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

Patent metadata

Field	Value
Publication number	US-12226522-B2
Application number	US-202418410900-A
Country	US
Kind code	B2
Filing date	Jan 11, 2024
Priority date	Nov 5, 2018
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 of administering tumor infiltrating lymphocytes (TILs) to a subject with endometrial cancer, wherein the method comprises:
(a) adding into a closed system a plurality of tumor fragments comprising a first population of TILs obtained by processing a sample of tumor tissue resected from the subject with endometrial cancer into the plurality of tumor fragments;
(b) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising 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 (a) to step (b) occurs without opening the system;
(c) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional 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 second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (b) to step (c) occurs without opening the system;
(d) harvesting the third population of TILs obtained from step (c), wherein the transition from step (c) to step (d) occurs without opening the system;
(e) transferring the harvested third TIL population from step (d) to an infusion bag, wherein the transfer from step (d) to (e) occurs without opening the system;
(f) cryopreserving the infusion bag comprising the harvested TIL population from step (e) using a cryopreservation process; and
(g) administering a therapeutically effective dosage of the third population of TILs from the infusion bag in step (f) to the subject.

2. 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.

3. The method according to claim 1 , wherein the third population of TILs harvested in step (d) comprises a therapeutic population of TILs.

4. The method according to claim 1 , wherein the therapeutically effective dosage in step (g) comprises from about 1×10 9 to about 1×10 11 TILs.

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

6. The method according to claim 5 , wherein the PBMCs are allogenic irradiated PBMCs.

7. The method according to claim 5 , wherein a ratio of TILs: PBMCs is about 1:25.

8. The method according to claim 1 , wherein prior to administering the therapeutically effective dosage of TIL cells in step (g), a non-myeloablative lymphodepletion regimen has been administered to the subject.

9. The method according to claim 8 , where the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg/m 2 /day for two days followed by administration of fludarabine at a dose of 25 mg/m 2 /day for five days.

10. The method according to claim 1 , further comprising a step of treating the subject with an IL-2 regimen starting on the day after administration of the TIL cells to the subject in step (g).

11. The method according to claim 10 , wherein the high dose IL-2 regimen comprises 600,000 or 720,000 IU/kg administered as a 15-minute bolus intravenous infusion every eight hours.

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

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

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

15. The method according to claim 1 , wherein the closed container in step (b) and/or step (c) is a gas-permeable bag.

Assignees

• Iovance Biotherapeutics Inc
• Lovance Biotherapeutics Inc

Inventors

• Wardell Seth
• Moreno Maritza Lienlaf

Classifications

• A61K40/42

  Cancer antigens · CPC title

• A61K40/11

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

• C12N2502/11

  blood or immune system cells · CPC title

• C12N2501/2302

  Interleukin-2 (IL-2) · CPC title

• C07K16/2809

  against the T-cell receptor (TcR)-CD3 complex · CPC title