Anti-CD25 antibody and denileukin diftitox deplete regulatory T cells in ID8 ovarian cancer equally, but αCD25 promotes more T cell cytotoxicity that correlates with better survival (VAC12P.1112)

Abstract

Abstract In ovarian cancer (OC) regulatory T cells (Tregs) block anticancer immunity, suggesting Treg depletion could be beneficial. In our phase 2 denileukin diftitox (DDT) trial we found no clinical efficacy in 19 OC patients despite Treg depletion. αCD25 depletes Tregs but reportedly only works as cancer prophylaxis. We found that αCD25 did not treat subcutaneous B16 mouse melanoma whereas DDT did, and both reduced Tregs equally. We further show that in intraperitoneal ID8 challenge, αCD25 depletes Tregs in ascites and strikingly extends survival better than DDT, the first demonstration that αCD25 is effective cancer treatment (vs prophylaxis). Treg suppression of T cell proliferation in vitro from ID8-bearing mice was equal after DDT or αCD25. DDT and αCD25 could thus target or modulate Treg subsets or other immune cells differentially, as neither is Treg-specific. Despite reduced clinical efficacy, DDT increased beneficial IFN-γ+CD4+ and ID8-specific CD8+ T cells and NK cells in ascites better than αCD25, but also increased pro-tumorigenic IL-17+ and TNF-α+ CD4+ T cells, whereas αCD25 did not. αCD25 increased numbers of ascites GzB+CD107a+CD8+ T cells whereas DDT did not, suggesting increased cytotoxicity that could explain better clinical efficacy. These observations show that Treg depletion agents available for clinical use have distinct effects on antitumor immunity, help define clinical indications for αCD25 versus DDT and identify responsive cancers or anatomic compartments.