Treatment of Mammary Carcinomas in HER-2 Transgenic Mice through Combination of Genetic Vaccine and an Agonist of Toll-Like Receptor 9

被引：34

作者：

Aurisicchio, Luigi ^{[1
]}

Peruzzi, Daniela ^{[1
]}

Conforti, Antonella ^{[1
]}

Dharmapuri, Sridhar ^{[1
]}

Biondo, Antonella ^{[1
]}

Giampaoli, Saverio ^{[1
]}

Fridman, Arthur ^{[2
]}

Bagchi, Ansu ^{[2
]}

Winkelmann, Christopher T. ^{[3
]}

Gibson, Raymond ^{[3
]}

Kandimalla, Ekambar R. ^{[4
]}

Agrawal, Sudhir ^{[4
]}

Ciliberto, Gennaro ^{[1
]}

La Monica, Nicola ^{[1
]}

机构：

[1] Ist Ric Biol Mol P Angeletti, Oncol Funct Dept, Merck Res Labs, Rome, Italy

[2] Merck Res Labs, Rahway, NJ USA

[3] Merck Res Labs, Dept Imaging, West Point, PA USA

[4] Idera Pharmaceut, Cambridge, MA USA

来源：

CLINICAL CANCER RESEARCH | 2009年 / 15卷 / 05期

关键词：

2ND-GENERATION IMMUNOMODULATORY OLIGONUCLEOTIDES; SINGLE-AGENT PERTUZUMAB; BREAST-CANCER; DIMERIZATION INHIBITOR; PEPTIDE VACCINES; IMMUNE-RESPONSE; TLR9; AGONISTS; IN-VIVO; SAFETY; TRASTUZUMAB;

D O I：

10.1158/1078-0432.CCR-08-2628

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1575 / 1584

页数：10

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