Treatment with tumor infiltrating lymphocyte therapies in combination with CTLA-4 and PD-1 inhibitors
The present invention provides improved and/or shortened processes and methods for preparing TILs in order to prepare therapeutic populations of TILs with increased therapeutic efficacy for the treatment of cancer with TILs in combination with CTLA-4 and PD-1 inhibitors and/or PD-L1 inhibitors as described herein.
1 . A method of treating melanoma in a patient or subject who has received no prior PD-1 therapy and no prior PD-L1 therapy, comprising administering to the patient or subject a therapeutically effective amount of a therapeutic population of tumor infiltrating lymphocytes (TILs) and a therapeutically effective amount of pembrolizumab, wherein a first amount of a non-myeloablative lymphodepletion regimen is administered to the patient or subject in advance of the administration of the therapeutically effective amount of the therapeutic population of TILs to the patient or subject, and subjecting the patient or subject to administration of an amount of pembrolizumab every six weeks after the administration of the therapeutically effective amount of the therapeutic population of TILs to the patient or subject.
2 . The method of claim 1 , wherein the second amount of pembrolizumab administered every six weeks after the administration of the therapeutic population of TILs is 400 mg.
3 . The method of claim 1 , further comprising the step of treating the patient with an IL-2 regimen starting three to twenty-four hours after administration of the therapeutically effective amount of the therapeutic population of TILs to the patient or subject.
4 . The method of claim 3 , wherein the IL-2 regimen is a high-dose IL-2 regimen comprising up to six doses of 600,000 IU/kg of aldesleukin administered as a 15-minute bolus intravenous infusion every eight to twelve hours.
5 . The method of claim 3 , wherein pembrolizumab is administered to the patient or subject after the treatment of the patient or subject with the IL-2 regimen.
6 . The method of claim 1 , wherein the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg/kg/day for two days followed by administration of fludarabine at a dose of 25 mg/m 2 /day for five days.
7 . The method of claim 1 , wherein the melanoma is metastatic melanoma.
8 . The method of claim 1 , further comprising administering an additional dose of pembrolizumab to the patient or subject after resection of a tumor sample from the patient or subject for manufacture of the therapeutic population of TILs and before the patient or subject is treated with the non-myeloablative lymphodepletion regimen.
9 . A method of treating metastatic melanoma in a patient or subject who has received no prior PD-1 therapy and no prior PD-L1 therapy, the method comprising the steps of:
(a) obtaining and/or receiving a first population of tumor infiltrating lymphocytes (TILs) from a tumor resected from the subject or patient;
(b) 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 for about 3-14 days to obtain the second population of TILs;
(c) 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 7-14 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs;
(d) harvesting the therapeutic population of TILs obtained from step (c);
(e) administering a therapeutically effective amount of the therapeutic population of TILs from step (d) to the patient or subject; and
(f) administering a therapeutically effective amount of pembrolizumab every six weeks after the administration of the therapeutically effective amount of the therapeutic population of TILs to the patient or subject;
wherein the patient or subject is treated with a non-myeloablative lymphodepletion regimen prior to step (e).
10 . The method of claim 9 , wherein the therapeutically effective amount of pembrolizumab second amount is 400 mg.
11 . The method of claim 9 , wherein the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg/kg/day for two days followed by administration of fludarabine at a dose of 25 mg/m 2 /day for five days.
12 . The method of claim 9 , further comprising the step of treating the patient with an IL-2 regimen starting three to twenty-four hours after administration of the therapeutically effective amount of the therapeutic population of TILs to the patient or subject.
13 . The method of claim 12 , wherein the IL-2 regimen is a high-dose IL-2 regimen comprising up to six doses of 600,000 IU/kg of aldesleukin administered as a 15-minute bolus intravenous infusion every eight to twelve hours.
14 . The method of claim 12 , wherein the therapeutically effective amount of pembrolizumab is administered to the patient or subject after the treatment of the patient or subject with the IL-2 regimen.
15 . The method of claim 9 , wherein the first expansion is performed over a period of about 11 days.
16 . The method of claim 9 , wherein the second expansion is performed over a period of about 11 days.
17 . The method of claim 9 , wherein the first expansion is performed over a period of about 11 days and the second expansion is performed over a period of about 11 days.
18 . The method of claim 9 , further comprising administering an additional dose of pembrolizumab to the patient or subject after resecting the tumor from the patient or subject and before the patient or subject is treated with the non-myeloablative lymphodepletion regimen.