Processes for the production of tumor infiltrating lymphocytes (TILs) and methods of using the same

Patent metadata

Field	Value
Publication number	US-12516291-B2
Application number	US-202017778309-A
Country	US
Kind code	B2
Filing date	Dec 8, 2020
Priority date	Dec 11, 2019
Publication date	Jan 6, 2026
Grant date	Jan 6, 2026

Abstract

The present invention relates to methods for expanding TILs from tumor tissue using a long first expansion process and a shorter second expansion process. A method for expanding TIL includes obtaining a first population of TILs from a tumor resected from a subject, performing a first expansion for a period of about 21 day to about 35 days by culturing the first population of TILs in a cell culture medium comprising 4-1BB agonist, IL-2, and OKT-3 to produce a second population of TILs, and performing a second expansion for a period of about 7 days to about 10 days by supplementing the cell culture medium of the second population of TILs with antigen presenting cells (APCs) and additional 4-1BB agonist, IL-2, and OKT-3, and culturing to produce a third population of TILs, wherein the third population of TILs is a therapeutic population of TILs.

First claim

What is claimed is:

1 . A method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising:
(a) obtaining a first population of TILs from a tumor resected from a subject; (b) performing a first expansion for a period of about 21 day to about 35 days by culturing the first population of TILs in a cell culture medium comprising 4-1BB agonist, IL-2, and OKT-3 to produce a second population of TILs; and (c) performing a second expansion for a period of about 7 days to about 10 days by supplementing the cell culture medium of the second population of TILs with antigen presenting cells (APCs) and additional 4-1BB agonist, IL-2, and OKT-3 and culturing to produce a third population of TILs, wherein the third population of TILs is a therapeutic population of TILs.

2 . The method of claim 1 , further comprising:
(d) harvesting the therapeutic population of TILs obtained from step (c); and (e) transferring the harvested TIL population from step (d) to an infusion bag.

3 . The method of claim 1 , further comprising performing the culturing step (b) in the presence of antigen presenting cells (APCs).

4 . The method of claim 1 , wherein the APCs are peripheral blood mononuclear cells (PBMCs).

5 . The method of claim 3 , wherein the ratio of the number of APCs in the second expansion to the number of APCs in the first expansion is in a range of from about 1.5:1 to about 20:1.

6 . The method of claim 1 , wherein the second population of TILs is cryopreserved.

7 . The method of claim 1 , wherein the first expansion is performed over a period of about 21 to 28 days, and the second expansion is performed over a period of about 7 days to 9 days.

8 . The method of claim 1 , wherein the first expansion is performed over a period of about 28 days to 35 days, and the second expansion is performed over a period of about 7 days to 9 days.

9 . The method of claim 1 , wherein the first expansion is performed over a period of about 21 days, and the second expansion is performed over a period of about 7 days to 9 days.

10 . The method of claim 1 , wherein one or both of the second or third population of TILs comprises an increased subpopulation of effector T cells and/or central memory T cells relative to the first or second population of TILs.

11 . The method of claim 1 , wherein one or both of the second or third population of TILs comprises an increased subpopulation of cells expressing one or more of BTLA, Ki67, LAG3, TIGIT, and TIM3.

12 . The method of claim 1 , wherein one or both of the second or third population of TILs comprises a decreased subpopulation of cells expressing one or more of CTLA-4, ICOS, PD-1, CD103+CD69+, and CD103+CD69−.

13 . The method of claim 1 , wherein one or both of the second or third population of TILs comprises an increased subpopulation of CD45+ cells.

14 . The method of claim 1 , wherein one or both of the second or third population of TILs comprises an increased subpopulation of CD45+CD3+ cells.

15 . The method of claim 1 , wherein one or both of the second or third population of TILs comprises an increased subpopulation of CD8+ cells.

16 . The method of claim 1 , wherein one or both of the second or third population of TILs comprises a decreased subpopulation of CD4+ cells.

17 . The method of claim 1 , wherein the tumor is a of a cancer type selected from the group consisting of thyroid cancer, melanoma, cervical cancer, endometrial cancer, colon cancer, and colorectal cancer.

18 . The method of claim 1 , wherein the second population of TILs is at least 50-fold greater in number than the first population of TILs.

19 . The method of claim 1 , wherein the second population of TILs is at least 4×10 7 cells.

20 . The method of claim 1 , wherein the 4-1BB agonist is utomilumab or urelumab.

Assignees

• Iovance Biotherapeutics Inc

Inventors

• Chartier-Courtaud Cecile
• Wardell Seth
• Moreno Maritza Lienlaf

Classifications

• A61K40/428

  Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K2239/38

  characterised by the dose, timing or administration schedule · CPC title

• A61K2239/31

  characterized by the route of administration · CPC title

• C12N2502/11

  blood or immune system cells · CPC title