A CHECKPOINT INHIBITOR AND A WHOLE CELL MYCOBACTERIUM FOR USE IN CANCER THERAPY

• US 20170028047A1
• Filed: 12/16/2014
• Published: 02/02/2017
• Est. Priority Date: 12/20/2013
• Status: Active Grant

• Current Assignee: Immodulon Therapeutics Limited (Lifexx SA)
• Original Assignee: Immodulon Therapeutics Limited (Lifexx SA)
• Inventors: AKLE, Charles, GRANGE, John, BILYARD, Kevin
• Granted Patent: US 10,610,577 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/521 inactivated (killed)
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 39/04 Mycobacterium, e.g. Mycobacterium tuberculosis
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

An immunomodulator is for use in the treatment, reduction, inhibition or control of a neoplastic disease in a patient intended to undergo checkpoint inhibition therapy, simultaneously, separately or sequentially with administration of the immunomodulator. The immunomodulator preferably includes a whole cell Mycobacterium, such as M. vaccaeor M. obuense.

Claims

1. A non-pathogenic heat killed Mycobacterium for use in the treatment, reduction, inhibition or control of a neoplastic disease in a patient intended to undergo checkpoint inhibition therapy simultaneously, separately or sequentially with administration of the Mycobacterium.

2. The non-pathogenic heat killed Mycobacterium for use according to claim 1, wherein said checkpoint inhibition therapy comprises administration of a blocking agent, selected from a cell, protein, peptide, antibody or antigen binding fragment thereof, directed against CTLA-4, PD-1, PD-L1, TIM-3, BTLA, VISTA, LAG-3 and combinations thereof.

3. The non-pathogenic heat killed Mycobacterium for use according to claim 1, wherein said checkpoint inhibition therapy comprises administration of a sub-therapeutic amount and/or duration of said blocking agent, selected from a cell, protein, peptide, antibody or antigen binding fragment thereof.

4. The non-pathogenic heat killed Mycobacterium for use according to claim 1, wherein said neoplastic disease 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, skin cancer and soft tissue sarcoma.

5. The non-pathogenic heat killed Mycobacterium for use according to claim 4, wherein said neoplastic disease is associated with pancreatic cancer.

6. The non-pathogenic heat killed Mycobacterium for use according to claim 1, wherein said neoplastic disease is metastatic.

7. The non-pathogenic heat killed Mycobacterium for use according to claim 1, wherein the Mycobacterium comprises a whole cell Mycobacterium.

9. The non-pathogenic heat killed Mycobacterium for use according to claim 7, wherein the non-pathogenic heat-killed Mycobacterium is selected from M. vaccae, M. obuense, M. parafortuitum, M. aurum, M. indicus pranii and combinations thereof.

10. The non-pathogenic heat killed Mycobacterium for use according to claim 9, wherein the nonpathogenic heat-killed Mycobacterium is the rough variant.

11. The non-pathogenic heat killed Mycobacterium for use according to claim 9, wherein the nonpathogenic heat-killed Mycobacterium is for administration via the parenteral, oral, sublingual, nasal or pulmonary route.

12. The non-pathogenic heat killed Mycobacterium for use according to claim 11, wherein the parenteral route is selected from subcutaneous, intradermal, subdermal, intraperitonal, or intravenous.

13. The non-pathogenic heat killed Mycobacterium for use according to claim 12, wherein the parenteral route excludes intratumoural injection.

14. The non-pathogenic heat killed Mycobacterium for use according to claim 1, wherein said checkpoint inhibition therapy comprises administration of a blocking agent, selected from a cell, protein, peptide, antibody or antigen binding fragment thereof, directed against PD-L1 or PD-1.

15. The non-pathogenic heat killed Mycobacterium for use according to claim 1, wherein administration of said immunomodulator is prior to and/or after the checkpoint inhibition therapy.

8. (canceled)

16. A method of treating, reducing, inhibiting or controlling a neoplasia, tumour or cancer in a subject, wherein said method comprises simultaneously, separately or sequentially administering to the subject, (i) a checkpoint inhibitor, and (ii) non-pathogenic heat killed Mycobacterium, wherein said method results in enhanced therapeutic efficacy relative to administration of the checkpoint inhibitor or immunomodulator alone.

17. A method according to claim 16, wherein said checkpoint inhibition therapy comprises administration of a blocking agent, selected from a cell, protein, peptide, antibody or antigen binding fragment thereof, directed against CTLA-4, PD-1, PD-L1, TIM-3, BTLA, VISTA, LAG-3 and combinations thereof.

18. A method according to claim 16, wherein said checkpoint inhibitor is a blocking agent, selected from a cell, protein, peptide, antibody or antigen binding fragment thereof, directed against PD-1 or PD-L1.

19. A method according to claim 16, wherein said checkpoint inhibition therapy comprises administering a sub-therapeutic amount of said blocking agent, selected from a cell, protein, peptide, antibody or antigen binding fragment thereof.

20. A method according to claim 16, 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, skin cancer and soft tissue sarcoma.

21. A method according to claim 20, wherein said neoplasia, tumour or cancer is associated with pancreatic cancer.

22. A method according to claim 16, wherein the neoplasia, tumour or cancer is metastatic.

23. A method according to claim 16, wherein the non-pathogenic heat killed Mycobacterium comprises a whole cell Mycobacterium.

31. A method according to claim 16, wherein enhanced therapeutic efficacy is measured by increased overall survival time.

32. A method according to claim 16, wherein enhanced therapeutic efficacy is measured by increased progression-free survival.

33. A method according to claim 16, wherein enhanced therapeutic efficacy is measured by a decrease or stabilisation of tumour size.

34. A method according to claim 16, wherein enhanced therapeutic efficacy is measured by increased quality of life.

24. (canceled)

25. A method according to claim 24, wherein the non-pathogenic heat-killed Mycobacterium is selected from M. vaccae, M. obuense, M. parafortuitum, M. aurum, M. indicus pranii and combinations thereof.

26. The method according to claim 24 or 25, wherein the non-pathogenic heat-killed Mycobacterium is the rough variant.

27. A method according to claim 25, wherein the non-pathogenic heat-killed Mycobacterium is administered via the parenteral, oral, sublingual, nasal or pulmonary route.

28. A method according to claim 27, wherein the parenteral route is selected from subcutaneous, intradermal, subdermal, intraperitonal, or intravenous.

29. A method according to claim 27, wherein the parenteral route excludes intratumoural injection.

30. A method according to claim 24, wherein the amount of non-pathogenic heat-killed Mycobacterium administered is from 10⁷ to 10⁹ cells.