Protocol Number: 09-C-0139

Title:

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

Number:

09-C-0139

Summary:

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 study 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).

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 > 3 months and < 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 consecutive rises in PSA > 0.3ng/ML (per NCCN guidelines).

- Normal level of testosterone (prior ADT allowed).

- HLA-A*0201 positive.

- Performance Status: ECOG 0-1 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 3,000/mm3, ALC greater than or equal to 800/ mm(3), ANC greater than or equal to 1,500/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; 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.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male

Referral Letter Required: No

Population Exclusion(s): Female

Children

Eligibility Criteria: Currently Not Provided

Special Instructions:

Currently Not Provided

Keywords:

Epotope-Enhanced TARP Peptide

Prostate Cancer

TARP Peptide-Pulsed Dendritic Cells

PSADT

HLA-A*0201

Recruitment Keyword(s):

None

Condition(s):

Prostatic Neoplasms

Prostate Specific Antigens

Investigational Drug(s):

TARP 27-35 -9V Peptide Epitope Enchanced Peptide

TARP 29-35 Peptide (Native Peptide)

Investigational Device(s):

None

Intervention(s):

Drug: TARP 27-35 -9V Peptide Epitope Enchanced Peptide

Drug: TARP 29-35 Peptide (Native Peptide)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Stern LJ, Wiley DC. Antigenic peptide binding by class I and class II histocompatibility proteins. Behring Inst Mitt. 1994 Jul;(94):1-10. Review.

Berzofsky JA, Ahlers JD, Belyakov IM. Strategies for designing and optimizing new generation vaccines. Nat Rev Immunol. 2001 Dec;1(3):209-19. Review.

Rivoltini L, Squarcina P, Loftus DJ, Castelli C, Tarsini P, Mazzocchi A, Rini F, Viggiano V, Belli F, Parmiani G. A superagonist variant of peptide MART1/Melan A27-35 elicits anti-melanoma CD8+ T cells with enhanced functional characteristics: implication for more effective immunotherapy. Cancer Res. 1999 Jan 15;59(2):301-6.

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