Claims for Patent: 10,272,113

Summary for Patent: 10,272,113

Title:	Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy
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.
Inventor(s):	Wardell; Seth (Tampa, FL), Bender; James (Rancho Santa Margarita, CA), Lotze; Michael T. (Pittsburgh, PA)
Assignee:	IOVANCE BIOTHERAPEUTICS, INC. (San Carlos, CA)
Application Number:	16/136,147
Patent Claims:	1. A method for treating a subject with cancer, the method comprising administering a combination of expanded tumor infiltrating lymphocytes (TILs) and an anti-PD-1 antibody, 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 3-11 days to obtain the second population of TILs, wherein the second population of TILs is at least 50-fold greater in number than the first 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 7-11 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs which comprises an increased subpopulation of effector T cells and/or central memory T cells relative to the second 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; (g) cryopreserving the infusion bag comprising the harvested TIL population from step (f) using a cryopreservation process; and (h) administering to the subject: i) a therapeutically effective dosage of the third population of TILs from the infusion bag in step (g); and ii) the anti-PD-1 antibody. 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 administering a therapeutically effective dosage of the TILs in step (h). 4. The method according to claim 3, wherein the number of TILs sufficient for administering a therapeutically effective dosage in step (h) is from about 1.times.10.sup.9 to about 9.times.10.sup.10. 5. The method according to claim 1, wherein the APCs are peripheral blood mononuclear cells (PBMCs). 6. 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. 7. The method according to claim 5, wherein the PBMCs are supplemented at a ratio of about 1:25 TIL:PBMCs. 8. The method according to claim 1, wherein prior to administering a therapeutically effective dosage of TIL cells in step (h), 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.sup.2/day for two days followed by administration of fludarabine at a dose of 25 mg/m.sup.2/day for five days. 10. The method according to claim 1, further comprising the step of treating the subject with a high-dose IL-2 regimen starting on the day after administration of the TIL cells to the subject in step (h). 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 until tolerance. 12. A method according to claim 1, wherein the third population of TILs in step (d) provides for increased efficacy, increased interferon-gamma (IFN-.gamma.) production, increased polyclonality, increased average IP-10, and/or increased average MCP-1 when administered to the subject. 13. The method 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. 14. The method according to claim 13, wherein the cancer is selected from the group consisting of melanoma, HNSCC, cervical cancer, and NSCLC. 15. The method according to claim 13, wherein the cancer is selected from the group consisting of melanoma or metastatic melanoma. 16. The method according to claim 13, wherein the cancer is HNSCC. 17. The method according to claim 13, wherein the cancer is cervical cancer. 18. The method according to claim 13, wherein the cancer is NSCLC. 19. 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. 20. The method according to claim 1, wherein steps (a) through (f) are performed in about 10 days to about 22 days. 21. The method according to claim 1, wherein the anti-PD-1 antibody is nivolumab. 22. The method according to claim 1, wherein the anti-PD-1 antibody is pembrolizumab. 23. The method according to claim 13, wherein the cancer is bladder cancer.

Details for Patent 10,272,113

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	For Injection	125514	09/04/2014		2037-03-29
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	Injection	125514	01/15/2015		2037-03-29
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	12/22/2014		2037-03-29
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	10/04/2017		2037-03-29
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	08/27/2021		2037-03-29