Gene-Modified T Cells, Vaccine Therapy, and Ipilimumab in Treating Patients With Locally Advanced or Metastatic Malignancies

PRIMARY OBJECTIVES:

I. The safety of NY-ESO-1 T-cell receptor (TCR) transgenic adoptive cell transfer (ACT) has
been reported. The current protocol includes the addition of the cytotoxic
T-lymphocyte-associated protein 4 (CTLA4) blocking monoclonal antibody ipilimumab to NY ESO
TCR ACT in a dose escalation scheme in two study cohorts at 1 and 3 mg/kg of ipilimumab
intravenous (i.v.) every three weeks with a maximum of 4 doses (q3wx4).

SECONDARY OBJECTIVES:

I. To determine the feasibility of delivering the TCR transgenic cell dose and CTLA blockade
to patients.

II. To determine the persistence of NY-ESO-1 TCR-engineered peripheral blood mononuclear
cells (PBMC) in serial peripheral blood samples and in biopsies of accessible metastatic
lesions.

III. To explore the use of positron emission tomography (PET)-based imaging using the PET
tracer [18F] fluorodeoxy-glucose ([18F]FDG) with the goal of determining if the adoptively
transferred NY-ESO-1 TCR-engineered PBMC when administered with ipilimumab home and expand in
secondary lymphoid organs and tumor deposits.

IV. Clinical antitumor activity recording objective response rate will be an exploratory
endpoint in this pilot clinical trial.

OUTLINE: This is a dose-escalation study of ipilimumab.

CONDITIONING CHEMOTHERAPY REGIMEN: Patients receive cyclophosphamide IV on days -5 and -4 and
fludarabine phosphate IV over 30 minutes daily on days -4 to -1.

NY-ESO-1 TCR PBMC INFUSION: Patients receive NY-ESO-1 reactive TCR retroviral vector
transduced autologous T cells IV on day 0.

IPILIMUMAB ADMINISTRATION: Patients receive ipilimumab IV over 90 minutes before the NY-ESO-1
TCR PBMC infusion on day 0 or after the infusion on day 1. Treatment repeats every 3 weeks
for up to 4 doses in the absence of disease progression or unacceptable toxicity.

NY-ESO-1(157-165) PEPTIDE PULSED DENDRITIC CELL (DC) ADMINISTRATION: Patients receive
NY-ESO-1(157-165) peptide pulsed DC vaccine intradermally (ID) on days 1, 14, and 30.

LOW DOSE INTERLEUKIN-2 (IL-2) ADMINISTRATION: Patients receive aldesleukin (IL-2)
subcutaneously (SC) twice daily (BID) on days 1-14.

After completion of study treatment, patients are followed up periodically for 90 days, every
3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Inclusion Criteria:

- Stage IV or locally advanced cancers for which no alternative therapies with proven
survival advantage are available

- At least 1 lesion amenable for outpatient biopsies; this should be a cutaneous or
palpable metastatic site or a deeper site accessible by image-guided biopsy that is
deemed safe to access by the treating physicians and interventional radiologists;
patients without accessible lesions for biopsy but with prior tissue available from
metastatic disease would be eligible at the investigator's discretion

- NY-ESO-1 positive malignancy by immunohistochemistry (IHC) utilizing commonly
available NY-ESO-1 antibodies

- Human leukocyte antigen (HLA)-A*0201 (HLA-A2.1) positivity by molecular subtyping

- Life expectancy greater than 3 months assessed by a study physician

- A minimum of one measurable lesion defined as:

- Meeting the criteria for measurable disease according to Response Evaluation
Criteria in Solid Tumors (RECIST)

- Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be
accurately measured and recorded by color photography with a ruler to document
the size of the target lesion(s)

- No restriction based on prior treatments

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Absolute neutrophil count >= 1.5 x 10^9 cells/L

- Platelets >= 100 x 10^9/L

- Hemoglobin >= 10 g/dL

- Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x upper limit of normal
(ULN) (=< 5 x ULN, if documented liver metastases are present)

- Total bilirubin =< 2 x ULN (except patients with documented Gilbert's syndrome)

- Creatinine < 2 mg/dl (or a glomerular filtration rate > 60)

- Must be willing and able to accept two leukapheresis procedures

- Must be willing and able to provide written informed consent

Exclusion Criteria:

- Previously known hypersensitivity to any of the agents used in this study

- Received systemic treatment for cancer, including immunotherapy, within one month
prior to initiation of dosing within this protocol

- History of, or significant evidence of risk for, chronic inflammatory or autoimmune
disease (eg, Addison's disease, multiple sclerosis, Graves' disease, Hashimoto's
thyroiditis, inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic
lupus erythematosus, hypophysitis, pituitary disorders, etc.); patients will be
eligible if prior autoimmune disease is not deemed to be active (e.x. fibrotic damage
of the thyroid after thyroiditis or its treatment, with stable thyroid hormone
replacement therapy); vitiligo will not be a basis for exclusion

- History of inflammatory bowel disease, celiac disease, or other chronic
gastrointestinal conditions associated with diarrhea or bleeding, or current acute
colitis of any origin

- Potential requirement for systemic corticosteroids or concurrent immunosuppressive
drugs based on prior history or received systemic steroids within the last 4 weeks
prior to enrollment (inhaled or topical steroids at standard doses are allowed)

- Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired
immune deficiency state, which would increase the risk of opportunistic infections and
other complications during chemotherapy-induced lymphodepletion; if there is a
positive result in the infectious disease testing that was not previously known, the
patient will be referred to their primary physician and/or infectious disease
specialist

- Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would
increase the likelihood of hepatic toxicities from the chemotherapy conditioning
regimen and supportive treatments; if there is a positive result in the infectious
disease testing that was not previously known, the patient will be referred to their
primary physician and/or infectious disease specialist

- Dementia or significantly altered mental status that would prohibit the understanding
or rendering of informed consent and compliance with the requirements of this protocol

- Clinically active brain metastases; radiological documentation of absence of active
brain metastases at screening is required for all patients; prior evidence of brain
metastasis successfully treated with surgery or radiation therapy will not be
exclusion for participation as long as they are deemed under control at the time of
study enrollment

- Pregnancy or breast-feeding; female patients must be surgically sterile or be
postmenopausal for two years, or must agree to use effective contraception during the
period of treatment and 6 months after; all female patients with reproductive
potential must have a negative pregnancy test (serum/urine) within 14 days from
starting the conditioning chemotherapy; the definition of effective contraception will
be based on the judgment of the study investigators

- Since IL-2 is administered following cell infusion:

- Patients will be excluded if they have a history of clinically significant
electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia or
arrhythmias and have a left ventricular ejection fraction (LVEF) < 45% on a
cardiac stress test (stress thallium, stress multi gated acquisition (MUGA) scan,
dobutamine echocardiogram, or other stress test)

- Similarly, patients who are 50 years old with a baseline LVEF < 45% will be
excluded

- Patients with ECG results of any conduction delays (PR interval > 200 ms,
corrected QT interval [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50
beats per minute), sinus tachycardia (heart rate > 120 beats per minute) will be
evaluated by a cardiologist prior to starting the trial; patients with any
arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy
(defined as > 20 PVCs per minute), ventricular tachycardia, 3rd degree heart
block will be excluded from the study unless cleared by a cardiologist

- Patients with pulmonary function test abnormalities as evidenced by a forced
expiratory volume of the lung in 1 second (FEV1)/forced vital capacity (FVC) <
70% of predicted for normality will be excluded

- Evidence of diverticulitis at baseline, including evidence limited to computed
tomography (CT) scan only