IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

Abstract

IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8+ T (mCD8+ T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8+ T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8+ T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA–induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA–mediated immunotoxicity.

Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent

“…Our group showed mice developed lethal toxicity at high doses of IL-15 superagonist, presenting with hypothermia, cachexia, acute liver injury and death (37). We also showed that hyperproliferation and hyperactivation of NK cells and production of IFN-γ, mediated IL-15 superagonist-associated immunotoxicity, whereas CD8 + T cells played a protective role.…”

“…Our lab, for the first time, showed soluble IL-15/IL-15 Rα complex treatment could cause marked hypothermia, weight loss, splenomegaly and a modest increase in liver enzymes in wild type mice when given at 2 μg for 4 consecutive days but not at lower doses (37). Thus, the toxicity profile of IL-15 family immunobiologicals is similar among species.…”

Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

“…Monomeric IL-15 is a small unstable protein with a short serum t 1/2 , necessitating supraphysiological dosing to attain in vivo responses (22). However, physiological transpresentation of IL-15 uses the IL-15 receptor alpha chain (IL-15Rα) (23,24). Recombinant soluble IL-15 bound to a recombinant soluble IL-15Rα (referred to as IL-15 complex) augments T-cell antitumor activity (22), likely due to the qualitatively different signaling achieved upon mimicking transpresentation (25).…”

Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression

“…IL-15 has also been shown to have potential toxic effects. It caused liver injury and cachexia in a mouse model [129] and caused fever, grade 3 hypotension and liver injury in a clinical trial for cancer patients [130]. Therefore, though IL15 possesses stimulating effects on numerous immune cells, its toxicity profile also needs to be taken into consideration.…”