Long-Term TARP Vaccination Using a Multi-Epitope TARP Peptide Autologous Dendritic Cell Vaccination in Previously Vaccinated Men on NCI 09-C-0139

TARP

• T-cell receptor gamma alternate reading frame protein (TARP) is an amino acid protein expressed by both normal and malignant prostate cancer tissue; 95% of prostate cancer specimens are positive for TARP expression. TARP is highly expressed in prostate cancers of all Gleason types, in primary as well as metastatic disease, and in hormone sensitive and castrate resistant prostate cancer. Therefore, TARP is an ideal tumor antigen target for a vaccine.
• A prospective, randomized pilot study of 1st generation TARP Peptide vaccination National Cancer Institute (NCI 09-C- 0139) utilizing TARP WT 27-35 and EE29-37-9V peptides was conducted in HLAA* 0201positive men with stage D0 prostate cancer prostate specific-antigen (PSA) biochemical recurrence) and a PSA doubling time (PSADT) of greater than or equal to 3 months and less than or equal to 15 months. TARP vaccination was found to be immunogenic, safe and well tolerated, with adverse events limited to injection site reactions less than or equal to Grade 2. TARP vaccination was also associated with a decreased slope log PSA compared to pre-vaccination baseline in 72% of subjects reaching 24 weeks and 74% reaching 48 weeks (p=0.0012 and p=0.0004 for overall changes in slope log PSA, respectively); TARP vaccination also resulted in a 50% decrease in calculated tumor growth rate constant: prevaccine g = 0.0042/day, post-vaccine g = 0.0021/day (p=0.003); TARP-specific IFN- >= enzyme-linked immunosorbent spot (ELISPOT) responses were detected in the majority of subjects but did not correlate with decreases in slope log (PSA).

Multi-Epitope (ME) TARP Vaccine

• The vaccine platform includes the original two 9-mer HLA-A*0201 binding TARP peptide epitopes (WT27-35 and EE29-37-9V) utilized in NCI 09-C-0139 as well as an additional five 20-mer TARP peptides overlapping by 10 amino acids for a total of 7 peptides that span the amino acid sequence of the entire TARP protein.
• The advantage of this multi-epitope TARP peptide vaccine platform is that the overlapping epitopes cover the entire TARP protein, resulting in potential for induction of a multi-valent anti-TARP response. In addition, these longer synthetic peptides include TARP-specific MHC class II CD4 T lymphocytes (CD4+ T) cell helper epitopes that will allow generation of better cyctotoxic T cells (CD8+ T) cell responses with improved functional avidity and longevity as well as humoral anti-TARP antibody responses.

Study Objectives

Primary Objective:

-To assess the long-term safety of repeated TARP peptide vaccination following the use of a 1st generation bivalent (09-C-0139) and a 2nd generation ME TARP peptide vaccine. Specifically, to document if less than 10% of enrolled patients experience a vaccine-related Grade 3 adverse event (local injection site reactions or systemic reactions).

Eligibility Criteria All Patients

• Males greater than or equal to 18 years of age with histologically confirmed adenocarcinoma of the prostate.
• Prior enrollment in NCI protocol 09-C-0139 with receipt of at least 5 doses of TARP peptide vaccine (i.e. completion of primary vaccination series).
• Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-1 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, 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 1.5X upper limit of normal (ULN) unless receiving clinically indicated anticoagulant therapy; serum glutamate-pyruvate transaminase (SGPT)/serum glutamic oxaloacetic transaminase (SGOT) less than or equal to 2.5X ULN, total bilirubin less than or equal to 1.5X ULN; creatinine less than or equal to 1.5X ULN and 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.
• Standard of care medical management of current prostate cancer disease status by the patients local oncologist e.g., androgen deprivation therapy is allowed.
• Must be able/willing to adhere to protocol requirements and vaccination timeline.

Exclusion criteria

All Patients

• Patients with active infection or other significant or uncontrolled medical illness. Patients with a remote history of asthma or active mild asthma may participate.
• Patients on immunosuppressive therapy including systemic corticosteroid therapy for any reason. Patients receiving inhaled or topical corticosteroids may participate.
• Patients who, in the opinion of the Principal Investigator, have significant medical or psychosocial problems that warrant exclusion.

Study Design

• Open label, prospective, non-randomized, long-term follow-up pilot study of 96 weeks to assess the long-term safety of repeated TARP vaccination in patients that have already received the first generation TARP vaccine. Sample size: N equals 40 maximum.
• All patients will undergo an 18L apheresis for mononuclear cell collection at Week 0.
• All patients will receive a total of 6 doses of autologous ME TARP peptide dendritic cell (DC) vaccine: 20x10^6 viable cells/dose) delivered intradermally at Weeks 3, 6, 9, 12, 15, and 24.

• INCLUSION CRITERIA:
• Males greater than or equal to 18 years of age with histologically confirmed adenocarcinoma of the prostate.
• Prior enrollment in National Cancer Institute (NCI) protocol 09-C-0139 with receipt of at least 5 doses of T cell receptor gamma alternate reading frame protein (TARP) peptide vaccine (i.e. completion of primary vaccination series).
• Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-1, life expectancy of 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.
• Prothrombin time (PT)/partial thromboplastin time (PTT) less than or equal to 1.5X upper limit of normal (ULN) unless receiving clinically indicated anticoagulant therapy.
• Serum glutamic-oxaloacetic transaminase (SGOT)/serum glutamic-pyruvic transaminase (SGPT) less than or equal to 2.5X ULN, total bilirubin less than or equal to 1.5X ULN, creatinine (Cr) less than or equal to 1.5X ULN, 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 (including Intravenous immune globulin (IVIG) within 8 weeks of study entry. Note: Use of topical, inhaled and intranasal steroid therapy is permitted.
• Greater than or equal to 6 weeks since the receipt of chemotherapy or radiation therapy.
• Standard of care medical management of current prostate cancer disease status by the patients local oncologist, e.g., androgen deprivation therapy is allowed.
• Able to understand and provide Informed Consent.
• Must be able and willing to adhere to protocol requirements, visits and vaccination timeline.

Exclusion criteria

• Patients with a second malignancy requiring active treatment.
• Patients with an active infection.
• Patients on immunosuppressive therapy including:

--Systemic corticosteroid therapy for any reason. Patients receiving inhaled, intranasal or topical corticosteroids may participate.

• Other significant or uncontrolled medical illness. Patients with a remote history of or active mild asthma may participate.
• Patients who, in the opinion of the Principal Investigator, have significant medical or psychosocial problems that warrant exclusion including:

• Other serious non-malignancy-associated medical conditions that may be expected to limit life expectancy to less than 2 years.
• Any condition- medical, psychiatric or otherwise, that would preclude informed consent, consistent follow-up or compliance with any aspect of the study.