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

 -  PSA (prostate specific antigen) is a protein found on normal and cancerous prostate
 cells. Levels of this protein are used to identify men who are at risk for prostate
 cancer and to monitor responses to treatment in men who have been diagnosed with
 prostate cancer.

 -  Research has shown that men who continue to have an elevated PSA level following primary
 treatment for prostate cancer are at increased risk for cancer progression. Studies have
 shown that the change in PSA levels over time, or PSA doubling time (PSADT), can be
 accurate in predicting how quickly the cancer is likely to progress. Individuals with a
 PSADT of less than 3 months are at extremely high risk for disease progression and death
 from prostate cancer. Individuals with a PSADT of greater than 15 months have a very low
 risk of death from prostate cancer.

 -  TARP is a protein that is found in about 95% of prostate cancers and is known to
 stimulate the immune system. The TARP prostate cancer vaccine is made from pieces of the
 TARP protein called peptides and includes peptides that have been modified to make them
 more effective at stimulating immunity. Although these TARP peptides have been shown to
 stimulate the immune systems of mice, information is needed to determine if they also
 stimulate the immune system in humans. Since it is unclear what is the best way to give
 peptide vaccines, the TARP peptides will be given with substances known to stimulate the
 immune system or in a vaccine made with the patient s own cells.

 Objectives:

 -  To determine the immune system s response to vaccination with TARP peptides.

 -  To determine the safety and toxicity of TARP peptide vaccination.

 -  To determine if vaccination with the TARP prostate cancer vaccine can slow down PSADT in
 men with an intermediate PSADT of 3 to 15 months.

 Eligibility:

 -  Males 18 years of age and older who have completed their primary treatment for prostate
 cancer, have stage D0 disease, are HLA A*0201 positive and who have a PSADT greater than
 3 and less than 15 months.

 Design:

 -  Patients will be randomized to one of two treatment arms:

 -  Arm A will receive the TARP vaccine with other substances that stimulate the immune
 system.

 -  Arm B will receive the TARP vaccine that includes a patient s own white blood cells.

 -  First week of study, after screening for eligibility has been completed:

 -  Day 1: Apheresis procedure to extract white blood cells to test the immune response to
 the vaccine.

 -  Day 3: Flu vaccine to allow researchers to determine how well a patient s immune system
 is working.

 -  Clinic visits in Weeks 3, 6, 9, 12, and 15 for physical examination, blood samples, and
 administration of the TARP peptide vaccine.

 -  Physical examination and blood samples only in Weeks 18 and 36.

 -  Additional blood samples and apheresis procedures in Weeks 24 and 48.

 -  A 6th dose of TARP peptide vaccine will be administer to those patients who have a
 response to vaccination at week 24.

 -  No follow-up or long-term study is associated with this study.
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 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:

 -  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
 ISA 51 VG plus Sargramostim or autologous dendritic cells as measured by tetramer
 staining, IFN-gamma ELISPOT and (51)Cr release CTL assays.

 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 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 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 ) 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.
-  INCLUSION CRITERIA:

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

 -  HLA-A*201 positive

 -  Patients 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 a rising PSA.

 -  No evidence of metastatic disease by physical examination, CT scan or bone scan.

 -  For patients following definitive radiation therapy or cryotherapy: a rise in PSA of
 >2ng/mL above the nadir.

 -  For patients following radical prostatectomy: 2 absolute PSA values > 0.3 ng/mL

 -  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).

 -  A Pre-Enrollment/Baseline PSADT > 3 months and less than 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 receiving 5-alpha reductase inhibitors (5ARI) e.g. finasteride or
 dutasteride, only PSA values obtained after at least 3 months on therapy may be used
 to calculate PSADT.

 -  Performance Status: ECOG 0-2 or Karnofsky 70-100%

 -  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/mm3, ANC greater than or equal to
 1,000/mm(3), platelet count greater than or equal to 100,000/mm(3).

 -  PT/PTT less than or equal to 1.5 times ULN unless receiving clinically indicated
 anticoagulant therapy.

 -  SGOT/SGPT < 2.5 times ULN, total bilirubin < 1.5 times ULN, Cr < 1.5 times ULN,
 estimated GFR (eGFR) > 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.

 -  No use of immunosuppressive (cytotoxic chemotherapy, systemic steroids) or
 immunomodulating agents (including IVIG) within 8 weeks of study entry. Note: topical
 and intranasal steroid therapy is permitted.

 -  No other concurrent anticancer therapy.

 -  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.

 -  No prior prostate cancer vaccines expressing TARP or HLA A2.

 -  Able to understand and provide Informed Consent.

 EXCLUSION CRITERIA:

 -  HLA-A*201 negative

 -  Patients with an active second malignancy other than adequately treated squamous or
 basal cell carcinoma of the skin, or superficial bladder carcinoma.

 -  Patients with active infection.

 -  Patients with brain, visceral or bony metastatic disease.

 -  Patients in who live attenuated intranasal influenza vaccine (FluMist ) is
 contraindicated including individuals with asthma or reactive airways disease,
 cardiovascular or pulmonary disease, chronic metabolic diseases (including diabetes
 mellitus), renal dysfunction or hemoglobinopathies.