Immunopharmacological and antitumor effects of second-generation immunomodulatory oligonucleotides containing synthetic CpR motifs

Wang, Daqing; Li, Yukui; Yu, Dongfang; Song, Sam S; Kandimalla, Ekambar R.; Agrawal, Sudhir

doi:10.3892/ijo.24.4.901

Cited by 26 publications

(39 citation statements)

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“…The synthetic peptides, β-gal, TPHPARIGL (representing the naturally processed H-2 L d restricted epitope spanning amino acids 876-884 of β-gal; refs. 18,19), AH1, SPSYVYHQF (containing a CTL determinant from CT26 tumor cells; ref. 20), and OVA 257-264 (control peptide), were synthesized by New England Peptide, Inc., to a purity of >99% as determined by high-performance liquid chromatography.…”

Section: Reagentsmentioning

confidence: 99%

“…Blood collected by retro-orbital bleeding at 2 hours after the first administration of dual TLR7/8 agonist was used to determine serum levels of IL-12 by sandwich ELISA (PharMingen) as described previously (19). Selected serum samples were further evaluated for cytokine/ chemokine profiles using Mouse 20-Plex Panel according to the manufacturer's recommendations (Invitrogen).…”

Section: Assessment Of Serum Cytokine/chemokine Levelsmentioning

confidence: 99%

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Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

Wang

Precopio

Lan

et al. 2010

Molecular Cancer Therapeutics

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Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptors 7 and 8 (TLR7 and TLR8). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immunemodulatory RNA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8 depending on the sequence composition and the presence of specific chemical modifications. In the present study, we evaluated the antitumor activity of a dual TLR7/8 agonist in tumor-bearing mice with peritoneal disseminated CT26.CL25 colon and 3LL-C75 lung carcinomas. Peritoneal administration of dual TLR7/8 agonist in mice bearing CT26.CL25 colon carcinomas had potent dose-dependent antitumor activity, which was associated with a marked decrease in CD4 + CD25 + Foxp3 + T regulatory cells and a significant increase in tumor antigen-specific IFN-γ-secreting effector cell responses in splenocytes and local tumor-infiltrating cells. In 3LL-C75 lung carcinoma, dual TLR7/8 agonist induced strong immune responses and antitumor effects in C57BL/6 and TLR9 −/− mice, but not in TLR7 −/− and MyD88 −/− mice, indicating that the agonist induces immune responses via TLR7 and through the MyD88-dependent signaling pathway. TLR8 is not functional in mice. Additionally, s.c. administration of TLR7/8 agonist effectively prevented lung metastasis of tumors in the CT26.CL25 pulmonary metastasis model. These studies show that the dual TLR7/8 agonist induced Th1-type immune responses and potent antitumor activity in mice via TLR7 and through the MyD88-dependent pathway. Mol Cancer Ther; 9(6); 1788-97. ©2010 AACR.

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Section: Reagentsmentioning

confidence: 99%

Section: Assessment Of Serum Cytokine/chemokine Levelsmentioning

confidence: 99%

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

Wang

Precopio

Lan

et al. 2010

Molecular Cancer Therapeutics

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“…IMOs have been shown to induce distinct cytokine profiles in vitro and in vivo (25,26) and showed higher metabolic stability (27) compared with conventional toll-like receptor 9 agonists. IMOs have been shown to elicit antitumor activity by inducing Th1-type innate and adaptive immune responses (28). In preclinical tumor models, IMOs enhanced antitumor activity in combination with peptide and DNA vaccines inducing Th1-type antigen-specific antibody production and cytotoxic Tlymphocyte responses (28,29).…”

mentioning

confidence: 99%

“…IMOs have been shown to elicit antitumor activity by inducing Th1-type innate and adaptive immune responses (28). In preclinical tumor models, IMOs enhanced antitumor activity in combination with peptide and DNA vaccines inducing Th1-type antigen-specific antibody production and cytotoxic Tlymphocyte responses (28,29). Previous studies with IMOs have shown potent antitumor activity in combination with chemotherapeutic agents, mAbs, and radiation (28,30).…”

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confidence: 99%

A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action

Damiano¹,

Garofalo²,

Rosa³

et al. 2009

Clinical Cancer Research

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Purpose: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel toll-like receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment. Experimental Design: In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers. Results: IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HERdependent signal inhibition also in vitro by modulating a functional interaction between toll-like receptor 9 and HER receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling. Conclusions: We showed a cooperative effect of IMO plus trastuzumab in trastuzumabresistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a toll-like receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers. (Clin Cancer Res 2009;15(22):6921-30) The aberrant activity of HER2 signaling is associated with breast cancer development and progression, and ∼20% to 25% of invasive breast cancers exhibit overexpression of HER2. Because elevated HER2 levels are associated with reduced disease-free and overall survival in metastatic breast cancer, therapeutic strategies are being developed to target this oncoprotein (1). Trastuzumab, a recombinant humanized monoclonal antibody (mAb) directed against an extracellular region of HER2, was the first HER2-targeted therapy approved by the U.S. Food and Drug Administration for the treatment of HER2-overexpressing metastatic breast cancer. In addition, trastuzumab with adjuvant chemotherapy (either in sequence or in combination) significantly improved disease-free and overall survival rates in patients with early stage HER2-overexpressing breast cancer (2). However, despite the great Authors' Affiliations:

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“…Previous studies have demonstrated potent antitumor activity of IMOs as monotherapies and in combination with chemotherapeutic agents and mAbs (11,12). Currently, a synthetic agonist of TLR9, IMO-2055, is under clinical evaluation, in combination with chemotherapy and other agents in cancer patients.…”

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confidence: 99%

TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts

Damiano¹,

Caputo²,

Garofalo³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic agonists of Toll-like receptor 9 (TLR9), a class of agents that induce specific immune response, exhibit antitumor activity and are currently being investigated in cancer patients. Intriguingly, their mechanisms of action on tumor growth and angiogenesis are still incompletely understood. We recently discovered that a synthetic agonist of TLR9, immune modulatory oligonucleotide (IMO), acts by impairing epidermal growth factor receptor (EGFR) signaling and potently synergizes with anti-EGFR antibody cetuximab in GEO human colon cancer xenografts, whereas it is ineffective in VEGF-overexpressing cetuximab-resistant GEO cetuximab-resistant (GEO-CR) tumors. VEGF is activated by EGFR, and its overexpression causes resistance to EGFR inhibitors. Therefore, we used IMO and the anti-VEGF antibody bevacizumab as tools to study IMO's role on EGFR and angiogenesis and to explore its therapeutic potential in GEO, LS174T, and GEO-CR cancer xenografts. We found that IMO enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of cetuximab, that bevacizumab has no ADCC, and IMO is unable to enhance it. Nevertheless, the IMO-plus-bevacizumab combination synergistically inhibits the growth of GEO and LS174T as well as of GEO-CR tumors, preceded by inhibition of signaling protein expression, microvessel formation, and human, but not murine, VEGF secretion. Moreover, IMO inhibited the growth, adhesion, migration, and capillary formation of VEGF-stimulated endothelial cells. The antitumor activity was irrespective of the TLR9 expression on tumor cells. These studies demonstrate that synthetic agonists of TLR9 interfere with growth and angiogenesis also by EGFR-and ADCCindependent mechanisms affecting endothelial cell functions and provide a strong rationale to combine IMO with bevacizumab and EGFR inhibitory drugs in colon cancer patients.angiogenesis ͉ cancer therapy ͉ growth factor receptors

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Immunopharmacological and antitumor effects of second-generation immunomodulatory oligonucleotides containing synthetic CpR motifs

Cited by 26 publications

References 0 publications

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action

TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts

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