Interferon-α augments the clinical efficacy of regulatory T cell depletion in ovarian cancer through direct and indirect T cell effects (VAC3P.941)

Abstract

Abstract Tregs blunt anti-tumor immunity, and their depletion effectively treats tumor in mouse cancer models. However, Treg depletion in human trials is only partially effective. In our phase II ovarian cancer trial, denileukin diftitox (DT) effected significant Treg depletion in blood and the tumor microenvironment but did not produce significant clinical efficacy. Interferon-α is not an effective ovarian cancer treatment, but we show here that it significantly augments immune and clinical DT-mediated Treg depletion efficacy in human ovarian cancer. In a mouse ovarian cancer model, DT modestly improved anti-tumor immunity and survival. Interferon-α alone did not alter Treg numbers or function, but boosted CD8+ T cell anti-tumor immunity. Interferon-α plus DT significantly prolonged mouse survival over either individual agent. Using type I IFNR-/- mice that cannot mediate interferon-α signals, we showed that interferon-α directly boosted CD8+ T cell function independent of CD4+ T cell help, and in combination with DT reduced Treg function (without further numerical reduction) through indirect effects on tumor microenvironmental dendritic cells. When three ovarian cancer patients failed DT alone, two experienced immunologic and clinical benefit by adding pegylated interferon-α2a, with manageable toxicities. These studies demonstrate novel immune and clinical interferon-α anti-cancer benefits that augment Treg depletion using FDA-approved agents for rapid clinical translation.