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

-INCLUSION CRITERIA:

1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation.
2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of NCI.
3. Patients must have received at least one prior therapy for metastatic melanoma.
4. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
5. Greater than or equal to 18 years and less than or equal to 72 years.
6. All participants must sign a written informed consent.
7. All participants must be willing to sign a durable power of attorney
8. Clinical performance status of ECOG 0 or 1.
9. Patients of both sexes must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
10. Serology:

    * Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.)
    * Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
11. Individuals of child-bearing potential must be willing to undergo a pregnancy test prior to the start of treatment because of the potentially dangerous effects of the treatment on the fetus.
12. Individuals of child-bearing potential (IOCBP) must agree to use highly effective contraception (hormonal, intrauterine device \[IUD, abstinence, surgical sterilization starting at the time of study entry, for the duration of study therapy, and 12 months after the last dose of combined chemotherapy

    Individuals that can father children must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) for the duration of the study treatment and for 4 months after the last dose of combined chemotherapy. We also will recommend individuals that can father children ask their partners to be on highly effective birth control (hormonal, intrauterine device (IUD), surgical sterilization).

    NOTE: IOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.

    NOTE: Certain malignancies may secrete hormones that produce false positive pregnancy tests. Serial blood testing (e.g. HCG measurements) and/ or ultrasound may be performed for clarification.

    IOCBP must not donate, or retrieve for their own use, ova from the time of study treatment initiation and throughout the study treatment period, and for at least 12 months after the final study drug(s) administration. Individuals that can father children must not freeze or donate sperm for at least 12 months after the final study drug(s) administration.
13. Nursing participants must be willing to discontinue nursing from study treatment initiation through 4 months after the last dose of the study drug(s).
14. Hematology

    * Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim/biosimilar
    * WBC greater than or equal to 2500/mm3
    * Platelet count greater than or equal to 800,000/mm3
    * Hemoglobin \> 8.0 g/dl
15. Chemistry

    * Serum ALT/AST less than or equal to 2.5 times ULN
    * Serum Creatinine less than or equal to 1.6 mg/dl
    * Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL.
16. Patients must have completed any prior systemic therapy at the time of enrollment.
17. Patients must demonstrate progressive disease at the time of treatment. (Note: Patients who have received tyrosine kinase inhibitors (e.g. vemurafinib) may be treated if they present with stable disease at the time of treatment).
18. Patients must be co-enrolled in protocol 03-C-0277.

EXCLUSION CRITERIA:

1. Individuals of child-bearing potential who are pregnant or nursing because of the potentially dangerous effects of the treatment on the fetus or infant.
2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
3. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
4. Active systemic infections requiring anti-infective treatment, coagulation disorders or any other active major medical illnesses.
5. History of major organ autoimmune disease
6. Concurrent systemic steroid therapy.
7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
8. Grade 3 or 4 major organ Immune-related Adverse Events (IRAEs) clinically attributed to anti PD-1/PD-L1 monotherapy. Previously screened participants that experience these IRAEs after resection for creation of TIL are excluded from Arm 2, but may be eligible for assignment to Arm 3. NOTE: For the purposes of this protocol, thyroid is not considered a major organ.
9. History of coronary revascularization or ischemic symptoms.
10. For select patients with a clinical history prompting cardiac evaluation: last LVEF less than or equal to 45%
11. For select patients with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50%.
12. Patients who are receiving any other investigational agents.