High efficacy of CpG-ODN, Cetuximab and Cisplatin combination for very advanced ovarian xenograft tumors

Journal of Translational Medicine

Andrea Balsari¹  Elda Tagliabue¹  Nadia Zaffaroni²  Alessandra Cataldo¹  Alessandra Meini¹  Michelandrea de Cesare²  Michele Sommariva¹ 

[1] Molecular Targeting Unit, Fondazione IRCCS - Istituto Nazionale Tumori, via Amadeo 42, 20133, Milan, Italy;Molecular Pharmacology Unit, Fondazione IRCCS - Istituto Nazionale Tumori, via Amadeo 42, 20133, Milan, Italy

关键词: Cisplatin;    Monoclonal Antibody;    Ascites;    Ovarian cancer;    TLR9;    CpG-ODN;   

Others  :  828160
DOI  :  10.1186/1479-5876-11-25

 received in 2012-11-28, accepted in 2013-01-23,  发布年份 2013

【 摘 要 】

Background

To mimic clinical treatment situations in advanced human ovarian disease, we tested the efficacy of CpG-oligodeoxynucleotides (CpG-ODN), synthetic DNA sequences recognized by Toll-like receptor 9 and able to induce innate/adaptive immune responses, in combination with other possible therapeutic reagents in ovarian carcinoma ascites-bearing athymic mice.

Methods

Mice injected i.p. with IGROV-1 ovarian cancer cells were treated at different stages of ascites progression for 4 weeks with CpG-ODN, alone or in combination with Bevacizumab, Polyinosinic:Polycytidylic acid (Poly(I):Poly(C)), Gefitinib, Cetuximab and Cisplatin. Median survival time (MST) was calculated for each group. IGROV-1 cells treated or not with Cetuximab were assayed for antibody-dependent cellular cytotoxicity by ⁵¹Cr-release assay, and for macrophage antibody-dependent cell-mediated phagocytosis by flow cytometry.

Results

In mice treated when ascitic fluid began to accumulate, CpG-ODN combined with Bevacizumab, Poly(I):Poly(C) or Gefitinib did not significantly increase MST as compared with that using CpG-ODN alone, whereas MST in mice treated with CpG-ODN plus Cetuximab was significantly increased (>103 days for combination vs 62 days for CpG alone; P = 0.0008), with 4/8 mice alive at the end of the experiment. In experiments in mice showing increased abdominal volume and body weight (27.9 ± 0.8 g after vs 23 ± 1.1 g before tumor cell injection), treatment with Cisplatin in addition to CpG-ODN/Cetuximab led to significantly increased MST (105.5 days; P = 0.001), with all mice still alive at 85 days, over that using CpG-ODN/Cetuximab (66 days), Cetuximab/Cisplatin (18.5 days), Cisplatin (23 days) or saline (16 days). At a very advanced stage of disease (body weight: 31.4 ± 0.9 g), when more than half of control mice had to be sacrificed 6 days after starting treatments, the triple-combination therapy still increased MST (45 days; P = 0.0089) vs controls.

Conclusions

CpG-ODN combination therapies that enhance the immune response in the tumor microenvironment and concomitantly target tumor cells are highly efficacious even in experimental advanced malignancies. Although differences in the distribution of TLR9 in mice and humans and the enrichment of this receptor on innate immune cells of athymic mice must be considered, our results indicate a promising strategy to treat ovarian cancer patients with bulky ascites.

【 授权许可】

   
2013 Sommariva et al.; licensee BioMed Central Ltd.

【 图 表 】

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