Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy

Patent metadata

Field	Value
Publication number	US-12226434-B2
Application number	US-202117147096-A
Country	US
Kind code	B2
Filing date	Jan 12, 2021
Priority date	Mar 29, 2017
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

Abstract

The present invention provides improved and/or shortened methods for expanding TILs and producing therapeutic populations of TILs, including novel methods for expanding TIL populations in a closed system that lead to improved efficacy, improved phenotype, and increased metabolic health of the TILs in a shorter time period, while allowing for reduced microbial contamination as well as decreased costs. Such TILs find use in therapeutic treatment regimens.

First claim

What is claimed is:

1. A method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs, the method comprising:
(a) obtaining a first population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments;
(b) adding the tumor fragments into a closed system;
(c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising pegylated IL-2 to produce a second population of TILs, wherein the first expansion is performed in a closed container providing a first gas-permeable surface area, wherein the first expansion is performed for about 3-11 days to obtain the second population of TILs, and wherein the transition from step (b) to step (c) occurs without opening the system;
(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional pegylated IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-11 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, wherein the second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (c) to step (d) occurs without opening the system;
(e) harvesting the therapeutic population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system;
(f) transferring the harvested TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (f) occurs without opening the system; and
(g) cryopreserving the infusion bag comprising the harvested TIL population from step (f) using a cryopreservation process.

2. The method according to claim 1 , wherein the pegylated IL-2 is NKTR-214.

3. The method according to claim 1 , wherein the medium in the first expansion and/or the second expansion is free of human serum.

4. The method according to claim 1 , wherein the therapeutic population of TILs harvested in step (e) comprises sufficient TILs for use in administering a therapeutically effective dosage to a subject.

5. The method according to claim 4 , wherein the number of TILs sufficient for administering a therapeutically effective dosage is from about 1×10 9 to about 9×10 10 .

6. The method according to claim 1 , wherein the APCs are peripheral blood mononuclear cells (PBMCs).

7. The method according to claim 1 , wherein the therapeutic population of TILs harvested in step (e) exhibits an increased subpopulation of CD8+ cells relative to the first and/or second population of TILs.

8. The method according to claim 6 , wherein the PBMCs are supplemented at a ratio of about 1:25 TIL:PBMCs.

9. The method according to claim 1 , wherein the first expansion in step (c) and the second expansion in step (d) are each individually performed within a period of 11 days.

10. The method according to claim 1 , wherein steps (a) through (f) are performed in about 10 days to about 22 days.

11. The method according to claim 1 , wherein steps (a) through (f) are performed in about 15 days to about 22 days.

12. The method according to claim 1 , wherein steps (a) through (f) are performed in about 20 days to about 22 days.

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

Assignees

• Iovance Biotherapeutics Inc

Inventors

• Wardell Seth
• Bender James
• Lotze Michael T

Classifications

• C12N2501/2321

  Interleukin-21 (IL-21) · CPC title

• C12N2501/2315

  Interleukin-15 (IL-15) · CPC title

• C12N5/0636

  T lymphocytes · CPC title

• A61K40/50

  characterised by the use of allogeneic cells · CPC title

• A61K40/428

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