Efficacy and Mechanism-of-Action of a Novel Superagonist Interleukin-15: Interleukin-15 Receptor α/Fc Fusion Complex in Syngeneic Murine Models of Multiple Myeloma

摘要

ALT-803, a complex of an interleukin-15 (IL-15) superagonist mutant and a dimeric IL-15 receptor α/Fc fusion protein, was found to exhibit significantly stronger in vivo biological activity on NK and T cells than IL-15. In this study, we show that a single dose of ALT-803, but not IL-15 alone, eliminated well-established 5T33P and MOPC-315P myeloma cells in the bone marrow of tumor-bearing mice. ALT-803 treatment also significantly prolonged survival of myeloma-bearing mice and provided resistance to rechallenge with the same tumor cells through a CD8⁺ T cell-dependent mechanism. ALT-803 treatment stimulated CD8⁺ T cells to secrete large amounts of interferon-γ (IFN-γ) and promoted rapid expansion of CD8⁺CD44^high memory T cells in vivo. These memory CD8⁺ T cells exhibited ALT-803-mediated up-regulation of NKG2D (KLRK1) but not PD-1 (PDCD1) or CD25 (IL2RA) on their cell surfaces. ALT-803-activated CD8⁺ memory T cells also exhibited non-specific cytotoxicity against myeloma and other tumor cells in vitro, whereas IFN-γ had no direct effect on myeloma cell growth. ALT-803 lost its anti-myeloma activity in tumor-bearing IFN-γ knockout mice but retained the ability to promote CD8⁺CD44^high memory T cell proliferation, indicating that ALT-803-mediated stimulation of CD8⁺CD44^high memory T cells is IFN-γ-independent. Thus, besides well-known IL-15 biological functions in host immunity, this study demonstrates that IL-15-based ALT-803 could activate CD8⁺CD44^high memory T cells to acquire a unique innate-like phenotype and secrete IFN-γ for non-specific tumor cell killing. This unique immune modulatory property of ALT-803 strongly supports its clinical development as a novel immunotherapeutic agent against cancer and viral infections.