Autologous CD8+ SLC45A2-Specific T Lymphocytes With Cyclophosphamide, Aldesleukin, and Ipilimumab in Treating Participants With Metastatic Uveal Melanoma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of adoptively transferred SLC45A2-specific
cytotoxic T-lymphocytes (CTL) for the treatment of patients with metastatic uveal melanoma.

SECONDARY OBJECTIVES:

I. To establish the anti-tumor efficacy as measured by immune-related response criteria
(irRC) and duration of response in metastatic uveal melanoma patients receiving autologous
CD8+ T cells against SLC45A2.

II. To assess the safety and tolerability of adoptively transferred SLC45A2-specific CTL in
combination with immune checkpoint blockade in metastatic uveal melanoma patients.

III. To quantify in vivo numeric and functional persistence of transferred CTL, and
development of antigen spreading.

IV. To assess overall survival and progression-free survival in metastatic uveal melanoma
patients.

OUTLINE: This is a dose escalation study of autologous CD8+ SLC45A2-specific T lymphocytes.

PREPARATIVE REGIMEN: Participants receive cyclophosphamide intravenously (IV) over 30-60
minutes on day -2.

T-CELL INFUSION: Participants receive autologous CD8+ SLC45A2-specific T lymphocytes via
hepatic arterial infusion over 60 minutes on day 0. Within 6 hours of T-cell infusion,
participants also receive aldesleukin twice daily (BID) subcutaneously (SC) for 14 days in
the absence of disease progression or unacceptable toxicity.

POST T-CELL INFUSION: Participants in dose expansion receive ipilimumab IV over 90 minutes on
days 1, 22, 43, and 64 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at days 84 and 168, and
then every 3 months for up to 5 years.

Inclusion Criteria:

- Eligibility for pheresis: (Turnstile 1) Histopathologic documentation of melanoma
concurrent with the diagnosis of metastatic disease. A diagnosis of uveal melanoma can
be made clinically without primary tissue evaluation, based on history and records. A
prior history of brachytherapy to the eye is sufficient clinical support for a
diagnosis of uveal melanoma.

- Hematocrit (HCT) >= 24% or hemoglobin (HB) >= 8g/dL.

- Platelets > 50,000.

- Expression of human leukocyte antigen (HLA)-A:0201 or HLA-A:2402.

- Eastern Cooperative Oncology Group (ECOG)/ Zubrod performance status of 0-1.

- Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study in such a manner that the risk
of pregnancy is minimized. Suggested precautions should be used to minimize the risk
or pregnancy for at least 1 month before start of therapy, and while women are on
study for up to 3 months after completion of the study. WOCBP include any female who
has experienced menarche and who has not undergone successful surgical sterilization
(hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not
postmenopausal.

- Male patients must be willing and able to use an acceptable method of birth control,
during and for at least 3 months after completion of the study, if their sexual
partners are WOCBP.

- Toxicity related to prior therapy must either have returned to =< grade 1, baseline,
or been deemed irreversible. Certain non-serious exceptions include alopecia,
hypothyroidism, neuropathy, nausea, adrenocortical deficiency requiring physiologic
replacement dose of steroids, and other conditions noted and approved by the principal
investigator (PI).

- Eligibility for T-cell infusion (includes cyclophosphamide, T cell, anti-CTLA4
infusions and s.c. IL-2) (Turnstile 2) (Note: evaluate at least 1 week before T-cell
infusion): ECOG/Zubrod performance status of 0-1.

- Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic
imaging per immune-related response criteria (irRC).

- At least 4 weeks must have elapsed since the last chemotherapy, targeted therapy,
immunotherapy, radiotherapy, liver-directed therapy, or major surgery. At least 6
weeks for nitrosoureas, mitomycin C and liposomal doxorubicin. If started before
T-cell administration, ipilimumab infusions must be least 21 days apart.

- Toxicity related to prior therapy must either have returned to =< grade 1, baseline,
or been deemed irreversible. Certain non-serious exceptions include alopecia,
hypothyroidism, neuropathy, nausea, adrenocortical deficiency requiring physiologic
replacement dose of steroids, and other conditions noted and approved by the PI.

- Persons of reproductive potential must agree to use and utilize an adequate method of
contraception throughout treatment and for at least 3 months after completion of
study.

- Willing and able to give informed consent.

- Patients must have liver metastases.

Exclusion Criteria:

- Exclusion criteria for leukapheresis: Any other malignancy from which the patient has
been disease-free for less than 2 years, with the exception of adequately treated and
cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in
situ of the cervix or breast, or melanoma in-situ.

- Pregnant women, nursing mothers, men or women of reproductive ability who are
unwilling to use effective contraception. Women of childbearing potential with a
positive pregnancy test within 3 days prior to pheresis.

- Clinically significant pulmonary dysfunction, as determined by medical history and
physical exam. Patients so identified will undergo pulmonary functions testing and
those with forced expiratory volume in one second (FEV1) < 2.0 L or diffusion lung
capacity [DLCO] corrected [corr] for hemoglobin [Hgb]) < 50% will be excluded.

- Significant cardiovascular abnormalities as defined by any one of the following:

- Congestive heart failure

- Clinically significant hypotension

- Symptoms of coronary artery disease (angina, dyspnea)

- Presence of cardiac arrhythmias on electrocardiogram (EKG) requiring drug therapy

- Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded
from this study, as are patients with a history of autoimmune disease (e.g. systemic
lupus erythematosus, vasculitis, infiltrating lung disease) whose possible progression
during treatment would be considered by the investigator to be unacceptable.
Acceptable exclusions include: Hashimoto's thyroiditis, type 1 diabetes mellitus, and
other localized or inactive conditions with approval of the PI.

- Any underlying medical or psychiatric condition, which in the opinion of the
investigator, will make the administration of study drug hazardous or obscure the
interpretation of adverse events, such as a condition associated with frequent
diarrhea.

- Positive screening tests for human immunodeficiency virus (HIV), hepatitis B virus
(Hep B), and hepatitis C virus (Hep C). If positive results are not indicative of true
active or chronic infection, the patient can be treated.

- Prior to cyclophosphamide and T cell infusions: white blood cells (WBC) =< 2000/uL

- Prior to cyclophosphamide and T cell infusions: Hct =< 24% or Hb =< 8 g/dL

- Prior to cyclophosphamide and T cell infusions: absolute neutrophil count (ANC) =<
1000

- Prior to cyclophosphamide and T cell infusions: platelets =< 50,000

- Prior to cyclophosphamide and T cell infusions: creatinine >= 3.0 x upper limit of
normal (ULN)

- Prior to cyclophosphamide and T cell infusions: aspartate aminotransferase
(AST)/alanine aminotransferase (ALT) =< 5 x ULN (since all patients will have liver
metastasis)

- Prior to cyclophosphamide and T cell infusions: bilirubin >=3 x ULN

- Pregnant women, nursing mothers, men or women of reproductive ability who are
unwilling to use effective contraception. Women of childbearing potential with a
positive pregnancy test within 3 days prior to entry.

- Steroids (at prednisone equivalent doses > 10 mg) are not permitted 3 days prior to T
cell infusion and concurrently during therapy. Exceptions include use of systemic
prednisone equivalent doses =< 10 mg/ day, topical steroids or physiologic replacement
dose of steroids for adrenocortical deficiency.

- Any non-oncology vaccine therapy used for the prevention of infectious disease within
1 month before or after any ipilimumab dose

- Patients may not be on any other treatments for their cancer aside from those included
in the protocol. Patients may not undergo another form of treatment concurrently with
this study. Oncology supportive treatments such as growth factors, bone modifying
agents, pain or nausea management are allowed.

- Participation in any other immunotherapy treatment, that in the opinion of the
principal investigator would be unsafe to receive further checkpoint blockade
immunotherapy.