Background: For men with elevation of their prostate specific antigen (PSA) as the only sign of progression after initial definitive treatment, immune therapies could impact further disease progression. Epitopes from prostate-specific membrane antigen (PSMA) and T-cell receptor gamma alternate reading frame protein (TARP) capable of inducing in-vitro T-cell responses against prostatic tumors were used to synthesize the vaccine peptide. Each has a class II epitope and an HLA-A2 specific class I epitope. Working from prior studies showing responses of both cytotoxic T lymphocytes and T helper cells are more immunogenic than either alone, this prospective pilot study set to estimate the frequency that this peptide vaccine and poly-IC:LC adjuvant would induce ELISPOT identifiable improved titers. Secondary objectives included evaluation of the safety and toxicity of vaccination and impact on PSA change.
Methods: Estimation of immunologic efficacy was accomplished using an ELISPOT assay of peripheral blood which assessed interferon-gamma secretion by activated T-cells in response to vaccination with PSMA-derived and TARP-derived peptides. Patients were vaccinated every 2 weeks for 8 total injections. Twenty-one patients had full ELISPOT data for analysis, which included pre-vaccination, on-treatment, and follow-up titers of PBMS alone, PSMA CD4, PSMA CD8, TARP CD4, and TARP CD8. Twenty-nine patients had PSA data, which were normalized by both date and PSA measurement. A table recorded the frequencies of adverse effects and dose-limiting toxicities (DLT).
Results: Quarter-root power means were found to be the best for normalization of the ELISPOT results. The averaged PSMA CD4, PSMA CD8, TARP CD4, and TARP CD8 titers were all increased from baseline PBMC at time points 6 and 8. PSMA and TARP CD4 ELISPOT titers were also increased from PBMC baseline at time points 4 and 10. When restricted to time points 4, 6, and 8, the mean expression of PSMA CD4 and TARP CD4 compared to PBMC alone were significantly different, with a power mean fold increase of 2.70 (p=0.0001) and 2.45 (p=0.0006) respectively. The PSMA CD8 and TARP CD8 compared to PBMC were not significantly up during time points 4, 6, and 8. There were no DLT observed. Ten of the 29 patients had excellent stabilization of the PSA and did not have a PSA doubling before their last study visit; the last study date for this subset was a mean of 458 days from baseline PSA (55-613 days). Nineteen of the 29 patients had either a doubling of the PSA or proceeded to another therapy, occurring at a mean of 248 days (23-526 days). In these retrospectively divided subsets, the group with the longer PSA-doubling time appeared to have higher ELISPOT titer increases than the shorter PSA-doubling time group.
Conclusions: A continued need for less intensive, nontoxic therapy such as vaccines exists in the treatment of prostate cancer patients, including those with biochemical failure. This pilot study showed feasibility of the class I + class II + poly-IC: LC combination protocol. Interestingly, significant increases in PMSA CD4 and TARP CD4 ELISPOT titers, as opposed to CD8 titer changes, were observed. A third of the subjects did not have PSA-doubling during the study period. The higher ELISPOT titers in the longer PSA-doubling time group also suggest an association, but not proof of causation, for better vaccine response and longer disease progression timelines. This pilot experience supports further clinical testing using peptide and poly-IC:LC vaccination combination therapies.
Citation Format: Matthew Whitehurst, Xiuhua Zhao, Michael Schell, Esteban Celis, Andres Salazar, Mayer Fishman. Pilot study of combination PSMA peptide and TARP peptide vaccine with poly-IC:LC adjuvant in HLA-A2 positive patients with elevated PSA after initial definitive treatment of prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B38.