CD137 ENRICHMENT FOR EFFICIENT TUMOR INFILTRATING LYMPHOCYTE SELECTION

• US 20160215262A1
• Filed: 09/16/2014
• Published: 07/28/2016
• Est. Priority Date: 09/16/2013
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Powell, Daniel J. Jr.
• Granted Patent: US 10,233,425 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2239/57 Skin; melanoma
• CPC Class Codes: A61K 2239/59 Reproductive system, e.g. uterus, ovaries, cervix or testes
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/464417 Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30
• CPC Class Codes: A61K 39/464491 Melan-A/MART
• CPC Class Codes: C12N 5/0636 T lymphocytes
• CPC Class Codes: C12N 5/0638 Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
• CPC Class Codes: C12N 5/0646 Natural killers cells [NK], NKT cells

Abstract

The invention includes compositions and methods to rapidly isolate and culture cells that are potent for use in adoptive immunotherapy. In one embodiment, the isolated cells of the invention are tumor infiltrating lymphocytes (TIL) that express CD137 (also known as 4-1BB and TNFSFR9).

Claims

1. A method of culturing tumor-reactive T cells, the method comprising isolating and culturing a population of CD137+ cells from a sample of solid tumor tissue, wherein the population of CD137+ cells comprises the tumor-reactive T cells.

2. The method of claim 1, wherein the population of CD137+ cells comprises one or more of tumor-infiltrating lymphocytes (TIL), cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and lymphokine-activated killer (LAK) cells.

3. The method of claim 1, wherein the population of CD137+ cells comprises PD-1+ cells.

4. The method of claim 1, wherein the solid tumor tissue comprises cancer cells.

5. The method of claim 1, wherein the solid tumor tissue comprises tumor antigens that have been exposed to the tumor-reactive T cells.

6. The method of claim 1 further comprising enzymatically digesting the solid tumor tissue prior to isolating and culturing the population of CD137+ cells.

7. The method of claim 1 further comprising culturing the population of CD137+ cells in the presence of at least one of IL-2, IL-7 and IL-15.

8. The method of claim 1 further comprising administering the population of CD137+ cells to a subject in need thereof.

9. The method of claim 8 further comprising culturing the population of CD137+ cells for about 7 days prior to administering to the subject.

10. The method of claim 8 further comprising expanding the population of CD137+ cells prior to administering to the subject.

11. The method of claim 1 further comprising culturing the population of CD137+ cells in a presence of an immune cell stimulating ligand.

12. The method of claim 11, wherein the immune cell stimulating ligand is at least one selected from the group consisting of an anti-CD3 antibody and an anti-CD28 antibody.

13. The method of claim 1 further comprising co-culturing the population of CD137+ cells with a HLA-matched tumor cell line.

14. The method of claim 13, wherein the population of CD137+ cells produce IFN-γ

after co-culturing with the HLA-matched tumor cell line.

15. A tumor-reactive T cell isolated according to the method of claim 1.

16. A method of treating a tumor in a patient, the method comprising administering to a patient in need thereof an effective amount of a population of CD137+ cells, wherein the cells are isolated and cultured from a sample of solid tumor tissue.

17. The method of claim 16, wherein the population of CD137+ cells are autologous to the patient.

18. The method of claim 16, wherein the population of CD137+ cells comprises at least one selected from the group consisting of tumor-infiltrating lymphocytes (TIL), cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and lymphokine-activated killer (LAK) cells.

19. The method of claim 16, wherein the population of CD137+ cells comprises PD-1+ cells.

20. The method of claim 16, wherein the solid tumor tissue comprises cancer cells.

21. The method of claim 16, wherein the solid tumor tissue comprises tumor antigens that have been exposed to the tumor-reactive T cells.

22. The method of claim 16 further comprising enzymatically digesting the solid tumor tissue prior to isolating and culturing the population of CD137+ cells.

23. The method of claim 16 further comprising culturing the population of CD137+ cells in the presence of at least one of IL-2, IL-7 and IL-15.

24. The method of claim 16 further comprising culturing the population of CD137+ cells in the presence of an immune cell stimulating ligand prior to administering to the patient.

25. The method of claim 24, wherein the immune cell stimulating ligand is one or more of an anti-CD3 and anti-CD28 antibody.

26. Use of a population of CD137+ cells in the manufacture of a medicament for the treatment of a solid tumor.

27. A method of culturing tumor-reactive T cells, the method comprising isolating and culturing CD137+ cells from a sample of solid tumor tissue in a closed-chamber, wherein the population of CD137+ cells comprises the tumor-reactive T cells.