Antitumor Immunotherapeutic and Toxic Properties of an HDL-Conjugated Chimeric IL-15 Fusion Protein

Abstract

Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Ra) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Ra's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Ra's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 mg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 mg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Ra À/À mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease. Cancer Res; 73(1);

Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells Producing IL15 Eradicate Established Pancreatic Tumor in Syngeneic Mice

“…Toxic effects related to IL15 have been described in several reports that high systemic level of IL15 could lead to NK or T leukemias (40,12). In this study, there was an absence of high systemic level of IL15, suggesting that MSC-IL15 may be able to reduce undesired side effects.…”

IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

“…1,[30][31][32] To determine if the antitumor immunity-restoring effect of IL-15 can be further enhanced if IL-15 is ubiquitously overexpressed, AOM/DSS was induced in Il15tg mice. 33 These mice had a significantly reduced tumor load compared to both CD11c-Il15, and WT mice (Fig.…”

Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)

“…To do so, in immunodeficient Rag2 À/À IL2Rg À/À mice-bearing HT29 tumor xenografts to transfer of IL8 to the liver. This procedure achieves transient gene expression of IL8 in the liver of mice without detectable expression in other organs (42). Indeed, hydrodynamic gene transfer of IL8 augmented the absolute number of MDSC in the liver of mice in the course of experiments described in Fig.…”