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 prostate-specific antigen (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 dendritic cells (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, interferon (IFN)-gamma enzyme-linked immune absorbent spot (ELISpot) and (51)Cr release cytotoxic T lymphocytes (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, computed tomography (CT) scan or bone scan.
• Prostate-specific antigen doubling time (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 Radiation Therapy Oncology Group (RTOG)-American Society for Radiation Oncology (ASSTRO) consensus criteria).
• For patients following radical prostatectomy: 2 absolute PSA values > 0.3ng/ml (per National Comprehensive Cancer Network (NCCN) guidelines).
• Non-castrate level of testosterone: greater than or equal to 50 ng/dL (prior androgen deprivation therapy (ADT) allowed; must be greater than or equal to 6 months since last dose of ADT).
• HLA-A*0201 positive.
• Performance Status: Eastern Cooperative Oncology Group (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, white blood cell (WBC) greater than or equal to 2,500/mm(3), absolute lymphocyte count (ALC) greater than or equal to 500/ mm(3), absolute neutrophil count (ANC) greater than or equal to 1,000/mm(3), platelet count greater than or equal to 100,000/mm(3), and prothrombin time (PT)/partial thromboplastin time (PTT) less than or equal to 1.5 times upper limits of normal (ULN) unless receiving clinically indicated anticoagulant therapy; serum glutamic pyruvic transaminase (SGPT)/Serum glutamic oxaloacetic transaminase (SGOT) less 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 glomerular filtration rate (GFR) estimated glomerular filtration rate (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); human immunodeficiency virus (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 human leukocyte antigen (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, interleukin 4 (IL4), 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 Sargramostim given 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.