A study of mature alpha-DC-1 vaccine to induce immune responses in ovarian cancer.
ABSTRACT
Background: Ovarian cancer (OvCa) is usually diagnosed at an advanced stage and relapse is common despite current treatments. The number of circulating CD4+ T regulatory cells (Tregs) correlates inversely with outcome in advanced OvCa. Novel immunotherapy is needed to stimulate anti-tumor host immune responses. Patients were treated with a mature dendritic cell (DC) vaccine (α-DC-1), to determine if this strategy reduces circulating Tregs and augments IFN-γ immune responses.
Methods: Patients with relapsed/refractory or suboptimally debulked ovarian or primary peritoneal carcinoma were eligible. IL-12p70 secretion is an indicator of DC potency and primer of tumor-specific cytotoxic T cell responses. Vaccines consisted of 1-28 x 106 mature α-DC-1 cells, loaded with autologous tumor lysate and KLH (195-3195 pg/ml IL-12p70), harvested day 7. The cells were injected intranodally every other week for 3 doses per cycle, up to 3 cycles. CD4+CD25highFoxP3+CD127low Tregs were monitored weekly by monoclonal antibody labeling of PBMC and flow cytometry. Levels of IFN-γ secreted by PBMC were studied with ELISpot at leukapheresis and 2 points after cycle 1. Standard methods were used to assess disease.
Results: Eight women, 6 of whom had minimal residual disease, received ≥ 1 cycle (median 2.3).No grade 3-4 toxicities were seen. Median progression free survival was 5.6 months (range 2.2-15.0), and median overall survival has not been reached. PBMC from all subjects were positive for IFN-γ secretion on 48-hr stimulation with positive control PMA/ionomycin and with KLH, and 2/8 (25%) on tumor lysate challenge. PBMC analysis at baseline and 2 or 3 weeks post cycle 1 showed that 4 of 7 evaluable patients (57%) had ≥ 20% Treg reduction. Mean Tregs/CD3+ T cells for controls were .92% (range .69-1.29). Mean Tregs/CD3+ T cells for vaccine subjects were 1.68% (range 1.22-2.13) at baseline. For 6 patients who received ≥ 2 vaccine cycles, mean Tregs/CD3+ T cells were 1.55% (range 1.13-2.08) after cycle 2, and 1.36% (n = 3) after cycle 3 (range .81-2.26).
Conclusions: Administration of mature α-DC-1 vaccine resulted in anti-tumor IFN-γ immunity to tumor lysate antigens in 25% of subjects. Overall there was a modest reduction in CD4+ Tregs with DC vaccine therapy. Clinical trial information: NCT00703105