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1. WO2020002905 - CANCER THERAPY

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CLAIMS

1. A non-viable, whole-cell Mycobacterium for use in the treatment, reduction, inhibition or control of one or more tumours in a checkpoint inhibitor refractory patient, wherein said checkpoint inhibitor refractory patient is intended to undergo checkpoint inhibition therapy simultaneously, separately or sequentially with administration of the Mycobacterium.

2. The non-viable, whole-cell Mycobacterium for use according to claim 1 , wherein said checkpoint inhibition therapy comprises administration of one or more blocking agents, selected from a cell, protein, peptide, antibody, ADC (antibody-drug conjugate), Fab fragment (Fab), F(ab')2 fragment, diabody, triabody, tetrabody, probody, single-chain variable region fragment (scFv), disulfide-stabilized variable region fragment (dsFv), or other antigen binding fragment thereof, directed against CTLA-4, PD-1 , PD-L1 , PD-L2, B7-H3, B7-H4, B7-H6, A2AR, IDO, TIM-3, BTLA, VISTA, TIGIT, LAG-3, CD40, KIR, CEACAM1 , GARP, PS, CSF1 R, CD94/NKG2A, TDO, TNFR, DcR3 and combinations thereof.

3. The non-viable whole-cell Mycobacterium for use according to claim 1 or 2, wherein said checkpoint inhibition therapy comprises administration of a sub-therapeutic amount and/or duration of said one or more blocking agents.

4. The non-viable whole-cell Mycobacterium for use according to any of claims 1 to 3, wherein said one or more tumours is associated with a sarcoma, preferably a soft tissue or non-soft tissue sarcoma.

5. The non-viable whole-cell Mycobacterium for use according to any of claims 1 to 4, wherein said one or more tumours is associated with a cancer selected from prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, breast cancer, pancreatic cancer, brain cancer, hepatocellular cancer, lymphoma, leukaemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, carcinoma, head and neck cancer and skin cancer.

6. The non-viable whole-cell Mycobacterium for use according to claim 5, wherein said one or more tumours is associated with pancreatic, colorectal, prostate, skin or ovarian cancer.

7. The non-viable whole cell Mycobacterium for use according to any of claims 1 to 6, wherein said one or more tumours is metastatic.

8. The non-viable whole cell Mycobacterium for use according to any of claims 2 to 7, wherein said one or more blocking agents are selected from ipilimumab, nivolumab, pembrolizumab, azetolizumab, durvalumab, tremelimumab, spartalizumab, avelumab, sintilimab, toripalimab, MGA012, MGD013, MGD019, enoblituzumab, MGD009, MGC018, MEDI0680, PDR001 , FAZ053, TSR022, MBG453, relatlinab (BMS986016), LAG525, IMP321 ,

REGN2810(cemiplimab), REGN3767, pexidartinib, LY3022855, FPA008,

BLZ945, GDC0919, epacadostat, indoximid, BMS986205, CPI-444, MEDI9447, PBF509, lirilumab and combinations thereof, preferably wherein said one or more blocking agents are selected from ipilimumab, nivolumab.

9. The non-viable whole-cell Mycobacterium for use according to any of claims 1 to 8, wherein the non-viable, whole-cell Mycobacterium is a non-pathogenic heat-killed Mycobacterium.

10. The non-viable whole-cell Mycobacterium for use according to any of claims 1 to 9, wherein the non-viable whole-cell Mycobacterium is selected from M. vaccae, M. obuense, M. parafortuitum, M. aurum, M. indicus pranii and combinations thereof.

1 1. The non-viable whole-cell Mycobacterium for use according to claim 10, wherein the non-viable whole-cell Mycobacterium is preferentially the rough variant.

12. The non-viable whole-cell Mycobacterium for use according to any

preceding claim, wherein said non-viable whole-cell Mycobacterium is for administration via the parenteral, oral, sublingual, nasal or pulmonary route.

13. The non-viable whole-cell Mycobacterium for use according to claim 12, wherein the parenteral route is selected from subcutaneous, intradermal, subdermal, intraperitoneal, or intravenous, preferably intradermal.

14. The non-viable whole-cell Mycobacterium for use according to claim 13, wherein the parenteral route comprises intratumoral, peritumoral, perilesional or intralesional administration.

15. The non-viable whole-cell Mycobacterium for use according to any preceding claim, further comprising co-stimulatory checkpoint therapy, simultaneously, separately or sequentially with administration of the Mycobacterium, wherein said co-stimulatory checkpoint therapy comprises administration of one or more binding agents selected from a cell, protein, peptide, antibody, ADC (antibody-drug conjugate), Fab fragment (Fab), F(ab')2 fragment, diabody, triabody, tetrabody, probody, single-chain variable region fragment (scFv), disulfide-stabilized variable region fragment (dsFv), or other antigen binding fragment thereof, directed against CD27, CD28, CD40, CD122, CD137, 0X40, GITR, ICOS and combinations thereof.

16. The non-viable whole-cell Mycobacterium for use according to claim 14, wherein said one or more binding agents are selected from utomilumab, urelumab, MOXR0916. PF04518600, MEDI0562, GSK3174988, MEDI6469. R07009789, CP870893, BMS986156, GWN323, JTX-201 1 , varlilumab, MK-4166, NKT-214 and combinations thereof.

17. The non-viable whole-cell Mycobacterium for use according to any preceding claim, wherein administration of said non-viable whole-cell Mycobacterium is prior to and/or after the checkpoint inhibition therapy and/or the co-stimulatory checkpoint therapy.

18. The non-viable whole-cell Mycobacterium for use according to any preceding claim, further comprising administering one or more additional anticancer treatments or agents, simultaneously, separately or sequentially with administration of the Mycobacterium, and/or checkpoint inhibition therapy and/or the co-stimulatory checkpoint therapy

19. The non-viable whole-cell Mycobacterium for use according to claim 18, wherein the one or more additional anticancer treatments or agents is selected from: adoptive cell therapy, surgical therapy, chemotherapy, radiation therapy, hormonal therapy, small molecule therapy such as metformin, receptor kinase inhibitor therapy, hyperthermia treatment, phototherapy, radioablation therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy, biological therapy, HDAC inhibitor e.g. OKI-179, BRAF inhibitor, MEK inhibitor, EGFR inhibitor, VEGF inhibitor, P13K delta inhibitor, PARP inhibitor, mTOR inhibitor, hypomethylating agents, oncolytic virus, TLR agonist including TLR2, 3, 4, 5, 7, 8 or 9 agonists, such as MRx0518 (4D Pharma), STING agonists (including MIW815 and SYNB1891), and cancer vaccines such as GVAX or CIMAvax.

20. The non-viable whole-cell Mycobacterium for use according to claim 19, wherein said TLR agonists include mifamurtide (Mepact), Krestin (PSK), MRx0518 (4D Pharma), IMO-2125 (tilsotolimod), CMP-001 , MGN-1703

(lefitolimod), entolimod, SD-101 , GS-9620, imiquimod, resiquimod, MEDI4736, poly l:C, CPG7909, DSP-0509, VTX-2337 (motolimod), MEDI9197, NKTR-262, G 100 or PF-3512676 and combinations thereof, and, wherein said chemotherapy comprises administration of one or more agents selected from: cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, cisplatin, epirubicin, capecitabine, leucovorin, folinic acid, carboplatin, oxaliplatin, gemcitabine, FOLFINROX, paclitaxel, pemetrexed, irinotecan and combinations thereof.

21. The non-viable whole-cell Mycobacterium for use according to claim 19, wherein said chemotherapy comprises administration of one or more agents selected from: cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin,

mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, cisplatin, epirubicin, capecitabine, leucovorin, folinic acid, carboplatin, oxaliplatin, gemcitabine, FOLFINROX, paclitaxel, pemetrexed, irinotecan and combinations thereof.

22. The non-viable whole-cell Mycobacterium for use according to any of claims 18 to 21 , wherein said one or more additional anticancer treatments or agents is administered intratumorally, intraarterially, intravenously, intravascularly, intrapleuraly, intraperitoneally, intratracheally, intranasally, pulmonarily, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, stereotactically, orally or by direct injection or perfusion.

23. The non-viable whole-cell Mycobacterium for use according to any preceding claim, wherein said checkpoint inhibitor refractory patient exhibits an innate (primary) resistance to checkpoint inhibitor therapy or an acquired (secondary) resistance to checkpoint inhibitor therapy.

24. The non-viable whole-cell Mycobacterium for use according to claim 23, wherein said checkpoint inhibitor refractory patient exhibits an innate (primary) resistance to checkpoint inhibitor therapy as demonstrated by a lack of response or an insufficient response to said checkpoint inhibitor therapy for at least about 8 weeks, or 12 weeks from the first dose.

25. The non-viable whole-cell Mycobacterium for use according to claim 23, wherein said checkpoint inhibitor refractory patient exhibits an acquired (secondary) resistance to checkpoint inhibitor therapy as demonstrated by an initial response to said checkpoint therapy but with a subsequent relapse and progression of one or more tumours.

26. The non-viable whole-cell Mycobacterium for use according to any preceding claim, wherein said checkpoint inhibitor refractory patient exhibits an innate (primary) resistance or an acquired (secondary) resistance to treatment

with one or more CTLA-4, PD-1 , PD-L1 , PD-L2, B7-H3, B7-H4, B7-H6, A2AR, IDO, TIM-3, BTLA, VISTA, LAG-3 inhibitors.

27. The non-viable whole-cell Mycobacterium for use according to any preceding claim wherein said immunomodulator is to be administered into the skin of said subject via a microneedle device comprising a plurality of microneedles.

28. A method of treating, reducing, inhibiting or controlling a neoplasia, tumour or cancer in a checkpoint inhibitor refractory subject, wherein said method comprises simultaneously, separately or sequentially administering to the subject, (i) one or more checkpoint inhibitors, selected from a cell, protein, peptide, antibody, ADC (antibody-drug conjugate), Fab fragment (Fab), F(ab')2 fragment, diabody, triabody, tetrabody, probody, single-chain variable region fragment (scFv), disulfide-stabilized variable region fragment (dsFv), or other antigen binding fragment thereof, directed against CTLA-4, PD-1 , PD-L1 , PD-L2, B7-H3, B7-H4, B7-H6, A2AR, IDO, TIM-3, BTLA, VISTA, TIGIT, LAG-3, CD40, KIR, CEACAM1 , GARP, PS, CSF1 R, CD94/NKG2A, TDO, TNFR, DcR3 and combinations thereof., and (ii) a non-viable, whole cell Mycobacterium, wherein said method results in enhanced therapeutic efficacy relative to administration of the one or more checkpoint inhibitors or non-viable, whole cell Mycobacterium alone.

29. The method according to claim 28, wherein said method comprises administration of a sub-therapeutic amount of said one or more checkpoint inhibitors.

30. A method according to claim 28, wherein said one or more checkpoint inhibitors are selected from a cell, protein, peptide, antibody, ADC (antibody-drug conjugate), Fab fragment (Fab), F(ab')2 fragment, diabody, triabody, tetrabody, probody, single-chain variable region fragment (scFv), disulfide-stabilized variable region fragment (dsFv), or other antigen binding fragment thereof, directed against CTLA-4, PD-1 or PD-L1 , and combinations thereof.

31. A method according to any of claims 28 to 30, wherein said one or more blocking agents are selected from ipilimumab, nivolumab, pembrolizumab, azetolizumab, durvalumab, tremelimumab, spartalizumab, avelumab, sintilimab, toripalimab, MGA012, MGD013, MGD019, enoblituzumab, MGD009, MGC018, MEDI0680, PDR001 , FAZ053, TSR022, MBG453, relatlinab (BMS986016), LAG525, IMP321 , REGN2810(cemiplimab), REGN3767, pexidartinib, LY3022855, FPA008, BLZ945, GDC0919, epacadostat, indoximid, BMS986205, CPI-444, MEDI9447, PBF509, lirilumab and combinations thereof, preferably wherein said one or more blocking agents are selected from ipilimumab, nivolumab.

32. A method according to any of claims 28 to 31 wherein said checkpoint inhibition therapy further comprises co-stimulatory checkpoint therapy, simultaneously, separately or sequentially with administration of the Mycobacterium, wherein said co-stimulatory checkpoint therapy comprises administration of one or more binding agents, selected from a cell, protein, peptide, antibody, ADC (antibody-drug conjugate), Fab fragment (Fab), F(ab')2 fragment, diabody, triabody, tetrabody, probody, single-chain variable region fragment (scFv), disulfide-stabilized variable region fragment (dsFv), or other antigen binding fragment thereof, directed against CD27, CD28, CD40, CD122, CD137, 0X40, GITR, ICOS and combinations thereof, wherein said method results in enhanced therapeutic efficacy relative to administration of the one or more checkpoint inhibitors, co-stimulatory checkpoint therapy, or non-viable, whole cell Mycobacterium alone.

33. A method according to any claim 32, wherein said one or more binding agents are selected from utomilumab, urelumab, MOXR0916. PF04518600, MEDI0562, GSK3174988, MEDI6469. R07009789, CP870893, BMS986156, GWN323, JTX-201 1 , varlilumab, MK-4166, NKT-214 and combinations thereof.

34. A method according to any of claims 28 to 33, further comprising administering one or more additional anticancer treatments or agents, simultaneously, separately or sequentially with administration of the Mycobacterium, wherein said method results in enhanced therapeutic efficacy relative to administration of the one or more checkpoint inhibitors, co-stimulatory checkpoint therapy, one or more additional anticancer treatments or agents, or non-viable, whole cell Mycobacterium alone.

35. A method according to claim 34, wherein the one or more additional anticancer treatments or agents is selected from: adoptive cell therapy, surgical therapy, chemotherapy, radiation therapy, hormonal therapy, small molecule therapy such as metformin, receptor kinase inhibitor therapy, hyperthermia treatment, phototherapy, radioablation therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy, biological therapy, HDAC inhibitor e.g. OKI-179, BRAF inhibitor, MEK inhibitor, EGFR inhibitor, VEGF inhibitor, P13K delta inhibitor, PARP inhibitor, mTOR inhibitor, hypomethylating agents, oncolytic virus, TLR agonist including TLR2, 3, 4, 5, 7, 8 or 9 agonists, such as MRx0518 (4D Pharma), STING agonists (including MIW815 and SYNB1891), and cancer vaccines such as GVAX or CIMAvax.

36. A method according to claim 35, wherein said TLR agonists include mifamurtide (Mepact), Krestin (PSK), MRx0518 (4D Pharma), IMO-2125 (tilsotolimod), CMP-001 , MGN-1703 (lefitolimod), entolimod, SD-101 , GS-9620, imiquimod, resiquimod, MEDI4736, poly l:C, CPG7909, DSP-0509, VTX-2337 (motolimod), MEDI9197, NKTR-262, G100 or PF-3512676 and combinations thereof.

37. A method according to claim 35, wherein said chemotherapy comprises administration of one or more agents selected from: cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, cisplatin, epirubicin, capecitabine, leucovorin, folinic acid, carboplatin, oxaliplatin, gemcitabine, FOLFINROX, paclitaxel, pemetrexed, irinotecan and combinations thereof.

38. A method according to claims 34 to 37, wherein said one or more additional anticancer treatments or agents is administered intratumorally, intraarterially, intravenously, intravascularly, intrapleuraly, intraperitoneally, intratracheally, intranasally, pulmonarily, intrathecally, intramuscularly,

endoscopically, intralesionally, percutaneously, subcutaneously, regionally, stereotactically, orally or by direct injection or perfusion.

39. A method according to any of claims 28 to 38 wherein said neoplasia, tumour or cancer is associated with a sarcoma, preferably a soft tissue or non-soft tissue sarcoma.

40. A method according to any of claims 28 to 39, wherein said neoplasia, tumour or cancer is associated with a cancer selected from prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, breast cancer, pancreatic cancer, brain cancer, hepatocellular cancer, lymphoma, leukaemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, carcinoma, head and neck cancer and skin cancer.

41. A method according to claim 40, wherein said neoplasia, tumour or cancer is associated with pancreatic, colorectal, prostate, skin or ovarian cancer.

42. A method according to claim 28 or any of claims 40 or 41 , wherein the neoplasia, tumour or cancer is metastatic.

43. A method according to any of claims 28 to 42, wherein the non-viable, whole cell Mycobacterium is selected from M. vaccae, M. obuense, M. parafortuitum, M. aurum, M. indicus pranii, M. phlei and combinations thereof.

44. A method according to any of claims 28 to 43, wherein the non-viable whole cell Mycobacterium is the rough variant.

45. A method according to any of claims 28 to 44, wherein the non-viable whole cell Mycobacterium and/or checkpoint inhibitor is administered via the parenteral, oral, sublingual, nasal or pulmonary route.

46. A method according to claim 45, wherein the parenteral route is selected from subcutaneous, intradermal, subdermal, intraperitoneal, or intravenous.

47. A method according to claim 45 or 46, wherein the parenteral route comprises intratumoral, peritumoral, perilesional or intralesional administration.

48. A method according to any of claims 28 to 47, wherein the non-viable whole cell Mycobacterium is administered in an amount of from about 104 to about 1010 cells, preferably about 107 to about 109 cells.

49. A method according to any of claims 28 to 48, wherein enhanced therapeutic efficacy is measured by increased overall survival time.

50. A method according to any of claims 28 to 49, wherein enhanced therapeutic efficacy is measured by increased progression-free survival.

51. A method according to any of claims 28 to 50, wherein said enhanced therapeutic efficacy is measured by a decrease or stabilisation of tumour size of one or more said tumours, as defined by RECIST 1.1 , including stable diseases (SD), a complete response (CR) or partial response (PR) of the target tumour; and/or stable disease (SD) or complete response (CR) of one or more non-target tumours.

52. A method according to any of claims 28 to 51 , wherein enhanced therapeutic efficacy is measured by an improved overall response rate and/or increased quality of life.

53. A method according to any of claims 28 to 52, wherein said checkpoint inhibitor refractory patient exhibits an innate (primary) resistance to checkpoint inhibitor therapy or an acquired (secondary) resistance to checkpoint inhibitor therapy.

54. A method according to claim 53, wherein said checkpoint inhibitor refractory patient exhibits an innate (primary) resistance to checkpoint inhibitor therapy as demonstrated by a lack of response or an insufficient response to said checkpoint inhibitor therapy, for at least about 8 weeks, or 12 weeks.

55. A method according to claim 54, wherein said checkpoint inhibitor refractory patient exhibits an acquired (secondary) resistance to checkpoint inhibitor therapy as demonstrated by an initial response to said checkpoint therapy but with a subsequent relapse and progression of one or more tumours.

56. A method of treating, reducing, inhibiting or controlling a neoplasia, tumour or cancer in a checkpoint inhibitor refractory patient according to any of claims 28 to 55, wherein said method comprises:

(i) providing a microneedle device comprising a plurality of microneedles,

(ii) causing the microneedles to penetrate into the skin of the subject and assume an anchored state in which the microneedles are anchored in the skin and project from the microneedle device,

(iii) delivering into the skin via the microneedle a quantity of an immunomodulator, wherein said immunomodulator comprises a whole cell, non-viable Mycobacterium.

57. A kit of parts for delivering at least one immunomodulator into the skin of a checkpoint inhibitor refractory patient, comprising:

a microneedle device comprising a plurality of microneedles, and,

one or more immunodulators selected from:

a whole cell non-viable Mycobacterium such as M. vaccae, such as NCTC 1 1569, M. obuense, such as NCTC 13365, M. parafortuitum, M. aurum, M. indicus pranii, M. phlei and combinations thereof, and;

a checkpoint inhibitor, selected from a cell, protein, peptide, antibody or antigen binding fragment thereof, directed against CTLA-4, PD-1 , PD-L1 , PD-L2, LAG-3, B7-H3, B7-H4, B7-H6, A2AR, or IDO, and combinations thereof.