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

Abstract

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+CD44high 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+CD44high memory T cell proliferation, indicating that ALT-803-mediated stimulation of CD8+CD44high 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+CD44high 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.

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

“…IL-15 SA has more potent and prolonged action than native IL-15 and preliminary studies suggest enhanced efficacy in experimental models of cancer (25,28). The mechanisms of IL-15 SA-mediated immunotoxicity and antitumor efficacy may be mediated through different cellular mechanisms.…”

“…Recent preclinical studies showed that IL-15 SA is more effective than IL-15 in causing regression of established melanoma and pancreatic cancer in mice (26,27). IL-15/IL-15Ra fusion proteins and IL-15 SA-expressing adenovirus expression systems have also been efficacious in experimental tumor models (28)(29)(30). These promising preclinical studies have generated robust interest in the application of IL-15 SA as an anticancer agent.…”

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses

“…Also, ALT-803 has greater binding activity with the IL-2R␤␥ C complex displayed on the surface of immune cells, a substantially longer serum half-life, and better biodistribution and retention in lymphoid tissues than native IL-15 (3,4,12). Exhibiting potent immunostimulatory and antitumor properties, ALT-803 is an effective agent against various tumors in animal models either as a single agent or in combination with other therapies (5,6). For example, ALT-803 stimulation significantly increased rituximab-mediated ADCC by human NK cells against B cell lymphoma cell lines or primary follicular lymphoma cells in vitro.…”

“…Our previous studies have demonstrated that this IL-15 variant, when associated with a soluble IL-15R␣ sushi domain fusion to IgG1 Fc (IL15R␣SuFc), could form a heterodimeric complex, IL-15N72D⅐ IL-15R␣SuFc (designated , that also exhibits increased binding activity to the IL-2R␤␥ C complex, enhanced capacity to stimulate NK and T cells, and has a longer biological half-life compared with native IL-15 (4). In various animal models, ALT-803 acts as a potent immunostimulant that is capable of simultaneously activating the innate and adaptive arms of the immune system to elicit both rapid and long-lasting protective responses against neoplastic challenges (5). Moreover, ALT-803, in combination with checkpoint blockade or therapeutic antibodies, is effective in reducing the tumor burden and prolonging survival in mouse tumor models (6,7).…”

Dendritic cell-derived interleukin-15 is crucial for therapeutic cancer vaccine potency

“…18 IL-15 agonists (e.g., IL-15/IL15Ra-Fc complex and IL-15/IL-15Ra fusion protein) reduce the dose of delivered IL-15 required to reach biologicallymeaningful levels in vivo. [19][20][21][22][23] However, cell (particularly DC) contact-dependent trans-presentation of membrane-bound IL-15/IL-15Ra appears required for optimal IL-15-mediated signaling in vivo. 24,25 In vivo, IL-15 derived from DC (DCIL-15) can "auto"-activate DC and substitute for the functional licensing events normally associated with DC interaction with CD4…”