Granted Patent
B2
US 12,642,816 · App. 17/147,080 · Granted Jun 2, 2026
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 (42)
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, and optionally IL-15 or IL-21, 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 10 days, 11 days, or 12 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, antigen presenting cells (APCs), and optionally IL-15 or IL-21, to produce a third population of TILs, wherein the second expansion is performed for about 10 days, 11 days, or 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, wherein the transition from step (c) to step (d) occurs without opening the system, and wherein the cell culture medium in either step (c) or step (d) comprises IL-15 or IL-21;
(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 medium in the first expansion and/or the second expansion is free of human serum.
3 . 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.
4 . The method according to claim 3 , wherein the therapeutically effective dosage comprises from about 1×10 9 to about 9×10 10 TILs.
5 . The method according to claim 1 , wherein the APCs comprise peripheral blood mononuclear cells (PBMCs).
6 . The method according to claim 5 , wherein the PBMCs are supplemented at a ratio of about 1:25 TIL:PBMCs.
7 . The method according to claim 1 , wherein the third 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 . A method according to claim 1 , wherein the third population of TILs in step (d) provides for increased efficacy, increased interferon-gamma (IFN-γ) production, increased polyclonality, increased average IP-10, and/or increased average MCP-1 when administered to the subject.
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 in a period of about 11 days.
10 . The method according to claim 1 , wherein the second expansion in step (d) is performed in about 10 days.
11 . The method according to claim 1 , wherein the second expansion in step (d) is performed in about 12 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.
14 . The method according to claim 1 , wherein the cell culture medium in step (c) and/or (d) comprises IL-15 and IL-21.
15 . 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, and optionally IL-15 or IL-21, 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 IL-2, OKT-3, antigen presenting cells (APCs), and optionally IL-15 or IL-21, 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, wherein the transition from step (c) to step (d) occurs without opening the system and wherein the cell culture medium in either step (c) or step (d) comprises IL-15 or IL-21;
(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.
16 . The method according to claim 15 , wherein the medium in the first expansion and/or the second expansion is free of human serum.
17 . The method according to claim 15 , 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 therapeutically effective dosage comprises from about 1×10 9 to about 9×10 10 TILs.
19 . The method according to claim 15 , wherein the APCs comprise peripheral blood mononuclear cells (PBMCs).
20 . The method according to claim 15 , wherein the third population of TILs harvested in step (e) exhibits an increased subpopulation of CD8+ cells relative to the first and/or second population of TILs.
21 . The method according to claim 19 , wherein the PBMCs are supplemented at a ratio of about 1:25 TIL:PBMCs.
22 . A method according to claim 15 , wherein the third population of TILs in step (d) provides for increased efficacy, increased interferon-gamma (IFN-γ) production, increased polyclonality, increased average IP-10, and/or increased average MCP-1 when administered to the subject.
23 . The method according to claim 15 , wherein the first expansion in step (c) and the second expansion in step (d) are each individually performed within a period of 11 days.
24 . The method according to claim 15 , wherein steps (a) through (f) are performed in about 10 days to about 22 days.
25 . The method according to claim 15 , wherein steps (a) through (f) are performed in about 15 days to about 22 days.
26 . The method according to claim 15 , wherein steps (a) through (f) are performed in about 20 days to about 22 days.
27 . The method according to claim 15 , wherein the second population of TILs is at least 50-fold greater in number than the first population of TILs.
28 . The method according to claim 15 , wherein the cell culture medium in step (c) and/or (d) comprises IL-15 and IL-21.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 14, 2021
From: BENDER, JAMES; WARDELL, SETH; LOTZE, MICHAEL T.
To: LION BIOTECHNOLOGIES, INC.
Reel/Frame 054922/0149 →
CHANGE OF NAME
Recorded Jan 14, 2021
From: LION BIOTECHNOLOGIES, INC.
To: IOVANCE BIOTHERAPEUTICS, INC.
Reel/Frame 054963/0131 →
Continuity (11)
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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