Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy
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.
1. A method for treating a subject with cancer, the method comprising administering to the subject a tumor infiltrating lymphocyte (TIL) pharmaceutical composition comprising:
i) an expanded population of tumor infiltrating lymphocytes (TILs), and
ii) a cryopreservant;
wherein the expanded population of TILs exhibit IFN-γ secretion of at least five-fold in vitro as compared to a non-expanded population of TILs.
2. The method of claim 1 , wherein the cryopreservant comprises DMSO.
3. The method of claim 1 , wherein the cryopreservant comprises 7% to 10% DMSO.
4. The method of claim 1 , wherein the cryopreservant is a cryopreservation medium.
5. The method of claim 4 , wherein the cryopreservation medium is CS10.
6. The method of claim 1 , wherein the composition is free of human serum.
7. The method of claim 1 , wherein the composition further comprises 1% human serum albumin (HSA).
8. The method of claim 1 , wherein the composition further comprises 1% human serum albumin (HSA) and the cryopreservant is dimethylsulfoxide.
9. The method of claim 1 , wherein the IFN-γ secretion is measured in vitro by enzyme-linked immunosorbent assay.
10. The method of claim 1 , wherein the expanded population of TILs is capable of increasing IP-10 and/or MCP-1 at least one-fold to at least five-fold in vivo in the treated subject as compared to an untreated subject.
11. The method of claim 10 , wherein the increase in IP-10 is measured as an increase in the blood of the treated subject.
12. The method of claim 10 , wherein the increase in MCP-1 is measured as an increase in the blood of the treated subject.
13. The method of claim 1 , wherein about 1×10 9 to about 9×10 10 TILs are administered to the subject.
14. The method according to claim 1 , wherein prior to administering the TIL pharmaceutical composition, a non-myeloablative lymphodepletion regimen has been administered to the subject.
15. The method according to claim 14 , 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.
16. 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 pharmaceutical composition to the subject.
17. The method according to claim 16 , 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.
18. The method according to claim 1 , wherein the cancer is melanoma.
19. The method according to claim 1 , wherein the cancer is cervical cancer.
20. The method according to claim 1 , wherein the cancer is lung cancer.
21. The method according to claim 1 , wherein the cancer is head and neck cancer (including head and neck squamous cell carcinoma (HNSCC)).
22. The method according to claim 1 , wherein the method comprises administering the TIL pharmaceutical composition to the subject by movement of such composition from a container into the subject's body.
23. The method according to claim 22 , wherein the container is a bag.
24. The method according to claim 23 , wherein the container is an infusion bag.