title: 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 (IL)-15 superagonist mutant and a dimeric IL-15 receptor αSu/Fc fusion protein, was found to exhibit significantly stronger in vivo biologic 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 IFN-γ and promoted rapid expansion of CD8(+)CD44(high) memory T cells in vivo. These memory CD8(+) T cells exhibited ALT-803-mediated upregulation of NKG2D (KLRK1) but not PD-1 (PDCD1) or CD25 (IL2RA) on their cell surfaces. ALT-803-activated CD8(+) memory T cells also exhibited nonspecific cytotoxicity against myeloma and other tumor cells in vitro, whereas IFN-γ had no direct effect on myeloma cell growth. ALT-803 lost its antimyeloma 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 biologic functions in host immunity, this study shows 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 nonspecific tumor cell killing. This unique immunomodulatory property of ALT-803 strongly supports its clinical development as a novel immunotherapeutic agent against cancer and viral infections.
authors: Altor BioScience Corporation, Miramar, FL 33025, USA.
authors: Wenxin
authors: W
authors: Xu
authors: Monica
authors: M
authors: Jones
authors: Bai
authors: B
authors: Liu
authors: Xiaoyun
authors: X
authors: Zhu
authors: Christopher B
authors: CB
authors: Johnson
authors: Ana C
authors: AC
authors: Edwards
authors: Lin
authors: L
authors: Kong
authors: Emily K
authors: EK
authors: Jeng
authors: Kaiping
authors: K
authors: Han
authors: Warren D
authors: WD
authors: Marcus
authors: Mark P
authors: MP
authors: Rubinstein
authors: Peter R
authors: PR
authors: Rhode
authors: Hing C
authors: HC
authors: Wong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000819:agonists*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology; D011506:Proteins / Q000627:therapeutic use*; D053647:Receptors, Interleukin-15 / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins
chemical_list: C582303:ALT-803; D000970:Antineoplastic Agents; D019409:Interleukin-15; D011506:Proteins; D053647:Receptors, Interleukin-15; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma
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