A Study of Denileukin Diftitox to Treat Refractory Ovarian Cancer

e13121 Background: The number of circulating CD4+ regulatory T-cells (Tregs) has been correlated with outcome in advanced ovarian cancer. A prior report (Barnett, et al; AACR Abstracts 2006: 1148) suggested that denileukin diftitox, a fusion toxin containing interleukin-2 fused to diphtheria toxin, may be of therapeutic value in this disease acting via Treg depletion. As part of a larger study of denileukin diftitox with dendritic cell-based vaccination, we treated patients with the agent alone to determine if it depletes circulating CD4+CD25HiFoxP3+CD127Low Tregs and induces clinical responses. Methods: Patients with relapsed/refractory ovarian or primary peritoneal carcinoma were eligible. No chemotherapy or immunotherapy was allowed for the preceding 4 weeks. Denileukin diftitox 18 μg/kg IV was given every 28 days for up to 4 cycles. Weekly monitoring of CD4 Tregs and CD8+CD28- Tregs was done by monoclonal antibody labeling of PBMC and flow cytometry studies. Clinical responses were measured by standard methods of disease assessment including CA125 testing. Results: Seven women were treated, of whom 3 had minimal residual disease (MRD). No Grade III-IV toxicities were seen. Unlike the prior report, no clinical responses were seen in 4 patients with bulky measurable disease. Median progression free survival was 5.5 months (range 0.5-20.5) and median overall survival will exceed 21.6 months (range 1.4-26.5+) with MRD a marker for prolonged remissions and survival. We saw no Treg depletion after the 1st cycle; i.e., no patient had ≥25% reduction in Tregs at the expected nadir at day 14. Mean CD4+CD25HiFoxP3+CD127Low Tregs/CD4 cells for controls was 1.16% (range .35-2.13) at baseline, with no significant temporal variation. Mean Tregs/CD4 cells for treated subjects was 2.89% (range 1.06-5.40) at baseline and 3.11% (range .81-5.13) at day 14. For 6 patients who received ≥2 cycles, mean Tregs/CD4 cells dropped to 1.95% (range .71-3.74) at day 42 and 1.65% (range .78-2.36) at day 70. CD8+CD28- Tregs were only increased (>50% of CD8 T-cells) in 2 patients and not correlated with remission duration. Conclusions: These data suggest that denileukin diftitox depletes Tregs in relapsed ovarian cancer only with repeated dosing and may be of clinical value in MRD.