A Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab

Background: \- Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine. \- Pembrolizumab, a monoclonal antibody that binds to PD-1 and blocks the PD-1/PD-L1 axis, facilitates the activity of anti-tumor lymphocytes in the tumor micro environment. Pembrolizumab administration can result in objective tumor responses in patients with metastatic melanoma and is approved for use by the FDA for the treatment of these patients. * Administered TIL express low levels of PD-1, though PD-1 can be re-expressed on TIL in vivo following TIL administration. * In pre-clinical models, the administration of an anti-PD1 antibody enhances the anti-tumor activity of transferred T-cells. Objectives: Primary Objectives: -Revised Study Design: Determine the objective response rate with the addition of pembrolizumab to the standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2 in patients with metastatic melanoma who have received prior anti-PD-1/PD-L1 therapy (Cohorts 1 and 3). Original Study Design (retained for historical purposes): * Determine in a prospective randomized trial whether the addition of pembrolizumab to the standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2 can improve complete response rates in patients with metastatic melanoma who have received prior anti-PD-1/PD-L1 therapy (Cohort 1). * Determine the complete response rate to the standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2 in combination with pembrolizumab in patients with metastatic melanoma who have not received prior anti-PD-1/PD-L1 therapy (Cohort 2). Eligibility: Patients must be/have: * Age greater than or equal to 18 years and less than or equal to 72 years * Evaluable metastatic melanoma * Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL * No allergies or hypersensitivity to high-dose aldesleukin administration * No concurrent major medical illnesses or any form of immunodeficiency Design: * Patients with metastatic melanoma will have lesions resected for TIL. * Patients will be assigned to one of three cohorts: (1) patients who are refractory to prior anti-PD-1/PD-L1 therapy (randomized); (2) patients who have not received prior anti-PD-1/PD-L1 therapy; and (3) patients who are refractory to anti PD-1/PD-L1 (nonrandomized). Note: Cohorts 1 and 2 were closed upon the addition of Cohort 3. * After TIL growth is established: * Original Study Design: Patients assigned to Cohort 1 will be randomized to either receive or not receive pembrolizumab in combination with the standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2. All patients assigned to Cohort 2 will receive the standard non-myeloablative conditioning regimen, TIL, and high-dose IL-2 in combination with pembrolizumab. --Revised Study Design: Patients assigned to Cohort 3 without contraindications to pembrolizumab, will be assigned to receive pembrolizumab in combination with the standard non-myeloablative (NMA) conditioning regimen, TIL, and high-dose IL-2 (Arm 2). Patients in Cohort 3 with relative contraindications to pembrolizumab will be assigned to receive standard NMA, TIL, and high dose IL-2 (Arm 3). * For those patients receiving pembrolizumab, pembrolizumab will be administered immediately prior to TIL administration and continue for an additional three cycles following the cell infusion. * Up to 53 patients may be enrolled over 3-4 years.