ADOPTIVE CELL THERAPY WITH YOUNG T CELLS

• US 20110052530A1
• Filed: 08/26/2010
• Published: 03/03/2011
• Est. Priority Date: 08/28/2009
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Original Assignee: The United States of America As Represented By The Secretary of Agriculture
• Inventors: Dudley, Mark E., Rosenberg, Steven A.
• Granted Patent: US 8,383,099 B2
• Time in Patent Office: Days
• US Class Current: 424/85.2
• CPC Class Codes: A61K 2039/515 Animal cells
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/57 Skin; melanoma
• 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 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 35/26 Lymph; Lymph nodes; Thymus; Spleen; Splenocytes; Thymocytes
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/2046 IL-7
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 38/2086 IL-13 to IL-16
• 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 39/4644 Cancer antigens
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 2501/23 Interleukins [IL]
• CPC Class Codes: C12N 2501/515 CD3, T-cell receptor complex
• CPC Class Codes: C12N 5/0636 T lymphocytes

Abstract

The invention provides a method of promoting regression of a cancer in a mammal comprising (i) culturing autologous T cells; (ii) expanding the cultured T cells; (iii) administering to the mammal nonmyeloablative lymphodepleting chemotherapy; and (iv) after administering nonmyeloablative lymphodepleting chemotherapy, administering to the mammal the expanded T cells, wherein the T cells administered to the mammal are about 19 to about 35 days old and have not been screened for specific tumor reactivity, whereupon the regression of the cancer in the mammal is promoted.

Claims

1. A method of promoting regression of a cancer in a mammal comprising:

(i) culturing autologous T cells;

(ii) expanding the cultured T cells using OKT3 antibody, IL-2, and feeder lymphocytes, wherein the cultured T cells are enriched for CD8+ T cells prior to expansion of the T cells;

(iii) administering to the mammal nonmyeloablative lymphodepleting chemotherapy; and

(iv) after administering nonmyeloablative lymphodepleting chemotherapy, administering to the mammal the expanded T cells, wherein the T cells administered to the mammal are about 19 to about 35 days old and have not been screened for specific tumor reactivity, whereupon the regression of the cancer in the mammal is promoted.

2. The method according to claim 1, wherein the administered T cells have a higher expression of CD27 than T cells that are about 44 days old.

3. The method according to claim 1, wherein the administered T cells have a higher expression of CD28 than T cells that are about 44 days old.

4. The method according to claim 1, wherein the administered T cells have a mean telomere length that is longer than that of T cells that are about 44 days old.

5. The method according to claim 1, wherein either

a) the T-cells are modified to express a T-cell growth factor that promotes the growth and activation of the autologous T-cells;

or

b) a T-cell growth factor that promotes the growth and activation of the autologous T-cells is administered to the mammal either concomitantly with the autologous T-cells or subsequently to the autologous T-cells.

6. The method of claim 5, wherein the T-cell growth factor is interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-15 (IL-15), interleukin-12 (IL-12) or a combination of two or all of the foregoing.

7. The method of claim 1 wherein the nonmyeloablative lymphodepleting chemotherapy comprises the administration of cyclophosphamide and fludarabine.

8. The method of claim 7, wherein around 60 mg/kg of cyclophosphamide are administered for two days after which around 25 mg/m² fludarabine are administered for five days.

9. The method of claim 6, wherein a dose of about 720,000 IU/kg of IL-2 is administered three times daily until tolerance.

10. The method of claim 9, wherein from about 5 to about 15 doses of IL-2 are administered.

11. The method of claim 9, wherein the dose of IL-2 is administered as a bolus intravenous injection.

12. The method of claim 1, wherein from about 1.0×

10¹⁰ T-cells to about 13.7×

10¹⁰ T-cells are administered.

13. The method of claim 9, wherein around 5.0×

10¹⁰ T-cells are administered.

14. The method of claim 1, wherein the cancer is melanoma.

15. The method of claim 14, wherein the T-cells bind to melanoma antigen recognized by T-cells-1 (MART-1).

16. The method of claim 1, wherein the cancer is metastatic.

17. The method of claim 1, wherein the mammal is a human.

18. The method of claim 1, wherein the administered T cells have a higher frequency of CD4+ cells than T cells that are about 44 days old.

19. The method of claim 1, wherein the T cells are modified to express a T cell receptor having antigenic specificity for a cancer antigen.

20. The method of claim 1, further comprising testing the expanded T cells for potency.

21. A method of promoting regression of a cancer in a mammal comprising:

(i) culturing autologous T cells;

(ii) expanding the cultured T cells using OKT3 antibody, IL-2, and feeder lymphocytes, wherein the cultured T cells are enriched for CD8+ T cells prior to expansion of the T cells;

(iii) administering to the mammal nonmyeloablative lymphodepleting chemotherapy; and

(iv) after administering nonmyeloablative lymphodepleting chemotherapy, administering to the mammal the expanded T cells, wherein the T cells administered to the mammal are about 19 to about 29 days old, whereupon the regression of the cancer in the mammal is promoted.

22. The method of claim 21, wherein the T cells administered to the mammal have not been screened for specific tumor reactivity.