Objectives:

The primary objective will be to determine whether patients receiving the combination of dendritic cells and high dose IL-2 (Cohort A) have sustained persistence of infused T cells compared to patients treated with T cells and high dose IL-2 alone.

Secondary endpoints will include evaluations for tumor response and studies to determine whether dendritic cells enhance the infused T cells in anti-tumor activity and their ability to migrate to the tumor site. In addition, we will evaluate the characteristics of the infused T cells that correspond with effectiveness in vivo.

Additionally, secondary objectives will include correlation of clinical parameters with survival (overall survival and progression-free survival) for all cohorts.

COHORT C

In a separate cohort (Cohort C) the primary endpoint will be the overall response rate of TIL treatment for patients who have not achieved PR or CR or have progressive disease from treatment of the BRAF inhibitor alone.

COHORT D

The primary objective of Cohort D is to confirm the safety of adoptively transferred, TIL into the CSF.

The secondary objective is the evaluation of clinical imaging and CSF response. Correlative objectives will assess if the intrathecally-infused T cells persist in the CSF, assess circulating tumor cells in the CSF, and assess various cytokine and other analyses,as feasible.

COHORT E

The primary objective of Cohort E is to determine the overall response rate of TIL treatment with cells grown by the TIL 3.0 pre-REP (Turnstile 1) phase of cellular growth.

Inclusion Criteria:

1. Patients must have metastatic melanoma, uveal melanoma or stage III in-transit or regional nodal disease. (Turnstile I)
2. Patients must receive an MRI/CT of the brain or PET/CT within 6 months of consenting. If new lesions are present, PI or his designee should make final determination regarding enrollment. (Turnstile I)
3. Age greater than or equal to 12 years. (Turnstile I)
4. Clinical performance status of ECOG 0-2. (Turnstile I)
5. Patients previously treated with immunotherapy, targeted therapy, or no therapy will be eligible. Patients receiving cytotoxic agents will be evaluated by the PI or his designee as to suitable eligibility. (Turnstile I)
6. Patients must be HLA-A2 for cohort A. (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
7. Patients must have adequate TIL available. (Turnstile II)
8. Patients must have measurable metastatic melanoma. (Turnstile II - Chemotherapy/Cell Infusion -Inclusion Criteria).
9. Patients may have brain lesions which measure </= 1cm each. Lesions that are >1 cm that have been treated with SRS and in the opinion of the PI or his designee no longer represents active disease will also be allowed. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
10. Patients of both genders must practice birth control for four months after receiving the preparative regimen. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
11. Patients must have a documented negative pregnancy test (urine or serum) for women who have menstruation in the past 12 months and without sterilization surgery.
12. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the patient agrees to continue to use a barrier method of contraception throughout the study such as: condom, diaphragm, hormonal, IUD, or sponge plus spermicide. Abstinence is an acceptable form of birth control. (Turnstile II)
13. Pregnancy testing will be performed within 7 days prior to treatment. (Turnstile II)
14. Clinical performance status of ECOG 0 - 2 at the time of chemotherapy infusion. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
15. Absolute neutrophil count greater than or equal to 750/mm3. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
16. Platelet count greater than or equal to 75,000/mm3. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
17. Hemoglobin greater than or equal to 8.0 g/dl. (Turnstile II - Chemotherapy/Cell Infusion).
18. Serum ALT less than three times the upper limit of normal. (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria).
19. Serum creatinine less than or equal to 1.6 mg/dl. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
20. 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. (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria).
21. Patients in Cohort A will be randomized to receive either TIL alone or TIL plus Dendritic cells.
22. A stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) within 6 months of lymphodepletion. (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria).
23. Pulmonary function tests (FEV1>65% or FVC>65%of predicted) within 6 months of lymphodepletion. (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria).
24. MRI/CT of the brain within 42 days of lymphodepletion. CT scan of chest/abdomen/pelvis or PET/CT within 30 days of lymphodepletion. Exception: Patients randomized to receive dendritic cells may have an MRI of the brain within 30 days of lymphodepletion. (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
25. Patients must be receiving a B-RAF inhibitor and failed to achieve PR or CR or have progressive disease in response to B-RAF treatment (Cohort C).
26. i. Patients with MRI evidence of LMD, with or without evidence of malignant cells in CSF ("positive cytology"), or ii. Patients with evidence of malignant cells in the CSF (positive cytology), with or without MRI evidence of LMD, or iii. Patients with surgically-proven LMD (leptomeningeal involvement on pathology review) +/- MRI or CSF evidence by MRI or CSF cytology (Cohort D)
27. a. Many patients present with concomitant systemic disease outside of the central nervous system. Extra-CNS disease status should meet the following criteria: i. Patients with concomitant systemic disease under control with current or prior systemic treatment, as per primary treating physician ii. Patients without any evidence of systemic disease, either receiving systemic treatment or on active observation (Cohort D)
28. c. Previous Therapies i. Patients who are currently being treated with IT IL-2 for LMD are eligible. No wash out period is required. ii. Patients who have been previously treated with other IT therapies are eligible, as long as there is at least a 2 week wash out period iii. Patients who have previously received therapy with systemic TIL therapy are eligible.
29. (contd #28) iv. Patients with VP shunts must have VP shunts with on/off valves and must be expected to tolerate VP shunt valve off for more than 6 hours Patients who have received CNS irradiation, including whole brain radiation or stereotactic radiosurgery, are eligible, if they are at least 1 weeks post CNS-irradiation (Cohort D)Patients who are currently being treated with IT IL-2 for LMD are eligible. No wash out period is required. (Cohort D)
30. d. Other Requirements i. Patients must be able to give informed consent ii. Patients must have ECOG performance status 0, 1 or 2 and/or KPS > 50 iii. Patients must be able to swallow iv. Patients must be able to sit up with or without assistance v. Patients must be able to undergo contrast-enhanced MRI. (Cohort D)

Exclusion Criteria:

1. Has had prior systemic cancer cytotoxic chemotherapy within the past four weeks at the time of the start of the lymphodepletion regimen.
2. Has had prior B-RAF or MEK targeted therapy within 7 days prior to the start of the lymphodepletion regimen (Cohort A and Cohort B).
3. Is not receiving B-RAF treatment (Cohort C) (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
4. Achieves PR or CR in response to B-RAF treatment (Cohort C).
5. Women who are pregnant or nursing will be excluded because of the potentially dangerous effects of the preparative chemotherapy on the fetus. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
6. Any active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, such as abnormal stress test and/or abnormal PFT. PI or his designee shall make the final determination regarding appropriateness of enrollment.(Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
7. Any form of primary or secondary immunodeficiency. Must have recovered immune competence after chemotherapy or radiation therapy as evidenced by lymphocyte counts (> 500/mm3), WBC (> 3,000/mm3) or absence of opportunistic infections. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
8. Require steroid therapy or steroid-containing compounds, or have used systemic steroids in the past 30 days, or have used topical or inhalational steroids in the past 2 weeks prior to lymphodepletion. Exception: Patients on physiologic dose of steroid (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
9. 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. (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
10. Patients with rapidly advancing systemic disease, especially those without good options of systemic treatment for their disease outside the CNS. (Cohort D)
11. Patients with rapidly advancing parenchymal brain metastases (Cohort D)
12. Pregnant patients (Cohort D)
13. Patients with rapid decline in neurological function as documented on exam and/or as per clinical judgment of treating physician (Cohort D)