Gene and Vaccine Therapy in Treating Patients With Advanced Malignancies

PRIMARY OBJECTIVES:

I. To evaluate whether we can safely administer NY-ESO-1 T cell receptor transduced
autologous peripheral blood mononuclear cells (PBMCs) (up to 1x10^9 cells) along with an
NY-ESO-1 dendritic cell vaccine and low dose IL-2 to patients with advanced malignancies.

II. To evaluate the feasibility of delivering two patient-specific cell therapies, the
NY-ESO-1 TCR transgenic peripheral blood mononuclear cell (PBMC) and NY-ESO-1 (157-165)
peptide pulsed dendritic cells (DC), within a technically challenging study design that
requires other significant interventions, like a lymphodepleting conditioning regimen and
post-infusion of subcutaneous low dose interleukin (IL)-2 (aldesleukin).

III. To determine the rate of objective tumor responses, by Response Evaluation Criteria in
Solid Tumors (RECIST) objective response criteria.

SECONDARY OBJECTIVES:

I. To determine the persistence of NY-ESO-1 TCR-engineered cells. This will be determined by
temporally analyzing peripheral blood samples for the presence of T cells with the transduced
NY-ESO-1 TCR by tetramer or dextramer analysis.

II. To explore the homing and persistence of the adoptively transferred NY-ESO-1
TCR-engineered PBMC in secondary lymphoid organs and tumor deposits via positron emission
tomography (PET)-based imaging using the PET tracer fluorodeoxyglucose ([18F]FDG).

OUTLINE:

CONDITIONING: Patients receive cyclophosphamide intravenously (IV) over 1 hour on days -5 to
-4 and fludarabine phosphate IV over 30 minutes on days -4 to -1.

TRANSPLANT: Patients receive NY-ESO-1 TCR transduced autologous PBMC IV on day 0. Patients
also receive NY-ESO-1 (157-165) peptide pulsed dendritic cell vaccine therapy intradermally
(ID) on days 1, 14, and 30 and aldesleukin subcutaneously (SC) twice daily (BID) on days
1-14. Patients may receive 3 additional doses of NY-ESO-1 (157-165) peptide pulsed dendritic
cell vaccine therapy after day 90.

After completion of study treatment, patients are followed up at 30, 45, 60, and 75 days;
every 3 months for 2 years; every 6 months for 3 years; and 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 an outpatient biopsy; 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 IHC utilizing commonly available NY-ESO-1 antibodies.

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

- Age greater than or equal to 16 years old.

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

- A minimum of one measurable lesion defined as:

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

- For patients with skin metastases, lesions 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.

- ECOG performance status (PS) 0 or 1.

- Adequate bone marrow and hepatic function determined within 30-60 days prior to
enrollment, defined as:

1. Absolute neutrophil count > or = 1.5 x 109 cells/L.

2. Platelets > or = 100 x 109/L.

3. Hemoglobin > or = 10 g/dL.

4. Aspartate and alanine aminotransferases (AST, ALT) < or = 2.5 x ULN (< or = 5 x
ULN, if documented liver metastases are present).

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

6. Creatinine < 2 mg/dl (or a glomerular filtration rate > 60 mL/min).

- Must be willing and able to accept at least two leukapheresis procedures.

- Must be willing and able to accept at least two tumor biopsies.

- 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. However, cell harvesting by
leukapheresis may be performed before one month from prior therapy if the study
investigators consider that it will not have a detrimental impact on the generation of
the two cell therapies in 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).

- HIV seropositivity or other congenital or acquired immune deficiency state, which
would increase the risk of opportunistic infections and other complications during
chemotherapy-induced lympho-depletion. 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:

1. Patients will be excluded if they have a history of clinically significant 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 MUGA, dobutamine echocardiogram, or other stress test)

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

3. Patients with ECG results of any conduction delays (PR interval >200ms, QTC >
480ms), sinus bradycardia (resting heart rate <50 beats per minute), sinus
tachycardia (HR>120 beats per minute) will be evaluated by a cardiologist prior
to starting the trial. Patients with any arrhythmias, including atrial
fibrillation/atrila 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.

4. Patients with pulmonary function test abnormalities as evidenced by a FEV1/FVC<
70% of predicted for normality will be excluded.

- Received 3 or more prior myelotoxic treatment regimens.