Myxoma virus expressing a fusion protein of interleukin-15 (IL15) and IL15 receptor alpha has enhanced antitumor activity.
Myxoma virus expressing a fusion protein of interleukin-15 (IL15) and IL15 receptor alpha has enhanced antitumor activity.
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DOI：
10.1371/journal.pone.0109801
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Roy EJ
中科院分区：
文献类型：
--
作者：
Tosic V;Thomas DL;Kranz DM;Liu J;McFadden G;Shisler JL;MacNeill AL;Roy EJ
粘液瘤病毒是一种兔痘病毒，可以有效感染各种类型的小鼠和人类癌细胞。它是一种严格的兔特异性病原体，并且被认为在所有测试的非兔宿主（包括小鼠和人类）中作为治疗剂是安全的。白细胞介素-15（IL-15）是一种免疫调节细胞因子，具有刺激抗肿瘤T淋巴细胞和NK细胞的显著潜力。IL 15与IL 15受体α亚基（IL 15 R α）的共表达大大增强了IL 15的稳定性和生物利用度。因此，我们设计了一种新的重组粘液瘤病毒（vMyx-IL 15 R α-tdTr），其表达IL 15 R α-IL 15融合蛋白和tdTomato红色荧光报告蛋白。用vMyx-IL 15 R α-tdTr感染的容许性兔肾上皮（RK-13）细胞表达并分泌IL 15 R α-IL 15融合蛋白。功能活性通过证明分泌的融合蛋白刺激依赖于精氨酸的CTLL-2细胞的增殖来证实。多步生长曲线显示小鼠黑色素瘤（B16-F10和B16.SIY）细胞系允许vMyx-IL 15 R α-tdTr感染。在RAG 1-/-小鼠中的体内实验显示，与PBS对照和对照病毒（vMyx-IL 15-tdTr和vMyx-tdTr）相比，用vMyx-IL 15 R α-tdTr处理的皮下B16-F10肿瘤显示出肿瘤生长减弱和处理组的显著存活益处。皮下肿瘤的免疫组织学分析显示，与对照相比，vMyx-IL 15 R α-tdTr处理的肿瘤中NK细胞的浸润显著增加。免疫活性C57 BL/6小鼠的体内实验显示，NK细胞和CD 8 + T细胞对vMyx-IL 15 R α-tdTr的应答均强烈浸润，并延长了存活期。我们得出结论，在粘液瘤病毒载体中递送IL 15 R α-IL 15刺激免疫系统的先天和适应性组分。
Myxoma virus, a rabbit poxvirus, can efficiently infect various types of mouse and human cancer cells. It is a strict rabbit-specific pathogen, and is thought to be safe as a therapeutic agent in all non-rabbit hosts tested including mice and humans. Interleukin-15 (IL15) is an immuno-modulatory cytokine with significant potential for stimulating anti-tumor T lymphocytes and NK cells. Co-expression of IL15 with the α subunit of IL15 receptor (IL15Rα) greatly enhances IL15 stability and bioavailability. Therefore, we engineered a new recombinant myxoma virus (vMyx-IL15Rα-tdTr), which expresses an IL15Rα-IL15 fusion protein plus tdTomato red fluorescent reporter protein. Permissive rabbit kidney epithelial (RK-13) cells infected with vMyx-IL15Rα-tdTr expressed and secreted the IL15Rα-IL15 fusion protein. Functional activity was confirmed by demonstrating that the secreted fusion protein stimulated proliferation of cytokine-dependent CTLL-2 cells. Multi-step growth curves showed that murine melanoma (B16-F10 and B16.SIY) cell lines were permissive to vMyx-IL15Rα-tdTr infection. In vivo experiments in RAG1-/- mice showed that subcutaneous B16-F10 tumors treated with vMyx-IL15Rα-tdTr exhibited attenuated tumor growth and a significant survival benefit for the treated group compared to the PBS control and the control viruses (vMyx-IL15-tdTr and vMyx-tdTr). Immunohistological analysis of the subcutaneous tumors showed dramatically increased infiltration of NK cells in vMyx-IL15Rα-tdTr treated tumors compared to the controls. In vivo experiments with immunocompetent C57BL/6 mice revealed a strong infiltrate of both NK cells and CD8+ T cells in response to vMyx-IL15Rα-tdTr, and prolonged survival. We conclude that delivery of IL15Rα-IL15 in a myxoma virus vector stimulates both innate and adaptive components of the immune system.
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DOI：
10.4049/jimmunol.181.12.8237
发表时间：
2008-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Rowley J;Monie A;Hung CF;Wu TC
通讯作者：
Wu TC
影响因子：
3.8
作者：
Castillo, Eliseo F.;Schluns, Kimberly S.
通讯作者：
Schluns, Kimberly S.
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
6.7
作者：
Doty, Rosalinda A.;Liu, Jia;MacNeill, Amy L.
通讯作者：
MacNeill, Amy L.
影响因子：
11.2
作者：
Liu RB;Engels B;Arina A;Schreiber K;Hyjek E;Schietinger A;Binder DC;Butz E;Krausz T;Rowley DA;Jabri B;Schreiber H
通讯作者：
Schreiber H