Adjuvant Treatment With Polyadenylic-Polyuridylic Acid (POLYA.POLYU) in Operable Breast Cancer

Lacour, J; Spira, Alfred; Petit, Jean‐Yves; Sarrazin, D.; Lacour, F; Michelson, M; Delage, G.; Contesso, G.; Viguier, J.

doi:10.1016/s0140-6736(80)90057-4

Cited by 80 publications

(37 citation statements)

References 11 publications

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“…Interestingly, tumor cells such as breast cancers (6) or melanoma (7) can also express TLR3, which triggering may lead to apoptosis and/or to chemoattraction of cytotoxic lymphocytes to tumor beds (6)(7)(8)(9). Six randomized trials carried out between 1970 and 1990 have evaluated the efficacy of dsRNA in oncology (10)(11)(12)(13)(14)(15). Administration of dsRNA was associated with a significant clinical benefit in 2 trials (10,11) and with a trend for a more favorable outcome in 3 other trials (12,14,15).…”

Section: Introductionmentioning

confidence: 99%

“…Six randomized trials carried out between 1970 and 1990 have evaluated the efficacy of dsRNA in oncology (10)(11)(12)(13)(14)(15). Administration of dsRNA was associated with a significant clinical benefit in 2 trials (10,11) and with a trend for a more favorable outcome in 3 other trials (12,14,15). This reproducible effect in small number of patients suggested that dsRNA could be highly effective in a subset of individuals that remained to be determined.…”

Section: Introductionmentioning

confidence: 99%

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TLR3 as a Biomarker for the Therapeutic Efficacy of Double-stranded RNA in Breast Cancer

et al. 2011

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The discovery of a targeted therapeutic compound along with its companion predictive biomarker is a major goal of clinical development for a personalized anticancer therapy to date. Here we present evidence of the predictive value of TLR3 expression by tumor cells for the efficacy of Poly (A:U) dsRNA in 194 breast cancer patients enrolled in a randomized clinical trial. Adjuvant treatment with double-stranded RNA (dsRNA) was associated with a significant decrease in the risk of metastatic relapse in TLR3 positive but not in TLR3-negative breast cancers. Moreover, we show the functional relevance of TLR3 expression by human tumor cells for the antitumor effects mediated by dsRNA in several preclinical mouse models carried out in immunocompromised animals. These 2 independent lines of evidence relied upon the generation of a novel tool, an anti-TLR3 antibody (40F9.6) validated for routine detection of TLR3 expression on paraffin-embedded tissues. Altogether, these data suggest that dsRNA mediates its therapeutic effect through TLR3 expressed on tumor cells, and could therefore represent an effective targeted treatment in patients with TLR3-positive cancers. Cancer Res; 71(5);

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TLR3 as a Biomarker for the Therapeutic Efficacy of Double-stranded RNA in Breast Cancer

et al. 2011

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“…When combined with a candidate protein or viral antigen in mice, poly(A:U) can promote antigen-specific Th1-immune responses and boost antibody production (10,11). Poly(A:U) has been safely used with moderate success for treating breast or gastric cancers as a monotherapy (12)(13)(14). Retrospective analyses highlighted that TLR3-expressing breast cancers may be selectively sensitive to the antitumor effects of poly(A:U).…”

Section: Introductionmentioning

confidence: 99%

Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands

et al. 2010

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Many cancer cells express Toll-like receptors (TLR) that offer possible therapeutic targets. Polyadenylicpolyuridylic acid [poly(A:U)] is an agonist of the Toll-like receptor TLR3 that displays anticancer properties. In this study, we illustrate how the immunostimulatory and immunosuppressive effects of this agent can be uncoupled to therapeutic advantage. We took advantage of two TLR3-expressing tumor models that produced large amounts of CCL5 (a CCR5 ligand) and CXCL10 (a CXCR3 ligand) in response to type I IFN and poly(A:U), both in vitro and in vivo. Conventional chemotherapy or in vivo injection of poly(A:U), alone or in combination, failed to reduce tumor growth unless an immunochemotherapeutic regimen of vaccination against tumor antigens was included. CCL5 blockade improved the efficacy of immunochemotherapy, whereas CXCR3 blockade abolished its beneficial effects. These findings show how poly(A:U) can elicit production of a range of chemokines by tumor cells that reinforce immunostimulatory or immunosuppressive effects. Optimizing the anticancer effects of TLR3 agonists may require manipulating these chemokines or their receptors. Cancer Res; 70(2); 490-500. ©2010 AACR.

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“…TLR3 agonists have been used in the past, with variable efficiency, as an adjuvant to treat cancer patients, with the aim of inducing an IFN-mediated anticancer immune response (16,17). Recent studies in mouse models have highlighted the adjuvant role of dsRNA in tumor vaccination, most notably through the promotion of Ag cross-presentation by dendritic cells and the induction of enhanced primary and memory CD8 ϩ T cell responses (18, 19) However, because TLR3 is also expressed on nonimmune cells, such as keratinocytes (20) or endothelial cells (15), the question of a putative expression and role of this receptor in tumor cells needs to be investigated.…”

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confidence: 99%

TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells

Salaun¹,

Coste²,

Rissoan³

et al. 2006

The Journal of Immunology

424

433

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TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-β and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-κB downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers.

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Adjuvant Treatment With Polyadenylic-Polyuridylic Acid (POLYA.POLYU) in Operable Breast Cancer

Cited by 80 publications

References 11 publications

TLR3 as a Biomarker for the Therapeutic Efficacy of Double-stranded RNA in Breast Cancer

TLR3 as a Biomarker for the Therapeutic Efficacy of Double-stranded RNA in Breast Cancer

Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands

TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells

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