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Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

Abstract

Although still early in clinical development, agonists of Toll-like receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists in patients with solid tumors and hematologic malignancies. In preclinical studies, TLR9 agonists have shown activity not only as monotherapy, but also in combination with multiple other therapies, including vaccines, antibodies, cellular therapies, other immunotherapies, antiangiogenic agents, radiotherapy, cryotherapy and some chemotherapies. Phase I and II clinical trials have indicated that these agents have antitumor activity as single agents and enhance the development of antitumor T-cell responses when used as therapeutic vaccine adjuvants. The activity and safety of these novel anticancer agents are being explored in a wide range of tumor types as part of a variety of therapeutic strategies with the goal of harnessing the immune response to fight cancer.

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References

  • Akira S, Uematsu S, Takeuchi O . (2006). Pathogen recognition and innate immunity. Cell 124: 783–801.

    Article  CAS  Google Scholar 

  • Appay V, Jandus C, Voelter V, Reynard S, Coupland SE, Rimoldi D et al. (2006). New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J Immunol 177: 1670–1678.

    Article  CAS  Google Scholar 

  • Baines J, Celis E . (2003). Immune-mediated tumor regression induced by CpG-containing oligodeoxynucleotides. Clin Cancer Res 9: 2693–2700.

    CAS  Google Scholar 

  • Carpentier A, Laigle-Donadey F, Zohar S, Capelle L, Behin A, Tibi A et al. (2006). Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol 8: 60–66.

    Article  CAS  Google Scholar 

  • Daftarian P, Song GY, Ali S, Faynsod M, Longmate J, Diamond DJ et al. (2004). Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors. Cancer Res 64: 5407–5414.

    Article  CAS  Google Scholar 

  • Damiano V, Caputo R, Bianco R, D'Armiento FP, Leonardi A, De Placido S et al. (2006). Novel Toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors. Clin Cancer Res 12: 577–583.

    Article  CAS  Google Scholar 

  • Damiano V, Caputo R, Garofalo S, Bianco R, Rosa R, Merola G et al. (2007). TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts. Proc Natl Acad Sci USA 104: 12468–12473.

    Article  CAS  Google Scholar 

  • Davila E, Kennedy R, Celis E . (2003). Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade. Cancer Res 63: 3281–3288.

    CAS  Google Scholar 

  • Decker T, Schneller F, Sparwasser T, Tretter T, Lipford GB, Wagner H et al. (2000). Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood 95: 999–1006.

    CAS  Google Scholar 

  • Droemann D, Albrecht D, Gerdes J, Ulmer AJ, Branscheid D, Vollmer E et al. (2005). Human lung cancer cells express functionally active Toll-like receptor 9. Respir Res 6: 1.

    Article  Google Scholar 

  • Friedberg JW, Kim H, McCauley M, Hessel EM, Sims P, Fisher DC et al. (2005). Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-alpha/beta-inducible gene expression, without significant toxicity. Blood 105: 489–495.

    Article  CAS  Google Scholar 

  • Gelman AE, LaRosa DF, Zhang J, Walsh PT, Choi Y, Sunyer JO et al. (2006). The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation. Immunity 25: 783–793.

    Article  CAS  Google Scholar 

  • Hayashi F, Means TK, Luster AD . (2003). Toll-like receptors stimulate human neutrophil function. Blood 102: 2660–2669.

    Article  CAS  Google Scholar 

  • Hofmann MA, Kors C, Audring H, Walden P, Sterry W, Trefzer U . (2007). Safety and activity of intralesionally injected TLR9 ligand CpG DNA in basal cell carcinoma and melanoma (submitted).

  • Iwasaki A, Medzhitov R . (2004). Toll-like receptor control of the adaptive immune responses. Nat Immunol 5: 987–995.

    Article  CAS  Google Scholar 

  • Jahrsdorfer B, Hartmann G, Racila E, Jackson W, Muhlenhoff L, Meinhardt G et al. (2001). CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens. J Leukoc Biol 69: 81–88.

    CAS  Google Scholar 

  • Jahrsdorfer B, Wooldridge JE, Blackwell SE, Taylor CM, Griffith TS, Link BK et al. (2005). Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells. J Leukoc Biol 77: 378–387.

    Article  Google Scholar 

  • Kim Y, Girardi M, Duvic M, Kuzel T, Rook A, Link B et al. (2004). TLR9 agonist immunomodulator treatment of cutaneous T-cell lymphoma (CTCL) with CPG7909 [abstract]. ASH Annual Meeting Abstracts 104, Abstract 743.

  • Krieg AM . (2004). Antitumor applications of stimulating Toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 6: 88–95.

    Article  Google Scholar 

  • Krieg AM . (2006). Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 5: 471–484.

    Article  CAS  Google Scholar 

  • Krieg AM . (2007). Development of TLR9 agonists for cancer therapy. J Clin Invest 117: 1184–1194.

    Article  CAS  Google Scholar 

  • Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC et al. (2007). Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol 8: 772–779.

    Article  CAS  Google Scholar 

  • Lebre MC, van der Aar AM, van Baarsen L, van Capel TM, Schuitemaker JH, Kapsenberg ML et al. (2007). Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. J Invest Dermatol 127: 331–341.

    Article  CAS  Google Scholar 

  • Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT et al. (2006). Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol 8: 1327–1336.

    Article  CAS  Google Scholar 

  • Leonard JP, Link B, Emmanouilides C, Gregory SA, Weisdorf D, Andrey J et al. (2007). Phase I trial of Toll-like receptor 9 agonist PF-3512676 (CpG 7909) with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin's lymphoma. Clin Cancer Res. (in press).

  • Li J, Ma Z, Tang ZL, Stevens T, Pitt B, Li S . (2004). CpG DNA-mediated immune response in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 287: L552–L558.

    Article  CAS  Google Scholar 

  • Link BK, Ballas ZK, Weisdorf D, Wooldridge JE, Bossler AD, Shannon M et al. (2006). Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J Immunother 29: 558–568.

    Article  CAS  Google Scholar 

  • Manegold C, Gravenor D, Woytowitz D, Mezger J, Hirsh V, Albert G et al. (2007). Randomized phase II trial of a Toll-like receptor 9 (TLR9) agonist oligodeoxynucleotide, PF-3512676 (CPG 7909), in combination with first-line taxane/platinum chemotherapy for advanced-stage non-small-cell lung cancer. J Clin Oncol. (in press).

  • Milas L, Mason KA, Ariga H, Hunter N, Neal R, Valdecanas D et al. (2004). CpG oligodeoxynucleotide enhances tumor response to radiation. Cancer Res 64: 5074–5077.

    Article  CAS  Google Scholar 

  • Molenkamp BG, van Leeuwen PA, Meijer S, Sluijter BJ, Wijnands PG, Baars A et al. (2007). Intradermal CpG-B activates both plasmacytoid and myeloid dendritic cells in the sentinel lymph node of melanoma patients. Clin Cancer Res 13: 2961–2969.

    Article  CAS  Google Scholar 

  • Pashenkov M, Goess G, Wagner C, Hormann M, Jandl T, Moser A et al. (2006). Phase II trial of a Toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma. J Clin Oncol 24: 5716–5724.

    Article  CAS  Google Scholar 

  • Pedersen G, Andresen L, Matthiessen MW, Rask-Madsen J, Brynskov J . (2005). Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium. Clin Exp Immunol 141: 298–306.

    Article  CAS  Google Scholar 

  • Platz J, Beisswenger C, Dalpke A, Koczulla R, Pinkenburg O, Vogelmeier C et al. (2004). Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J Immunol 173: 1219–1223.

    Article  CAS  Google Scholar 

  • Readett DRJ, Denis L, Krieg AM, Benner RJ, Hanson DC . (2007). PF-3512676 (CPG 7909), a Toll-like receptor 9 agonist—status of development for non-small cell lung cancer (NSCLC) [poster]. Presented at: 12th World Congress on Lung Cancer; September 2–6; Seoul, Korea. Abstract PD3-1-6.

  • Sabel MS, Sondak VK . (2003). Pros and cons of adjuvant interferon in the treatment of melanoma. Oncologist 8: 451–458.

    Article  CAS  Google Scholar 

  • Saikh KU, Kissner TL, Sultana A, Ruthel G, Ulrich RG . (2004). Human monocytes infected with Yersinia pestis express cell surface TLR9 and differentiate into dendritic cells. J Immunol 173: 7426–7434.

    Article  CAS  Google Scholar 

  • Siren J, Pirhonen J, Julkunen I, Matikainen S . (2005). IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. J Immunol 174: 1932–1937.

    Article  CAS  Google Scholar 

  • Speiser DE, Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F et al. (2005). Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 115: 739–746.

    Article  CAS  Google Scholar 

  • Thompson JA, Kuzel T, Bukowski R, Masciari F, Schmalbach T . (2004). Phase Ib trial of a targeted TLR9 CpG immunomodulator (CPG 7909) in advanced renal cell carcinoma (RCC). J Clin Oncol 22 (Suppl): 416. Abstract 4644.

    Google Scholar 

  • Trefzer U, Kors C, Pelzer K, Walden P, Sterry W, O'Keefe E . (2002). Preliminary results of a phase I trial of intralesional injection of CPG 7909 in patients with basal cell carcinoma or melanoma. Proc Am Soc Clin Oncol 21, Abstract: 1902.

  • Van Den Eertwegh AJ, Lensen RJ, Scheper RJ, Giaccone G, Meijer CJ, Bontkes HJ et al. (2006). Autologous tumor cell vaccination with PF-3512676 (CPG 7909) and GM-CSF followed by subcutaneous PF-3512676 and IFN-alpha for patients with metastatic renal cell carcinoma. J Clin Oncol 24 (Suppl): 107s Abstract 2530.

    Google Scholar 

  • van Ojik H, Kruit W, Portielje J, Brichard V, Verloes R, Delire M et al. (2002). Phase I/II study with CPG 7909 as adjuvant to vaccination with MAGE-3 protein in patients with MAGE-3 positive tumors. Ann Oncol 13 (Suppl): 157–158. Abstract 579O.

    Google Scholar 

  • Weeratna RD, Bourne LL, Sullivan SM, Davis HL, Krieg AM . (2004). Combination of a new TLR9 agonist immunomodulator (CpG 7909) and paclitaxel for treatment of metastatic Lewis lung carcinoma (LLC). J Clin Oncol 22 (Suppl): 699 Abstract 7346.

    Google Scholar 

  • Weigel BJ, Rodeberg DA, Krieg AM, Blazar BR . (2003). CpG oligodeoxynucleotides potentiate the antitumor effects of chemotherapy or tumor resection in an orthotopic murine model of rhabdomyosarcoma. Clin Cancer Res 9: 3105–3114.

    CAS  Google Scholar 

  • Wooldridge JE, Weiner GJ . (2003). CpG DNA and cancer immunotherapy: orchestrating the antitumor immune response. Curr Opin Oncol 15: 440–445.

    Article  CAS  Google Scholar 

  • Wooldridge JE, Ballas Z, Krieg AM, Weiner GJ . (1997). Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma. Blood 89: 2994–2998.

    CAS  Google Scholar 

  • Wysocka M, Benoit BM, Newton S, Azzoni L, Montaner LJ, Rook AH . (2004). Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15. Blood 104: 4142–4149.

    Article  CAS  Google Scholar 

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Acknowledgements

Financial support for medical editorial assistance was provided by Pfizer Pharmaceuticals. I thank Todd Parker, PhD, ProEd Communications Inc., for expert editorial assistance with manuscript preparation.

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Correspondence to A M Krieg.

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Arthur M Krieg is a founder, employee and shareholder in Coley Pharmaceutical Group and has a financial interest in the development of TLR9 agonists for cancer therapy.

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Krieg, A. Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27, 161–167 (2008). https://doi.org/10.1038/sj.onc.1210911

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