Use of mTOR Inhibitors to Enhance T Cell Immune Responses

• US 20110129496A1
• Filed: 08/05/2009
• Published: 06/02/2011
• Est. Priority Date: 08/05/2008
• Status: Active Grant

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Araki, Koichi, Larsen, Christian P., Ahmed, Rafi
• Granted Patent: US 8,840,899 B2
• Time in Patent Office: Days
• US Class Current: 424/204.1
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 2039/5258 Virus-like particles
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• 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 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2710/24122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2710/24143 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2730/10134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2740/13023 : Virus like particles [VLP]
• CPC Class Codes: C12N 2740/13043 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2760/10034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2770/10022 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Abstract

It is disclosed herein that treatment of a subject with an mTOR inhibitor enhances antigen-specific T cell immune responses. Thus, provided herein is a method of enhancing an antigen-specific T cell response in a subject by administering to the subject a therapeutically effective amount of an mTOR inhibitor. The antigen can be any antigen, such as an antigen from a pathogen or a vaccine, or a tumor antigen. In some embodiments, the method further comprises administering to the subject a vaccine, such as a virus vaccine or a cancer vaccine. The mTOR inhibitor can be administered either before or after vaccination to enhance the quantity and quality of the T cell immune response and immunological memory. In some examples, the mTOR inhibitor is rapamycin or a rapamycin analog.

Claims

1. A method of enhancing an antigen-specific T cell response in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an antigen and a therapeutically effective amount of an mTOR inhibitor, thereby enhancing an antigen-specific T cell response against the antigen, wherein enhancing an antigen-specific T cell response in the subject comprises increasing the number of antigen-specific T cells or enhancing the quality of antigen-specific T cells in the subject.

2. The method of claim 1, wherein the T cells are CD8⁺ T cells.

3. The method of claim 2, wherein the CD8⁺ T cells are CD8⁺ memory T cells.

4. The method of claim 3, wherein enhancing the quality of CD8⁺ memory T cells in the subject is characterized by an increase in expression of CD127, an increase in expression of CD62L, an increase in expression of Bcl-2, an increase in expression of CD27, a decrease in expression of KLRG-1, or a combination thereof, relative to expression in the absence of treatment with an mTOR inhibitor.

5. The method of claim 2, wherein the CD8⁺ T cells are CD8⁺ effector T cells.

6. The method of claim 5, wherein enhancing the quality of CD8⁺ effector T cells in the subject is characterized by an increase in the proportion of CD127^HighKLRG-1^Low CD8⁺ T cells, relative to the proportion of CD127^HighKLRG-1^Low CD8⁺ T cells in the absence of treatment with an mTOR inhibitor.

7. The method of claim 1, wherein the T cells are CD4⁺ T cells.

8. The method of claim 7, wherein the CD4⁺ T cells are CD4⁺ memory T cells.

9. The method of any one of claims 1-8, wherein the antigen is from a vaccine.

10. The method of claim 9, wherein the vaccine comprises an antigen from a pathogen.

11. The method of claim 10, wherein the pathogen is a virus, bacterium, fungus or parasite.

12. The method of claim 11, wherein the pathogen is a virus.

13. The method of claim 11, wherein the subject in need of treatment has an acute infection.

14. The method of claim 11, wherein the subject in need of treatment has a chronic infection.

15. The method of claim 9, wherein the vaccine comprises a tumor antigen.

16. The method of claim 15, wherein the tumor is a hematologic cancer or a solid tumor.

17. The method of claim 16, wherein the hematologic cancer is a leukemia or a lymphoma.

18. The method of claim 16, wherein the solid tumor is a carcinoma, melanoma, sarcoma or central nervous system tumor.

19. The method of any one of claims 1-18, wherein the mTOR inhibitor is administered prior to administering the antigen.

20. The method of claim 19, wherein the mTOR inhibitor is administered up to three days prior to administering the antigen.

21. The method of claim 19, wherein the mTOR inhibitor is administered up to one day prior to administering the antigen.

22. The method of any one of claims 1-18, wherein the mTOR inhibitor is administered after administering the antigen.

23. The method of claim 22, wherein the mTOR inhibitor is administered up to 20 days after administering the antigen.

24. The method of claim 22, wherein the mTOR inhibitor is administered up to 10 days after administering the antigen.

25. The method of any one of claims 1-18, wherein the mTOR inhibitor is administered on the same day as the antigen.

26. The method of any one of claims 1-25, wherein the mTOR inhibitor is administered in a single dose.

27. The method of any one of claims 1-25, wherein the mTOR inhibitor is administered daily.

28. The method of any one of claims 1-25, wherein the mTOR inhibitor is administered continuously.

29. The method of claim 28, wherein the mTOR inhibitor is administered in a patch.

30. The method of any one of claims 1-29, wherein the mTOR inhibitor is rapamycin or a rapamycin analog.

31. The method of claim 30, wherein the mTOR inhibitor is rapamycin.

32. The method of claim 31, wherein the dose of rapamycin is about 0.01 to about 0.15 mg/kg.

33. The method of claim 32, wherein the blood concentration of rapamycin in the subject is about 5 to about 20 ng/ml.

34. The method of any one of claims 22-24, wherein the mTOR inhibitor is administered during the T cell contraction phase.

35. The method of claim 34, wherein the mTOR inhibitor is rapamycin and the dose of rapamycin is about 0.2 to about 1.0 mg/kg.

36. The method of claim 35, wherein the blood concentration of rapamycin in the subject is about 40 to about 100 ng/ml.

37. The method of any one of claims 1-36, further comprising measuring the number of antigen-specific T cells in a sample obtained from the subject.

38. The method of any one of claims 1-37, further comprising measuring the expression of one or more of CD127, CD62L, Bcl-2, CD27 and KLRG-1 in T cells from a sample obtained from the subject.

40. The method of claim 37, further comprising measuring the proportion of antigen-specific CD127^HighKLRG-1^Low CD8⁺ T cells in the subject relative to the proportion of CD127^H1 KLRG-1^Low CD8⁺ T cells in the absence of treatment.

39. A method of increasing the proportion of antigen-specific CD127^HighKLRG-1^Low CD8⁺ T cells in a subject, comprising administering to the subject a therapeutically effective amount of an antigen and a therapeutically effective amount of an mTOR inhibitor, thereby increasing the proportion of antigen-specific CD127^HighKLRG-1^Low CD8⁺ T cells in the subject.

43. The method of any one of claims 39-42, wherein the subject (a) has an acute or chronic infection;

or (b) has a tumor.

41. A method of increasing expression of CD127, CD62L, Bcl-2 and CD27, and decreasing expression of KLRG-1, in CD8⁺ T cells of a subject, comprising administering to the subject an antigen and a therapeutically effective amount of an mTOR inhibitor, thereby increasing expression of CD127, CD62L, Bcl-2 and CD27, and decreasing expression of KLRG-1, in CD8⁺ T cells of the subject.

42. The method of claim 41, further comprising measuring expression of CD127, CD62L, Bcl-2, CD27 and KLRG-1 in CD8⁺ T cells of the subject relative to expression in the absence of treatment.

44. Use of an mTOR inhibitor and a vaccine comprising an antigen in the manufacture of a medicament for enhancing an antigen-specific T cell response in a subject, wherein enhancing an antigen-specific T cell response in a subject comprises increasing the number of antigen-specific T cells or enhancing the quality of antigen-specific T cells in the subject.

45. A composition comprising (i) an mTOR inhibitor and (ii) a purified antigen and/or a vaccine.

46. The composition of claim 45, further comprising a pharmaceutically acceptable carrier.

47. Use of the composition of claim 45 or claim 46 in the manufacture of a medicament for enhancing an antigen-specific T cell response in a subject, wherein enhancing an antigen-specific T cell response in a subject comprises increasing the number of antigen-specific T cells or enhancing the quality of antigen-specific T cells in the subject.

48. The composition of claim 45 or claim 46 for use in a method of enhancing an antigen-specific T cell response in a subject, wherein enhancing an antigen-specific T cell response in a subject comprises increasing the number of antigen-specific T cells or enhancing the quality of antigen-specific T cells in the subject.