A Phase I Trial of Anti-PD-1, Anti-CD137 and TIL

Inclusion Criteria:

- Patients must have unresectable metastatic stage IV melanoma, and in the opinion of
the institutional PI is an acceptable candidate for adoptive cell transfer (ACT) with
high dose IL-2

- Residual measurable disease after resection of target lesion(s) for TIL growth

- Tumor may have a B-RAF V600 mutation or be BRAF wild type, and patients may nor may
not have been previously treated with ipilimumab

- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1

- Patients may have been previously treated for metastatic disease, or may have not had
prior systemic treatment. Patients with a V600 BRAF mutated tumor may or may not have
previously received a prior BRAF inhibitor.

- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within seven days of screening.

- 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,
aspartate aminotransferase (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 mcL and total granulocytes of 1000 per mcL or more, and
platelets of 100,000 per mcL 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.

- 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 ≤ 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.

- 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.

- All laboratory and imaging studies must be completed and satisfactory within 30 days
of signing the consent document, with the exceptions of: negative serum pregnancy
test for women of child-bearing potential which must be negative within 7 days of
screening, human leukocyte antigen (HLA)-typing which will not be repeated if
performed previously, and pulmonary function tests (PFTs)/cardiac stress tests whose
results are valid for 6 months if performed previously.

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 principal investigator (PI)
or treating co-investigator is not acceptable risk for ACT, are excluded.

- Patients testing positive for HIV titre, Hepatitis B surface antigen, Hepatitis B
core antibody, Hepatitis C antibody, Human T-Lymphotropic Virus (HTLV) I or II
antibody, or both Rapid Plasma Reagin (RPR) and fluorescent treponemal antibodies
(FTA) positive are excluded.

- Patients who are pregnant or nursing are excluded.

- Patients needing chronic, immunosuppressive systemic steroids are excluded

- Patients with a history of autoimmune disease that require immunosuppressive
medications at the time of screening are excluded.

- Patients with 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 will be excluded.

- 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 invasive malignancy other than melanoma at the time of enrollment and
within 2 years prior to the first TIL administration are excluded, except for
adequately treated (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 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.

- Patients unable to comprehend and give informed consent are 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 anti-PD-1 antibody therapy and up to at
least 6 months after ACT are excluded.

- Female patients of childbearing potential who do not agree to use two FDA forms of
contraception during sexual intercourse from the start of anti-PD-1 antibody and up
to at least 6 months after ACT are excluded.

- Patients who have had prior systemic therapy with any form of anti-PD-1 blocking
antibody will be excluded.

- 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 in one second (FEV1), forced vital capacity (FVC), or
diffusing lung capacity oxygenation (DLCO) is less than 65% of predicted.