Granted Patent
B2
US 12,611,429 · App. 17/817,247 · Granted Apr 28, 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 (24)
1 . A cryopreserved therapeutic population of tumor infiltrating lymphocytes (TILs) produced by a method comprising:
(a) performing a first expansion by culturing a first population of TILs from tumor fragments obtained from a tumor resected from a subject with cancer 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 a first period of about 11 days to obtain the second population of TILs;
(b) performing a second expansion by supplementing the cell culture medium 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 a second period of about 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 (a) to step (b) occurs without opening the system;
(c) harvesting the third population of TILs obtained from step (b), wherein the transition from step (b) to step (c) occurs without opening the system;
(d) transferring the harvested third TIL population from step (c) to an infusion bag, wherein the transfer from step (c) to (d) occurs without opening the system; and
(e) cryopreserving the infusion bag comprising the harvested TIL population from step (d) using a cryopreservation process.
2 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the third population of TILs harvested in step (c) comprises sufficient TILs for administering a therapeutically effective dosage of the TILs in step (f).
3 . The cryopreserved therapeutic population of TILs according to claim 2 , wherein the therapeutically effective dosage in step (f) comprises from about 1×10 9 to about 9×10 10 TILs.
4 . The cryopreserved therapeutic population of TILs according to claim 2 , wherein the therapeutically effective dosage in step (f) comprises from about 1×10 9 to about 5×10 9 TILs.
5 . The cryopreserved therapeutic population of TILs according to claim 2 , wherein the therapeutically effective dosage in step (f) comprises from about 5×10 9 to about 1×10 10 TILs.
6 . The cryopreserved therapeutic population of TILs according to claim 2 , wherein the therapeutically effective dosage in step (f) comprises from about 1×10 10 to about 5×10 10 TILs.
7 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the APCs comprise peripheral blood mononuclear cells (PBMCs).
8 . The cryopreserved therapeutic population of TILs according to claim 7 , wherein the PBMCs are supplemented at a ratio of about 1:25 TIL:PBMCs.
9 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the therapeutic population of TILs harvested in step (c) exhibits an increased subpopulation of CD8+ cells relative to the first and/or second population of TILs.
10 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the closed container in step (a) and/or step (b) is a gas-permeable bag.
11 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the cancer is selected from the group consisting of melanoma (including metastatic melanoma), ovarian cancer, cervical cancer, non-small-cell lung cancer (NSCLC), lung cancer, bladder cancer, breast cancer, cancer caused by human papilloma virus, head and neck cancer (including head and neck squamous cell carcinoma (HNSCC)), renal cancer, and renal cell carcinoma.
12 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the cancer is a melanoma.
13 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the cancer is non-small-cell lung cancer (NSCLC).
14 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the cryopreservation process is performed using a 1:1 ratio of harvested TIL population to cryopreservation media.
15 . The cryopreserved therapeutic population of TILs according to claim 7 , wherein the PBMCs are irradiated and allogeneic.
16 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the tumor fragments comprise about 4 to about 50 fragments, wherein each fragment has a volume of about 27 mm 3 .
17 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the tumor fragments comprise about 30 to about 60 fragments with a total volume of about 1300mm 3 to about 1500 mm 3 .
18 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the cell culture medium in step (b) further comprises IL-15 and/or IL-21.
19 . The cryopreserved therapeutic population of TILs according to claim 1 , wherein the IL-2 concentration is about 10,000 IU/mL to about 5,000 IU/mL.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 12, 2022
From: BENDER, JAMES; WARDELL, SETH; LOTZE, MICHAEL T.
To: LION BIOTECHNOLOGIES, INC.
Reel/Frame 060799/0678 →
CHANGE OF NAME
Recorded Aug 12, 2022
From: LION BIOTECHNOLOGIES, INC.
To: IOVANCE BIOTHERAPEUTICS, INC.
Reel/Frame 061165/0375 →
Continuity (13)
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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