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.
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.
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DOI：
10.1158/0008-5472.can-12-2357
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发表时间：
2013-05-15
期刊：
影响因子：
11.2
通讯作者：
Wong HC
中科院分区：
文献类型：
--
作者：
Xu W;Jones M;Liu B;Zhu X;Johnson CB;Edwards AC;Kong L;Jeng EK;Han K;Marcus WD;Rubinstein MP;Rhode PR;Wong HC
ALT-803 是白细胞介素 15 (IL-15) 超级激动剂突变体和二聚体 IL-15 受体 α/Fc 融合蛋白的复合物，被发现对 NK 和 T 细胞表现出比 IL-15 明显更强的体内生物活性。在这项研究中，我们发现单剂量的 ALT-803（而非单独的 IL-15）可以消除荷瘤小鼠骨髓中已确定的 5T33P 和 MOPC-315P 骨髓瘤细胞。 ALT-803 治疗还显着延长了患有骨髓瘤的小鼠的生存期，并通过 CD8+ T 细胞依赖性机制提供了对相同肿瘤细胞再次攻击的抵抗力。 ALT-803处理刺激CD8+T细胞分泌大量干扰素-γ(IFN-γ)并促进CD8+CD44高记忆T细胞在体内快速扩增。这些记忆 CD8+ T 细胞在细胞表面表现出 ALT-803 介导的 NKG2D (KLRK1) 上调，但不上调 PD-1 (PDCD1) 或 CD25 (IL2RA)。 ALT-803激活的CD8+记忆T细胞在体外也表现出针对骨髓瘤和其他肿瘤细胞的非特异性细胞毒性，而IFN-γ对骨髓瘤细胞生长没有直接影响。 ALT-803 在荷瘤 IFN-γ 敲除小鼠中失去了其抗骨髓瘤活性，但保留了促进 CD8+CD44high 记忆 T 细胞增殖的能力，表明 ALT-803 介导的 CD8+CD44high 记忆 T 细胞的刺激是 IFN-γ 独立的。因此，除了众所周知的IL-15在宿主免疫中的生物学功能外，本研究证明基于IL-15的ALT-803可以激活CD8+CD44高记忆T细胞以获得独特的先天样表型并分泌IFN-γ用于非特异性肿瘤细胞杀伤。 ALT-803 这种独特的免疫调节特性有力地支持了其作为抗癌症和病毒感染的新型免疫治疗剂的临床开发。
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.