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

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 10; pp. 3075 - 3086
• Main Authors: Xu, Wenxin, Jones, Monica, Liu, Bai, Zhu, Xiaoyun, Johnson, Christopher B., Edwards, Ana C., Kong, Lin, Jeng, Emily K., Han, Kaiping, Marcus, Warren D., Rubinstein, Mark P., Rhode, Peter R., Wong, Hing C.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2013
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cytotoxicity, Immunologic - drug effects; Female; Hematologic and hematopoietic diseases; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunologic Memory; Immunopathology; Interferon-gamma - biosynthesis; Interleukin-15 - agonists; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; Pharmacology. Drug treatments; Proteins - therapeutic use; Receptors, Interleukin-15 - therapeutic use; Tumors; Immunopathology; Animal model; Treatment efficiency; Rodentia; Cytokine; Malignant hemopathy; Interleukin 15 receptor; Interleukin 15; Myeloma; Vertebrata; Mammalia; Immunoglobulinopathy; Mouse; Lymphoproliferative syndrome; Syngeneic system; Mechanism of action; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-2357

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+CD44high 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+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 biologic functions in host immunity, this study shows 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 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. Cancer Res; 73(10); 3075–86. ©2013 AACR.