Viral Oncoprotein Targeted Autologous T Cell Therapy for Merkel Cell Carcinoma

PRIMARY OBJECTIVES:

I. Determine the safety and potential toxicities associated with treating patients with
metastatic merkel cell carcinoma (MCC) by combined myosin heavy chain (MHC) up-regulation
therapy and adoptive transfer of merkel cell polyomavirus (MCPyV) T-antigen (TAg)-specific
polyclonal autologous cluster of differentiation (CD)8+ T cells.

II. Determine the antitumor efficacy associated with treating patients with metastatic MCC
by combined MHC up-regulation therapy and adoptive transfer of MCPyV TAg-specific polyclonal
autologous CD8+ T cells.

SECONDARY OBJECTIVES:

I. Determine the in vivo persistence and where evaluable, migration to tumor sites of
adoptively transferred polyclonal CD8+ T cells targeting the MCPyV TAg.

II. Determine the in vivo functional capacity of adoptively transferred polyclonal CD8+ T
cells targeting the MCPyV TAg.

OUTLINE:

Patients undergo radiation therapy or recombinant interferon beta intralesional injection
within day -3 to day -1.

Patients receive MCPyV TAg-specific polyclonal autologous CD8-positive T cell vaccine
intravenously (IV) on day 1 and aldesleukin subcutaneously (SC) every 12 hours on days 1-14.
Treatment repeats at least every 28 days for up to 2 courses in the absence of disease
progression or unacceptable toxicity.

Patients with continued presence of detectable metastatic disease 8 weeks after the first
infusion may repeat the treatment regimen including radiation therapy or recombinant
interferon beta injection.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Histopathological documentation of MCC concurrent with the diagnosis of metastatic
disease

- Evidence of MCPyV TAg tumor expression

- Available peptide-MHC pair that can be folded into a tetramer for which MCPyV
TAg-specific cells can be generated and reactivity to cell lines expressing MCPyV TAg
with the corresponding human leukocyte antigen (HLA)

- Bi-dimensionally measurable disease by palpation, clinical exam, or radiographic
imaging (x-ray, computed tomography [CT] scan, positron emission tomography [PET]
scan, magnetic resonance imaging [MRI], or ultrasound)

- At least 3 weeks must have passed since any of the following: systemic
corticosteroids, immunotherapy (for example, interleukins, MCC vaccines, intravenous
immunoglobulin, expanded polyclonal tumor infiltrating lymphocyte [TIL] or
lymphokine-activated killer [LAK] therapy), pentoxifylline, other small molecule or
chemotherapy cancer treatment, other investigational agents or other agents that
target merkel cell carcinoma

- Cardiac ejection fraction >= 40% (multigated acquisition [MUGA] or echocardiogram);
for patients with significant risk factors for coronary artery disease (CAD)
(including family history, hypertension, and/or dyslipidemia), or age > 50, stress
echo or stress thallium testing is required

Exclusion Criteria:

- Unable to generate antigen-specific MCPyV TAg-specific CD8+ T cells for infusions

- Active infections prior to receiving study treatment or systemic infection requiring
chronic maintenance or suppressive therapy

- Eastern Cooperative Oncology Group (ECOG) performance status > 2

- White blood cell (WBC) < 2000/mcl

- Hemoglobin (Hb) < 8 g/dL

- Absolute neutrophil count (ANC) < 1000/mcl

- Platelets < 50,000/mcl

- New York Heart Association functional class III-IV heart failure, symptomatic
pericardial effusion, stable or unstable angina, symptoms of coronary artery disease,
congestive heart failure, clinically significant hypotension, or an ejection fraction
of =< 40 % (echocardiogram or MUGA)

- 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 diffusing
capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin [Hgb]) <
50% will be excluded

- Creatinine clearance < 30 ml/min which cannot be attributed to MCC metastasis

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 5 x upper limit of
normal (ULN)

- Bilirubin > 3 x ULN which cannot be attributed to MCC metastasis

- Active autoimmune disease (e.g. systemic lupus erythematosus, vasculitis,
infiltrating lung disease, inflammatory bowel disease) whose possible progression
during treatment would be considered unacceptable by the investigators

- Symptomatic and untreated central nervous system (CNS) metastasis; however, patients
with 1-2 asymptomatic, less than 1 cm brain/CNS metastases without significant edema
may be considered for treatment; if sub-centimeter CNS lesions are noted at study
entry, then a repeat imaging will be performed if more than 4 weeks have elapsed from
the last scan

- Any condition or organ toxicity that is deemed by the principal investigator (PI) or
the attending physician to place the patient at unacceptable risk for treatment on
the protocol

- Pregnant women, nursing mothers, men or women of reproductive ability who are
unwilling to use effective contraception or abstinence; women of childbearing
potential must have a negative pregnancy test within two weeks prior to entry

- Clinically significant and ongoing immune suppression including, but not limited to,
systemic immunosuppressive agents such as cyclosporine or corticosteroids, chronic
lymphocytic leukemia (CLL), uncontrolled human immunodeficiency virus (HIV)
infection, or solid organ transplantation

- 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