Introduction

Interleukin-15 (IL-15) is a pleiotropic cytokine that plays a pivotal role in both innate and adaptive immunity. IL-15 is also a promising cytokine for treating cancer. Despite a growing interest in the use of IL-15 as an immunotherapeutic agent, it has not been reported the immunological and clinical effects of IL-15 on cancers in dogs.

Objectives

In this study, we generated a recombinant canine IL-15 (rcIL-15), and determined its biological effects on immune effector cells, and confirmed its safety in vivo. After then, clinical and immunomodulatory effects of rcIL-15 in combination with metronomic cyclophosphamide were evaluated in canine patients with various tumor types.

Methods

To determine the safety and immunologic effects, rcIL-15 was injected intravenously in doses of 20 µg/kg daily for 8 days and monitored for 32 days. Treatment outcomes in dogs with cancers were evaluated in a prospective clinical trial. Low dose of cyclophosphamide (15 mg/m², PO, SID) was continuously administrated for 7 weeks. From day 14 after administration of cyclophosphamide, rcIL-15 (20 µg/kg daily) was injected intravenously for 8 days.

Results

Although several dogs experienced temporal and mild pyrexia, any other significant adverse events were not detected during and after injection of rcIL-15. Administration of rcIL-15 in combination with metronomic cyclophosphamide remarkably increased the number of NK cells and its anti-cancer activities, and significantly decreased the number of regulatory T cells in the peripheral blood of all patients, which were associated with improved clinical outcomes.

Conclusions

Our results suggest rcIL-15 is safe and has tremendous potential for antitumor therapy for dogs.