CANCER THERAPY VIA A COMBINATION OF EPIGENETIC MODULATION AND IMMUNE MODULATION

• US 20160193239A1
• Filed: 09/05/2014
• Published: 07/07/2016
• Est. Priority Date: 09/05/2013
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Baylin, Stephen B., Pardoll, Drew M., Topalian, Suzanne L.
• Granted Patent: US 10,966,998 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 38/15 Depsipeptides; Derivatives thereof
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/154 Methylation markers

Abstract

Cancer therapies that combine epigenetic modulating agent(s) with immune modulating agent(s), which were remarkably identified to provide an improved treatment regimen over single agent therapy, are disclosed. In particular embodiments, the invention provides for improved treatment of NSCLC in patients via administration of exemplary immune modulating agents anti-PD-1 antibody or anti-PD-L1 antibody, which were observed to show enhanced activity in combination with the exemplary epigenetic modulating agent 5-deoxyazacytidine. Further, expression markers of responsive neoplastic cells are also disclosed.

Claims

1. A method of treating or preventing a neoplastic condition in a subject in need thereof comprising administering (i) an epigenetic modulating agent and (ii) an immune modulating agent, thereby treating or preventing the neoplastic condition in the subject.

2. The method of claim 1, wherein said epigenetic modulating agent is administered before said immune modulating agent, or wherein said epigenetic modulating agent and said immune modulating agent are administered concurrently.

4. The method of claim 1, wherein said epigenetic modulating agent is a demethylating agent.

5. The method of claim 1, wherein said epigenetic modulating agent is selected from the group consisting of a DNA methyl transferase (DNMT) inhibitor and a histone deacetylase (HDAC) inhibitor.

6. The method of claim 1, wherein said epigenetic modulating agent is selected from the group consisting of 5-azacytidine, 5-aza-2′

-deoxycytidine, a dinucleotide containing 5-aza-CdR, Vorinostat, Romidepsin, Panobinostat and HDAC inhibitor CI-994.

7. The method of claim 1, wherein said epigenetic modulating agent is 5-azadeoxycytidine.

8. The method of claim 1, further comprising administering a MAC inhibitor.

9. The method of claim 1, wherein said immune modulating agent is selected from the group consisting of an antibody, a compound and a recombinant molecule.

10. The method of claim 1, wherein said immune modulating agent is selected from the group consisting of an anti-PD-1 antibody and an anti-PD-L1 antibody.

11. The method of claim 1, wherein said immune modulating agent inhibits an immune checkpoint pathway, wherein said immune checkpoint pathway is selected from the group consisting of CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200 and PD-1.

13. The method of claim 1, wherein said immune modulating agent is a cancer vaccine.

14. The method of claim 13, further comprising administering an agent that inhibits an immune checkpoint pathway.

15. The method of claim 1, wherein said immune modulating agent is an agonist for a co-stimulatory immune receptor, wherein said agonist is selected from the group consisting of an antibody, a drug and a recombinant molecule.

17. The method of claim 15, wherein said immune receptor is selected from the group consisting of CD40, OX-40 and CD27.

18. The method of claim 15, further comprising administering a cancer vaccine.

19. The method of claim 1, wherein said neoplastic condition is selected from the group consisting of lung cancer, colon cancer and ovarian cancer.

20. The method of claim 19, wherein said lung cancer is NSCLC.

21. The method of claim 1, wherein shrinkage of the neoplastic condition in said subject occurs.

22. The method of claim 1, wherein said administering stabilizes the neoplastic condition in said subject.

23. The method of claim 22, wherein said stabilization is for a duration selected from the group consisting of one month or more, two months or more, three months or more, four months or more, six months or more and eight months or more.

3. (canceled)

12. (canceled)

16. (canceled)

24. A method for selectively inhibiting the growth of a cell comprising contacting a cell with an amount of (i) an epigenetic modulating agent and (ii) an immune modulating agent sufficient to inhibit the growth of the cell.

25. The method of claim 24, wherein said cell is a cancer cell of a subject, and wherein said cancer cell is selected from the group consisting of a lung cancer cell, an ovarian cancer cell and a colon cancer cell.

27. The method of claim 24, wherein said lung cancer cell is a non-small cell lung cancer cell.

28. The method of claim 24, wherein said cell is a tumor cell of a subject or wherein said cell is a human cell.

29. The method of claim 24, wherein said cell is a tumor cell in vitro.

26. (canceled)

30. (canceled)

31. A method for improving the anti-neoplastic effect of an immune modulating agent in a subject comprising administering an epigenetic modulating agent and the immune modulating agent to a subject, wherein said anti-neoplastic effect of the immune modulating agent in the subject is enhanced as compared to an appropriate control subject;

or

a method of assessing the potential or realized anti-neoplastic effect of an epigenetic modulating agent and an immune modulating agent in a subject comprising measuring the expression of one or more genes selected from the group consisting of IRF7 and the genes of FIG. 25, as a biomarker for the potential or realized anti-neoplastic effect of the epigenetic modulating agent and the immune modulating agent in the subject.

32. (canceled)