Genetically Engineered PBMC and PBSC Expressing NY-ESO-1 TCR After a Myeloablative Conditioning Regimen to Treat Patients With Advanced Cancer

PRIMARY OBJECTIVE:

I. To determine the safety of administering the combination of autologous peripheral blood
mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) following a reduced
intensity conditioning regimen, both of which have been genetically modified to express
NY-ESO-1 TCR.

SECONDARY OBJECTIVES:

I. To determine the feasibility of delivering the combination of TCR transduced autologous
PBMC and CD34+ PBSC to patients.

II. To determine the persistence of NY-ESO-1 TCR transduced PBMC and the progeny of TCR
transduced PBSC in serial peripheral blood samples.

III. Objective response rate (ORR).

EXPLORATORY OBJECTIVE:

I. To explore the use of positron emission tomography (PET)-based imaging using the PET
tracer 9-4-[18F]fluoro-3-(hydroxymethyl)butylguanine ([18F]FHBG) with the goal of determining
whether the adoptively transferred NY-ESO-1 TCR transduced PBSC home to bone marrow,
differentiate into T cells and expand in secondary lymphoid organs and tumor deposits.

OUTLINE:

G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of
cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem
cells. Patients receive G-CSF subcutaneously (SC) on mobilization days 1-8 and plerixafor SC
on mobilization days 4-7, during mobilization, patients will undergo mobilized leukapheresis
to obtain PBSC. Patients also undergo an unmobilized leukapheresis on day -5 before infusion
of cells in order to obtain PBMC.

CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) on days -4 to
-2 and fludarabine IV over 30 minutes on days -3 to -2.

Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours,
patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive
aldesleukin (interleukin-2 (IL) or IL-2) SC twice daily (BID) for up to 7 days. Patients
undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60,
90, and 120. Patients receive the PET tracer 18F-FHBG IV, and after 1 hour, undergo
PET/computed tomography (CT) on days 25 and 120.

After completion of study treatment, patients are followed up every 2-3 months for 2 years,
every 6 months for 5 years, and annually for 15 years.

Inclusion Criteria:

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

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

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

- Age greater than or equal to 16 years old; if patients 16-17 years old are enrolled in
the trial, they will only be enrolled after 3 patients >= 18 years old have been
treated, and the treatment has been shown to be safe

- 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)

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

- Adequate bone marrow and major organ function to undergo a PBSC transplant determined
within 30-60 days prior to enrollment using standard phase 1 criteria for organ
function defined as:

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

- Platelets >= 100 x 10^9/L

- Hemoglobin >= 9 g/dL

- Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x ULN (upper limit of
normal) (=< 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 at least three leukapheresis procedures

- Must be willing and able to undergo three research PET scans

- Must be willing and able to provide written informed consent

Exclusion Criteria:

- Inability to purify >= 2.5 x 10^6 CD34-enriched cells/kg of patient weight from the
pooled G-CSF mobilized leukapheresis products

- Previously known hypersensitivity to any of the agents used in this study; known
sensitivity to busulfan or fludarabine

- Received systemic treatment for cancer, including immunotherapy, within 28 days prior
to initiation of conditioning chemotherapy administration within this protocol

- Potential requirement for systemic corticosteroids or concurrent immunosuppressive
drugs based on prior history or received systemic steroids within the last 2 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

- Known clinically active brain metastases; 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
and there are no neurological signs of potential brain metastases

- 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 for 6 months afterwards; 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 with evidence
of ischemia on a cardiac stress test (stress thallium, stress multigated
acquisition [MUGA], dobutamine echocardiogram or other stress test)

- Similarly, patients with a baseline left ventricular ejection fraction (LVEF) <
45% will be excluded.

- Patients with ECG results of any conduction delays (PR interval > 200 ms,
corrected QT [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 premature ventricular contractions [PVCs] per minute),
ventricular tachycardia or 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 1 [FEV1]/forced vital capacity [FVC ] < 70% of predicted for
normality will be excluded

- Bone marrow involvement based on PET/CT scan at screening

- Active or recent herpes simplex virus (HSV) infection or cytomegalovirus (CMV) based
on symptoms with positive swab culture and/or positive IgM (immunoglobulin M)
screening

- Liver metastases with no other metastatic sites