Granted Patent
B2
US 12,485,145 · App. 18/957,327 · Granted Dec 2, 2025
Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy
Inventors:
Seth Wardell (Tampa, FL); James Bender (Rancho Santa Margarita, CA); Michael T. Lotze (Pittsburgh, PA)
Assignee:
Iovance Biotherapeutics, Inc.
A61K35/17A01N1/162A61K9/0019A61K31/675A61K31/7076A61K38/2013A61K40/11A61K40/428A61P35/00C12N5/0634C12N5/0636C12N5/0638A61K38/217A61K39/0011A61K2039/5154A61K2039/5156A61K2039/5158A61K2039/55533A61K40/50C12N2501/04C12N2501/2302C12N2501/2315C12N2501/2321C12N2501/24C12N2501/603C12N2502/11C12N2506/30
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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.
Claims (28)
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 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 7-11 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 IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-12 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 (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 first expansion in step (c) is performed for about 11 days.
3 . The method according to claim 1 , wherein the second expansion in step (d) is performed for about 11 days to about 12 days.
4 . The method according to claim 1 , wherein the second expansion in step (d) is performed for about 11 days.
5 . The method according to claim 1 , wherein the second expansion in step (d) is performed for about 12 days.
6 . The method according to claim 1 , wherein the second expansion in step (d) is performed for about 288 hours.
7 . The method according to claim 1 , wherein the first expansion in step (c) is performed for about 11 days and the second expansion in step (d) is performed for about 11 days to about 12 days.
8 . The method according to claim 1 , wherein the first expansion in step (c) is performed for about 11 days and the second expansion in step (d) is performed for about 12 days.
9 . The method according to claim 1 , wherein steps (a) through (f) are performed in about 14 days to about 23 days.
10 . The method according to claim 1 , wherein steps (a) through (f) are performed in about 22 days to about 23 days.
11 . The method according to claim 1 , wherein steps (a) through (f) are performed in about 23 days.
12 . The method according to claim 1 , wherein about 30 to about 60 tumor fragments are added to the closed system in step (b).
13 . The method according to claim 1 , wherein the first expansion is performed in a closed container bioreactor.
14 . The method according to claim 13 , wherein the closed container bioreactor is a G-REX-100MCS bioreactor.
15 . The method according to claim 1 , wherein the second expansion is performed in a closed container bioreactor.
16 . The method according to claim 15 , wherein the closed container bioreactor is a G-REX-500MCS bioreactor.
17 . 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.
18 . The method according to claim 17 , wherein the number of TILs sufficient for administering a therapeutically effective dosage is from about 1×10 9 to about 10×10 10 .
19 . The method according to claim 17 , wherein the number of TILs sufficient for administering a therapeutically effective dosage is from about 7×10 9 to about 10×10 10 .
20 . The method according to claim 1 , wherein the APCs are peripheral blood mononuclear cells (PBMCs).
21 . The method according to claim 20 , wherein the PBMCs are supplemented at a ratio of about 1:25 TIL:PBMCs.
Continuity (12)
Provisional Application
62596374
· Dec 8, 2017
Provisional Application
62582874
· Nov 7, 2017
Provisional Application
62577655
· Oct 26, 2017
Provisional Application
62567121
· Oct 2, 2017
Provisional Application
62559374
· Sep 15, 2017
Provisional Application
62554538
· Sep 5, 2017
Provisional Application
62548306
· Aug 21, 2017
Provisional Application
62539410
· Jul 31, 2017
Provisional Application
62478506
· Mar 29, 2017
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