Immunotherapy with in vitro-selected antigen-specific lymphocytes after non-myeloablative lymphodepleting chemotherapy

• US 8,034,334 B2
• Filed: 09/05/2003
• Issued: 10/11/2011
• Est. Priority Date: 09/06/2002
• Status: Active Grant

• Current Assignee: Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Rosenberg, Steven A, Dudley, Mark E, Wunderlich, John R
• Primary Examiner(s): BELYAVSKYI, MICHAIL A
• Application Number:
  US10/526,697
• Publication Number:
  US 20060165652A1
• Time in Patent Office: 2,958 Days
• Field of Search: None
• US Class Current: 424/93.7
• CPC Class Codes: A61K 2039/515 Animal cells
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-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 31/66 Phosphorus compounds
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/2046 IL-7
• CPC Class Codes: A61K 38/2086 IL-13 to IL-16
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/461 characterised by the cell type used
• 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 39/464491 Melan-A/MART
• CPC Class Codes: A61K 39/464492 Glycoprotein 100 [Gp100]
• 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: A61P 35/04 specific for metastasis

Abstract

A method of promoting the regression of a cancer in a mammal comprising: (i) administering to the mammal nonmyeloablative lymphodepleting chemotherapy, and (ii) subsequently administering: (a) autologous T-cells, which have been previously isolated, selected for highly avid recognition of an antigen of the cancer, the regression of which is to be promoted, and rapidly expanded in vitro only once, and, either concomitantly with the autologous T-cells or subsequently to the autologous T-cells, by the same route or a different route, a T-cell growth factor that promotes the growth and activation of the autologous T-cells, or (b) autologous T-cells, which have been previously isolated, selected for highly avid recognition of an antigen of the cancer, the regression of which is to be promoted, modified to express a T-cell growth factor that promotes the growth and activation of the autologous T-cells, and rapidly expanded in vitro only once, whereupon the regression of the cancer in the mammal is promoted.

Claims

1. A method of promoting the regression of a cancer in a mammal, which method comprises:

(i) administering to the mammal nonmyeloablative lymphodepleting chemotherapy, and

(ii) subsequently administering;

(a) autologous T-cells, which have been previously isolated, and selected for highly avid recognition of an antigen of the cancer, the regression of which is to be promoted, by stimulation of the T-cells in vitro with the antigen of the cancer, followed by one cycle of rapid expansion using irradiated allogeneic feeder cells, OKT3 antibody, and IL-2, and, either concomitantly with the autologous T-cells or subsequently to the autologous T-cells, by the same route or a different route, a T-cell growth factor that promotes the growth and activation of the autologous T-cells, or

(b) autologous T-cells, which have been previously isolated, selected for highly avid recognition of an antigen of the cancer, the regression of which is to be promoted, by stimulation of the T-cells in vitro with the antigen of the cancer, and modified to express a T-cell growth factor that promotes the growth and activation of the autologous T-cells, followed by one cycle of rapid expansion using irradiated allogeneic feeder cells, OKT3 antibody, and IL-2 whereupon the regression of the cancer in the mammal is promoted.

2. The method of claim 1, wherein the T-cell growth factor is IL-2, IL-7, IL-15, or a combination of two or all of the foregoing.

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

4. The method of claim 3, wherein around 60 mg/kg of cyclophosphamide are administered for two days after which around 25 mg/m² fludarabine are administered for five days.

5. The method of claim 4, wherein the cyclophosphamide and fludarabine are administered intravenously.

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

7. The method of claim 6, wherein from about 5 to about 12 doses of IL-2 are administered.

8. The method of claim 7, wherein around 9 doses of IL-2 are administered.

9. The method of claim 6, wherein the dose of IL-2 is administered as a bolus intravenous injection.

10. The method of claim 1, wherein from about 1.2×

10¹⁰ T-cells to about 4.3×

10¹⁰ T-cells are administered.

11. The method of claim 1, wherein the T-cells are administered as an intravenous infusion.

12. The method of claim 11, wherein the intravenous infusion lasts approximately 30-60 min.

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

14. The method of claim 13, wherein the T-cells bind to MART-1 (SEQ ID NO:

1).

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

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

17. The method of claim 1, wherein the antigen of the cancer consists of amino acids 26-35 of MART-1 (SEQ ID NO:

1), in which amino acid 27 has been replaced with leucine.

18. The method of claim 1, wherein the antigen of the cancer is the gp100:

209-217 (210M) peptide (SEQ ID NO;

     2).