A very long-acting IL-15: implications for the immunotherapy of cancer

Background Interleukin-15 (IL-15) is an important cytokine necessary for proliferation and maintenance of natural killer (NK) and CD8(+) T cells, and with great promise as an immuno-oncology therapeutic. However, IL-15 has a very short half-life and a single administration does not provide the sustained exposure required for optimal stimulation of target immune cells. The purpose of this work was to develop a very long-acting prodrug that would maintain IL-15 within a narrow therapeutic window for long periods-similar to a continuous infusion. Methods We prepared and characterized hydrogel microspheres (MS) covalently attached to IL-15 (MS similar to IL-15) by a releasable linker. The pharmacokinetics and pharmacodynamics of MS similar to IL-15 were determined in C57BU6J mice. The antitumor activity of MS similar to IL-15 as a single agent, and in combination with a suitable therapeutic antibody, was tested in a CD8(+) T cell-driven bilateral transgenic adenocarcinoma mouse prostate (TRAMP)-C2 model of prostatic cancer and a NK celldriven mouse xenograft model of human ATL (MET-1) murine model of adult T-cell leukemia. Results On subcutaneous administration to mice, the cytokine released from the depot maintained a long halflife of about 168 hours over the first 5days, followed by an abrupt decrease to about similar to 30 hours in accordance with the development of a cytokine sink. A single injection of MS similar to IL-15 caused remarkably prolonged expansions of NK and gamma delta T cells for 2 weeks, and CD44(hi )CD8(+) T cells for 4 weeks. In the NK cell-driven MET-1 murine model of adult T-cell leukemia, single-agent MS similar to IL-15(50)(mu g) or anti-CCR4 provided modest increases in survival, but a combination-through antibody-depedent cellular cytotoxicity (ADCC)-significantly extended survival. In a CD8(+) T cell-driven bilateral TRAMP-C2 model of prostatic cancer, single agent subcutaneous MS similar to IL-15 or unilateral intratumoral agonistic anti-CD40 showed modest growth inhibition, but the combination exhibited potent, prolonged bilateral antitumor activity. Conclusions Our results show MS similar to IL-15 provides a very long-acting IL-15 with low C-max that elicits prolonged expansion of target immune cells and high anticancer activity, especially when administered in combination with a suitable immuno-oncology agent.

Automated summary

This study developed a very long-acting prodrug of IL-15 that can maintain sustained release and provide prolonged stimulation of target immune cells. The prodrug exhibited remarkable expansion of NK and gamma delta T cells, as well as high anticancer activity when administered in combination with a suitable immuno-oncology agent.