Treatment of Mammary Carcinomas in HER-2 Transgenic Mice through Combination of Genetic Vaccine and an Agonist of Toll-Like Receptor 9
Treatment of Mammary Carcinomas in HER-2 Transgenic Mice through Combination of Genetic Vaccine and an Agonist of Toll-Like Receptor 9
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DOI：
10.1158/1078-0432.ccr-08-2628
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发表时间：
2009-03-01
影响因子：
11.5
通讯作者：
La Monica, Nicola
中科院分区：
文献类型：
--
作者：
Aurisicchio, Luigi;Peruzzi, Daniela;La Monica, Nicola
目的：含未甲基化CpG二核苷酸的寡脱氧核苷酸通过Toll样受体9（TLR 9）诱导天然免疫和获得性免疫。在本研究中，我们已经研究了一种新的TLR 9激动剂，称为免疫调节颗粒（IMO），以增强HER-2/neu质粒DNA电穿孔/腺病毒（DNA-EP/Ad）vaccine.Experimental Design的效果的能力：BALB/NeuT小鼠与DNA-EP疫苗单独，IMO单独，或两种药物的组合，在第13周开始，当所有小鼠表现出乳腺肿瘤。记录肿瘤生长和存活。测定抗体和CD 8（+）T细胞应答。进行血清的肽微阵列分析以鉴定免疫反应性表位。此外，microCT和microPET成像进行了在第17周开始治疗的BALB/NeuT小鼠的晚期肿瘤模型。结果：DNA-EP和IMO的组合导致显着的肿瘤消退或延迟肿瘤进展。小鼠的2-脱氧-2-[F-18]氟-D-葡萄糖microPET和microCT成像显示DNA-EP/IMO联合治疗组的肿瘤尺寸减小。与DNA-EP疫苗治疗的小鼠相比，用该组合治疗的小鼠产生更高的IgG（2a）同种型转换抗体滴度和抗体依赖性细胞毒性活性。通过微阵列分析鉴定HER-2二聚化结构域内的免疫原性B细胞线性表位r70。结论：HER-2/neu基因疫苗与新型TLR 9激动剂联合应用具有较强的抗肿瘤活性，其机制可能与抗体同种型转换和抗体依赖性细胞毒活性有关。这些结果支持基于DNA-EP/Ad的癌症疫苗和IMO组合的可能临床试验。
Puepose: Oligodeoxynucleotides containing unmethylated CpG dinucleoticles induce innate and adaptive immunity through Toll-like receptor 9 (TLR9). In the present study, we have examined the ability of a novel agonist of TLR9, called immunomodulatory oligonucleoticle (IMO), to enhance effects of a HER-2/neu plasmid DNA electroporation/adenovirus (DNA-EP/Ad) vaccine.Experimental Design: BALB/NeuT mice were treated with DNA-EP vaccine alone, IMO alone, or the combination of two agents starting at week 13, when all mice showed mammary neoplasia. Tumor growth and survival were documented. Antibody and CD8(+) T-cell responses were determined. Peptide microarray analysis of sera was carried out to identify immunoreactive epitopes. Additionally, microCT and microPET imaging was carried out in an advanced-stage tumor model starting treatment at week 17 in BALB/NeuT mice.Results: The combination of DNA-EP and IMO resulted in significant tumor regression or delay to tumor progression. 2-Deoxy-2-[F-18]fluoro-D-glucose microPET and microCT imaging of mice showed reduced tumor size in the DNA-EP/IMO combination treatment group. Mice treated with the combination produced greater antibody titers with IgG(2a) isotype switch and antibody-dependent cellular cytotoxicity activity than did mice treated with DNA-EP vaccine. An immunogenic B-cell linear epitope, r70, within the HER-2 dimerization domain was identified through microarray analysis. Heterologous DNA-EP/Ad vaccination combined with IMO increased mice survival.Conclusion: The combination of HER-2/neu genetic vaccine and novel agonist of TLR9 had potent antitumor activity associated with antibody isotype switch and antibody-dependent cellular cytotoxicity activities. These results support possible clinical trials of the combination of DNA-EP/Ad-based cancer vaccines and IMO.