Combining PD-1 Blockade, CD137 Agonism and Adoptive Cell Therapy for Metastatic Melanoma

Inclusion Criteria:

* Must have unresectable cutaneous or mucosal metastatic stage III/IV melanoma, and in the opinion of the institutional principal investigator (PI) is an acceptable candidate for adoptive cell therapy (ACT) with high dose IL-2.
* Must have anticipated residual measurable disease after resection of target lesion(s) for TIL growth.
* Patients who have been previously treated for metastatic melanoma may be included (e.g., prior treatment with Rapidly Accelerated Fibrosarcoma (BRAF) inhibitors and/or ipilimumab will be allowed), provided that they have had a three week 'washout' prior to signing consent and have not been treated with a Programmed Death-1 (PD-1) blocking antibody.
* Age greater than or equal to 18 years.
* Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1.
* Women of childbearing potential must have a negative serum pregnancy test within seven days of screening and within 24 hours prior to the start of each nivolumab dose.
* Adequate renal, hepatic and hematologic function.
* Patients must have a positive screening Epstein Barr Virus (EBV) antibody titer on screening test as this is required to protect against EBV infection during the time of lymphodepletion.
* 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.
* 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 (MRI or CT if MRI is contraindicated), and if the patients with CNS metastases are not taking prednisone \>10 mg or equivalent daily.
* At screening, patients with ≤ 3 CNS metastases and each ≤ 1 cm size that were 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 30 days after definitive treatment, and if the patients with CNS metastases are not taking prednisone \>10 mg or equivalent daily.
* At screening, patients with\> 1 cm or \> 3 in number treated CNS metastases may be included if there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy, and if the patients with CNS metastases are not taking prednisone \>10 mg or equivalent daily.

Exclusion Criteria:

* Patients with active systemic infections requiring intravenous antibiotics, coagulation disorders, or other major medical illness of the cardiovascular, respiratory or immune system, which in the opinion of the PI or treating co-investigator is not acceptable risk for ACT, are excluded.
* Patients who have received prior immunotherapy whose side effects have resulted in a requirement of immunosuppressive medications (\>10 mg of prednisone daily or equivalent daily steroid daily, or infliximab, cyclosporine or equivalent immunosuppressive medication) or who have other autoimmune conditions that require immunosuppressive medications as above at the time of screening are excluded.
* Patients who test positive for Human Immunodeficiency Virus (HIV), Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody, Human T-lymphotropic Virus (HTLV) I or II antibody, or are both Rapid plasma reagin (RPR) and Fluorescent treponemal antibody (FTA) positive are excluded.
* Patients who are pregnant or nursing are excluded.
* Patients with a significant psychiatric disease, who in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe will be excluded.
* Patients with \> 3 untreated CNS metastases or evidence of peri-tumoral edema will be excluded, or patients with CNS metastases of any status who are taking prednisone \>10 mg or equivalent steroid daily will be excluded.
* Patients with ≤ 3 untreated CNS metastases but with at least one lesion \>1 cm or peri-tumoral edema will be excluded, or patients with CNS metastases of any status who are taking prednisone \>10 mg or equivalent steroid daily will be excluded.
* Patients with invasive malignancy other than melanoma at the time of enrollment and within 2 years of screening are excluded, except for: adequately treated (i.e. with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other any other cancers from which the patient has been disease-free for at least 2 years.
* 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, or patients with CNS metastases of any status who are taking prednisone \>10 mg or equivalent will be excluded.
* Male patients with female partners of childbearing potential who do not agree to use two FDA-accepted forms of contraception during sexual intercourse with women of child-bearing potential from the start of PD-1 antibody therapy and up to at least 31 weeks from the last dose of nivolumab are excluded.
* Females of childbearing potential who do not agree to use 2 FDA forms of contraception according to study guidelines
* Prior systemic therapy with a PD-1 blocking antibody
* Patients who are greater than age 50, or who have a history of coronary artery disease, will be required to undergo cardiac stress testing within 6 months of screening and will be excluded if there is evidence of reversible ischemia.
* Patients who have a significant history of pulmonary disease that necessitates the use of supplemental oxygen, is associated with dyspnea on walking one block or less, or requires inhaler therapy more than once per week will be required to undergo pulmonary function testing within 6 months of screening and will be excluded if forced expiratory volume 1 (FEV1), forced vital capacity (FVC), or diffusion lung capacity for carbon monoxide (DLCO) is less than 65% of predicted.