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Review Article

Immunotherapeutic potential of CpG oligodeoxynucleotides in veterinary species

, , , &
Pages 535-544 | Received 21 Jun 2012, Accepted 22 Jul 2013, Published online: 28 Aug 2013

References

  • Medzhitov R, Preston HP, Janeway, JrCA. A human homologue of the Drosophila Toll protein signal activation of adaptive immunity. Nature 1997;388:394–397
  • Lemaitre B, Nicolas E, Michaut L, et al. The dorsoventral regulatory gene cassette sptazle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973–983
  • Leulier F, Lemaitre B. Toll-like receptors – taking an evolutionary approach. Nat Rev Genet 2008;9:165–178
  • Temperley ND, Berlin S, Paton IR, et al. Evolution of the chicken Toll-like receptor gene family: a story of gene gain and gene loss. BMC Genomics 2008;9:62
  • Brownlie R, Zhu J, Allan B, et al. Chicken TLR21 acts as a functional homologue to mammalian TLR9 in the recognition of CpG oligodeoxynucleotides. Mol Immunol 2009;46:3163–3170
  • Hemmi H, Takeuchi O, Kawai T, et al. A toll-like receptor recognizes bacterial DNA. Nature 2000;408:740–745
  • Griebel PJ, Brownlie R, Manuja A, et al. Bovine toll like receptor 9: a comparative analysis of molecular structure, function and expression. Vet Immunol Immunopathol 2005;108:11–16
  • Cardon LR, Burge C, Claydon DA, Karlin S. Pervasive CpG suppression in animal mitochondrial genomes. Proc Natl Acad Sci USA 1994;91:3799–3803
  • Krieg AM. Antiinfective application of Toll-like receptor 9 Agonists. Proc American Thoracic Society 2007;4:289–294
  • Blazar BR, Krieg AM, Taylor PA. Synthetic unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides are potent stimulators of antileukemia responses in naive and bone marrow transplant recipients. Blood 2001;98:1217–1225
  • Olbrich ARM, Schimmer S, Heeg K, et al. Effective postexposure treatment of retrovirus-induced disease with immunostimulatory DNA containing CpG motifs. J Virol 2002;76:11397–11404
  • Pyles RB, Higgins D, Chalk C, et al. Use of immunostimulatory sequence-containing oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection. J Virol 2002;76:11387–11396
  • Sparwasser T, Hultner L, Koch ES, et al. Immunostimulatory CpG-oligodeoxynucleotides cause extramedullary murine hemopoiesis. J Immunol 1999;162:2368–2374
  • Stacey KJ, Blackwell JM. Immunostimulatory DNA as an adjuvant in vaccination against Leishmania major. Infect Immun 1999;67:3719–3726
  • Wild JS, Sur S. CpG oligonucleotide modulation of allergic inflammation. Allergy 2001;56:365–376
  • Zimmermann S, Egeter O, Hausmann S, et al. CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. J Immunol 1998;160:3627–3630
  • Mutwiri G. TLR9 agonists: immune mechanisms and therapeutic potential in domestic animals. Vet Immunol Immunopathol 2012;148:85–89
  • Latz E, Schoenemeyer A, Visintin A, et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 2004;5:190–198
  • Takeshita F, Gursel I, Ishii KJ, et al. Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9. Semin Immunol 2004;16:17–22
  • Hacker H, Mischak H, Miethke T, et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J 1998;17:6230–6240
  • Vollmer J, Krieg AM. Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv Drug Delivery Rev 2009;61:195–204
  • Rutz M, Metzger J, Gellert T, et al. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 2004;34:2541–2550
  • Cornélie S, Hoebeke J, Schacht AM, et al. Direct evidence that toll-like receptor 9 (TLR9) functionally binds plasmid DNA by specific cytosine-phosphate-guanine motif recognition. J Biol Chem 2004;279:15124–15129
  • Chen J, Nag S, Vidi P-A, Irudayaraj J. Single molecule in vivo analysis of toll-like receptor 9 and CpG DNA interaction. PLoS ONE 2011;6:e17991
  • Peter ME, Kubarenko AV, Weber AN, Dalpke AH. Identification of an N-terminal recognition site in TLR9 that contributes to CpG-DNA-mediated receptor activation. J Immunol 2009;182:7690–7697
  • Mutwiri G, Pontarollo R, Babiuk S, et al. Biological activity of immunostimulatory CpG DNA motifs in domestic animals. Vet Immunol Immunopathol 2003;91:89–103
  • Rankin R, Pontarollo R, Ioannou X, et al. CpG motif identification for veterinary and laboratory species demonstrates that sequence recognition is highly conserved. Antisense Nucleic Acid Drug Dev 2001;11:333–340
  • Krieg AM, Yi AK, Matson S, et al. CpG Motifs in bacterial-DNA trigger direct B-cell activation. Nature 1995;374:546–549
  • Yi AK, Klinman DM, Martin TL, et al. Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway. J Immunol 1996;157:5394–5402
  • Kindrachuk J, Potter JE, Brownlie R, et al. Nucleic acids exert a sequence-independent cooperative effect on sequence-dependent activation of Toll-like receptor 9. J Biol Chem 2007;282:13944–13953
  • Jurk M, Schulte B, Kritzler A, et al. C-Class CpG ODN: sequence requirements and characterization of immunostimulatory activities on mRNA level. Immunobiology 2004;209:141–154
  • Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 2004;4:249–258
  • Ballas ZK, Rasmussen WL, Krieg AM. Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J Immunol 1996;157:1840–1845
  • Krug A, Rothenfusser S, Hornung V, et al. Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells. Eur J Immunol 2001;3:2154–2163
  • Sands H, Gorey-Feret LJ, Cocuzza AJ, et al. Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and a phosphorothioate. Mol Pharmacol 1994;45:932–943
  • Zhao Q, Yu D, Agrawal S. Site of chemical modifications in CpG containing phosphorothioate oligodeoxynucleotide modulates its immunostimulatory activity. Bioorg Med Chem Lett 1999;9:3453–3458
  • Hartmann G, Battiany J, Poeck H, et al. Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells. Eur J Immunol 2003;33:1633–1641
  • Marshall JD, Fearon KL, Higgins D, et al. Superior activity of the type C class of ISS in vitro and in vivo across multiple species. DNA Cell Biol 2005;24:63–72
  • Klinman DM, Yi AK, Beaucage SL, et al. CpG motifs presentn bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc Natl Acad Sci USA 1996;93:2879–2883
  • Sparwasser T, Miethke T, Lipford G, et al. Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor-alpha-mediated shock. Eur J Immunol 1997;27:1671–1679
  • Bohle, Jahn-Schmid B, Maurer D, et al. Oligodeoxynucleotides containing CpG motifs induce IL-12, IL-18 and IFN-gamma production in cells from allergic individuals and inhibit IgE synthesis in vitro. Eur J Immunol 1999;29:2344–2353
  • Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 2005;23:275–306
  • Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006;5:471–484
  • Dasari P, Nicholson IC, Hodge G, et al. Expression of toll-like receptors on B lymphocytes. Cellular Immunol 2005;236:140–145
  • Wilson HL, Dar A, Napper SK, et al. Immunemechanisms and therapeutic potential of CpG oligodeoxynucleotides. Int Rev Immunol 2006;25:183–213
  • Hanagata N. Structure-dependent immunostimulatory effect of CpG oligodeoxynucleotides and their delivery system. Int J Nanomedicine 2012;7:2181–2195
  • Jung J, Yi AK, Zhang X, et al. Distinct response of human B cell subpopulations in recognition of an innate immune signal, CpG DNA. J Immunol 2002;169:2368–2373
  • Bernasconi NL, Traggiai E, Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science 2002;298:2199–2202
  • Askew D, Chu RS, Krieg AM, Harding CV. CpG DNA induces maturation of dendritic cells with distinct effects on nascent and recycling MHC-II antigen processing mechanisms. J Immunol 2000;165:6889–6895
  • Jakob T, Walker PS, Krieg AM, et al. Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: a role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA. J Immunol 1998;161:3042–3049
  • Lipford GB, Sparwasser T, Bauer M, et al. Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines. Eur J Immunol 1997;27:3420–3426
  • Bendigs S, Salzer U, Lipford GB, et al. CpG oligodeoxynucleotides co-stimulate primary T cells in the absence of antigen presenting cells. Eur J Immunol 1999;29:1209--1218
  • Ballas ZK. Modulation of NK cell activity by CpG oligodeoxynucleotides. Immunol Res 2007;39:15–21
  • Weiner GJ. The immunobiology and clinical potential of immunostimulatory CpG oligodeoxynucleotides. J Leukoc Biol 2000;68:455–463
  • Moga E, Alvarez E, Cantó E, et al. NK cells stimulated with IL-15 or CpG ODN enhance rituximab-dependent cellular cytotoxicity against B-cell lymphoma. Exp Hematol 2008;36:69–77
  • Ravindran C, Cheng YC, Liang SM. CpG-ODNs induces up-regulated expression of chemokine CCL9 in mouse macrophages and microglia. Cell Immunol 2010;260:113–118
  • Booth JS, Buza JJ, Potter A, et al. Co-stimulation with TLR7/8 and TLR9 agonists induce down-regulation of innate immune responses in sheep blood mononuclear and B cells. Dev Comp Immunol 2010;34:572–578
  • Manuja A, Manuja BK, Dhingra M, Sarkar S. Differential expression of toll-like receptor 9 by various immune compartments of buffalo (Bubalus bubalis). Ind J Anim Sci 2012;82:427–429
  • Manuja A, Manuja BK, Kataria RS, et al. Comparative analysis of molecular structure, function and expression of buffalo (Bubalus bubalis) toll-like receptor 9. J Buffalo Sci 2013;2:63--71
  • Booth JS, Nichani AK, Benjamin P, et al. Innate immune responses induced by classes of CpG oligodeoxynucleotides in ovine lymph node and blood mononuclear cells. Vet Immunol Immunopathol 2007;115:24–34
  • Booth JS, Griebel PJ, Babiuk LA, Mutwiri GK. A novel regulatory B-cell population in sheep Peyer's patches spontaneously secretes IL-10 and downregulates TLR9-induced IFN alpha responses. Mucosal Immunol 2009;2:265–275
  • Booth JS, Jimbo S, Mutwiri GK. Novel Bregs downregulate TLR9-induced cytokine responses in sheep Peyer's patches. Vet Immunol Immunopathol 2012;148:157–160
  • Klaschik S, Gursel I, Klinman DM. CpG-mediated changes in gene expression in murine spleen cells identified by microarray analysis. Mol Immunol 2007;44:1095–1104
  • Liu N, Ohnishi N, Ni L, et al. CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells Nat. Immunol 2003;4:687–693
  • Sun S, Sprent J. Role of type I interferons in T cell activation induced by CpG DNA. Curr Top Microbiol Immunol 2000;247:107–117
  • Ramshaw IA, Ramsay AJ, Karupiah G, et al. Cytokines and immunity to viral infections. Immunol Rev 1997;159:119–135
  • Krieg AM. Now I know my CpGs. Trends Microbiol 2001;9:249–252
  • Sun S, Kishimoto H, Sprent J. DNA as an adjuvant: capacity of insect DNA and synthetic oligodeoxynucleotides to augment T-cell responses to specific antigen. J Exp Med 1998;187:1145–1150
  • Walker PS, Scharton-Kersten T, Krieg AM, et al. Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-12- and IFN-gamma-dependent mechanisms. Proc Natl Acad Sci USA 1999;96:6970–6975
  • Yamamoto S, Yamamoto T, Shimada S, et al. DNA from bacteria, but not from vertebrates, induces interferons, activates natural killer cells and inhibits tumor growth. Microbiol Immunol 1992;36:983–997
  • Toma B, Eloit M, Savey M. Animal diseases caused by retroviruses: enzootic bovine leukosis, equine infectious anaemia and caprine arthritis-encephalitis. Rev Sci Tech Off Int Epiz 1990;9:1039–1076
  • Kamstrup S, Frimann TH, Barfoed AM. Protection of Balb/c mice against infection with FMDV by immunostimulation with CpG oligonucleotides. Antiviral Res 2006;72:42–48
  • Nichani AK, Mena A, Kaushik RS, et al. Stimulation of innate immune responses by CpG oligodeoxynucleotide in newborn lambs can reduce bovine herpesvirus-1 shedding. Oligonucleotides 2006;16:58–67
  • Robert-Tissot C, Meli ML, Riond B, et al. Induction of a systemic antiviral state in vivo in the domestic cat with a class A CpG oligonucleotide. Vet Immunol Immunopathol 2012;150:1–9
  • Christopher ME, Wong JP. Broad-spectrum drugs against viral agents. Int J Mol Sci 2008;9:1561–1594
  • Nichani AK, Dar MA, Mirakhur KK, et al. Subcutaneous, but not intratracheal administration of the TLR9 agonist, CpG DNA transiently reduces parainfluenza-3 virus shedding in newborn lambs. Comp Immunol Microbiol Infect Dis 2010;33:e111–e117
  • Portnoy DA. Innate immunity to a facultative intracellular bacterial pathogen. Curr Opin Immunol 1992;4:20--24
  • Elkins KL, Rhinehart-Jones TR, Culkin SJ, et al. Minimal requirements for murine resistance to infection with Francisella tularensis LVS. Infect Immun 1996;64:3288--3293
  • Izzo AA, North RJ. Evidence for an α/β T cell-independent mechanism of resistance to mycobacteria: bacillus-Calmette-Guerin causes progressive infection in severe combined immunodeficient mice, but not in nude mice or in mice depleted of CD4+and CD8+T cells. J Exp Med 1992;176:581--586
  • Palmer MV, Welsh MD, Hostetter JM. Mycobacterial diseases of animals. Veterinary Medicine International 2011. Article ID 292469, 2 pp., doi:10.4061/2011/292469
  • Gomis S, Babiuk L, Godson DL, et al. Protection of chickens against Escherichia coli infections by DNA containing CpG motifs. Infect Immun 2003;71:857–863
  • Gomis S, Babiuk L, Allan B, et al. Protection of neonatal chicks against a lethal challenge of Escherichia coli using DNA containing cytosine-phosphodiester-guanine motifs. Avian Dis 2004;48:813–822
  • Taghavi A, Allan B, Mutwiri G, et al. Protection of neonatal broiler chicks against Salmonella typhimurium septicemia by DNA containing CpG motifs. Avian Dis 2008;52:398–406
  • Mackinnon KM, He H, Swaggerty CL, et al. In ovo treatment with CpG oligodeoxynucleotides decreases colonization of Salmonella enteriditis in broiler chickens. Vet Immunol Immunopathol 2009;127:371–375
  • Dalloul RA, Lillehoj HS, Okamura M, et al. In vivo effects of CpG oligodeoxynucleotide on Eimeria infection in chickens. Avian Dis 2004;48:783–790
  • Verthelyi D, Gursel M, Kenney RT, et al. CpG oligodeoxynucleotides protect normal and SIV infected macaques from Leishmania infection. J Immunol 2003;170:4717–4723
  • Fakher FHA, Rachinel N, Klimczak M, et al. TLR9-dependent activation of dendritic cells by DNA from Leishmania major favors TH1 cell development and the resolution of lesions. J Immunol 2009;182:1386–1396
  • Bartholomeu DC, Ropert C, Melo MB, et al. Recruitment and endo-lysosomal activation of TLR9 in dendritic cells infected with Trypanosoma cruzi. J Immunol 2008;181:1333–1344
  • Rees DG, AJ Gates, M Green, et al. CpG-DNA protects against a lethal orthopoxvirus infection in a murine model. Antivir Res 2005;65:87–95
  • Krieg AM, Love-Homan L, Yi AK, Harty JT. CpG DNA induces sustained IL-12 Expression in vivo and resistance to Listeria monocytogenes challenges. J Immunol 1998;161:2428–2434
  • Ray NB, Krieg AM. Oral pretreatment of mice with CpG DNA reduces susceptibility to oral or intraperitoneal challenge with virulent Listeria monocytogenes. Infect Immun 2003;71:4398–4404
  • Deng JC, Moore TA, Newstead MW, et al. CpG oligodeoxynucleotides stimulate protective innate immunity against pulmonary Klebsiella infection. J Immunol 2004;173:5148–5155
  • Harris TH, Mansfield JM, Paulnock DM. CpG oligodeoxynucleotide treatment enhances innate resistance and acquired immunity to African trypanosomes. Infect Immun 2007;75:2366–2373
  • Sajic D, Ashkar AA, Patrick AJ, et al. Parameters of CpG oligodeoxynucleotide-induced protection against intravaginal HSV-2 challenge. J Med Virol 2003;71:561–568
  • Klinman DM, Conover J, Coban C. Repeated administration of synthetic oligodeoxynucleotides expressing CpG motifs provides long-term protection against bacterial infection. Infect Immun 1999;67:5658–5663
  • Kline JN, Waldschmidt TJ, Businga TR, et al. Modulation of airway inflammation by CpG oligodeoxynucleoutides in a murine model of asthma. J Immunol 1998;160:2555–2559
  • Kline JN, Kitagaki K, Businga TR, Jain VV. Treatment of established asthma in a murine model using CpG oligodeoxynucleotides. Am J Physiol Lung Cell Mol Physiol 2002;283:L170–179
  • Kline JN. Eat dirt: CpG DNA and Immunomodulation of Asthma. Proc American Thoracic Society 2007;4:283–288
  • Reinero CR, Cohn LA, Delgado CM, et al. Adjuvanted rush immunotherapy using CpG oligodeoxynucleotides in experimental feline allergic asthma. Vet Immunol Immunopathol 2008;121:241–250
  • Weeratna RD, McCluskie MJ, Xu Y, Davis HL. CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine 2000;18:1755–1762
  • McCluskie MJ, Davis HL. CpG DNA is a potent enhancer of systemic and mucosal immune responses against hepatitis B surface antigen with intranasal administration to mice. J Immunol 1998;161:4463–4466
  • Gallichan WS, Woolstencroft RN, Guarasci T, et al. Intranasal immunization with CpG oligodeoxynucleotides as an adjuvant dramatically increases IgA and protection against herpes simplex virus-2 in the genital tract. J Immunol 2001;166:3451–3457
  • Nesburn AB, Ramos TV, Zhu X, et al. Local and systemic B cell and Th1 responses induced following ocular mucosal delivery of multiple epitopes of herpes simplex virus type 1 glycoprotein D together with cytosine-phosphate-guanine adjuvant. Vaccine 2005;23:873–883
  • Nichani AK, Dar MA, Krieg AM, et al. Systemic innate immune responses following intrapulmonary delivery of CpG oligodeoxynucleotides in sheep. Vet Immunol Immunopathol 2007;115:357–368
  • Cooper CL, Davis HL, Morris ML, et al. Safety and immunogenicity of CpG 7909 injection as an adjuvant to Fluarix influenza vaccine. Vaccine 2004;22:3136–3143
  • Cooper CL, Davis HL, Angel JB, et al. CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 2005;19:1473–1479
  • Klinman DM, Currie D, Lee G, et al. Systemic but not mucosal immunity induced by AVA prevents inhalational anthrax. Microbes Infect 2007;9:1478–1483
  • Gu M, Hine PM, Jackson WJ, et al. Increased potency of BioThrax anthrax vaccine with the addition of the C-class CpG oligonucleotide adjuvant CPG 10109. Vaccine 2007;25:526–534
  • Klinman DM, Xie H, Little SF, et al. CpG oligonucleotides improve the protective immune response induced by the anthrax vaccination of rhesus macaques. Vaccine 2004;22:2881–2886
  • Singh M, Ott G, Kazzaz J, et al. Cationic microparticles are an effective delivery system for immune stimulatory CpG DNA. Pharm Res 2001;18:1476–1479
  • Kovacs-Nolan J, Latimer L, Landi A, et al. The novel adjuvant combination of CpG ODN, indolicidin and polyphosphazene induces potent antibody- and cell-mediated immune responses in mice. Vaccine 2009;27:2055–2064
  • Huang MH, Lin SC, Hsiao CH, et al. Emulsified nanoparticles containing inactivated influenza virus and CpG oligodeoxynucleotides critically influences the host immune responses in mice. PLoS ONE 2010;5:e12279
  • Chunyi Z, Wenjun M, Tomohiko Y, et al. BN nanospheres as CpG ODN carriers for activation of toll like receptor 9. J Mater Chem 2011;2:5219–5222
  • Fu ML, Ying SC, Wu M, et al. Regulating effects of novel CpG chitosan-nanoparticles on immune responses of mice to porcine paratyphoid vaccines. Biomed Environ Sci 2006;19:315–322
  • Moldoveanu Z, Love-Homan L, Huang WQ, Krieg AM. CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 1998;16:1216–1224
  • Eastcott JW, Holmberg CJ, Dewhirst FE, et al. Oligonucleotide containing CpG motifs enhances immune response to mucosally or systemically administered tetanus toxoid. Vaccine 2001;19:1636–1642
  • Dong JL, Liang BG, Jin YS, et al. Oral immunization with pBsVP6-transgenic alfalfa protects mice against rotavirus infection. Virology 2005;339:153–163
  • Berry LJ, Hickey DK, Skelding KA, et al. Transcutaneous immunization with combined cholera toxin and CpG adjuvant protects against Chlamydia muridarum genital tract infection. Infect Immun 2004;72:1019–1028
  • Carpentier AF, Chen L, Maltonti F, Delattre JY. Oligodeoxynucleotides containing CpG motifs can induce rejection of a neuroblastoma in mice. Cancer Res 1999;59:5429–5432
  • De Cesare M, Calcaterra C, Pratesi G, et al. Eradication of ovarian tumor xenografts by locoregional administration of targeted immunotherapy. Clin Cancer Res 2008;14:5512–5518
  • Link BK, Ballas ZK, Weisdorf D, et al. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J Immunother 2006;29:558–568
  • Krieg AM. Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 2008;27:161–167
  • Hofmann MA, Kors C, Audring H, et al. Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma. J Immunother 2008;31:520–527
  • Leonard JP, Link BK, Emmanouilides C, et al. Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non Hodgkin's lymphoma. Clin Cancer Res 2007;13:6168–6174
  • Weiner GJ. CpG oligodeoxynucleotide-based therapy of lymphoid malignancies. Adv Drug Deliv Rev 2009;61:263–267
  • Krieg AM. Antitumor applications of stimulating Toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 2004;6:88–95
  • Wooldridge JE, Weiner GJ. Therapeutic modalities CpG DNA and cancer immunotherapy: orchestrating the antitumor immune response. Curr Opin Oncol 2003;15:440–445
  • Auf G, Carpentier AF Chen L, et al. Implication of macrophages in tumor rejection induced by CpG-oligodeoxynucleotides without antigen. Clin Cancer Res 2001;7:3540
  • Ballas ZK, Krieg AM, Warren T, et al. Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs. J Immunol 2001;167:4878–4886
  • Shimada S, Yano O, Tokunaga T. In vivo augmentation of natural killer cell activity with a deoxyribonucleic acid fraction of BCG. Japan J Cancer Res 1986;77:808–816
  • Tokunaga T, Yamamoto H, Shimada S, et al. Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. Isolation, physicochemical characterization, and antitumour activity. J Natl Cancer Inst 1984;72:955–962
  • Wooldridge JE, Weiner GJ. CpG DNA and cancer immunotherapy: orchestrating the antitumor immune response. Curr Opin Oncol 2003;15:440–445
  • Kataoka T, Yamamoto S, Yamamoto T, et al. Antitumor activity of synthetic oligonucleotides with sequences from cDNA encoding proteins of Mycobacterium bovis BCG. Jpn J Cancer Res 1992;83:244–247
  • Hegele A, Dalpke A, Heeg K, et al. Immunostimulatory CpG oligonucleotides reduce tumor burden after intravesical administration in an orthotopic murine bladder cancer model. Tumour Biol 2005;26:274–280
  • Shukoor MI, Natalio F, Tahir MN, et al. CpG-DNA loaded multifunctional MnO nanoshuttles for TLR9-specific cellular cargo delivery, selective immune-activation and MRI. J Mater Chem 2012;22:8826–8834
  • Jahrsdorfer B, Weiner GJ. CpG oligodeoxynucleotides as immunotherapy in cancer. Update Cancer Ther 2008;3:27–32
  • Thompson A, Kuzel T, Bukowski R, et al. Phase Ib trial of a targeted TLR9 CpG immunomodulator (CPG 7909) in advanced renal cell carcinoma (RCC). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004;22:4644
  • Sommariva M, De Cecco L, De Cesare M, et al. TLR9 agonists oppositely modulate DNA repair genes in tumor versus immune cells and enhance chemotherapy effects. Cancer Res 2011;71:6382–6390
  • Jurk M, Vollmer J. Therapeutic applications synthetic CpG oligodeoxynucleotides as TLR9 agonists for immune modulation. Bio Drugs 2007;21:387–401

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