title: Differential effects of denileukin diftitox IL-2 immunotoxin on NK and regulatory T cells in nonhuman primates.
abstract: Denileukin diftitox (DD), a fusion protein comprising IL-2 and diphtheria toxin, was initially expected to enhance antitumor immunity by selectively eliminating regulatory T cells (Tregs) displaying the high-affinity IL-2R (α-β-γ trimers). Although DD was shown to deplete some Tregs in primates, its effects on NK cells (CD16(+)CD8(+)NKG2A(+)CD3(-)), which constitutively express the intermediate-affinity IL-2R (β-γ dimers) and play a critical role in antitumor immunity, are still unknown. To address this question, cynomolgus monkeys were injected i.v. with two doses of DD (8 or 18 μg/kg). This treatment resulted in a rapid, but short-term, reduction in detectable peripheral blood resting Tregs (CD4(+)CD45RA(+)Foxp3(+)) and a transient increase in the number of activated Tregs (CD4(+)CD45RA(-)Foxp3(high)), followed by their partial depletion (50-60%). In contrast, all NK cells were deleted immediately and durably after DD administration. This difference was not due to a higher binding or internalization of DD by NK cells compared with Tregs. Coadministration of DD with IL-15, which binds to IL-2Rβ-γ, abrogated DD-induced NK cell deletion in vitro and in vivo, whereas it did not affect Treg elimination. Taken together, these results show that DD exerts a potent cytotoxic effect on NK cells, a phenomenon that might impair its antitumoral properties. However, coadministration of IL-15 with DD could alleviate this problem by selectively protecting potentially oncolytic NK cells, while allowing the depletion of immunosuppressive Tregs in cancer patients.
authors.affiliation: Department of Surgery, Transplant Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Yamada
authors.forename: Akihiro
authors.initials: A
authors.lastname: Aoyama
authors.forename: Georges
authors.initials: G
authors.lastname: Tocco
authors.forename: Svjetlan
authors.initials: S
authors.lastname: Boskovic
authors.forename: Ognjenka
authors.initials: O
authors.lastname: Nadazdin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Alessandrini
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
authors.forename: A Benedict
authors.initials: AB
authors.lastname: Cosimi
authors.forename: Gilles
authors.initials: G
authors.lastname: Benichou
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004167:Diphtheria Toxin / Q000494:pharmacology*; D005434:Flow Cytometry; D000922:Immunotoxins / Q000494:pharmacology*; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D000922:Immunotoxins; D019409:Interleukin-15; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox