The overall purpose of this research study is to find a better way to treat melanoma. This will be a single arm exploratory trial to evaluate prospectively the feasibility of, the toxicities of, and the persistence of TIL which can survive in vivo.

Patients are being offered admission to this study to test the side effects of an investigational treatment prepared from special immune cells (T cells) specific for melanoma. A T-cell is a type of lymphocyte. Lymphocytes are a type of white blood cell that protect people from viral infections; help other cells fight bacterial and fungal infections; produce antibodies; fight cancers; and coordinate the activities of other cells in the immune system. These special immune cells will be taken from a sample of the patient's tumor tissue that will be surgically removed from their body and grown in the laboratory. They will then given back to the patient in their veins. These cells are called tumor infiltrating lymphocytes (TIL). We wish to study the side effects of TIL when they are given with two chemotherapy drugs to temporarily decrease the patient's own immune cells and a drug called Interleukin-2 (IL-2). The two chemotherapy drugs called fludarabine and cytoxan are used to greatly reduce the number of normal lymphocytes circulating in the patient's body, called lymphodepletion, so that there will be more "space" for the cancer fighting lymphocytes (T-cells) that will be infused in their veins. We wish to find out how often these cells can shrink or slow the growth of the patient's melanoma. We also wish to find out the effects of lymphodepletion followed by TIL and high dose IL-2 on the patient's immune system. The lymphodepletion followed by TIL and high dose IL-2 is experimental, and has not been proven to help treat melanoma.

The IL-2 has been approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma that cannot be surgically removed. The chemotherapy drugs cytoxan and fludarabine used for lymphodepletion have been approved by the FDA, but not for the treatment of metastatic melanoma.

The combination of lymphodepletion followed by TIL and high dose IL-2 is not FDA approved but the FDA is permitting its use in this study.

Inclusion Criteria:

• Patients must have unresectable metastatic stage IV melanoma or stage III in-transit or regional nodal disease.
• Residual measurable disease after resection of target lesion(s) for TIL growth
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 -1. ECOG performance status of 0-1 will be inferred if the patient's level of energy is ≥ 50% of baseline.
• Patients may be treatment-naïve or may have been previously treated for metastatic disease.
• Patients with a negative pregnancy test (urine or serum) must be documented at screening for women of childbearing potential (WOCBP).
• Adequate renal, hepatic and hematologic function, including creatinine of less than or equal to 1.7 gm/dL, total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL, aspartic transaminase (AST) and alanine transaminase (ALT) of less than 3X institutional upper limit of normal (ULN), hemoglobin of 8 gm/dL or more, white blood count (WBC) of 3000 per mm³ and total granulocytes of 1000 per mm³ or more, and platelets of 100,000 per mm³ or more.
• Patients must have a positive screening Epstein-Barr virus (EBV) antibody titre on screening test.
• Patients with antibiotic allergies per se are not excluded; although the production of TIL for adoptive transfer includes antibiotics, extensive washing after harvest will minimize systemic exposure to antibiotics.
• Patients that had previously grown sterile, validated TIL under Good Manufacturing Practices (GMP) conditions on Moffitt Clinical trial protocol 15375 (Use of Excess Melanoma Tumor Specimens Not Required for Diagnostic Purposes for Validation of Tumor Infiltrating Lymphocyte [TIL] Growth Procedures) meeting the above criteria may be consented and enrolled in the current trial using the previously established TIL stored in the Cell therapies Core facility for up to 2 years.
• At screening, patients with ≤ 3 untreated central nervous system (CNS) metastases may be included provided none of the untreated lesions are > 1 cm in greatest dimension, and there is no peri-tumoral edema present on brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] if MRI is contraindicated).
• At screening, patients with CNS metastases treated with either surgical resection and/or radiation therapy may be included. Patients may be included if the largest lesion is ≤ 1 cm, and there is no evidence of progressive CNS disease on brain imaging at least 28 days after treatment.
• At screening, patients may be included if the largest lesion is > 1 cm or > 3 in number, and there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy.
• All laboratory and imaging studies must be completed and satisfactory within 30 days of signing the consent document.

Exclusion Criteria:

• Patients with active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system are excluded.
• Patients testing positive for human immunodeficiency virus (HIV) titre, Hepatitis B surface antigen, Hepatitis C antibody, Human T-lymphotropic virus (HTLV) I or II antibody, or both rapid plasma reagent (RPR) and fluorescein treponemal antibodies (FTA) positive are excluded.
• Patients who are pregnant or nursing
• Patients needing chronic, immunosuppressive systemic steroids
• Patients with autoimmune diseases that require immunosuppressive medications
• Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated
• Patients with > 3 untreated CNS metastases or evidence of peri-tumoral edema will be excluded.
• Patients with ≤ 3 untreated CNS metastases but with at least one lesion >1 cm or peri-tumoral edema will be excluded.
• Patients with treated CNS metastases > 1 cm or > 3 in number will be excluded if there is evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy.
• Inability to comprehend and give informed consent