may be C3, C4, C5, C6or C7 heterocyclyls or any combination of these different sized rings / ring systems, such as C3-6, C4-7or C5-6heterocyclyl groups.

[0013] Examples of C3-7heterocyclyl groups include, but are not limited to, those derived from: N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), pyrrole (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), pyridine (C6), azepine (C7), azepane (C7); N2: diazirine (C3) diazetidine (C4), imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), imidazole (C5), pyrazole (C5), piperazine (C6), pyrazine (C6), pyrimidine (C6), pyridazine (C6), diazepine (C7), diazepane (C7); O1: oxetane (C4), tetrahydrofuran (C5); oxane (C6); O2: dioxetane (C4), dioxolane (C5); dioxane (C6), dioxole (C5); N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), isoxazole (C5), oxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6); S1: thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiphene (C5), thiane (tetrahydrothiopyran) (C6), thiepane (C7); N1S1: thiazoline (C5), thiazolidine (C5), thiazole (C5), isothiazole (C5), thiomorpholine (C6), thiazine (C6); O1S1: oxathiolidene (C5), isoxthiolidine (C5), oxathiole (C5), isoxathiole (C5) and oxathiane (thioxane) (C6); N2O: oxadiazole (C5); N2S: thiadiazole (C5). 1005442107

[0014] C1-4Alkyl: The term “ C1-4alkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having from 1 to 4 carbon atoms.

[0015] Examples of saturated alkyl groups include, but are not limited to, Me: methyl (C1), Et: ethyl (C2), Pr: propyl (C3), and Bu: butyl (C4).

[0016] Examples of saturated linear alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), nPr: n-propyl (C3), and nBu: n-butyl (C4).

[0017] Examples of saturated branched alkyl groups include, but are not limited to, iPr: iso-propyl (C3, -C(CH3)2), iBu: iso-butyl (C4), sBu: sec-butyl (C4) and tBu: tert-butyl (C4).

[0018] C2-4Alkenyl: The term “ C2-4alkenyl” as used herein, pertains to an alkyl group having from 2 to 4 carbon atoms and having one or more carbon-carbon double bonds.

[0019] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (1-methylvinyl, -C(CH3)=CH2) and butenyl (C4).

[0020] C1-4fluoroalkyl: The term “C1-4fluoroalkyl” as used herein, pertains to a C1-4alkyl group, substituted with one or more fluorine atoms.

[0021] Alkoxy: -OR wherein R is a C1-4alkyl group as defined above. It can be represented as -O-C1-4alkyl. Examples of alkoxy groups include, but are not limited to, methoxy (OMe, C1), ethoxy (OEt, C2), propyloxy (C3), and butyloxy (C4).

[0022] Alkyl carbamoyl: -NHC(=O)OR wherein R is a C1-4alkyl group as defined above. Examples of alkyl carbamoyl groups include, but are not limited to, - N(H)C(=O)OCH3, -N(H)C(=O)OCH2CH3, and -N(H)C(=O)OC(CH3)3.

[0023] Alkyl carbamoyl ester: -OC(=O)NRR’ wherein R and R’ are independently selected from H and C1-4alkyl as defined above. Examples of alkyl carbamoyl ester groups include, but are not limited to, -OC(=O)N(CH3)2, and -OC(=O)N(H)CH3. 1005442107

[0024] Alkyl carboxyl ester: -OC(=O)OR wherein R is a C1-4alkyl group as defined above. Examples of alkyl carboxyl ester groups include, but are not limited to, -OC(=O)OCH3, -OC(=O)OCH2CH3, -OC(=O)OC(CH3)3, and -OC(=O)OCH(CH3)2.

[0025] Amino: -N(R)R’ wherein R and R’ are independently selected from H and C1-4alkyl as defined above. Examples of an amino group include, but are not limited to, - NH2, -N(H)CH3, -N(H)C(CH3)2, -N(CH3)2, -N(CH2CH3)2.

[0026] Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide, aminoacyl): –C(=O)N(R)R’ wherein R and R’ are independently selected from H and C1-4alkyl as defined above. Examples of an amido group include, but are not limited to, C(=O)NH2, -C(=O)N(H)CH3, -C(=O)N(CH3)2, -C(=O)N(H)CH2CH3, and -C(=O)N(CH2CH3)2.

[0027] Acylamido: -N(R)C(=O)R’ wherein R and R’ are independently selected from H and C1-4alkyl as defined above. Examples of an acylamido group include, but are not limited to, -N(H)C(=O)CH2CH3, -N(H)C(=O)CH3and -N(CH3)C(=O)CH3.

[0028] Phenyl: -C6H5, wherein the phenyl may itself be optionally substituted by one or more C1-4alkyl groups, one or more C1-4fluoroalkyl groups, one or more C1-4alkoxy groups, one or more halo substituents and one or more cyano substituents.

[0029] Benzyl: -CH2-phenyl, wherein phenyl is as defined above.

[0030] Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, wherein R is an ester substituent, for example, a C1-4alkyl group, a C3-7heterocyclyl group, or a phenyl group, as defined above, preferably a C1-4alkyl group. Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and - C(=O)OPh.

[0031] Acyloxy (reverse ester): -OC(=O)R, wherein R is an acyloxy substituent, for example, a C1-4alkyl group, a C3-7heterocyclyl group, or a phenyl group, as defined above, preferably a C1-4alkyl group. Examples of acyloxy groups include, but are not limited to, -OC(=O)CH3(acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3 and -OC(=O)Ph. Further examples of acyloxy groups include, but are not limited to, methylester (C1), ethylester (C2), propylester (C3) and butylester (C4).

[0032] Naturally occurring amino acid: The term “a naturally occurring amino acid”, as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom 1005442107from a carboxyl group or an amino group on one of the amino acid compounds found commonly in nature (for example, alanine, arginine, asparagine, aspartate, cysteine, glycine, glutamine, glutamate, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine). The amino acid is particularly selected from isoleucine, leucine and valine, most particularly valine.

[0033] In each of these groups the carbon atom which is bonded to both a carboxyl and an amino group is known as the α carbon and the carboxyl and amino groups to which it is attached are the α-carboxyl and α-amino groups. Naturally occurring amino acids are optionally substituted with a protecting group on the α-amino group or any other amino group on the moiety, protecting groups include but are not limited to acetyl, methyl, fluorenylmethoxycarbonyl (Fmoc), carboxybenzyl (Cbz; benzyloxycarbonyl), phthalimido and tertbutyl carbamate (boc) groups.

[0034] Phosphonate ester: -P(O)(OR)OR’, wherein R and R’ are independently selected from C1-4alkyl as defined above. Examples of a phosphonate ester include, but are not limited to –P(O)(OEt)2.

[0035] Cyano: -C≡N.

[0036] Pivaloyloxymethyl: A group of formula la

[0038] Oxo-thiadiazolyl: A 5 membered heterocyclic radical having two nitrogen ring atoms, a sulfur ring atom, and an oxo substituent. Examples of oxo-thiadiazolyl groups include: 10054421072-oxo-3H-1-thia-3,4-diazol-5-yl 2-oxo-3H-1-thia-3,5-diazol-4-yl ngatoms, a sufur ring atom, and a thiocarbonyl substituent. Examples of thio-thiadiazolyl groups include: 2-thio-3H-1-thia-3,4-diazol-5-yl 2-thio-3H-1-thia-3,5-diazol-4-ylng atoms, an oxygen ring atom, and a thiocarbonyl substituent. Examples of thio- oxadiazolyl groups include: 2-thio-3H-1-oxa-3,4-diazol-5-yl 2-thio-3H-1-oxa-3,5-diazol-4-yln ring atoms, a sufur ring atom, and a hydroxy substituent. These groups may be tautomeric with corresponding oxo-thiadiazolyl groups under some conditions. Examples of hydroxyl-thiadiazolyl groups include: 2-hydroxy-1-thia-3,4-diazol-5-yl 2-hydroxy-1-thia-3,5-diazol-4-yly y- y y g gen ring atoms, an oxygen ring atom, and a hydroxy substituent. These groups may be tautomeric with corresponding oxo-oxadiazolyl groups under some conditions. Examples of hydroxyl-oxadiazolyl groups include: 10054421072-hydroxy-1-oxa-3,4-diazol-5-yl 2-hydroxy-1-oxa-3,5-diazol-4-ylnitrogen ring atoms, a sufur ring atom, and a thiohydroxy substituent. These groups may be tautomeric with corresponding thio-thiadiazolyl groups under some conditions. Examples of thiohydroxyl-thiadiazolyl groups include: 2-thiohydroxy-1-thia-3,4-diazol-5-yl 2-thiohydroxy-1-thia-3,5-diazol-4-ylnitrogen ring atoms, an oxygen ring atom, and a thiohydroxy substituent. These groups may be tautomeric with corresponding thio-oxadiazolyl groups under some conditions. Examples of thiohydroxyl-oxadiazolyl groups include: 2-thiohydroxy-1-oxa-3,4-diazol-5-yl 2-thiohydroxy-1-oxa-3,5-diazol-4-ylg atom, an oxygen ring atom, and a hydroxy substitutuent. Examples of hydroxyl-oxazolyl groups include: 3-hydroxy-1-ox-2-azol-5-yl 4-hydroxy-1-ox-2-azol-5-ylso e e o e s, e y o y-o a oy ay e a - y o y- -o - - azol-5-yl.

[0047] Thiohydroxy-oxazolyl: A 5-membered heterocyclic radical having a nitrogen ring atom, an oxygen ring atom and a thiohydroxy substituent. Examples of thiohydroxy- oxazolyl groups include: 10054421073-thiohydroxy-1-ox-2-azol-5-yl 4-thiohydroxy-1-ox-2-azol-5-yl 2-azol-5-yl.

[0049] Hydroxy-thiazolyl: A 5-membered heterocyclic radical having a nitrogen ring atom, a sulfur ring atom, and a hydroxy substituent. Examples of hydroxy-thiazolyl groups include: 3-hydroxy-1-thia-2-azol-5-yl 4-hydroxy-1-thia-2-azol-5-ylazol-5-yl.

[0051] Thiohydroxy-thiazolyl: A 5-membered heterocyclic radical having a nitrogen ring atom, a sulfur ring atom and a thiohydroxy substituent. Examples of thiohydroxy-thiazolyl groups include: 3-thiohydroxy-1-thia-2-azol-5-yl 4-thiohydroxy-1-thia-2-azol-5-yl, a- 2-azol-5-yl.

[0053] Hydroxy-diazolyl: A 5-membered heterocyclic radical having two nitrogen ring atoms and a hydroxy substituent. Examples of hydroxydiazolyl groups include: 3-hydroxy-1H-1,2-diazol-5-yl 1-hydroxy-1,2-diazol-3-yl1005442107

[0054] 2H-Triazol-4-yl: A group of formula: . [less the context requires otherwise, where the terms “comprise”, “comprises” and “comprising” are used in the specification (including the claims) they are to be interpreted as specifying the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof.

[0056] It is to be further understood that terminology, such as “comprise”, or variations such as “comprises” or “comprising”, inherently include within their scope (without being limited to) versions of the invention that excludes other elements directly related to the invention. Accordingly, terminology, such as “consisting of” or “consisting essentially of”, can be substituted for terminology, such as “comprise”, “comprises” or “comprising” with the effect of limiting the scope of the invention to the specifically recited elements. Notably, where it is explicitly intended for the invention to be considered in an exhaustive manner, such limitations should be considered to relate only to the inventive concept disclosed herein and other features can be added, which fall outside of the scope of the inventive concept. Such features or elements may include, but are not limited to, excipients, formulations, additives, diluents, packaging, adjuvants and collocated features which are not to be excluded by terminology such as “consisting of” or “consisting essentially of”. Summary of the Invention

[0057] According to a first aspect of the present invention, there is provided a method of treating or inhibiting progression of cancer in a subject, comprising co- administering to the subject: a BH3-mimetic drug; and a STING agonist. In one embodiment, there is provided a method of treating or inhibiting progression of cancer in a subject, comprising co-administering to the subject: a BH3-mimetic drug; and a STING agonist, wherein the cancer comprises cells expressing STING protein. In one embodiment, there is provided a method of treating or inhibiting progression of cancer in a subject, comprising co-administering to the subject a synergistic combination of: a 1005442107BH3-mimetic drug; and a STING agonist. In one embodiment, there is provided a method of treating or inhibiting progression of cancer in a subject, comprising co- administering to the subject: a BH3-mimetic drug; and a STING agonist, wherein the cancer comprises cells expressing STING protein. In one embodiment, there is provided a method of treating or inhibiting progression of cancer in a subject, comprising co- administering to the subject a synergistic combination of: a BH3-mimetic drug; and a STING agonist, wherein the cancer comprises cells expressing STING protein.

[0058] According to a second aspect of the present invention, there is provided a method of inducing an immune response to cancer in a subject, the method comprising: co-administering to the subject a BH3-mimetic drug and a STING agonist, thereby eliciting the anti-cancer immune response in the subject. The method may comprise co-administering to the subject a synergistic combination of: a BH3-mimetic drug; and a STING agonist. In one embodiment, there is provided a method of inducing an immune response to cancer in a subject, the method comprising: co-administering to the subject a BH3-mimetic drug and a STING agonist, thereby eliciting the anti-cancer immune response in the subject, wherein the cancer comprises cells expressing STING protein. The method may comprise administering to the subject a synergistic combination of the BH3-mimetic drug and the STING agonist.

[0059] According to a third aspect of the present invention, there is provided a method of treating or inhibiting progression of a cancer in a subject, comprising: identifying the subject as a candidate for BH3-mimetic drug therapy; identifying the cancer as comprising cells expressing STING protein; and administering to the subject both a BH3-mimetic drug and a STING agonist, wherein the STING agonist is administered sequentially or simultaneously with the BH3-mimetic drug. The method may comprise administering to the subject a synergistic combination of both a BH3- mimetic drug and a STING agonist.

[0060] According to a fourth aspect of the present invention, there is provided a method of treating or inhibiting progression of cancer in a subject having received (or where the subject is receiving) BH3-mimetic therapy, the method comprising administering to the subject a STING agonist. In one embodiment, there is provided a method of treating or inhibiting progression of cancer in a subject having received (or where the subject is receiving) BH3-mimetic therapy, the method comprising administering to the subject a STING agonist, wherein the cancer comprises cells 1005442107expressing STING protein. In one embodiment, there is provided a method of treating or inhibiting progression of cancer in a subject having received (or where the subject is receiving) BH3-mimetic therapy, comprising administering to the subject a synergistic amount of a STING agonist, such that the STING agonist and the BH3-mimetic provide a synergistic combination. In one embodiment, there is provided a method of treating or inhibiting progression of cancer in a subject having received (or where the subject is receiving) BH3-mimetic therapy, comprising administering to the subject a STING agonist, wherein the cancer comprises cells expressing STING protein. In one embodiment, there is provided a method of treating or inhibiting progression of cancer in a subject having received (or where the subject is receiving) BH3-mimetic therapy, comprising administering to the subject a synergistic amount of a STING agonist to provide a synergistic combination of the BH3-mimetic and the STING agonist, wherein the cancer comprises cells expressing STING protein.

[0061] The following features may be used in conjunction with any one of the first to fourth aspects above either alone or in any suitable combination.

[0062] The cancer may comprise TP53-wildtype and TP53-mutant / deficient cells. The cancer may be refractory or resistant to BH3-mimetic drug monotherapy. The co- administering may comprise administering the BH3-mimetic drug and the STING agonist simultaneously or may comprise administering BH3-mimetic drug and the STING agonist sequentially. The BH3-mimetic drug may be administered orally or intravenously. The STING agonist may be administered intravenously or intratumorally, typically intravenously.

[0063] The BH3-mimetic drug and the STING agonist may each be administered in a therapeutically effective amount. The BH3 mimetic drug may be selected from a BCL- 2-selective inhibitor, such as venetoclax, a BCL-XL-selective inhibitor, such as A- 1331852, and an MCL-1-selective inhibitor, such as S63845. The BH3 mimetic drug may be selected from venetoclax, A-1331852, and S63845. In embodiments, the STING agonist may be selected from a non-nucleotide small molecule, such as MSA-2, a non-cyclic dinucleotide, such as diABZI STING agonist 1, and a synthetic cyclic dinucleotide, such as ADU-S100 / MIW815. The STING agonist may be selected from MSA-2, diABZI STING agonist 1, and ADU-S100 / MIW815. In embodiments, the STING agonist may be a compound of any of formulas (I) to (V). 1005442107

[0064] In some embodiments, the STING agonist is a compound of formula (I): RYY A1O I)W is O or NH; R1is selected from: H; C3-6cycloalkyl; C3-7heterocyclyl optionally substituted with a group selected from: methyl; and ester; and linear or branched C1-4alkyl optionally substituted with a group selected from: alkoxy; amino; amido; acylamido; acyloxy; alkyl carboxyl ester; alkyl carbamoyl; alkyl carbamoyl ester; phenyl; 1005442107phosphonate ester; C3-7heterocyclyl optionally substituted with a group selected from methyl and oxo; and a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl and boc; A1is CRAor N; A2is CRBor N; A3is CRCor N; A4is CRDor N; where no more than two of A1, A2, A3, and A4may be N; one or two of RA, RB, RCand RD, (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; the remainder of RA, RB, RCand RD, (if present) are H; Y is O, NH or CH2; RYis selected from: (a) );wherein Z1is CRZ1or N; Z2is CRZ2or N; Z4is CRZ4or N; Z5 is CRZ5or N; where no more than two of Z1, Z2, Z4and Z5may be N; 1005442107one or two of RZ1, RZ2, RZ4and RZ5, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF3, CH2OH, CH2OMe, C2-4alkenyl, and C5heterocyclyl; the remainder of RZ1, RZ2, RZ4and RZ5, (if present) are H; (b) );d from H, F, Cl, Br, OMe, cyano and CF3; with the proviso that when A1is CF; A2, A3and A4are CH; Y is O or NH; RYis RYA, where Z1, Z2, Z4and Z5are CH; R1is not Et; and when A1is CF; A2, A3and A4are CH; Y is NH; RYis RYA, where Z1and Z5are CH, one of Z2and Z4is CF, and the other of Z2and Z4is CH; R1is not Et.

[0065] In some embodiments, the STING agonist is a compound of formula (II): ),wherein; W1is O or NH; R2is selected from: i. H; ii. C3-6cycloalkyl; iii. C3-7heterocyclyl optionally substituted with a group selected from: methyl; and 1005442107ester; and iv. linear or branched C1-4alkyl optionally substituted with a group selected from: alkoxy; amino; amido; acylamido; acyloxy; alkyl carboxyl ester; alkyl carbamoyl; alkyl carbamoyl ester; phenyl; phosphonate ester; C3-7heterocyclyl optionally substituted with a group selected from methyl and oxo; and a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl and boc; A5is CREor N; A6is CRFor N; A7is CRGor N; A8is CRHor N; where no more than two of A5, A6, A7, and A8may be N; one or two of RA, RB, RCand RD, (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; 1005442107the remainder of RE, RF, RGand RH, (if present) are H; RN1is H or Me; one of RC2and RC3is C(=O)NH2; the other is selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C2-4alkenyl and C5heterocyclyl; RC1, and RC4are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C2-4alkenyl and C5heterocyclyl.

[0066] In some embodiments, the STING agonist is a compound of formula (III); ):e e Y is (CH2)n, where n is from 2 to 4; W2and W3are independently selected from OH and ORP, where RPis Me or Et; A11is CRIor N; A12is CRJor N; A13is CRKor N; A14is CRLor N; where no more than two of A11, A12, A13, and A14may be N; one or two of RI, RJ, RKand RL, (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; the remainder of RI, RJ, RKand RL, (if present) are H; A21is CRIAor N; 1005442107A22is CRJBor N; A23is CRKCor N; A24is CRLDor N; where no more than two of A21, A22, A23and A24may be N; one or two of RIA, RJB, RKCand RLD, (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; the remainder of RIA, RJB, RKCand RLD, (if present) are H; RC5, RC6and RC7are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C2-4alkenyl and C5heterocyclyl; RC15, RC16and RC17are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C2-4alkenyl and C5heterocyclyl.

[0067] In some embodiments, the STING agonist is a compound of formula (IV) V)wherein: Y is either (CH2)n, where n is from 2 to 4, or -CH2-CH=CH-CH2-; R1aand R11aare independently selected from the group consisting of: -C(=O)OH, - C(=O)ORP1, 1005442107Br, F, tetrazolyl, oxo-oxadiazolyl and (2H-triazol-4-yl), -S(=O)2OH, -P(=O)(OH)2, Br, F, tetrazolyl, oxo-oxadiazoly (4H-triazol-3-yl),(2H-triazol-4-yl), oxo-thiadiazolyl, thio-thiadiazolyl, thio-oxadiazolyl, hydroxy- lyl, hydroxy-thiadiazolyl, thiohydroxy-oxadiazolyl,thiohydroxy-thiadiazolyl, -C(CRaRbRc)(CRxRyRz)XH, hydroxy-oxazolyl, thiohydroxy- oxazolyl, hydroxy-diazolyl, hydroxy-thiazolyl, thiohydroxy-thiazolyl; RP1is selected from methyl, ethyl; each Ra, Rb, Rc, Rx, Ryand Rzis independently selected from H and F; X is selected from O and S; A31is CRA1or N; A32is CRB1or N; A33is CRC1or N; A34is CRD1or N; where no more than two of A31, A32, A33, and A34may be N; one, two or three of RA1, RB1, RC1and RD1, (if present) are selected from H, F, Cl, Br, I, Me, Et, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; the remainder of RA1, RB1, RC1and RD1, (if present) are H; A41is CRA2or N; A42is CRB2or N; A43is CRC2or N; A44is CRD2or N; 1005442107where no more than two of A41, A42, A43and A44may be N; one, two or three of RA2, RB2, RC2and RD2, (if present) are selected from H, F, Cl, Br, I, Me, Et, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; the remainder of RA2, RB2, RC2and RD2, (if present) are H; RC1a, RC3aand RC4aare independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C2-4alkenyl and C5heterocyclyl; RC11a, RC13aand RC14aare independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C2 -4alkenyl and C5heterocyclyl.

[0068] In some embodiments, the STING agonists are compounds according to formula (V): V)wherein: Z is a 3-6 atom linker comprising 1-6 -CH2- moieties and 0, 1 or 2 moieties independently selected from O, NH and -NHC(O)-; Y1is H and Y11is H, or Y1and Y11together form (CH2)n, where n is 2 or 3, or -CH2- CH=CH-CH2-; R1and R11are independently selected from -C(=O)OH, a carboxylic acid bioisostere, Br and F; A1is CRAor N; A2is CRBor N; 1005442107A4is CRDor N; where no more than two of A1, A2and A4may be N; RA, RBand RD, (if present) are independently selected from H, F, Cl, Br, I, Me, Et, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; A11is CRAAor N; A13is CRCCor N; A14is CRDDor N; where no more than two of A11, A13and A14may be N; RAA, RCCand RDD(if present) are independently selected from H, F, Cl, Br, I, Me, Et, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and OH; RC1, RC3and RC4are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C2-4alkenyl and C5heterocyclyl; RC11, RC13and RC14are independently selected from H, Cl, F, Br, Me, OMe, OEt, cyano, CF3, CH2OH, CH2OMe, C2-4alkenyl and C5heterocyclyl.

[0069] Compounds described herein, including compounds of formulas (I)-(V), may be provided in the form of a pharmaceutically acceptable salt, solvate, prodrug, isomer, tautomer, polymorph and / or N-oxide thereof.

[0070] The BH3-mimetic drug may be administered in an amount of from about 50 mg / day to about 600 mg / day. The BH3-mimetic drug may be administered in an amount equivalent to from about 50 mg / day to about 600 mg / day of venetoclax. In any of the methods described herein the STING agonist may be administered in any effective amount. The effective amount may be any amount that elicits a desirable physiological response in combination with the BH3 mimetic. The amount may vary based on a number of factors including the severity of disease and characteristics of the subject (including height, weight, sex, history, etc) as are typically adjusted for when determining a dose of a pharmaceutical ingredient. In some embodiments, the method may comprise administering the STING agonist in an amount of from about 10 µg / week to about 6,400 µg / week across from 1 dose every 3 weeks to 1 to 3 doses per week. 1005442107

[0071] The cancer may be a blood cancer. The blood cancer may be selected from leukaemia, such as acute myeloid leukaemia (AML), lymphoma such as T cell lymphoma and multiple myeloma (MM), or a relapsed / refractory form of any one of these. The blood cancer may be selected from acute myeloid leukaemia (AML), T cell lymphoma and multiple myeloma (MM), or a relapsed / refractory form of any one of these. The blood cancer may be selected from acute myeloid leukaemia (AML), Natural Killer / T cell lymphoma (NKTL), extra nodal NK / T cell lymphoma (ENKTL), and multiple myeloma (MM), or a relapsed / refractory form of any one of these. The cancer may be a leukaemia selected from acute myeloid leukaemia (AML), including promyelocytic leukaemia, chronic myelogenous leukaemia (CML), and acute lymphoblastic leukaemia (ALL), or a relapsed / refractory form of any one of these. The cancer may be a lymphoma. The cancer may be a non-Hodgkin's lymphoma (NHL), such as selected from adult T cell lymphoma, lymphoblastic lymphoma, peripheral T cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, Natural Killer / T cell lymphoma (NKTL), extra nodal NK / T cell lymphoma (ENKTL), marginal zone lymphoma, Waldenstrom's macroglobulinaemia, and mantle cell lymphoma, or a relapsed / refractory form of any one of these. The cancer may be a solid cancer. The solid cancer may be selected from small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, melanoma, breast cancer, ovarian cancer, neuroblastoma, prostate cancer, and colorectal cancer.

[0072] The subject may be a mammal, such as a human.

[0073] According to a fifth aspect of the present invention, there is provided a combination for treating or inhibiting progression of cancer, comprising: a BH3-mimetic drug; and a STING agonist. In one embodiment, there is provided a combination for treating or inhibiting progression of cancer, comprising: a BH3-mimetic drug; and a STING agonist, wherein the cancer comprises cells expressing STING protein. The combination may be a synergistic combination.

[0074] The following features may be used in conjunction with the fifth aspect above either alone or in any suitable combination.

[0075] The combination may be in the form of a pharmaceutical composition. The BH3-mimetic drug and the STING agonist may be separate preparations. The BH3- mimetic drug and the STING agonist may be for simultaneous administration. The BH3- 1005442107mimetic drug and the STING agonist may be for sequential administration. The BH3 mimetic drug may be selected from a BCL-2-selective inhibitor, such as venetoclax, a BCL-XL-selective inhibitor such as A-1331852, and an MCL-1-selective inhibitor, such as S63845. The BH3 mimetic drug may be selected from venetoclax, A-1331852, and S63845. In embodiments, the STING agonist may be selected from a non-nucleotide small molecule, such as MSA-2, a non-cyclic dinucleotide, such as diABZI STING Agonist 1, and a synthetic cyclic dinucleotide, such as ADU-S100 / MIW815. The STING agonist may be selected from MSA-2, diABZI STING Agonist 1, and ADU- S100 / MIW815. In embodiments, the STING agonist may be a compound of any of formulas (I) to (V).

[0076] The cancer may comprise cells expressing STING protein. The cancer may comprise TP53-wildtype and TP53-mutant cells. The cancer may be refractory or resistant to BH3-mimetic drug monotherapy.

[0077] According to a sixth aspect of the present invention, there is provided use of a BH3-mimetic drug and a STING agonist in the manufacture of a medicament for the treatment of cancer in a subject, wherein the BH3-mimetic drug and a STING agonist are for co-administration. The co-administration may be sequential or simultaneous administration.

[0078] According to a seventh aspect of the present invention, there is provided a use of a STING agonist in the manufacture of a medicament for conjoint administration with a BH3-mimetic drug for the treatment of cancer in a subject. The conjoint administration may be sequential or simultaneous administration

[0079] According to an eighth aspect of the present invention, there is provided use of a BH3-mimetic drug in the manufacture of a medicament for conjoint administration with a STING agonist for the treatment of cancer in a subject. The conjoint administration may be sequential or simultaneous administration

[0080] According to a ninth aspect of the present invention, there is provided a kit comprising in separate parts: ^ a BH3-mimetic drug ^ a STING agonist 1005442107^ and optionally instructions for the use of a combination of the BH3-mimetic drug and STING agonist, for example, in any of the methods described herein.

[0081] According to a tenth aspect of the present invention, there is provided a kit comprising in separate parts: ^ a BH3-mimetic drug ^ and instructions for the conjoint use of the BH3-mimetic drug with a STING agonist, for example, in any of the methods described herein.

[0082] According to an eleventh aspect of the present invention, there is provided a kit comprising in separate parts: ^ a STING agonist; and ^ instructions for the conjoint use of the STING agonist with a BH3-mimetic drug, for example, in any of the methods described herein. Brief Description of the Drawings

[0083] Embodiments of the invention will herein be illustrated by way of example only with reference to the accompanying drawings in which: Figure 1 shows BH3-mimetic drugs targeting MCL-1 or BCL-2 combined with STING agonist drugs to boost apoptosis in mouse Eµ-Myc lymphoma cells in culture. (A) Cell viability assays of isogenic non-targeting sgRNA (NT) control, Trp53 KO and Bak / Bax double KO mouse Eµ-Myc lymphoma cell lines treated in culture with the MCL-1 inhibitor S63845 in combination with the STING agonists ADU-S100, MSA-2 or diABZI for 24 h. (B) Cell competition assays of isogenic NT control lymphoma cells versus their Trp53 KO derivatives. Control (grey), S63845 (red), ADU-S100 (blue), or S63845 and ADU-S100 combined (purple). (C) Cell viability assays of mouse double hit lymphoma (DHL) cell lines treated in culture with the BCL-2 inhibitor venetoclax (10 nM) in combination with the STING agonists ADU-S100, MSA-2 or diABZI for 24 h. (D, E) Survival curves of Rag1 mice transplanted with isogenic NT control (D) or Trp53 KO (E) AH15A mouse Eµ-Myc lymphoma cells and then treated with vehicle (black), diABZI (blue), S63845 (yellow) or diABZI alongside S63845 (pink). Boxes show when diABZI (blue) and S63845 (yellow) were administered. 1005442107Figure 2 shows BH3-mimetic drugs targeting BCL-XL combined with STING agonist drugs to boost apoptosis in human extranodal natural killer / T (ENKT) lymphoma cell lines in culture. (A) Western blotting for STING protein expression in a panel of human ENKT lymphoma cell lines. (B) Western blotting for cGAS / STING pathway activation in two human ENKT lymphoma cell lines (SNK6 (wildtype TP53) and MEC04 (mutant TP53)). (C) Cell viability and proliferation data of SNK6 cells treated in culture with STING agonists for 72 h (ADU-S100: 10 µg / mL, MSA-2: 34 µM, diABZI 1 µM). (D) Cell viability assays of three human ENKT lymphoma cell lines (SNK6, MEC04, SNT15) treated in culture with the BCL-XL inhibitor A-1331852 in combination with STING agonists for 48 h. (E) Cell viability assays of ENKT lymphoma cell lines treated in culture with the BCL-XL inhibitor A-1331852 in combination with the STING agonist ADU-S100 for the indicated time points. (F) Brightfield microscopy images of human ENKT lymphoma cell lines treated in culture with A-1331852, ADU-S100 or both drugs in combination for 48 h. (G) SNK6 cells were xenografted subcutaneously into NSG mice and the mice were treated with either A-1331852, diABZI or both drugs in combination to test the impact of combined BH3-mimetic drug and STING agonist therapy on human ENKT lymphomas in vivo. (H) Tumour weights for mice treated with A-1331852, or A1331852 in combination with diABZI. (I) Representative tumours (outlined in yellow) on the right flank of mice treated with A-1331852, or A-1331852 in combination with diABZI. Figure 3 shows BH3-mimetic drugs targeting BCL-2 combined with STING agonist drugs to boost apoptosis in human acute myeloid leukaemia (AML) cell lines and primary AML patient samples in culture. (A) Western blotting for STING in three human AML cell lines. Blotting for HSP70 was used as a loading control. (B) Dose response curves of MOLM-13 (isogenic non-targeting sgRNA (NT) control and TP53 KO variants), MV4;11 (wild-type TP53) and THP-1 (mutant TP53) cells treated in culture with STING agonists for 24 h. (C) Cell viability assays of human AML cell lines treated in culture with the BCL-2 inhibitor venetoclax in combination with the STING agonist diABZI for 24 h. (D) Cell viability assays of leukemic blasts (CD117+) from human AML patient samples treated in culture with the BCL-2 inhibitor venetoclax alone (black), the STING agonist diABZl alone (orange) or the combination of venetoclax plus diABZI (red) for 48 h. (E) Cell viability assays of normal T cells (CD3+) from human AML patient samples treated in culture with the BCL-2 inhibitor venetoclax alone (black), the STING agonist diABZl alone (orange) or the combination of venetoclax plus diABZI (red) for 48 h. 1005442107Figure 4 shows analysis of SNK6 ENKT human lymphoma xenografted mice treated with STING agonist diABZI in combination with the BCL-XL inhibitor A-1331852. (A) Subcutaneous tumour volumes, of mice transplanted with SNK6 human NK T lymphoma cells. (B) Tumour weights of mice treated with vehicle or diABZI at predetermined ethical endpoint. (C) Weights of metastatic lymph node for mice treated with vehicle or diABZI at ethical endpoint. (D) Cell counts from peripheral blood taken from mice at ethical endpoint. (E) Weights of metastatic lymph node from mice, treated with A-1331852 alone or A-1331852 in combination with diABZI, at day 65 post- transplantation. (F) Cell counts from peripheral blood taken from mice, treated with A- 1331852 alone or A-1331852 in combination with diABZI, at day 65 post- transplantation. Figure 5 shows that human B lymphoma cell lines lack STING expression and do not respond to STING agonist treatment in culture. (A) Box and whisker plots of STING1 expression data from the Cancer Cell Line Encyclopedia (CCLE) for AML and NHL, and further stratified into NHL subtypes. (B) Western blotting for STING in a panel of human B lymphoma cell lines. (C) Cell viability assays of human B lymphoma cell lines treated in culture with the STING agonist ADU-S100 for 24 h. (D) Cell viability assays of the human DLBCL cell line DOHH2 treated in culture with S63845 (20 nM) and / or the STING agonist diABZI (100 nM) for 48 h. Figure 6 shows that STING agonists combine with venetoclax to induce potent killing of human AML cell lines in culture. Cell viability assays of isogenic parental MOLM-13 human AML cells containing a non-targeting control sgRNA (NT control) or made TP53- deficient using CRISPR / Cas9. Cells were treated in culture with the BCL-2 inhibitor venetoclax in combination with the STING agonists ADU-S100 or MSA-2 for 24 h. Figure 7 shows cell viability assays for MOLM-13 WT (A), OCI-AML3 (B), THP-1 (C), HL-60 (D), KG-1 (E) and TF-1 AML (F) cell lines treated with BCL-2 inhibitor ABT- 199 / venetoclax (thin line, circle markers) or Compound 4-46 (thick line, square markers) for 48h. Data is shown as mean ± SEM. Figure 8 and Figure 9 show cell viability assays for isogenic human MOLM-13s AML cells containing non-targeting sgRNA (thick line, square markers) control, TP53 KO (dotted line, circle markers), STING KO (green line, triangle markers) and Bak / Bax 1005442107double KO (purple line, diamond markers) treated in culture with the STING agonist Compound 4-46 (Figure 8) or with ABT-199 / venetoclax alone (Figure 9) for 48h. Figures 10A and 10B show viability assays of human AML cell lines MOLM-13 WT (Figure 10A) and OCI-AML3 (Figure 10B) treated in culture with the BCL-2 inhibitor ABT-199 / venetoclax (0-10 µM) in combination with the STING agonist Compound 4-46 (0-10 µM) for 24h. Figures 10C and 10D show heat maps of viability assays of human AML cell lines MOLM-13 WT (Figure 10C) and OCI-AML3 (Figure 10D) treated in culture with the BCL-2 inhibitor ABT-199 / venetoclax (0-10 µM) in combination with the STING agonist Compound 4-46 (0-10 µM) for 24h. The data presented in Figure 10A is the same as in Figure 10C, and the data presented in Figure 10D is the same as Figure 10B. Figures 11A-R each show a viability assay from 18 different leukaemic blast (LB) samples treated with STING agonist compound 4-46 (thick blue line; circle markers; 0.0001-10 µM), ABT-199 / venetoclax (dotted red line; square markers; 0.0001-10 µM) or the indicated concentration of a 1:1 dose of the combination of both agents (thin green line; triangle markers; 0.0001-10 µM). Figures 12A-C show results of viability assays of human AML primary cells treated in culture with (A) the STING agonist Compound 4-11 at various concentrations; (B) the BCL-2 inhibitor ABT-199 / venetoclax (0-10 µM); and (C) the BCL-2 inhibitor ABT- 199 / venetoclax (0-10 µM) in combination with the STING agonist Compound 4-11. Detailed Description

[0084] Provided herein are combination therapies comprising a BH3-mimetic drug and a STING agonist, and methods of treating proliferative diseases, such as cancer, in a subject that comprise co-administering a BH3-mimetic and a STING agonist to the subject.

[0085] Although BH3-mimetic drugs have been successfully deployed for the treatment of cancer, their TP53-dependence for maximal killing allows TP53 mutant cancer cells to survive treatment and proliferate, giving rise to relapse / refractory disease and reducing susceptibility of the post-treatment growths to additional rounds of BH3- mimetic drug treatment. Accordingly, it is not simply a problem in the art that BH3- 1005442107mimetic drugs treat cancer cells in a TP53-dependent manner; it is also a problem in the art that populations of cancer cells that remain after BH3-mimetic drug treatment are less vulnerable to further treatment and prone to cause further and often more severe disease. Against this backdrop, the present inventors have discovered that, when used as a monotherapy, BH3-mimetic drugs targeting MCL-1 or BCL-2 stabilise and functionally activate TRP53 / TP53, leading to induction of TRP53 / TP53 target genes in order to maximise apoptotic death of malignant cells, including malignant lymphoma and leukaemia cells, explaining the TP53-dependence of BH3-mimetic treatments. However, the present inventors have now exploited their discovery that TRP53 / TP53 mutant / deficient cells can still express TRP53 / TP53 target genes (albeit at a much reduced level) to find a TRP53-independent mechanism for induction of the expression of the genes encoding these BH3-only proteins that involves the cyclic GMP–AMP synthase (cGAS) stimulator of interferon gene (STING) signalling pathway. In particular, the present inventors have discovered that enforced activation of STING using relevant agonists is highly effective at triggering intrinsic apoptosis in a range of cancer cells in a TP53 / TRP53-independent manner. The present inventors have also discovered that a combination of a BH3-mimetic drug and a STING agonist synergistically enhances killing of certain cancer cells by exploiting the combination of promotion of apoptosis of even TP53-deficient cancers through upregulation of BH3- only proteins in a TP53-independent manner by a STING agonist with the partially TP53-dependent pro-apoptotic protein pathway activated by a BH3-mimetic drug. This new combination not only offers advantages in terms of increased cancer cell death relative to administration of either drug individually, but may additionally open up treatment options in patient groups with BH3-mimetic drug treatable cancers who were previously unable to receive BH3-mimetic monotherapy (e.g., due to DNA damage from prior treatment and / or TP53 mutant cancer cells) and / or avoid the creation of drug- resistant cancer cell subpopulations capable of causing relapse of malignant disease. BH3-mimetic drugs

[0086] The combinations described herein utilise a BH3-mimetic drug. There are several BH3-mimetic drugs known in the art that are considered suitable for use in accordance with the present disclosure. Generally, BH3-mimetic drugs need to bind with very high affinities to the large and mostly hydrophobic grooves that underpin the protein-protein interactions between pro-survival BCL-2 proteins (including BCL-2, BCL- 1005442107XL, BCL-W, MCL-1, A1 / BFL-1, and possibly BCL-B), and the BH3 domains of their pro- apoptotic relatives. As a result, all advanced BH3-mimetic drugs are characterised by relatively high molecular weight, lipophilicity, and chemical complexity.

[0087] By way of non-limiting example, suitable BH3-mimetic drugs may include small molecules, including ABT-737 (CAS no.852808-04-9), which targets pro-survival BCL-2, BCL-XL, and BCL-W, and the closely related drug, ABT-263 (navitoclax; CAS no.923564-51-6), which has the same binding profile as ABT-737 but has improved pharmacological properties and was the first BH3-mimetic to enter clinical trials. Other suitable BH3-mimetic drugs include the BCL-2-selective inhibitor, ABT-199 / venetoclax (sold as Venclexta® by Genentech USA, Inc. and AbbVie Inc.), which is FDA approved for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma or in combination with other drugs for the treatment of newly diagnosed acute myeloid leukemia (AML). The structures of these compound drugs are shown below:

[0088] Other BCL-2 inhibitor compound drugs suitable for use in the combination therapies described herein include those described in WO201114942 A1 and WO2010065824 A1, which describe alternative heterocycle compounds to venetoclax, WO2010080478 A1, which describes urea compounds, WO 2010080503 A1, which describes amide compounds, WO2019040573 A1, which describes a series of benzamide compounds, WO2019185025 A1, which describes trifluoromethyl- substituted sulfonamides, WO2019210828 A1, which describes nitrobenzene substituted sulfonamides, and US11053239, which discloses trifluoromethylsulfonate or nitrobenzene substituted sulfonamides, the disclosure of each of which publications is expressly incorporated herein by reference. 1005442107

[0089] MCL-1 specific BH3-mimetic compound drugs s suitable for use in the combination therapies described herein include S63845 (Servier; CAS No.1799633-27- 4) and related compound, S64315 / MIK665 (CAS No.1799631-75-6), AMG 176 (tapotoclax; Amgen; CAS No.1883727-34-1), AZD5991 (AstraZeneca; CAS No. 2143061-81-6), the structures of which are shown below:

[0090] BH3-mimetic drugs that are highly potent and selective inhibitors of BCL-XL may also be suitable for use in the combination therapies described herein, including A- 1155463 (AbbVie / Genentech; CAS No.1235034-55-5), A-1331852 (AbbVie / Genentech; CAS No.1430844-80-6), and WEHI-539 (Walter and Eliza Hall Institute of Medical Research; CAS No.2070018-33-4).

[0091] In one embodiment, the BH3-mimetic drug used in the combinations herein is an inhibitor of BCL-2, BCL-XL, BCL-W, or MCL-1, or an inhibitor of any two or more of these pro-survival proteins. In one embodiment, the BH3-mimetic drug used in the combinations herein is a selective inhibitor of BCL-2. In one embodiment, the BH3- mimetic drug used in the combinations herein is a selective inhibitor of MCL-1. In one embodiment, the BH3-mimetic drug used in the combinations herein is a selective inhibitor of BCL-XL. In one embodiment, the BH3-mimetic drug used in the combinations herein is an inhibitor of BCL-2, MCL-1 and BCL-XL.

[0092] Other BH3-mimetic compounds, including antibody-drug conjugates comprising a BH3-mimetic drug (such as any one of the aforementioned BH3-mimetic drugs) covalently attached to a monoclonal antibody or a ligand targeting a receptor of interest, and dendrimer-drug conjugates comprising a BH3-mimetic drug (such as any one of the aforementioned BH3-mimetic drugs) encapsulated within or conjugated to the surface of a dendrimer, are also envisaged to be useful in the combination therapies described herein. Accordingly, in one embodiment, the BH3-mimetic compound used in the combinations herein comprises one or more BH3-mimetic drugs conjugated to a 1005442107delivery component. In one embodiment, the BH3-mimetic compound used in the combinations herein comprises an inhibitor of BCL-2, BCL-XL, BCL-W, or MCL-1, or an inhibitor of any two or more of these pro-survival proteins, conjugated to a delivery component. In one embodiment, the delivery component is selected from a monoclonal antibody, a ligand, and a dendrimer. In one embodiment, the delivery component is a monoclonal antibody. In one embodiment, the delivery component is a ligand, in some embodiments selected from a protein, a protein fragment, a peptide, a small molecule, and a nucleic acid. In one embodiment, the delivery component is a dendrimer. In one embodiment, the BH3-mimetic drug used in the combinations herein comprises a selective inhibitor of BCL-2 conjugated to a delivery component. In one embodiment, the BH3-mimetic drug used in the combinations herein comprises a selective inhibitor of MCL-1 conjugated to a delivery component. In one embodiment, the BH3-mimetic drug used in the combinations herein is a selective inhibitor of BCL-XL. In one embodiment, the BH3-mimetic drug used in the combinations herein comprises an inhibitor of BCL-2, MCL-1 and BCL-XL conjugated to a delivery component. In each of these embodiments, the delivery component may be selected from a monoclonal antibody or a ligand and a dendrimer. For the avoidance of doubt, any references herein to BH3- mimetic drugs will be understood to encompass BH3-mimetic compounds.

[0093] It will be understood that BH3-mimetic drugs are useful for the treatment of a wide range of solid cancers including but not limited to breast cancer, ovarian cancer, neuroblastoma, non-small cell lung cancer, prostate cancer, colorectal cancer, and melanoma. BH3-mimetic drugs are also useful for the treatment of a wide range of so- called “liquid” tumours or blood cancers, including but not limited to certain lymphomas (such as follicular lymphoma and small lymphocytic lymphoma), leukaemia subtypes (such as chronic lymphocytic leukaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia), and multiple myeloma. In one embodiment, the cancer for treatment with the BH3-mimetic drug combination described herein is a TP53 wild type cancer, is a TP53-mutant cancer, or is a cancer comprising both TP53 wild type and TP53-mutant cell subpopulations. Although previous BH3-mimetic drug therapies are typically more successful for treating TP53 wild type cancers, the present inventors have expanded the range of cancers treatable by BH3-mimetics by combining the BH3-mimetic drug therapy with a STING agonist that can target cells in a TP53-independent manner. It will be appreciated that cancers deemed treatable with a BH3-mimetic drug, including those 1005442107specifically mentioned in this paragraph, are candidates for the combination therapies described herein, subject to those cancer cells also expressing STING proteins.

[0094] Any suitable pharmaceutically acceptable dose of BH3-mimetic drug may be used in the combinations as described herein. By way of non-limiting example, in some indications, guidance may be taken from venetoclax dosage regimes in which dosages of between 10 mg / day to about 400-600 mg / day are indicated for any suitable treatment period. These dosages may be reached using any suitable appropriate ramp-up schedule, including, but not limited to, weekly dosage increases starting at 20 mg / day and ramping up to 50 mg / day, to 100 mg / day, to 200 mg / day, and then to 400 mg / day. In some instances, faster dosage ramping increasing daily starting at 100 mg / day and increasing to 200 mg / day, to 400 mg / day, to 600 mg / day, may be appropriate. Dosages may be continued in monthly cycles for any suitable number of cycles, such as for from 1 to 24 monthly cycles, or from 6 to 12 cycles, or from 12 to 24 cycles. Preliminary dosing cycles for cancer treatment using BH3-mimetic drugs in the combinations and methods described herein may be calculated by those of skill in the art using any suitable methods. In some embodiments, the dosages may be calculated based on relative efficacy and molecular size of a given BH3-mimetic drug compared to venetoclax. In some embodiments, the dosage of the BH3 mimetic drug may be equivalent to or approximately equivalent to that of venetoclax, or may be up to 5%, 10%, 15%, 20%, 30%, 40% or 50% lower than that of venetoclax (or equivalent) when used in the combination therapies described herein as a result of the synergies gained by use of the BH3-mimetic drug in combination with the STING agonist.

[0095] BH3-mimetic drugs useful herein may be in any suitable dosage form. In one embodiment, the BH3-mimetic drug is for oral administration. In one embodiment, the BH3-mimetic drug is in the form of a tablet for oral administration. In other embodiments, alternative dosage forms, such as a capsule, solution, granules, or powder, may be used. In one embodiment, the BH3-mimetic drug is for intravenous administration. STING agonists

[0096] The combinations described herein utilise a STING agonist. There are numerous STING agonists known in the art that are considered suitable for use in accordance with the present disclosure. Generally, STING agonists include small 1005442107molecule nucleoside analogues, such as synthetic cyclic dinucleotides, and emerging second-generation noncyclic dinucleotides or non-nucleoside analogues.

[0097] By way of non-limiting example, suitable STING agonists may include MSA-2 (Merck; CAS No.129425-81-6), which is a non-nucleotide small molecule STING agonist; MK-1454 (ulevostinag; Merck; CAS No.2082743-96-0) which is a synthetic cyclic dinucleotide STING agonist being investigated for treatment of solid tumours, lymphomas, and head and neck squamous cell carcinoma; diABZI compound 3, also known as diABZI STING agonist 1 (GSK; CAS No.2138498-18-5), which is a non-cyclic dinucleotide STING agonist; TAK-676 (dazostinag; Takeda; CAS No.2553413-93-5), which is a synthetic cyclic dinucleotide STING agonist, ADU-S100 (also known as MIW815; Novartis; CAS No.1638750-96-5; now withdrawn) which is a synthetic cyclic dinucleotide STING agonist investigated for activity against solid tumours and lymphomas; E7766 (CAS No.2242635-03-4, Eisai, Inc.), which is a macrocycle-bridged STING agonist investigated for activity against solid tumours and lymphomas, MK-2118 (Merck), which is a small molecule STING agonist being investigated for activity against solid tumours and lymphomas, and SB 11285 (invoX Pharma) which is a small molecule STING agonist being investigated for activity against solid tumours, head and neck squamous cell carcinoma and melanoma), the structures of some of which are shown below:[ ] u a e agonss are escr e n ( , , 50), WO 2021 / 009362 (US 17 / 624,137), WO 2021 / 009365 (US17 / 624134), WO 2021 / 119753 (US 17 / 786792), WO 2022 / 266711 and WO 2024 / 130341, the entire disclosure of each of these is incorporated herein by reference. In particular, embodiments of the STING agonist compounds (I) to (V) described in these publications are incorporated herein.

[0099] Specific examples of STING agonists are given in Table 1, below. 1005442107Table 1. Examples of compounds of the present invention Compound Structure1005442107100544210710054421071005442107100544210710054421071005442107100544210710054421074-2010054421074-2610054421074-30 O H2N O NH210054421074-3510054421074-6510054421074-81.110054421074-901005442107

[0100] In some embodiments, the STING agonist is a compound of formula (I). In embodiments, the STING agonist is a compound selected from any one of compounds 1-1 to 1-172.

[0101] In some embodiments, the STING agonist is a compound of formula (II). In embodiments, the STING agonist is a compound selected from any one of compounds 2-1 to 2-25.

[0102] In some embodiments, the STING agonist is a compound of formula (III). In embodiments, the STING agonist is a compound selected from any one of claims 3-1.1 to 3-24.

[0103] In some embodiments, the STING agonist is a compound of formula (IV). In embodiments, the STING agonist is a compound selected from any one of compounds 4-1 to 4-112. In embodiments, the STING agonist is compound 4-11 or 4-46.

[0104] In some embodiments, the STING agonist is a compound of formula (V). In embodiments, the STING agonist is a compound selected any one of compounds 5-1 to 5-15.

[0105] In one embodiment, the STING agonist used herein is selected from a synthetic cyclic dinucleotide, a noncyclic dinucleotide, or a non-nucleoside small molecule. In one embodiment, the STING agonist used herein is a synthetic cyclic dinucleotide. In one embodiment, the STING agonist used herein is a noncyclic dinucleotide. In one embodiment, the STING agonist used herein is a non-nucleoside small molecule.

[0106] Other STING agonist compounds, including antibody-drug conjugates comprising a STING agonist (such as any one of the aforementioned STING agonists) covalently attached to a monoclonal antibody, and dendrimer-drug conjugates comprising a STING agonist (such as any one of the aforementioned STING agonists) encapsulated within or conjugated to the surface of a dendrimer, are also envisaged to be useful in the combination therapies described herein. Accordingly, in one embodiment, the STING agonist compound used in the combinations herein comprises one or more STING agonists conjugated to a delivery component. In one embodiment, the STING agonist compound used in the combinations herein comprises a synthetic cyclic dinucleotide, a noncyclic dinucleotide, or a non-nucleoside small molecule 1005442107conjugated to a delivery component. In one embodiment, the delivery component is selected from a monoclonal antibody, a ligand, and a dendrimer. In one embodiment, the delivery component is a monoclonal antibody. In one embodiment, the delivery component is a ligand, in some embodiments selected from a protein, a protein fragment, a peptide, a small molecule, and a nucleic acid. In one embodiment, the delivery component is a dendrimer. In one embodiment, the STING agonist compound used herein comprises a synthetic cyclic dinucleotide conjugated to a delivery component. In one embodiment, the STING agonist compound used herein comprises a noncyclic dinucleotide conjugated to a delivery component. In one embodiment, the STING agonist compound used herein comprises a non-nucleoside small molecule conjugated to a delivery component. In each of these embodiments, the delivery component may be selected from a monoclonal antibody, a ligand and a dendrimer. For the avoidance of doubt, any references herein to STING agonists will be understood to encompass STING agonist compounds.

[0107] It will be understood that STING agonists are useful for the treatment of a wide range of solid cancers, including but not limited to prostate cancer, squamous cell carcinoma, non-small cell lung cancer, melanoma, breast cancer, colorectal cancer, fibrosarcoma, and glioma. STING agonists are also useful for the treatment of blood cancers, including but not limited to certain lymphomas and acute myeloid leukaemia. In one embodiment, STING agonists are suitable for treatment of cancers that express STING protein. In one embodiment, STING agonists are not suitable for treatment of human B-cell lymphomas, as these malignant cells lack STING expression. In one embodiment, STING agonists are particularly suitable for treatment of malignant cells expressing STING and that carry a TP53 mutation. In one embodiment, STING agonists are suitable for treatment of malignant cells expressing STING in a TP53- independent manner. In one embodiment, the TP53-independence of STING agonists makes the combination described herein suitable for induction therapy treatment of patient groups who have in their malignant cells significant DNA damage as a result of previous radiation therapy and / or chemotherapy and that may otherwise not tolerate subsequent high-dose cancer treatment induction regimes. In one embodiment, the TP53-independence of STING agonists makes the combination described herein suitable for patient groups with high levels of TP53-mutant malignant cells, as these have a severely impaired capability to detect DNA damage and therefore initiate apoptosis through traditional innate pathways. It will be appreciated that cancers 1005442107deemed treatable with a STING agonist, including those specifically mentioned in this paragraph, are candidates for the combination therapies described herein, subject to those cancer cells also being vulnerable to treatment with a BH3-mimetic drug.

[0108] Any suitable pharmaceutically acceptable dose of STING agonist may be used in the combinations as described herein. STING agonists have been previously studied and used in combination immunotherapy with the aim of enhancing host anti- cancer immune responses, and therefore dosage regimes from such therapies may be useful in the present combinations and methods. By way of non-limiting example, in some indications, guidance may be taken from dosage regimes in which dosages of between 10 µg / week to about 6,400 µg / week, or between 10 µg / week to about 1,500 µg / week, or between 10 µg / week to about 3,000 µg / week, or between 90 µg / week to about 3,000 µg / week, are indicated for any suitable treatment period. These dosages may be suitable for intratumoral administration. In one embodiment, the STING agonist is administered once weekly. In one embodiment, the STING agonist is administered 2- 3 times weekly. In one embodiment, the STING agonist is administered once every 2-3 weeks. These dosages may be administered in any suitable appropriate ramp-up schedule or any suitable on / off schedule, such as in a monthly 3 weeks on / 1 week off treatment cycle. Dosages may be continued in monthly cycles for any suitable number of cycles, such as for from 1 to 6, or 1 to 12, or 1 to 24 monthly cycles. Intravenous dosage schedules may differ from the above-listed weekly dosages. Preliminary dosing cycles for cancer treatment using STING agonists in the combinations and methods described herein may be calculated by those of skill in the art using any suitable methods.

[0109] STING agonists useful herein may be in any suitable dosage form. In one embodiment, the STING agonist is in the form of a suspension or solution for intra- tumoural administration, intravenous administration, or subcutaneous administration. In one embodiment, the STING agonist is in a form suitable for intra-tumoural administration or intravenous administration. In one embodiment, the STING agonist is in the form of a suspension or solution for intravenous administration. In one embodiment, the STING agonist is for intravenous administration. In one embodiment, the STING agonist is for intra-tumoural administration. 1005442107Combinations

[0110] Disclosed herein are combinations for treating cancer to inhibit its progression, where the combinations comprise a BH3-mimetic drug and a STING agonist. In one embodiment, the combination is a synergistic combination. In some embodiments, the combination is in the form of a pharmaceutical composition. The pharmaceutical composition preferably comprises separate preparations of the BH3- mimetic drug and the STING agonist, especially in instances where the two drugs are indicated for different routes of administration and / or according to different dosage schedules. In certain embodiments, the combination is in the form of a kit comprising the separate preparations of the BH3-mimetic drug and the STING agonist and instructions directing that the two drugs are to be used in combination treatment for the specified indications. In one embodiment, the combination comprising a BH3-mimetic drug and a STING agonist comprises separate preparations of a BH3-mimetic drug, such as in oral dosage form, and a STING agonist, such as in injectable form. In one embodiment, the combination comprises separate preparations of a BH3-mimetic drug in oral dosage form and a STING agonist in intra-tumoural or intravenous injectable form.

[0111] In certain embodiments, the BH3-mimetic drug and the STING agonist are indicated for simultaneous or sequential administration. In one embodiment, the BH3- mimetic drug and the STING agonist are indicated for simultaneous administration. Simultaneous administration may include where the BH3-mimetic drug is administered on a dosage program that ensures there are pharmaceutically active levels of the BH3- mimetic drug in the system of the subject being treated when the STING agonist is administered. In some embodiments, the BH3-mimetic drug may be administered on a daily basis, and the STING agonist may be administered on a weekly basis, and it is envisaged that the two dosage programs will overlap to ensure the subject has both drugs in their system at the same time. Simultaneous administration may include where the BH3-mimetic drug and the STING agonist are administered to the subject at the same time. Accordingly, in some embodiments, the BH3-mimetic drug may be administered at the same frequency as the STING agonist, such as from 1-3 times per week, such that the dosage programs of the BH3-mimetic drug and the STING agonist are the same or substantially the same. 1005442107

[0112] In some embodiments, it may be appropriate for the BH3-mimetic drug and the STING agonist to be administered sequentially, for example, where the BH3- mimetic drug is administered orally and a delay is required for it to reach acceptable blood plasma levels before administration of the STING agonist intravenously or intra- tumourally. In other embodiments, it is sufficient for both the BH3-mimetic drug and the STING agonist to be administered at different times but within the same treatment window, such that there is not necessarily biological action of the two drugs at the same time, but there is action of the two drugs on the patient within the same treatment window.

[0113] It is also envisaged that the combinations herein could comprise one or more BH3-mimetic drugs and one or more STING agonists. In other embodiments, the combinations herein may further comprise one or more other chemotherapeutic agents known in the art in combination with the BH3-mimetic drugs and the STING agonist.

[0114] In one embodiment, the combination comprises a BH3 mimetic drug selected from a BCL-2-selective inhibitor, a BCL-XL-selective inhibitor, and an MCL-1-selective inhibitor. In one embodiment, the combination comprises a BH3 mimetic drug selected from a BCL-2-selective inhibitor, such as venetoclax, a BCL-XL-selective inhibitor, such as A-1331852, and an MCL-1-selective inhibitor, such as S63845. In one embodiment, the combination comprises a STING agonist selected from a non-nucleotide small molecule, a non-cyclic dinucleotide, and a synthetic cyclic dinucleotide. In one embodiment, the combination comprises a STING agonist selected from a non- nucleotide small molecule such as MSA-2, a non-cyclic dinucleotide such as diABZI STING Agonist 1, and a synthetic cyclic dinucleotide such as ADU-S100 / MIW815. In one embodiment, the combination comprises a BH3 mimetic drug selected from a BCL- 2-selective inhibitor, a BCL-XL-selective inhibitor, and an MCL-1-selective inhibitor and a STING agonist selected from a non-nucleotide small molecule, a non-cyclic dinucleotide, and a synthetic cyclic dinucleotide. In one embodiment, the combination comprises a BH3 mimetic drug selected from a BCL-2-selective inhibitor, such as venetoclax, a BCL-XL-selective inhibitor, such as A-1331852, and an MCL-1-selective inhibitor, such as S63845, and a STING agonist selected from a non-nucleotide small molecule such as MSA-2, a non-cyclic dinucleotide, such as diABZI STING agonist 1, and a synthetic cyclic dinucleotide, such as ADU-S100 / MIW815. In one embodiment, the combination comprises a BH3 mimetic drug selected from a BCL-2-selective 1005442107inhibitor, such as venetoclax, a BCL-XL-selective inhibitor, such as A-1331852, and an MCL-1-selective inhibitor, such as S63845, and compound 4-11. In one embodiment, the combination comprises a BH3 mimetic drug selected from a BCL-2-selective inhibitor, such as venetoclax, a BCL-XL-selective inhibitor, such as A-1331852, and an MCL-1-selective inhibitor, such as S63845, and compound 4-46.

[0115] In one embodiment, the combination comprises a BH3-mimetic drug comprising an MCL-1-selective inhibitor, such as S63845, in combination with a STING agonist selected from a non-nucleotide small molecule such as MSA-2, a non-cyclic dinucleotide such as diABZI STING Agonist 1, and a synthetic cyclic dinucleotide such as ADU-S100 / MIW815. In one embodiment, the combination comprises a BH3-mimetic drug comprising a BCL-2-selective inhibitor, such as venetoclax, in combination with a STING agonist selected from a non-nucleotide small molecule, such as MSA-2, a non- cyclic dinucleotide such as diABZI STING agonist 1, and a synthetic cyclic dinucleotide such as ADU-S100 / MIW815. In one embodiment, the combination comprises a BH3- mimetic drug comprising a BCL-XL-selective inhibitor, such as A-1331852, in combination with a synthetic cyclic dinucleotide STING agonist, such as ADU- S100 / MIW815. In some embodiments, the cancer treated by these combinations is a blood cancer, optionally selected from acute myeloid leukemia, NKT cell lymphoma, ENKT lymphoma, and multiple myeloma.

[0116] In one embodiment, the combination is a synergistic combination of one BH3-mimetic drug, selected from venetoclax or S63845 or A-1331852 and one STING agonist, selected from MSA-2 or ADU-S100. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, venetoclax and the STING agonist, MSA-2. In one embodiment, the combination is a synergistic combination of the BH3- mimetic drug, venetoclax and the STING agonist, ADU-S100. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, venetoclax and the STING agonist, diABZI. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, A-1331852, and the STING agonist, ADU-S100. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, S63845 and the STING agonist, MSA-2. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, A-1331852, and the STING agonist, ADU-S100. 1005442107

[0117] In one embodiment, the combination is a synergistic combination of one BH3-mimetic drug, selected from venetoclax or S63845 or A-1331852 and one STING agonist, selected from compound 4-46 or compound 4-11. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, venetoclax and the STING agonist, compound 4-46 or compound 4-11. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, venetoclax and the STING agonist, compound 4-46 or compound 4-11. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, venetoclax and the STING agonist, compound 4-46 or compound 4-11. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, A-1331852, and the STING agonist, compound 4-46 or compound 4-11. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, S63845 and the STING agonist, compound 4-46 or compound 4-11. In one embodiment, the combination is a synergistic combination of the BH3-mimetic drug, A-1331852, and the STING agonist, compound 4-46 or compound 4-11. Methods of treatment and uses

[0118] Also disclosed herein are methods of treating or inhibiting progression of cancer or tumour growth in a subject, comprising administering to the subject a BH3- mimetic and a STING agonist. In one embodiment, disclosed herein is a method of treating or inhibiting the progression of cancer in a subject, comprising co-administering to the subject a BH3-mimetic drug and a STING agonist. The term “co-administering” as used herein encompasses both simultaneous and sequential administration of the BH3-mimetic drug and the STING agonist, and is intended to encompass any administration schedule of the two drugs that ensure either both drugs are therapeutically active in the subject at a given point in time and / or during a given treatment window. In other words, and to be clear, co-administration refers to that both drugs must be administered to the subject as part of their cancer treatment, but is not intended to limit both drugs to being administered to the patient at the exact same time and / or in the exact same dosage form. The methods described herein treat cancer in a subject by administering to the subject a synergistic combination of a BH3-mimetic drug and a STING agonist.

[0119] The term “treating” as used herein refers to reducing, alleviating or ameliorating one or more symptoms of a disease or condition, inhibiting a disease or 1005442107condition or symptom thereof, alleviating or ameliorating a disease or condition, causing regression of a disease or condition, and preventing or inhibiting a disease from progression. In some embodiments, “treatment” includes induction therapy for newly diagnosed malignant disease, maintenance therapy to maintain regression, and / or therapy to treat refractory (non-drug responsive) or relapsed (progression after remission) malignant disease.

[0120] The term “cancer” as used herein refers to a disease characterised by neoplasm(s) or tumour(s) caused by abnormal, uncontrolled cell growth, and includes diseases involving both pre-malignant cells and malignant cells. Particularly suitable cancers for treatment with the combinations described herein are discussed further below.

[0121] The term “subject” as used herein refers to human and non-human mammals. In some embodiments, the subject is a mammal. In other embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal.

[0122] In some embodiments, the methods of treating or inhibiting progression of cancer in a subject herein comprise co-administering to the subject a therapeutically effective amount of a BH3-mimetic drug and a therapeutically effective amount of a STING agonist. The term “effective amount” as used herein in the context of a therapeutically effective amount refers to a dose of an active compound, such as of a BH3-mimetic drug or STING agonist, that prevents disease progression (in some embodiments, termed “manages”), alleviates, substantially reduces, or completely reduces one or more symptoms and / or causes of the disease or condition being treated. In some embodiments, the amount of BH3-mimetic drug and STING agonist used in the combination therapies described herein is an amount that provides a significant reduction in the clinical symptoms of the disease or condition being treated, in some embodiments without causing excessive or intolerable toxic side effects to the subject.

[0123] In one embodiment, the BH3-mimetic drug is orally administered. In one embodiment, the STING agonist is intravenously administered. In one embodiment, the method includes oral or intravenous administration of the STING agonist in combination with the BH3 mimetic drug. The administration may be simultaneous or sequential as described in the section above entitled “Combinations”. 1005442107

[0124] As further described above, in one embodiment, the BH3-mimetic drug is administered in an amount of from about 10 to 600 mg / day, and the STING agonist is administered in an amount of from about 50 µg / week to about 6,400 µg / week.

[0125] Also described herein is a method of treating or inhibiting progression of cancer or tumour growth in a subject with a cancer, comprising: identifying the subject as a candidate for BH3-mimetic drug therapy; identifying the cancer as comprising cells expressing STING protein; and administering to the subject both a BH3-mimetic drug and a STING agonist, wherein the STING agonist is administered sequentially or simultaneously with the BH3-mimetic drug.

[0126] Further described herein is a method of treating or inhibiting progression of cancer or tumour growth in a subject, wherein the cancer is refractory or resistant to BH3-mimetic drug monotherapy, the method comprising: co-administering to the subject a BH3-mimetic drug and a STING agonist.

[0127] Still further described herein is a method of inducing an immune response to a tumour or cancer in a subject, the method comprising: co-administering to the subject a BH3-mimetic drug and a STING agonist, thereby eliciting an anti-tumour or anti- cancer immune response in the subject.

[0128] In the methods described herein, the cancer may be a blood cancer, or it may be a solid cancer. In some embodiments, the cancer is a TP53 wild type cancer, is a TP53-mutant cancer, or is a cancer comprising both TP53 wild type and TP53-mutant cell subpopulations. In one embodiment, the cancer is one that expresses STING protein. In some embodiments, the cancer is a TP53 wild type cancer, is a TP53- mutant cancer, or is a cancer comprising both TP53 wild type and TP53-mutant cell subpopulations, that is treatable with a BH3-mimetic drug, and that expresses STING protein. In one embodiment, the cancer is a refractory / relapsed cancer. In one embodiment, the cancer is resistant to treatment with BH3-mimetic drug monotherapy. In one embodiment, the cancer is resistant to treatment with BH3-mimetic drug monotherapy and expresses STING protein.

[0129] When the cancer is a blood cancer, the blood cancer may be selected from leukaemia, malignant lymphoma (ML), multiple myeloma (MM), and myelodysplastic syndrome (MDS), or a relapsed / refractory form of any one of these. The cancer may be 1005442107a leukaemia subtype selected from acute myeloid leukaemia (AML), including promyelocytic leukaemia, chronic myeloid leukaemia (CML), and acute lymphoblastic leukaemia (ALL), or a relapsed / refractory form of any one of these. In some embodiments, the cancer being treated by the methods herein is a lymphoma. The lymphoma may be a non-Hodgkin's lymphoma (NHL). In such embodiments, the non- Hodgkin's lymphoma may be selected from adult T cell lymphoma, lymphoblastic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, peripheral T cell lymphoma, follicular lymphoma, B-cell acute lymphocytic leukaemia, chronic lymphocytic leukaemia / small lymphocytic lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinaemia, and mantle cell lymphoma, or a relapsed / refractory form of any one of these. In some embodiments, the non-Hodgkin's lymphoma may be selected from adult T cell lymphoma, lymphoblastic lymphoma, peripheral T cell lymphoma, follicular lymphoma, B-cell acute lymphocytic leukaemia, chronic lymphocytic leukaemia / small lymphocytic lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinaemia, and mantle cell lymphoma, or a relapsed / refractory form of any one of these. In some embodiments, the non-Hodgkin's lymphoma excludes B-cell lymphoma and Burkitt’s lymphoma. In some embodiments, the cancer is a blood cancer selected from acute myeloid leukaemia (AML), including TP53 mutant AML, Natural Killer / T cell lymphoma (NKTL), extra nodal NK / T cell lymphoma (ENKTL), TP53 mutant NKTL, chronic lymphocytic leukaemia (CLL) and multiple myeloma. In some embodiments, the cancer is a blood cancer selected from acute myeloid leukaemia (AML), including TP53 mutant AML, and extra-nodal Natural Killer / T cell lymphoma (ENKTL), and TP53 mutant NKTL.

[0130] In some embodiments, the cancer is a solid cancer. In some embodiments, the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, melanoma, breast cancer, ovarian cancer, neuroblastoma, prostate cancer, and colorectal cancer. The solid tumour is not particularly limited, provided it expresses STING protein and is vulnerable to BH3-mimetic induced apoptosis.

[0131] In some embodiments, the cancer is not breast cancer.

[0132] Also disclosed herein is use of a BH3-mimetic drug and a STING agonist in the manufacture of a medicament for the treatment of cancer in a subject, wherein the 1005442107BH3-mimetic drug and a STING agonist are for co-administration. As discussed above, the co-administration may be sequential or simultaneous administration.

[0133] There is also described use of a STING agonist in the manufacture of a medicament for conjoint administration with a BH3-mimetic drug for the treatment of cancer in a subject. The conjoint administration may be sequential or simultaneous. There is also described use of a BH3-mimetic drug in the manufacture of a medicament for conjoint administration with a STING agonist for the treatment of cancer in a subject.

[0134] The term “dose” as used herein, unless the context indicates otherwise, refers to a mass, conventionally in milligrams (mg) or micrograms (µg), of an active substance administered to a subject per kilogram (kg) of a subject's body weight.

[0135] The term “about” as used herein refers in some embodiments to an amount within ± 10%, or ± 5%, or ±2 % of the value modified by the term.

[0136] It should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of “from x to y” or “between x and y” is intended to include all sub-ranges between x and y and also range end points x and y.

[0137] As used herein, the singular forms “a,” “an,” and “the” may refer to plural articles unless specifically stated otherwise.

[0138] The salts of the compounds described herein are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, for example, as these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or in methods not requiring administration to a subject.

[0139] The term “pharmaceutically acceptable” may be used to describe any salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound or an active metabolite or residue thereof and typically that is not deleterious to the subject.

[0140] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, 1005442107phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0141] Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as “Handbook of Pharmaceutical salts” P.H.Stahl, C.G.Wermuth, 1st edition, 2002, Wiley-VCH.

[0142] In the case of compounds that are solids, it will be understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

[0143] The invention includes all crystalline forms of compounds described herein including anhydrous crystalline forms, hydrates, solvates and mixed solvates. If any of these crystalline forms demonstrates polymorphism, all polymorphs are within the scope of this invention.

[0144] The compounds described herein are intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, the compounds described herein include compounds having the indicated structures, including the hydrated or solvated forms, as well as the non-hydrated and non-solvated forms.

[0145] The compounds described herein or salts, tautomers, N-oxides, polymorphs or prodrugs thereof may be provided in the form of solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl 1005442107formamide (DMF), acetic acid, and the like with the solvate forming part of the crystal lattice by either non-covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water, alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the invention.

[0146] Basic nitrogen-containing groups may be quarternised with such agents as C1-6alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

[0147] Nitrogen containing groups may also be oxidised to form an N-oxide.

[0148] The compounds described herein or salts, tautomers, N-oxides, solvates and / or prodrugs thereof that form crystalline solids may demonstrate polymorphism. All polymorphic forms of the compounds, salts, tautomers, N-oxides, solvates and / or prodrugs are within the scope of the invention.

[0149] The compounds described herein may demonstrate tautomerism. Tautomers are two interchangeable forms of a molecule that typically exist within an equilibrium. Any tautomers of the compounds described herein are to be understood as being within the scope of the invention.

[0150] The compounds described herein may contain one or more stereocentres. All stereoisomers of the compounds of formula (I) are within the scope of the invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olephinic forms and cis and trans substitution patterns) and atropisomers. In some embodiments, the compound is a stereoisomerically enriched form of the compound of formula (I) at any stereocentre. The compound may be enriched in one stereoisomer over another by at least about 60, 70, 80, 90, 95, 98 or 99%.

[0151] The compounds described herein or salts, tautomers, solvates, N-oxides, and / or stereoisomers thereof, may be isotopically enriched with one or more of the isotopes of the atoms present in the compound. For example, the compound may be enriched with one or more of the following minor isotopes: 2H, 3H, 13C, 14C, 15N 1005442107and / or 17O, preferably 2H. An isotope may be considered enriched when its abundance is greater than its natural abundance.

[0152] A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.

[0153] Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, and amido groups of compounds of Formula (I). The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of compounds described herein through the carbonyl carbon prodrug sidechain. Examples Materials and methods Cancer cell lines and tissue culture Mice

[0154] All experiments with animals followed the guidelines of the Melbourne Directorate Animal Ethics Committee, according to The Walter and Eliza Hall Institute of 1005442107Medical Research Ethics Committee. For in vivo experiments with Eµ-Myc lymphoma cells, C57BL / 6 Cas9KI / KIor Rag1- / -mice were intravenously (IV) injected with 1x106AH15A wildtype or Trp53 KO cells on day 0. On day 4 to 8 post-transplantation, mice were treated with 25 mg / kg S63845 (Chemgood #C1370) or vehicle (50 mM PBS containing 2% vitamin E (Sigma #57668)) daily by IV injection. On days 4, 7 and 11 post-transplantation, mice were treated with 1.5 mg / kg diABZI Sting agonist compound 3 (diABZI; SYNthesis Med Chem) or vehicle (40% polyethylene glycol(PEG)-400 (Sigma #P3265) in saline) by IV injection. Mice were monitored for lymphoma by experienced animal technicians who were blinded to the nature of the transplanted tumour cells and the treatment applied and euthanized at predetermined ethical endpoint. Retro-orbital bleeds were analyzed by Advia to obtain blood cell counts, and enlarged organs (spleen, lymph nodes, thymus) were weighed. For in vivo xenograft experiments, NOD-SCID-gc− / −(NSG) mice were subcutaneously injected with 2x106SNK6 human NKT lymphoma cells on day 0. On day 7 to 13 post-transplantation, mice were treated with 50 mg / kg A-1331852 (a kind gift from Prof G Lessene, WEHI) or vehicle (2.5% DMSO, 10% EtOH, 27.5% PEG-400, 60% Phosal 50 PG (Lipoid)) by oral gavage. On days 7, 10 and 13 post-transplantation, mice were treated with 1.5 mg / kg diABZI or vehicle (40% PEG-400 in 0.9% saline) by IV injection. Tumours were measured using calipers every 4-5 days by an experienced animal technician who was blinded to the treatment applied, and tumour volume calculated using the equation π / 6 x length x width2. Mice were euthanized when tumours had reached 0.5 cm3. The volumes of tumours in mice treated with A-1331852, or A-1331852 in combination with diABZI, which arose later than those in mice treated with vehicle or diABZI alone, could not be accurately measured using calipers due to their varying positions. Therefore, these mice were collected on day 65 post-transplantation and tumour weights compared directly. For all mice, retro-orbital bleeds were analysed by Advia to obtain blood cell counts, and spleens, enlarged lymph nodes and tumours were weighed. Cancer cell lines and tissue culture

[0155] Mouse Eµ-Myc lymphoma cell lines AH15A, AF47A and 560 were derived from tumours arising in Eµ-Myc transgenic mice (C57BL / 6) and cultured in FMA medium consisting of high glucose DMEM supplemented with 10% heat-inactivated foetal bovine serum (FBS; Sigma #F9423)), 100 µM L-asparagine (Sigma #A4284), 50 µM β-mercaptoethanol (Sigma #M3148), 100 U / mL penicillin and 100 mg / mL 1005442107streptomycin (Gibco #15140122). Mouse cells were maintained at 37ºC with 10% CO2. Mouse double hit lymphoma cell lines 214DHL, 216DHL and 270DHL were derived from tumours arising in Eµ-Myc / dCas9a-SAM+ / - / sgBcl-2 mice as described previously (Deng, Diepstraten et al.2022) and cultured as above. The human Burkitt lymphoma cell line BL2 was supplied by The University of Birmingham, UK, and was cultured in RPMI- 1640 medium supplemented with 10% FBS, 1 mM sodium pyruvate (Gibco #11360070), 2 mM L-glutamine (Gibco #25030081), 50 µM α-thioglycerol (Sigma #M-6145), 100 U / mL penicillin and 100 µg / mL streptomycin. The human DLBCL line DOHH2, and AML cell lines MV4;11, THP-1 and MOLM-13 were cultured in RPMI-1640 medium supplemented with 10% heat-inactivated FBS, 100 U / mL penicillin and 100 µg / mL streptomycin. The human NKT lymphoma cell lines SNK6, MEC04 and SNT15, were supplied by The University of Birmingham, UK, and were cultured in RPMI-1640 medium supplemented with 10% heat-inactivated human serum (Sigma #H4552), 1 mM sodium pyruvate, 2 mM L-glutamine, 700 U / ml human IL-2 (PeproTech #200-02), 100 U / mL penicillin and 100 µg / mL streptomycin. Human lymphoma and leukaemia cell lines were maintained at 37ºC with 5% CO2 and verified by STR profiling at the Australian Genomics Research Facility (AGRF). HEK293T cells were cultured in DMEM supplemented with 10% FBS, 100 U / mL penicillin and 100 mg / mL streptomycin and maintained at 37ºC with 10% CO2. All cell lines were passaged in culture for <3 months and regularly tested negative for mycoplasma (Lonza MycoAlert).

[0156] The human AML cell lines MOLM-13 WT, MOLM-13s, OCI-AML3, THP-1, HL-60, KG-1, TF-1, were cultured were cultured in RPMI-1640 medium supplemented with 10% heat-inactivated FBS, 100 U / mL penicillin and 100 µg / mL streptomycin. Human leukaemia cell lines were maintained at 37°C with 5% CO2 and verified by STR profiling at the Australian Genomics Research Facility (AGRF). All cell lines were passaged in culture for <3 months and regularly tested negative for mycoplasma (Lonza MycoAlert). Generation of CRISPR / Cas9 gene knockout lymphoma and leukaemia cell lines

[0157] CRISPR / Cas9 gene editing was performed using FuCas9-Cherry (Addgene Plasmid #70182) and FgH1tUTG (Addgene Plasmid #70183) lentiviral constructs as described previously (Diepstraten, Young et al.2023). Parental cells expressing Cas9 and a non-targeting (NT) control sgRNA against human BIM (for mouse cell lines) or mouse Bim (for human cell lines) were used as control (NT control) cells for all 1005442107experiments involving CRISPR / Cas9 generated cell lines. Successful knockout of the targeted proteins was confirmed by Western blotting.

[0158] Human AML cell knock-out cell lines were generated as previous described (Thijssen, Diepstraten, Moujalled et al. Blood 2021). Briefly, sgRNA guides targeting human TP53, STING, BAX, BAK and non-targeting control guides were obtained from the Sanger Whole Genome CRISPR Arrayed Library or synthesized (Integrated DNA Technology) and cloned into pKLV-U6gRNA(Bbsl)-PGKpuro2ABFP (Addgene Plasmid #50946). All lentivirus was produced in 293T cells (ATCC #CRL-3216) and cell lines were transduced using established protocols. Stable Cas9-expressing human target cells were generated through transduction with FuCas9Cherry (Addgene Plasmid #70182). Human cell lines were subsequently transduced with lentiviral supernatants containing respective target sgRNAs. Successful knockouts were confirmed using Western Blot protein analysis and / or targeted next-generation sequencing. Cell line death assays

[0159] Cells were plated into 96-well flat-bottom plates in duplicate at 3x104cells / well and drugs added at indicated concentrations. The following drugs were used: S63845, A-1331852, ABT-199 / venetoclax (Active Biochem #A-1231), ADU-S100 (MedChemExpress #HY-12885A), MSA-2 (MedChemExpress #HY-136927), TPCA-1 (MedChemExpress #HY-10074), GSK8612 (MedChemExpress, dissolved in DMSO), diABZI Sting agonist compound 3, doxorubicin (Ebewe Interpharma), and ionomycin (Sigma-Aldrich #I9657). At the indicated time point, cells were transferred into a round- bottom 96-well plate, spun down at 1,500 rpm for 5 min, resuspended in Annexin V binding buffer containing Annexin V-A647 (made in house, 1:2000) and propidium iodide (PI; 1 µg / mL). Live cells (Annexin V / PI double-negative) were quantified on an LSR II flow cytometer (BD Biosciences). Data analysis was performed using FlowJo v10 and GraphPad Prism v9.

[0160] Combinations of compound 4-46 / ABT-199. Cells were plated into 96-well U-bottom plates in triplicate at 2x105 cells / well and drugs added at the indicated concentrations. The drugs used were Compound 4-46 and ABT-199 / venetoclax (Chemgood). After 48h, cells were harvested and spun at 300g for 5 min, then resuspended at 1:2000 in DAPI or PI for quantification of cell viability by Cytoflex 1005442107(Beckman Coulter). Data analysis was performed using FlowJo v10 and GraphPad Prism v9. Western blotting

[0161] Western blotting was performed as described previously (Diepstraten, Young et al.2023). Cells were treated with S63845, STING agonists or Nutlin-3a (MedChemExpress #HY-10029) after being pre-treated with 25 µM of the broad- spectrum caspase inhibitor QVD-O-Ph for 15 min (MedChemExpress #HY-12305). Protein concentration was measured using the Pierce BCA Protein Assay Kit (Thermo Fisher #23225).10 µg of protein was loaded per sample. Antibodies used are listed in Table 2 below:

[0162] Table 2 - List of antibodies used for Western blotting Target Reactivity Clone Species Dilution Source protein raised in , p E1005442107pTBK1 mouse / human D52C2 rabbit 1:1000 Cell Signaling Technology

[0163] RNA extraction, cDNA synthesis and TaqMan qRT-PCR were performed as described previously (Diepstraten, Young et al.2023). Cells were treated with S63845, STING agonists or Nutlin-3a after being pre-treated with 25 mM QVD-O-Ph caspase inhibitor for 15 min. Data were analysed using the ΔΔCt method, normalised to the housekeeping control gene (Hmbs) for each sample. Data were plotted in GraphPad Prism v9. TaqMan probes are listed in Table 3 below:

[0164] Table 3 - List of TaqMan probes Target gene Species Probe number 1005442107P21 / CDKN1A human Hs00355782_m1 C

[0165] To determine cell number and viability for cell proliferation analyses, an equal volume of 0.4% trypan blue (BioRad # 1450021) was added to samples and cells were counted on a TC20 Automated Cell Counter (BioRad). Data were plotted in GraphPad Prism v9. For cell cycle analyses, cells were treated with DMSO or diABZi for 24 h, then collected and fixed on ice for 30 min using the eBioscience Foxp3 / Transcription Factor Staining Buffer Set (Thermo Fisher #00-5523-00). Cells were then resuspended in 1x permeabilization buffer and incubated at 4°C for at least 48 h. Cells were spun down and resuspended in PBS containing 5% FBS and 0.5 µg / mL DAPI (Sigma # D9542) and analysed on an LSR II W flow cytometer (BD Biosciences). Data analysis was performed using FlowJo v10. Imaging

[0166] Brightfield imaging of NKT lymphoma cells was performed using the ZOE fluorescent cell imager (BioRad). AML patient samples

[0167] Bone marrow and peripheral blood samples were collected from patients treated at two hospitals in Australia (The Peter MacCallum Cancer Centre and The Alfred Hospital) who had newly diagnosed or morphologically relapsed AML (16 samples) or myelodysplastic syndrome with excess blasts (2 samples). Mononuclear cells were derived using a Ficoll density gradient. Freshly processed or thawed cryopreserved cells were used in drug sensitivity assays. Cells were cultured in Stempsan SFEM medium (Stem Cell Technologies #09650), supplemented with Stemreginin (500 nM; StemCell Technologies #72354), UM171 (35 nM; Selleckchem #S7608), and recombinant human cytokines IL-3 (1 ng / mL; R&D Systems #203-IL), IL-6 (2 ng / mL; R&D Systems #206-IL), FLT3-ligand (5 ng / mL; R&D Systems #308-KFN) and stem cell factor (5 ng / mL; R&D Systems #255-SC).15,000 to 50,000 cells were plated into 96 well U-bottomed plates and cultured at the indicated drug concentrations for 48 h at 37° C and 5% CO2. Cell viability was assessed by flow cytometry using the NovoCyte Quanteon (Agilent). Cells were first stained with antibodies detecting extracellular markers to enable lineage identification (CD45-FITC, CD34-PerCP-Cy5, 1005442107CD117-PE-Cy7, HLA-DR-APC-Cy7, CD33-BV650, CD14-Alexa Fluor 700, CD64- BV785, CD3-BV421, CD19-PE), followed by staining with PI for assessment of viability. Results – in culture Combined BH3-mimetic drug and STING agonist therapy exerts potent killing of TRP53- defective lymphoma cells

[0168] To determine the potential for STING agonists to enhance the activity of BH3-mimetic drugs, particularly against TP53-deficient haematological malignancies that frequently relapse after BH3-mimetic drug monotherapy, parental (NT control) and Trp53 KO Eµ-Myc lymphoma cells were treated in culture with the BH3-mimetic drug, S63845, a MCL-1 specific inhibitor, in combination with a STING agonist (either ADU- S100, MSA-2 or diABZI).

[0169] Figure 1A shows cell viability assays of isogenic non-targeting sgRNA (NT) control, Trp53 KO and Bak / Bax double KO mouse Eµ-Myc lymphoma cell lines treated in culture with the MCL-1 inhibitor S63845 (AH15A: 100 nM, AF47A: 200 nM) in combination with the STING agonists ADU-S100 (AH15A: 2 µg / mL; AF47A: 10 µg / mL), MSA-2 (AH15A: 12 µM, AF47A: 34 µM) or diABZI (AH15A: 20 nM, AF47A: 1 µM) for 24 h.

[0170] Figure 1B shows cell competition assays in culture of isogenic NT control lymphoma cells versus their Trp53 KO derivatives. Lymphoma cells were mixed at a 50:50 ratio and treated with DMSO (gray), S63845 (red; 50 nM), ADU-S100 (blue; 1 µg / mL), or S63845 and ADU-S100 combined (purple) for 7 days, and the proportion of lymphoma cells of each genotype monitored by flow cytometry over time. The proportion of Trp53 KO lymphoma cells at each time point are plotted.

[0171] Figure 1C shows cell viability assays of mouse DHL cell lines treated in culture with the BCL-2 inhibitor venetoclax (10 nM) in combination with the STING agonists ADU-S100 (DHL214: 2 µg / ml, DHL270: 5 µg / ml), MSA-2 (DHL214: 17 µM, DHL270: 34 µM) or diABZI (DHL214: 50 nM, DHL270: 100 nM) for 24 h.

[0172] Figure 1D and 1E show survival curves of Rag1 mice transplanted with isogenic NT control (D) or Trp53 KO (E) AH15A mouse Eµ-Myc lymphoma cells and then treated with vehicle (black), the STING agonist diABZI (blue), the MCL-1 inhibitor 1005442107S63845 (yellow) or diABZI alongside S63845 (pink). Boxes show when diABZI (blue) and S63845 (yellow) were administered.

[0173] Figure 1A shows that combination therapy enhanced killing in culture of both parental and Trp53 KO Eµ-Myc lymphoma cells in an additive and synergistic fashion. Bak / Bax double KO lymphoma cells were entirely resistant, confirming that that combination activity was reliant on apoptosis. Strikingly, this drug combination suppressed outgrowth of Trp53 KO over parental lymphoma cells in cell competition assays in culture, compared with treatment with BH3-mimetic drugs alone, Figure 1B. In mouse DHL cells, which are dependent on BCL-2 for survival, additive killing could be achieved in culture by combining a STING agonist with the BCL-2 selective inhibitor venetoclax (Figure 1D).

[0174] The safety and efficacy of combined BH3-mimetic drug and STING agonist therapy was then looked at in vivo. To delineate the direct, tumour cell intrinsic effects of STING agonists on cancer cells in vivo, parental (NT control) or Trp53 KO Eµ-Myc lymphoma cells were transplanted into Rag1-deficient mice, which lack mature T and B cells. Mice were treated with a BH3-mimetic drug targeting MCL-1, the STING agonist drug diABZI, or both drugs in combination. Mice which received parental lymphoma cells and were treated with diABZI had significantly longer survival compared to those treated with vehicle (Figure 1E; median survival 16 days vs 22 days). Furthermore, 3 out of 5 (60%) mice in the MCL-1 inhibitor + STING agonist combination arm remained alive at 90 days post-transplantation, compared to only 1 out of 6 (17%) mice receiving MCL-1 inhibitor monotherapy. For mice transplanted with highly aggressive Trp53 KO lymphoma cells (Figure 1F), combined MCL-1 inhibitor and STING agonist treatment significantly increased survival compared to MCL-1 inhibitor alone (median survival: 26 days vs 20 days). Overall, the drug combination was well tolerated with no adverse events. These results show that addition of a STING agonist to BH3-mimetic drug therapy can boost killing of both parental (wild-type Trp53) and Trp53 mutant cancer cells by directly targeting malignant cells, and that this prolongs survival independent of immune effector cell function. 1005442107BH3-mimetic drugs and STING agonists directly enhance apoptosis of human NK / T lymphoma cells

[0175] Intrinsic expression of STING protein is necessary for STING agonists to function, to become activated. Therefore, to determine which human blood cancers should ideally be targeted by this approach, mRNA expression of STING was surveyed in human cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE; Figure 5A). Lymphoma cell lines tended to have a dichotomous distribution of STING expression, with B cell lymphomas showing low expression and T cell lymphomas showing high expression. Western blot analysis of STING protein expression in a panel of human B cell lymphoma (diffuse large B cell lymphoma and Burkitt lymphoma) cell lines confirmed that these cells had no detectable STING expression (Figure 5). Consequently, none of these lymphoma cell lines showed any sensitivity to the STING agonist.

[0176] Since ENKT lymphomas are highly aggressive and patients currently have a dismal prognosis, the inventors explored the potential for STING agonists to treat this malignancy. STING agonists activated the cGAS / STING pathway in ENKT lymphoma cell lines in culture (Figure 2B) and exhibited potent anti-proliferative effects when used as monotherapy in culture (Figure 2C). Efficient killing of three ENKT lymphoma cell lines with defective TP53 pathways in culture, including one lymphoma cell line with a confirmed TP53 mutation (MEC04) could be achieved in culture by combination treatment with STING agonists and the BCL-XL-targeting BH3-mimetic drug A-1331852 (Figure 2D-F). To test the impact of combined BH3-mimetic drug and STING agonist therapy on human ENKT lymphomas in vivo, SNK6 cells were xenografted subcutaneously into NSG mice and the mice were treated with either A-1331852, diABZI or both drugs in combination (Figure 2G). The mice treated with vehicle or diABZI alone developed tumours first detected after 32 ± 2 (mean ± S.D.) days post- transplantation for vehicle-treated mice and 35 ± 1 days for diABZI-treated mice.

[0177] These mice were analysed once tumour volume reached the predetermined ethical endpoint, with no obvious differences between the two groups (Figure 4), tumour weight at endpoint (Figure 4B), weight of lymph node metastases (Figure 4C), or blood counts, with the exception of slightly reduced platelet counts in the vehicle-treated mice (Figure 4D). In the mice treated with A-1331852, tumours were first detected after an average of 35 ± 2 days post-transplantation, while the tumours in the mice treated with 1005442107A-1331852 in combination with diABZI remained undetectable for an average of 40 ± 2 days, with 2 / 6 mice remaining tumour-free until day 55 post-transplantation. The tumours in the mice from these two arms eventually grew out in shape and positioning such that standard external estimation of tumour volume (described in Methods) was no longer deemed to be an accurate measure. Therefore, all mice treated with A-1331852 alone or in combination with diABZI, were harvested on the same day (65 days post- transplantation), when the first mouse in these arms was judged to have reached the ethical endpoint for tumour size, so that tumour weights could be compared directly. The inventors found that mice treated with A-1331852 in combination with diABZI had significantly reduced tumour weight compared to those mice treated with A-1331852 alone (1.3 ± 0.3 g (mean ± SEM) vs 3 ± 0.4 g, respectively; Student’s t-test, p = 0.0025; Figure 2H, I). In addition, 6 / 6 mice treated with A-1331852 had an enlarged, metastatic axillary lymph node on the same side as the tumour xenograft, while 3 / 6 mice treated with the combination therapy had no lymph node metastasis, and the other 3 / 6 exhibited only a slightly enlarged axillary lymph node (Figure 4E). Blood counts between these treatment arms were similar (Figure 4F). Finally, it was observed that 2 / 6 mice treated with A-1331852 alone had tumours that had extended significantly into the peritoneum, forming a secondary mass within the abdomen of the mice. This was not observed in any mice that received the combination treatment of A-1331852 and diABZI. Overall, these results show that the combination of a BH3-mimetic drug and STING agonist can significantly suppress outgrowth of aggressive human ENKT lymphoma cells independently of immune effector cell function in vivo. BH3-mimetic drugs and STING agonists synergistically enhance killing of human AML cell lines and AML patient samples

[0178] According to data from the CCLE, myeloid cancer cell lines were among blood cancers showing the highest levels of STING expression. Robust expression of STING protein was confirmed in AML cell lines (Figure 1A), and all could be efficiently killed in culture by the STING agonists ADU-S100, MSA-2 or diABZI used as single agents (Figure 1B), including TP53 / KRAS mutant THP-1 cells. There is strong rationale to combine STING agonists with the BCL-2 inhibitor, venetoclax, to enhance activity in TP53 mutant AML cells, which are known to be sub-optimally responsive to BH3- mimetics alone or even in combination with chemotherapy. Combined STING activation and BCL-2 inhibition was confirmed to be effective in culture, regardless of TP53 1005442107mutation status (Figure 3C). A panel of AML patient samples with diverse genomic profiles, including TP53 defects (Figure 3D) was examined next. Interestingly, 4 / 7 of the samples were highly sensitive to diABZI alone in culture, while the remaining 3 / 7 could be efficiently killed by combined diABZI and venetoclax treatment in culture (Figure 3D). Strikingly, the STING agonist, either alone or in combination with venetoclax, could kill AML patient samples in culture that were only minimally sensitive to treatment with venetoclax alone (Figure 3D). Interestingly, normal T cells isolated from AML patient samples were resistant to killing in culture by diABZI alone, although the combination of venetoclax and diABZI could effectively kill these cells in culture (Figure 3E). These results indicate that STING agonists and their combination with venetoclax could play an important clinical role for patients with AML, including cases with poor risk TP53 mutations.

[0179] The data were analysed for their synergistic effect using a simple Bliss scoring. This scoring assumes that for the given drug BH3 mimetic drug (A) and STING agonist (b), each produces its anticancer effect by targeting different pathways, and that these pathways have no mechanistic connection other than the response outcome. If the outcome or response is measured as the percentage of cancer cells that died following drug treatment, the resulting percentage is frequently referred to as the inhibition rate. To determine the combination effect of the two drugs, the Bliss independence principle is considered. Thus, the Bliss predicted inhibition rate yabcan be calculated by Equation 1

[0180] Equation 1 yab=ya+yb−yayb, where yaand ybare the observed inhibition rates with drug A alone at dose a and drug B alone at dose b. If the observed inhibition rate yabat the combination dose of drug A and drug B is greater than the Bliss predicted inhibition rate yab, the drug combination effect is thought of as synergism at that specific dose combination. That is, if the result is <1 the combination is synergistic, if =0 then independent and if >1 the combination is antagonistic. Table 4 lists the various Bliss scores for the results. The results indicate that in all the results tested so far, a synergetic effect was observed. Some combinations showed a better score than others, the effect being dependant on the potency of the drugs tested and / or the sensitivity of the cell lines. Comparing the results of the Bliss scores of control parental cells (NT) along with the % live cells of the Figures 1-6, one sees that indicates that killing was independent of cell type. 1005442107

[0181] Table 4 – Bliss scores Cell line Venetoclax / ADU- Bliss S638845 / S100 / Scores 8 7 4 6 6 3 6 5 6

[0182] Work by the present inventors has shown that, in human and mouse lymphoma and leukaemia cell lines, doses of BH3-mimetic drugs that induce MOMP lead to induction of TP53 / TRP53 itself. This stabilised TP53 / TRP53 is functional, potently inducing expression of the genes for pro-apoptotic BH3-only proteins regulated 1005442107by TP53 and augmenting death of malignant cells that might not otherwise reach the threshold to undergo apoptosis. Importantly, this occurred with both MCL-1 and BCL-2 inhibitors and is therefore indicative of a class effect of BH3-mimetic drugs.

[0183] Armed with an understanding of the requirements to efficiently induce apoptosis in TP53 mutant blood cancer cells, the inventors identified that activation of the cGAS / STING pathway can boost expression of pro-apoptotic BH3-only proteins in a TP53-independent manner and thereby boost the pro-apoptotic signal in cells co-treated with BH3-mimetic drugs. STING agonists have already entered clinical trials in combination with immunotherapy with the aim of enhancing host anti-cancer immune responses, but thus far, these studies have reported limited efficacy from stimulation of the host immune response. Importantly, however, these drugs were demonstrated to be tolerated in humans.

[0184] In the above examples, this STING agonist drug class was repurposed and showed that both synthetic cyclic dinucleotide drugs and small molecule activators of STING could kill mouse and human blood cancer cells by triggering tumour cell-intrinsic apoptosis in vitro and in vivo without requirement to activate the immune system. The extent of lymphoma and leukaemia cell killing was TP53 agnostic but required presence of STING protein. Stringent characterisation of this pathway revealed that TBK1 and IRF3 were essential for efficient lymphoma and leukaemia cell killing, while triggering of NFκB signalling was dispensable, though, importantly, not antagonistic to cell killing. Understanding the critical regulators required for the cGAS / STING pathway to induce apoptosis may assist with patient selection for therapy and improve pro-apoptotic STING signalling.

[0185] Importantly, in this study, the inventors demonstrate that combining STING agonists with BH3-mimetics targeting MCL-1, BCL-2 or BCL-XL can boost apoptosis in both TP53 / TRP53 wild-type as well as mutant leukaemias and lymphomas. STING agonists alone or in combination with the BCL-2 inhibitor venetoclax were highly efficacious in AML patient samples regardless of TP53 status, even in samples that showed no sensitivity to venetoclax alone. In human ENKT lymphoma, the combination of a BCL-XL inhibitor and STING agonists potently killed malignant cells with non- functional TP53 both in vitro and in xenograft models in vivo. ENKT lymphoma and TP53 mutant AML represent two blood cancer subtypes of particular interest due to limited therapy options and dismal prognosis. As both BH3-mimetic drugs and STING 1005442107agonist drugs are already in clinical trials (or already widely approved and used, in the case of venetoclax), the presently claimed drug combination may be fast-tracked to the clinic for immediate translational impact. Results - human AML cell lines Combined BH3-mimetic drug and STING agonist therapy exerts potent killing of human AML cell lines and TP53-defective AML cells

[0186] To determine the potential for STING agonists to enhance the activity of BH3-mimetic drugs, particularly against TP53-deficient haematological malignancies with poor outcomes after BH3-mimetic drug monotherapy, human AML cell lines were treated in culture with the BH3-mimetic drug ABT-199 / venetoclax, or the STING agonist Compound 4-46 as single agents or in combination.

[0187] Figures 7A-7F show cell viability assays for MOLM-13 WT, OCI-AML3, THP- 1, HL-60, KG-1 and TF-1 AML cell lines treated with BCL-2 inhibitor ABT- 199 / venetoclax (thin red line, circle markers) or Compound 4-46 (thick blue line, square markers) for 48h. Data is reported as mean ± SEM.

[0188] Figure 8 and Figure 9 show cell viability assays for isogenic human MOLM- 13s AML cells containing non-targeting sgRNA (thick blue line, square markers) control, TP53 KO (dotted red line, circle markers), STING KO (green line, triangle markers) and Bak / Bax double KO (purple line, diamond markers) treated in culture with the STING agonist Compound 4-46 (Figure 8) or with ABT-199 / venetoclax alone (Figure 9) for 48h. Compound 4-46 and ABT-199 / venetoclax killed both parental and TP53 KO AML cells. STING deficient cells were completely resistant to Compound 4-46 killing but not to ABT-199 / venetoclax. Bak / Bax double KO AML cells were entirely resistant to both agents, confirming a reliance on apoptosis for their individual activities. Figures 10A and 10B show viability assays of human AML cell lines MOLM-13 WT (Figure 10A) and OCI- AML3 (Figure 10B) treated in culture with the BCL-2 inhibitor ABT-199 / venetoclax (0-10 µM) in combination with the STING agonist Compound 4-46 (0-10 µM) for 24h. The combination therapy enhanced killing of both AML cell types in an additive and synergistic manner. Figures 10C and 10D show heat maps of viability assays of human AML cell lines MOLM-13 WT (Figure 10C) and OCI-AML3 (Figure 10D) treated in culture with the BCL-2 inhibitor ABT-199 / venetoclax (0-10 µM) in combination with the 1005442107STING agonist Compound 4-46 (0-10 µM) for 24h. The data presented in Figure 10A is the same as in Figure 10C, and the data presented in Figure 10D is the same as Figure 10B. BH3-mimetic drugs and STING agonists synergistically enhance killing in AML patient samples

[0189] Next, a panel of AML patient samples with diverse genomic profiles, including TP53 mutations, were examined. Figures 11A-R each show a viability assay from 18 different leukaemic blast (LB) samples treated with STING agonist compound 4-46 (thick blue line; circle markers; 0.0001-10 µM), ABT-199 / venetoclax (dotted red line; square markers; 0.0001-10 µM) or a 1:1 dose of the combination of both agents (thin green line; triangle markers; 0.0001-10 µM). Of all samples tested, 10 / 18 were highly sensitive to Compound 4-46 alone, while only 3 / 18 were highly sensitive to ABT- 199 / venetoclax. Importantly, 17 / 18 AML patient samples displayed high sensitivity to killing when both agents were combined. Indeed, patient samples that were minimally sensitive to ABT-199 / venetoclax, could be effectively killed in culture by the combination therapy. Therefore, these results indicate the potential for combining STING agonists (including a compound of any of Formulas (I)-(V) such as Compound 4-46) and ABT- 199 / venetoclax for the treatment of AML, including those cases with TP53 mutations and poor outcomes. Discussion and conclusions

[0190] In the above examples, STING agonist Compound 4-46 was shown to effectively induce potent killing in human AML cell lines when administered as a single agent and when combined with BCL-2 inhibitor ABT-199 / venetoclax. Loss of STING by genetic knockout in AML cell lines completely abolished the effect of Compound 4-46, but not ABT-199 / venetoclax, confirming reliance of the former compound on the presence of STING protein. Moreover, the loss of Bax / bak completely abolished the pro-apoptotic activity of both agents, while knockout of TP53 had no effect. AML patient samples with genetic diversity demonstrated additive and synergistic killing when Compound 4-46 was combined with ABT-199 / venetoclax. Indeed, patient samples that were minimally sensitive to ABT-199 / venetoclax alone were robustly killed by the combination therapy. 1005442107Combination of Compound 4-11 and venetoclax

[0191] The combination of the BH3 mimetic, venetoclax, and STING agonist, compound 4-11, was tested against primary cells according to the same procedures as described above for combinations of venetoclax and compound 4-46.

[0192] The results of cell viability from these experiments are shown in Figures 12A- 12C. The cell viability for monotherapy with compound 4-11 are shown in Figure 12A. The cell viability for monotherapy with ventoclax are shown in Figure 12B. The cell viability for combination therapy with venetoclax and compound 4-11 is shown in Figure 12C.

[0193] While the present invention is described with reference to the above examples, it is to be understood that the examples are illustrative of and not limiting to the invention described herein.

[0194] It will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding, various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification. 1005442107

Claims

Claims 1. A method of treating or inhibiting progression of cancer in a subject, comprising co-administering to the subject: a BH3-mimetic drug; and a STING agonist.

2. A method of inducing an immune response to cancer in a subject, the method comprising: co-administering to the subject a BH3-mimetic drug and a STING agonist, thereby eliciting the anti-cancer immune response in the subject.

3. The method of any one of the preceding claims, wherein the cancer comprises cells expressing STING protein.

4. A method of treating or inhibiting progression of a cancer in a subject, comprising: identifying the subject as a candidate for BH3-mimetic drug therapy; identifying the cancer as comprising cells expressing STING protein; and administering to the subject both a BH3-mimetic drug and a STING agonist, wherein the STING agonist is administered sequentially or simultaneously with the BH3- mimetic drug.

5. The method of any one of the preceding claims, wherein the cancer comprises TP53-wildtype and TP53-mutant / deficient cells.

6. The method of any one of the preceding claims, wherein the cancer is refractory or resistant to BH3-mimetic drug monotherapy.

7. The method of any one of the preceding claims, wherein the co-administering comprises administering the BH3-mimetic drug and the STING agonist simultaneously.

8. The method of any one of the preceding claims, wherein the co-administering comprises administering the BH3-mimetic drug and the STING agonist sequentially.

9. The method of any one of the preceding claims, wherein the BH3-mimetic drug is administered orally or intravenously. 100544210710. The method of any one of the preceding claims, wherein the STING agonist is administered intravenously or intratumorally.

11. The method of any one of the preceding claims, wherein the BH3-mimetic drug and the STING agonist are each administered in a therapeutically effective amount.

12. The method of any one of the preceding claims, wherein the BH3 mimetic drug is selected from a BCL-2-selective inhibitor, such as venetoclax, a BCL-XL-selective inhibitor, such as A-1331852, and an MCL-1-selective inhibitor, such as S63845.

13. The method of any one of the preceding claims, wherein the STING agonist is selected from any one of compounds 1-1 to 1-172, 2-1 to 2-25, 3-1 to 3-24, 4-1 to 4-112 and 5-1 to 5-15.

14. The method of any one of the preceding claims, wherein the BH3-mimetic drug is administered in an amount of from about 50 mg / day to about 600 mg / day.

15. The method of any one of the preceding claims, wherein the STING agonist is administered in an amount of from about 10 µg / week to about 6,400 µg / week across from 1 dose every 3 weeks to 1 to 3 doses per week.

16. The method of any one of the preceding claims, wherein the cancer is a blood cancer.

17. The method of any one of the preceding claims, wherein the cancer is a blood cancer selected from leukaemia, such as acute myeloid leukaemia (AML), lymphoma such as T cell lymphoma and multiple myeloma (MM), or a relapsed / refractory form of any one of these.

18. The method of any one of the preceding claims, wherein the cancer is a blood cancer selected from acute myeloid leukaemia (AML), Natural Killer / T cell lymphoma (NKTL), extra nodal NK / T cell lymphoma (ENKTL), and multiple myeloma (MM), or a relapsed / refractory form of any one of these.

19. The method of any one of claims 1 to 16, wherein the cancer is a leukaemia selected from acute myeloid leukaemia (AML), including promyelocytic leukaemia, chronic myelogenous leukaemia (CML), and acute lymphoblastic leukaemia (ALL), or a relapsed / refractory form of any one of these. 100544210720. The method of any one of claims 1 to 16, wherein the cancer is a lymphoma.

21. The method of any one of claims 1 to 16, wherein the cancer is a non-Hodgkin's lymphoma (NHL).

22. The method of any one of claims 1 to 16, wherein the cancer is a non-Hodgkin's lymphoma selected from adult T cell lymphoma, lymphoblastic lymphoma, peripheral T cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, Natural Killer / T cell lymphoma (NKTL), extra nodal NK / T cell lymphoma (ENKTL), marginal zone lymphoma, Waldenstrom's macroglobulinaemia, and mantle cell lymphoma, or a relapsed / refractory form of any one of these.

23. The method of any one of claims 1 to 15, wherein the cancer is a solid cancer.

24. The method of any one of claims 1 to 15, wherein the cancer is a solid cancer selected from small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, melanoma, ovarian cancer, neuroblastoma, prostate cancer, and colorectal cancer.

25. The method of any one of the preceding claims, wherein the subject is a mammal.

26. The method of any one of the preceding claims, wherein the subject is a human.

27. The method of any one of the preceding claims, comprising co-administering a synergistic combination of the BH3-mimetic drug and the STING agonist.

28. A combination for treating or inhibiting progression of cancer, comprising: a BH3-mimetic drug; and a STING agonist.

29. The combination of claim 28, wherein the combination is in the form of a pharmaceutical composition.

30. The combination of claim 28 or claim 29, wherein the BH3-mimetic drug and the STING agonist are separate preparations. 100544210731. The combination of any one of claims 28 to 30, wherein the BH3-mimetic drug and the STING agonist are for simultaneous administration.

32. The combination of any one of claims 28 to 30, wherein the BH3-mimetic drug and the STING agonist are for sequential administration.

33. The combination of any one of claims 28 to 32, wherein the BH3 mimetic drug is selected from a BCL-2-selective inhibitor, such as venetoclax, a BCL-XL-selective inhibitor such as A-1331852, and an MCL-1-selective inhibitor, such as S63845.

34. The combination of any one of claims 28 to 33, wherein the STING agonist is selected from any one of compounds 1-1 to 1-172, 2-1 to 2-25, 3-1 to 3-24, 4-1 to 4-112 and 5-1 to 5-15.

35. The combination of any one of claims 28 to 34, wherein the cancer comprises cells expressing STING protein.

36. The combination of any one of claims 28 to 35, wherein the cancer comprises TP53-wildtype and TP53-mutant cells.

37. The combination of any one of claims 28 to 36, wherein the cancer is refractory or resistant to BH3-mimetic drug monotherapy.

38. The combination of any one of claims 28 to 37, wherein the combination is a synergistic combination of the BH3-mimetic drug and the STING agonist.

39. Use of a BH3-mimetic drug and a STING agonist in the manufacture of a medicament for the treatment of cancer in a subject, wherein the BH3-mimetic drug and a STING agonist are for co-administration.

40. The use of claim 39, wherein the co-administration is sequential or simultaneous administration.

41. Use of a STING agonist in the manufacture of a medicament for conjoint administration with a BH3-mimetic drug for the treatment of cancer in a subject.

42. Use of a BH3-mimetic drug in the manufacture of a medicament for conjoint administration with a STING agonist for the treatment of cancer in a subject. 100544210743. The use of claim 41 or claim 42, wherein the conjoint administration is sequential or simultaneous administration. 1005442107

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