Treatment of mammary carcinomas in HER-2 transgenic mice through combination of genetic vaccine and an agonist of toll-like receptor 9

Luigi Aurisicchio, Daniela Peruzzi, Antonella Conforti, Sridhar Dharmapuri, Antonella Biondo, Saverio Giampaoli, Arthur Fridman, Ansu Bagchi, Christopher T. Winkelmann, Raymond Gibson, Ekambar R. Kandimalla, Sudhir Agrawal, Gennaro Ciliberto, Nicola La Monica

Research output: Contribution to journalArticle

Abstract

Purpose: Oligodeoxynucleotides containing unmethylated CpG dinucleotides induce innate and adaptive immunity throughToll-like receptor 9 (TLR9). In the present study, we have examined the ability of a novel agonist of TLR9, called immunomodulatory oligonucleotide (IMO), to enhance effects of a HER-2/neu plasmid DNA electroporation/adenovirus (DNA-EP/Ad) vaccine. Experimental Design: BALB/NeuTmice 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, microCTand microPET imaging was carried out in an advanced-stage tumor model starting treatment at week 17 in BALB/NeuTmice. Results: The combination of DNA-EP and IMO resulted in significant tumor regression or delay to tumor progression. 2-Deoxy-2-[ 18F]fluoro-D-glucose microPETand 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.

Original languageEnglish
Pages (from-to)1575-1584
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number5
DOIs
Publication statusPublished - Mar 1 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Aurisicchio, L., Peruzzi, D., Conforti, A., Dharmapuri, S., Biondo, A., Giampaoli, S., Fridman, A., Bagchi, A., Winkelmann, C. T., Gibson, R., Kandimalla, E. R., Agrawal, S., Ciliberto, G., & Monica, N. L. (2009). Treatment of mammary carcinomas in HER-2 transgenic mice through combination of genetic vaccine and an agonist of toll-like receptor 9. Clinical Cancer Research, 15(5), 1575-1584. https://doi.org/10.1158/1078-0432.CCR-08-2628