Trial Information

A Pilot Study of Vaccination With Epitope-Enhanced TARP Peptide and TARP Peptide-Pulsed Dendritic Cells in the Treatment of Stage D0 Prostate Cancer

BACKGROUND:

- T-cell receptor alternate reading frame protein (TARP) is expressed by both normal and
malignant prostate cancer tissue and is found in about 95% of prostate cancer
specimens. TARP is immunogenic and hence is a target antigen for vaccination.

- The immunogenicity of TARP peptides can be augmented through epitope enhancement that
is achieved through amino acid substitutions resulting in increased peptide binding
affinity.

- Two HLA-A*0201 TARP peptide epitopes are associated with generation of catalytic T-cell
responses: TARP27-35 and TARP29-37. Substitution of Val for Leu at position 9 in
TARP29-37, results in a peptide with increased binding affinity (TARP29-37-9V) that
induces antigen specific T cells able to recognize wild type and multiple modified TARP
peptides. The affinity of the TARP 27-35 peptide, corresponding to a distinct but
overlapping epitope, is high enough that no enhancement was required.

- Stage D0 prostate cancer patients have no evidence of visceral or bony metastatic
disease but have persistently elevated or rising PSA levels (biochemical progression)
and are at increased risk for disease progression. Since they lack much of the immune
dysfunction associated with the high tumor burden characteristic of end-stage
metastatic disease, they are an ideal population in which to study therapeutic
vaccination to slow or prevent disease recurrence and progression.

- Dendritic cells (DC) are the most potent antigen-presenting cells of the immune system
and are being studied extensively for anti-tumor activity in a broad spectrum of cancer
patients.

- As the optimal method for therapeutic immunization with peptide vaccines in patients
with cancer is unclear, vaccination with TARP peptides in Montanide(Registered
Trademark) ISA 51 VG adjuvant plus Sargramostim will be studied in a randomized fashion
with autologous, TARP peptide-pulsed DCs in HLA-A*0201 Stage D0 prostate cancer
patients.

OBJECTIVES:

Primary:

- Determine the safety and toxicity of TARP peptide and TARP peptide-pulsed dendritic
cell vaccination in patients with Stage D0 prostate cancer.

- Determine the T-lymphocyte immune responses to TARP peptide vaccination with
Montanide(Registered Trademark) ISA 51 VG plus Sargramostim or autologous dendritic
cells as measured by tetramer staining, IFN-gamma ELISPOT and (51)Cr release CTL
assays.

Secondary:

- Determine the effect of TARP peptide vaccination on serum prostate specific antigen
doubling time (PSADT) in patients with PSADT greater than 3 months and less than 15
months.

- Determine the effect of TARP peptide vaccination on PSA growth rate and regression rate
constants.

ELIGIBILITY:

- Males greater than or equal to 18 years of age with histologically confirmed
adenocarcinoma of the prostate.

- Must have completed and recovered from all prior definitive therapy (surgery,
brachytherapy, cryotherapy or radiotherapy) for the primary tumor, or other
definitive-intent local therapy.

- Stage D0 disease with documented biochemical progression documented by rising PSA and
no evidence of metastatic disease by physical examination, CT scan or bone scan.

- PSADT greater than or equal to 3 months and less than or equal to or equal to 15
months:

- Patients must have greater than or equal to 3 PSA measurements over greater than
or equal to 3 months.

- The interval between PSA measurements must be greater than or equal to 4 weeks.

- For patients following definitive radiation therapy or cryotherapy: a rise in PSA of >
2ng/mL above the nadir (per RTOG-ASSTRO consensus criteria).

- For patients following radical prostatectomy: 2 absolute PSA values > 0.3ng/ml (per
NCCN guidelines).

- Non-castrate level of testosterone: greater than or equal to 50 ng/dL (prior ADT
allowed; must be greater than or equal to 6 months since last dose of ADT).

- HLA-A*0201 positive.

- Performance Status: ECOG 0-2 or Karnofsky 70-100% and life expectancy greater than or
equal to 1 year.

- Hemoglobin greater than or equal to 10.0 gm/dL, WBC greater than or equal to
2,500/mm(3), ALC greater than or equal to 500/ mm(3), ANC greater than or equal to
1,000/mm(3), platelet count greater than or equal to 100,000/mm(3), and PT/PTT less
than or equal to 1.5 times ULN unless receiving clinically indicated anticoagulant
therapy; SGPT/SGOTless than or equal to 2.5 times ULN, total bilirubin less than or
equal to 1.5 times ULN; creatinine less than or equal to 1.5 times ULN and estimated
GFR (eGFR) greater than or equal to 60 ml/min.

- Hepatitis B and C negative (unless the result is consistent with prior vaccination or
prior infection with full recovery); HIV negative.

- No use of investigational agents within 4 weeks of study enrollment or use of
immunosuppressive or immunomodulating agents within 8 weeks of study entry.

- No other concurrent anticancer therapy or prior prostate cancer vaccines expressing
TARP or HLA A2.

- No alternative medications known to alter PSA (e.g. phytoestrogens and saw palmetto).
Note: patients receiving medications for urinary symptoms such as Flomax or 5-alpha
reductase inhibitors (finasteride and dutasteride) on a chronic stable dose for at
least 3 months are allowed.

STUDY DESIGN:

- This is a randomized, prospective, pilot study of vaccination with a mixture of wild
type (TARP27-35) and epitope-enhanced (TARP29-37-9V) TARP peptides in HLA-A*0201
patients with stage D0 prostate cancer.

- Vaccination with TARP peptides admixed with Montanide(Registered Trademark) ISA 51 VG
plus Sargramostim administered by deep subcutaneous injection will be compared with
vaccination with TARP peptide-pulsed autologous dendritic cells (DCs) administered
intradermally.

- Autologous dendritic cells will be matured from peripheral blood monocytes with
Sargramostim, IL-4, IFN-gamma and LPS and pulsed with wild type and epitope-enhanced
TARP peptides.

- Apheresis will be performed on all patients at weeks 0, 24, 48 and 96.

- Randomization and assignment to received TARP peptide vaccine with Montanide(Registered
Trademark) ISA 51 VG plus Sargramostimgiven by deep subcutaneous injection or TARP
peptide-pulsed autologous DCs given ID will be performed at week 0.

- All patients will receive live, attenuated influenza vaccine (FluMist (Trademark)) when
seasonally available at the very end of their week 0 visit as a control vaccine to
assess cytotoxic T lymphocyte responses.

- TARP Peptide vaccines will be administered every three weeks at weeks 3, 6, 9, 12, and
15, with a sixth and seventh booster dose of vaccine at Week 48 and 96. Follow-up will
be through 144 weeks on study.

- The trial uses an optimal 2-stage design targeting an immunologic response between 10
and 40%. We will initially accrue 9 patients in each arm. If 0-1 patients develop an
immunologic response, then no further patients will be enrolled. If 2 or more of these
patients develop an immunologic response, we will accrue 11 additional patients for a
maximum total of up to 20 patients in each arm. A stopping rule for excessive toxicity
will be incorporated.