Interferon-α augments clinical efficacy of regulatory T cell depletion with denileukin diftitox in ovarian cancer.

PURPOSE Immunotherapy treats some cancers, but not ovarian cancer (OC). Regulatory T cells (Tregs) impede anti-OC immunity but effective human Treg-directed treatments are lacking. We tested Treg depletion with denileukin diftitox (DD) {plus minus} interferon-α as OC immunotherapy. EXPERIMENTAL DESIGN Mice with syngeneic ID8 OC challenge were treated with DD, interferon-α, or both. The phase 0/I trial tested one dose-escalated DD infusion for functional Treg reduction, safety and tolerability. The phase II trial adding interferonα-2a to DD if DD alone failed clinically. RESULTS DD depleted Tregs, and improved anti-tumor immunity and survival in mice. Interferon-α significantly improved anti-tumor immunity and survival with DD. Interferon-α did not alter Treg numbers or function but boosted tumor-specific immunity and reduced tumor Treg function with DD by inducing dendritic cell IL-6. DD alone was well-tolerated, depleted functional blood Tregs and improved immunity in patients with various malignancies in Phase 0/I. An OC patient in Phase 0/I experienced partial clinical response prompting a phase II OC trial, but DD alone failed Phase 2. Another Phase 2 trial added pegylated interferon-α2a to failed DD, producing immunologic and clinical benefit in 2/2 patients before a DD shortage halt. DD alone was well tolerated. Adding interferon-α increased toxicities but was tolerable, and reduced human Treg numbers in blood, and function through dendritic cell-induced IL-6 in vitro Conclusions: Treg depletion is clinically useful but unlikely alone to cure OC. Rational treatment agent combinations can salvage clinical failure of Treg depletion alone, even when neither single agent provides meaningful clinical benefit.