Peptide-pulsed autologous dendritic cell vaccine(Radboud University Nijmegen)

T-cell receptor alternate reading frame protein (TARP) is a 58-residue protein over-expressed in prostate and breast cancer. We investigated TARP peptide vaccination's impact on the rise in PSA (expressed as Slope Log(PSA) or PSA Doubling Time (PSADT)), validated tumor growth measures, and tumor growth rate in men with Stage D0 prostate cancer. HLA-A*0201 positive men were randomized to receive epitope-enhanced (29-37-9V) and wild-type (27-35) TARP peptides administered as a Montanide/GM-CSF peptide emulsion or as an autologous peptide-pulsed dendritic cell vaccine every 3 weeks for a total of five vaccinations with an optional 6th dose of vaccine at 36 weeks based on immune response or PSADT criteria with a booster dose of vaccine for all patients at 48 and 96 weeks. 41 patients enrolled with median on-study duration of 75 weeks at the time of this analysis. Seventy-two percent of patients reaching 24 weeks and 74% reaching 48 weeks had a decreased Slope Log(PSA) compared to their pre-vaccination baseline (p = 0.0012 and p = 0.0004 for comparison of overall changes in Slope Log(PSA), respectively). TARP vaccination also resulted in a 50% decrease in median tumor growth rate (g): pre-vaccine g = 0.0042/day, post-vaccine g = 0.0021/day (p = 0.003). 80% of subjects exhibited new vaccine-induced TARP-specific IFNγ ELISPOT responses but they did not correlate with decreases in Slope Log(PSA). Thus, vaccination with TARP peptides resulted in significant slowing in PSA velocity and reduction in tumor growth rate in a majority of patients with PSA biochemical recurrence.

Dendritic cells are critical for the induction of anti-tumor immunity. Recent studies suggest that some tumors may avoid immune destruction by inhibiting dendritic cell function. In this study, we investigated the effects of uveal melanoma on human dendritic cell phenotype and functions including surface antigen expression, cytokine production, and T cell activation. Dendritic cells were generated in the presence of GM-CSF and IL-4 from peripheral blood mononuclear cells of healthy donors. On day 5 of culture, dendritic cells were co-cultured with human uveal melanoma cells for 24 h, and then purified using magnetic beads. The maturation of dendritic cells was induced by TNF-α and the phenotype of dendritic cells was analyzed by flow cytometry. The expression of dendritic cell markers and antigen presenting cell markers decreased when dendritic cells were co-cultured with uveal melanoma cells. Moreover, co-culture with uveal melanoma cells led to apoptosis of dendritic cells as shown by 1.5-fold increase in surface phosphatidylserine. Also, dendritic cells co-cultured with uveal melanoma showed diminished ability to produce IL-12 and IL-10. Finally, dendritic cells co-cultured with uveal melanoma inhibited the proliferation of allogeneic T cells in mixed lymphocyte reaction. These findings suggest a mechanism by which uveal melanoma escape immune destruction and have significant implications for tumor-pulsed dendritic cell vaccines for the treatment of uveal melanoma.