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

Abstract

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∼IL-15) by a releasable linker. The pharmacokinetics and pharmacodynamics of MS∼IL-15 were determined in C57BL/6J mice. The antitumor activity of MS∼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 cell-driven 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 half-life of about 168 hours over the first 5 days, followed by an abrupt decrease to about ∼30 hours in accordance with the development of a cytokine sink. A single injection of MS∼IL-15 caused remarkably prolonged expansions of NK and I δT 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∼IL-15 50 μg 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∼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∼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.