Cancer immunotherapeutic potential of novel small molecule TLR7 and TLR8 agonists

References

• Alexopoulou, L., Holt, A.C., Medzhitov, R., and Flavell, R. A. 2001. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413:732–738.
   PubMed Web of Science ®Google Scholar
• Baenziger, S., Heikenwalder, M., Johansen, P., Schlaepfer, E., Hofer, U., Miller, R. C., Diemand, S., Honda, K., Kundig, T. M., Aguzzi, A., and Speck, R. F. 2009. Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology. Blood 113:377–388.
   PubMed Web of Science ®Google Scholar
• Bauer, S., Kirschning, C. J., Hacker, H., Redecke, V., Hausmann, S., Akira, S., Wagner, H., and Lipford, G. B. 2001. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl. Acad. Sci. USA 98:9237–9242.
   PubMed Web of Science ®Google Scholar
• Bong, A. B., Bonnekoh, B., Franke, I., Schon, M. P., Ulrich, J., and Gollnick, H. 2002. Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology 205:135–138.
   PubMed Web of Science ®Google Scholar
• Carpentier, A., Laigle-Donadey, F., Zohar, S., Capelle, L., Behin, A., Tibi, A., Martin-Duverneuil, N., Sanson, M., Lacomblez, L., Taillibert, S., Puybasset, L., Van Effenterre, R., Delattre, J. Y., and Carpentier, A. F. 2006. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neurol. Oncol. 8:60–66.
   PubMed Web of Science ®Google Scholar
• Chakrabarty, A., Hillman, G. G., Maughan, R. L., Ali, E., Pontes, J. E., and Haas, G. P. 1994. Radiation therapy enhances the therapeutic effect of immunotherapy on pulmonary metastases in a murine renal adenocarcinoma model. In Vivo 8:25–31.
   PubMedGoogle Scholar
• Dendorfer, M., Oppel, T., Wollenberg, A., and Prinz, J. C. 2003. Topical treatment with imiquimod may induce regression of facial keratoacanthoma. Eur. J. Dermatol. 13:80–82.
   PubMed Web of Science ®Google Scholar
• Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., and Reise Sousa C. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531.
   PubMed Web of Science ®Google Scholar
• Dumitru, C. D., Antonysamy, M. A., Gorski, K. S., Johnson, D. D., Reddy, L. G., Lutterman, J. L., Piri, M. M., Proksch, J., McGurran, S. M., Egging, E. A., Cochran, F. R., Lipson, K. E., Tomai, M. A., and Gullikson, G. W. 2009. NK1.1+ cells mediate the anti-tumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model. Cancer Immunol. Immunother. 58:575–587.
   PubMed Web of Science ®Google Scholar
• Dummer, R., Hauschild, A., Becker, J. C., Grob, J. J., Schadendorf, D., Tebbs, V., Skalsky, J., Kaehler, K. C., Moosbauer, S., Clark, R., Meng, T. C., and Urosevic, M. 2008. An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. Clin. Cancer Res. 14:856–864.
   PubMed Web of Science ®Google Scholar
• Geisse, J., Caro, I., Lindholm, J., Golitz, L., Stampone, P., and Owens, M. 2004. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: Results from two Phase III, randomized, vehicle-controlled studies. J. Am. Acad. Dermatol. 50:722–733.
   PubMed Web of Science ®Google Scholar
• Goldstein, D., Hertzog, P., Tomkinson, E., Couldwell, D., McCarville, S., Parrish, S., Cunningham, P., Newell, M., Owens, M., and Cooper, D. A. 1998. Administration of imiquimod, an interferon inducer, in asymptomatic human immunodeficiency virus-infected persons to determine safety and biologic response modification. J. Infect. Dis. 178:858–861.
   PubMed Web of Science ®Google Scholar
• Gorden, K. B., Gorski, K. S., Gibson, S. J., Kedl, R. M., Kieper, W. C., Qiu, X., Tomai, M. A., Alkan, S. S., and Vasilakos, J. P. 2005. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J. Immunol. 174:1259–1268.
   PubMed Web of Science ®Google Scholar
• Gorski, K. S., Waller, E. L., Bjornton-Severson, J., Hanten, J. A., Riter, C. L., Kieper, W. C., Gorden, K. B., Miller, J. S., Vasilakos, J. P., Tomai, M. A., and Alkan, S. S. 2006. Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists. Int. Immunol. 18:1115–1126.
   PubMed Web of Science ®Google Scholar
• Gunzer, M., Riemann, H., Basoglu, Y., Hillmer, A., Weishaupt, C., Balkow, S., Benninghoff, B., Ernst, B., Steinert, M., Scholzen, T., Sunderkotter, C., and Grabbe, S. 2005. Systemic administration of a TLR7 ligand leads to transient immune incompetence due to peripheral-blood leukocyte depletion. Blood 106:2424–2432.
   PubMed Web of Science ®Google Scholar
• Hadley, G., Derry, S., and Moore, R. A. 2006. Imiquimod for actinic keratosis: Systematic review and meta-analysis. J. Invest. Dermatol. 126:1251–1255.
   PubMed Web of Science ®Google Scholar
• Harrison, L.I., Astry, C., Kumar, S., and Yunis, C. 2007. Pharmacokinetics of 852A, an imidazoquinoline Toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans. J. Clin. Pharmacol. 47:962–969.
   PubMed Web of Science ®Google Scholar
• Hayashi, F., Smith, K. D., Ozinsky, A., Hawn, T. R., Yi, E. C., Goodlett, D. R., Eng, J. K., Akira, S., Underhill, D. M., and Aderem, A. 2001. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103.
   PubMed Web of Science ®Google Scholar
• Heckelsmiller, K., Rall, K., Beck, S., Schlamp, A., Seiderer, J., Jahrsdorfer, B., Krug, A., Rothenfusser, S., Endres, S., and Hartmann, G. 2002. Peritumoral CpG DNA elicits a coordinated response of CD8 T-cells and innate effectors to cure established tumors in a murine colon carcinoma model. J. Immunol. 169:3892–3899.
   PubMed Web of Science ®Google Scholar
• Heil, F., Ahmad-Nejad, P., Hemmi, H., Hochrein, H., Ampenberger, F., Gellert, T., Dietrich, H., Lipford, G., Takeda, K., Akira, S., Wagner, H., and Bauer, S. 2003. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol. 33:2987–2997.
   PubMed Web of Science ®Google Scholar
• Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H., and Bauer, S. 2004. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529.
   PubMed Web of Science ®Google Scholar
• Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda, K., and Akira, S. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3:196–200.
   PubMed Web of Science ®Google Scholar
• Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., and Akira, S. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745.
   PubMed Web of Science ®Google Scholar
• Hillman, G. G. 2002. Experimental animal models for renal cell carcinoma. In: Tumor Models in Cancer Research (Teicher, B. A., Ed.), Heidelberg: Springer, pp. 494–498.
   Google Scholar
• Honda, K., Yanai, H., Mizutani, T., Negishi, H., Shimada, N., Suzuki, N., Ohba, Y., Takaoka, A., Yeh, W.C., and Taniguchi, T. 2004. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl. Acad. Sci. USA 101:15416–15421.
   PubMed Web of Science ®Google Scholar
• Hornung, V., Rothenfusser, S., Britsch, S., Krug, A., Jahrsdorfer, B., Giese, T., Endres, S., and Hartmann, G. 2002. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J. Immunol. 168:4531–4537.
   PubMed Web of Science ®Google Scholar
• Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., and Akira, S. 1999. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the Lps gene product. J. Immunol. 162:3749–3752.
   PubMed Web of Science ®Google Scholar
• Ito, T., Amakawa, R., Kaisho, T., Hemmi, H., Tajima, K., Uehira, K., Ozaki, Y., Tomizawa, H., Akira, S., and Fukuhara, S. 2002. Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. J. Exp. Med. 195:1507–1512.
   PubMed Web of Science ®Google Scholar
• Kawai, T., Sato, S., Ishii, K.J., Coban, C., Hemmi, H., Yamamoto, M., Terai, K., Matsuda, M., Inoue, J., Uematsu, S., Takeuchi, O., and Akira, S. 2004. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5:1061–1068.
   PubMed Web of Science ®Google Scholar
• Kawarada, Y., Ganss, R., Garbi, N., Sacher, T., Arnold, B., and Hammerling, G. J. 2001. NK- and CD8+ T-cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides. J. Immunol. 167:5247–5253.
   PubMed Web of Science ®Google Scholar
• Klinman, D. M., Takeshita, F., Gursel, I., Leifer, C., Ishii, K. J., Verthelyi, D., and Gursel, M. 2002. CpG DNA: Recognition by and activation of monocytes. Microbes Infect. 4:897–901.
   PubMed Web of Science ®Google Scholar
• Korman, N., Moy, R., Ling, M., Matheson, R., Smith, S., McKane, S., and Lee, J. H. 2005. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: Results of two Phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch. Dermatol. 141:467–473.
   PubMed Web of Science ®Google Scholar
• Krieg, A. M., Efler, S. M., Wittpoth, M., Al Adhami, M. J., and Davis, H. L. 2004. Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J. Immunother. 27:460–471.
   PubMed Web of Science ®Google Scholar
• Krieg, A. M. 2007. Development of TLR9 agonists for cancer therapy. J. Clin. Invest. 117:1184–1194.
   PubMed Web of Science ®Google Scholar
• Larangé, A., Antonios, D., Pallardy, M., and Kerdine-Romer, S. 2009. TLR7 and TLR8 agonists trigger different signaling pathways for human dendritic cell maturation. J. Leukocyte Biol. 85:673–683.
   PubMed Web of Science ®Google Scholar
• Lee, J., Chuang, T. H., Redecke, V., She, L., Pitha, P. M., Carson, D. A., Raz, E., and Cottam, H. B. 2003. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7. Proc. Natl. Acad. Sci. USA 100:6646–6651.
   PubMed Web of Science ®Google Scholar
• Link, B. K., Ballas, Z. K., Weisdorf, D., Wooldridge, J. E., Bossler, A. D., Shannon, M., Rasmussen, W. L., Krieg, A. M., and Weiner, G. J. 2006. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J. Immunother. 29:558–568.
   PubMed Web of Science ®Google Scholar
• Liu, C., Lou, Y., Lizee, G., Qin, H., Liu, S., Rabinovich, B., Kim, G.J., Wang, Y. H., Ye, Y., Sikora, A. G., Overwijk, W. W., Liu, Y. J., Wang, G., and Hwu, P. 2008. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T-cell cross-priming and tumor regression in mice. J. Clin. Invest. 118:1165–1175.
   PubMed Web of Science ®Google Scholar
• Lund, J. M., Alexopoulou, L., Sato, A., Karow, M., Adams, N. C., Gale, N. W., Iwasaki, A., and Flavell, R. A. 2004. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl. Acad. Sci. USA 101:5598–5603.
   PubMed Web of Science ®Google Scholar
• Manegold, C., Gravenor, D., Woytowitz, D., Mezger, J., Hirsh, V., Albert, G., Al-Adhami, M., Readett, D., Krieg, A. M., and Leichman, C. G. 2008. Randomized Phase II trial of a toll-like receptor 9 agonist oligodeoxynucleotide, PF-3512676, in combination with first-line taxane plus platinum chemotherapy for advanced-stage non-small-cell lung cancer. J. Clin. Oncol. 26:3979–3986.
   PubMed Web of Science ®Google Scholar
• Nagase, H., Okugawa, S., Ota, Y., Yamaguchi, M., Tomizawa, H., Matsushima, K., Ohta, K., Yamamoto, K., and Hirai, K. (2003). Expression and function of Toll-like receptors in eosinophils: Activation by Toll-like receptor 7 ligand. J. Immunol. 171:3977–3982.
   PubMed Web of Science ®Google Scholar
• O’Neill, L. A. 2006. How Toll-like receptors signal: What we know and what we don’t know. Curr. Opin. Immunol. 18:3–9.
   PubMed Web of Science ®Google Scholar
• Pashenkov, M., Goess, G., Wagner, C., Hormann, M., Jandl, T., Moser, A., Britten, C. M., Smolle, J., Koller, S., Mauch, C., Tantcheva-Poor, I., Grabbe, S., Loquai, C., Esser, S., Franckson, T., Schneeberger, A., Haarmann, C., Krieg, A. M., Stingl, G., and Wagner, S. N. 2006. Phase II trial of a Toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma. J. Clin. Oncol. 24:5716–5724.
   PubMed Web of Science ®Google Scholar
• Pestka, S., Krause, C. D., and Walter, M. R. 2004. Interferons, interferon-like cytokines, and their receptors. Immunol. Rev. 202:8–32.
   PubMed Web of Science ®Google Scholar
• Pope, B. L., Sigindere, J., Chourmouzis, E., MacIntyre, P., and Goodman, M. G. 1994. 7-Allyl-8-oxoguanosine (loxoribine) inhibits the metastasis of B16 melanoma cells and has adjuvant activity in mice immunized with a B16 tumor vaccine. Cancer Immunol. Immunother. 38:83–91.
   PubMed Web of Science ®Google Scholar
• Qureshi, S. T., Lariviere, L., Leveque, G., Clermont, S., Moore, K. J., Gros, P., and Malo, D. 1999. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr-4). J. Exp. Med. 189:615–625.
   PubMed Web of Science ®Google Scholar
• Schulze, H. J., Cribier, B., Requena, L., Reifenberger, J., Ferrandiz, C., Garcia Diez, A., Tebbs, V., and McRae, S. 2005. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: Results from a randomized vehicle-controlled Phase III study in Europe. Br. J. Dermatol. 152:939–947.
   PubMed Web of Science ®Google Scholar
• Schwartz, M. J., Liu, H., Hwang, D. H., Kawamoto, H., and Scherr, D. S. 2009. Anti-tumor effects of an imidazoquinoline in renal cell carcinoma. Urology 73:1156–1162.
   PubMed Web of Science ®Google Scholar
• Shevach, E. M. 2005. Immunofluorescence and cell sorting. In: Short Protocols in Immunology (Coligan, J. E., Marguiles, D. H., Shevach, E. M., and Strober, W., Eds.), Hoboken, NJ: John Wiley & Sons, pp. 4-1–4-15.
   Google Scholar
• Smits, E. L., Ponsaerts, P., Berneman, Z. N., and Van Tendeloo, V. F. 2008. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist 13:859–875.
   PubMed Web of Science ®Google Scholar
• Sterry, W., Ruzicka, T., Herrera, E., Takwale, A., Bichel, J., Andres, K., Ding, L., and Thissen, M. R. 2002. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: Randomized studies comparing low-frequency dosing with and without occlusion. Br. J. Dermatol. 147:1227–1236.
   PubMed Web of Science ®Google Scholar
• Stockfleth, E., Meyer, T., Benninghoff, B., Salasche, S., Papadopoulos, L., Ulrich, C., and Christophers, E. 2002. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch. Dermatol. 138:1498–1502.
   PubMed Web of Science ®Google Scholar
• Swann, J. B., and Smyth, M. J. 2007. Immune surveillance of tumors. J. Clin. Invest. 117:1137–1146.
   PubMed Web of Science ®Google Scholar
• Szeimies, R. M., Bichel, J., Ortonne, J. P., Stockfleth, E., Lee, J., and Meng, T. C. 2008. A Phase II dose-ranging study of topical resiquimod to treat actinic keratosis. Br. J. Dermatol. 159:205–210.
   PubMed Web of Science ®Google Scholar
• Szeimies, R. M., Gerritsen, M. J., Gupta, G., Ortonne, J. P., Serresi, S., Bichel, J., Lee, J. H., Fox, T. L., and Alomar, A. 2004. Imiquimod 5% cream for the treatment of actinic keratosis: Results from a Phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J. Am. Acad. Dermatol. 51:547–555.
   PubMed Web of Science ®Google Scholar
• Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T. W., and Taniguchi, T. 2005. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434:243–249.
   PubMed Web of Science ®Google Scholar
• Takeda, K., and Akira, S. 2005. Toll-like receptors in innate immunity. Int. Immunol. 17:1–14.
   PubMed Web of Science ®Google Scholar
• Takeshita, F., Leifer, C. A., Gursel, I., Ishii, K. J., Takeshita, S., Gursel, M., and Klinman, D. M. 2001. Cutting edge: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J. Immunol. 167:3555–3558.
   PubMed Web of Science ®Google Scholar
• Takeuchi, O., Kawai, T., Muhlradt, P. F., Morr, M., Radolf, J. D., Zychlinsky, A., Takeda, K., and Akira, S. 2001. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13:933–940.
   PubMed Web of Science ®Google Scholar
• Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R. L., and Akira, S. 2002. Cutting edge: Role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169:10–14.
   PubMed Web of Science ®Google Scholar
• Ugurel, S., Wagner, A., Pfohler, C., Tilgen, W., and Reinhold, U. 2002. Topical imiquimod eradicates skin metastases of malignant melanoma but fails to prevent rapid lymphogenous metastatic spread. Br. J. Dermatol. 147:621–624.
   PubMed Web of Science ®Google Scholar
• Vollmer, J., Rankin, R., Hartmann, H., Jurk, M., Samulowitz, U., Wader, T., Janosch, A., Schetter, C., and Krieg, A. M. 2004a. Immunopharmacology of CpG oligodeoxynucleotides and ribavirin. Antimicrob. Agents Chemother. 48:2314–2317.
   PubMed Web of Science ®Google Scholar
• Vollmer, J., Weeratna, R., Payette, P., Jurk, M., Schetter, C., Laucht, M., Wader, T., Tluk, S., Liu, M., Davis, H. L., and Krieg, A. M. 2004b. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur. J. Immunol. 34:251–262.
   PubMed Web of Science ®Google Scholar
• Wang, H., Rayburn, E. R., Wang, W., Kandimalla, E. R., Agrawal, S., and Zhang, R. 2006. Chemotherapy and chemosensitization of non-small cell lung cancer with a novel immunomodulatory oligonucleotide targeting Toll-like receptor 9. Mol. Cancer Ther. 5:1585–1592.
   PubMed Web of Science ®Google Scholar
• Werts, C., Tapping, R. I., Mathison, J. C., Chuang, T. H., Kravchenko, V., Saint Girons, I., Haake, D. A., Godowski, P. J., Hayashi, F., Ozinsky, A., Underhill, D. M., Kirschning, C. J., Wagner, H., Aderem, A., Tobias, P. S., and Ulevitch, R. J. 2001. Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nat. Immunol. 2:346–352.
   PubMed Web of Science ®Google Scholar
• Whitmore, M. M., DeVeer, M. J., Edling, A., Oates, R. K., Simons, B., Lindner, D., and Williams, B. R. 2004. Synergistic activation of innate immunity by double-stranded RNA and CpG DNA promotes enhanced anti-tumor activity. Cancer Res. 64:5850–5860.
   PubMed Web of Science ®Google Scholar
• Wiltrout, R. H., Salup, R. R., Twilley, T. A., and Talmadge, J. E. 1985. Immunomodulation of natural killer activity by polyribonucleotides. J. Biol. Resp. Mod. 4:512–517.
   PubMedGoogle Scholar
• Yang, Q., Goding, S. R., Hokland, M. E., and Basse, P. H. 2006. Anti-tumor activity of NK cells. Immunol. Res. 36:13–25.
   PubMed Web of Science ®Google Scholar
• Yarovinsky, F., Zhang, D., Andersen, J. F., Bannenberg, G. L., Serhan, C. N., Hayden, M. S., Hieny, S., Sutterwala, F. S., Flavell, R. A., Ghosh, S., and Sher, A. 2005. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626–1629.
   PubMed Web of Science ®Google Scholar