Resiquimod, a topical drug for viral skin lesions and skin cancer

Expert Opinion on Investigational Drugs

Volumn 22, Issue 1, 2013, Pages 149-159

  Meyer, Thomas ^a   Surber, Christian ^b   French, Lars E ^c   Stockfleth, Eggert ^d  

^a UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^b UNIVERSITY OF BASEL   (Switzerland)

^c UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^d HUMBOLDT UNIVERSITY   (Germany)

Author keywords

Actinic keratosis; Basal cell cancer; Genital herpes; Immune response modifier; Resiquimod; TLR agonist; Vaccine adjuvant

Indexed keywords

ACICLOVIR; CIDOFOVIR; DICLOFENAC; FAMCICLOVIR; FLUOROURACIL; HEPATITIS B VACCINE; HYALURONIC ACID; IMIQUIMOD; INGENOL MEBUTATE; PENCICLOVIR; RESIQUIMOD; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; VALACICLOVIR; WART VIRUS VACCINE;

ACTINIC KERATOSIS; ARTICLE; CLINICAL TRIAL; CYTOKINE PRODUCTION; DENDRITIC CELL; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; ERYTHEMA; FLU LIKE SYNDROME; GENITAL HERPES; HEPATITIS B; HEPATITIS C; HERPES SIMPLEX VIRUS 2; HUMAN; NONHUMAN; PHARMACODYNAMICS; SKIN CANCER; UTERINE CERVIX CANCER; VIRAL SKIN DISEASE; VIRUS LOAD;

ADMINISTRATION, TOPICAL; ANIMALS; ANTINEOPLASTIC AGENTS; ANTIVIRAL AGENTS; HUMANS; IMIDAZOLES; SKIN DISEASES; TREATMENT OUTCOME; VIRUS DISEASES;

EID: 84870999117     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2013.749236     Document Type: Article

References (96)

1. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001;2:675-80
2. O'Neill JA. Signal transduction pathways activated by the IL-1 receptor/Toll-like receptor superfamily. Curr Top Microbiol Immunol 2002;270:47-62
3. Meyer T, Stockfleth E. Clinical investigations of toll-like receptor agonists. Expert Opin Investig Drugs 2008;17:1051-65
4. Horscroft NJ, Pryde DC, Bright H. Antiviral applications of Toll-like receptor agonists. J Antimicrob Chemother 2012;67:789-801
5. Kanzler H, Barrat FJ, Hessel EM, et al. Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists. Nat Med 2007;13:552-9
6. Tomai MA, Gibson SJ, Imbertson LM, et al. Immunomodulating and antiviral activities of the imidazochinolines S-28643. Antivir Res 1995;28:253-64
7. Kwissa M, Nakaya HI, Oluoch H, et al. Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates. Blood 2012;119:2044-55
8. Bernstein DI, Harrison CJ, Tomai MA, Miller RL. Daily or weekly therapy with resiquimod (R-848) reduces genital recurrences in herpes simplex virus-infected guinea pigs during and after treatment. J Infect Dis 2001;183:844-9
9. Miller RL, Imbertson LM, Reiter MJ, Gerster JF. Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod. Antiviral Res 1999;44:31-42
10. Harrison CJ, Miller RL, Bernstein DI. Posttherapy suppression of genital herpes simplex virus (HSV) recurrences and enhancement of HSV-specific T-cell memory by imiquimod in guinea pigs. Antimicrob Agents Chemother 1994;38:2059-64
11. Spruance SL, Tyring SK, Smith MH, Meng TC. Application of a topical immune response modifier, resiquimod gel, to modify the recurrence rate of recurrent genital herpes: a pilot study. J Infect Dis 2001;184:196-200
12. Fife KH, Meng TC, Ferris DG, Liu P. Effect of Resiquimod 0.01% gel on lesion healing and viral shedding when applied to genital herpes lesions. Antimicrob Agents Chemother 2008;52:477-82
13. Wu JJ, Huang DB, Tyring SK. Resiquimod: a new immune response modifier with potential as a vaccine adjuvant for Th1 immune responses. Antiviral Res 2004;64:79-83
14. Pockros PJ, Guyader G, Patton H, et al. Oral resiquimod in chronic HCV infections: safety and efficiency in 2 placebo-controlled, double-blind phase IIa studies. J Hepatol 2007;47:174-82
15. Tomai MA, Miller RL, Lipson KE, et al. Resiquimod and other immune response modifiers as vaccine adjuvants. Expert Rev Vaccines 2007;6:835-47
16. Ackerman AB, Mones JM. Solar (actinic) keratosis is squamous cell carcinoma. Br J Dermatol 2006;155:9-22
17. Memon AA, Tomensen JA, Bothwell J, et al. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol 2000;142:1154-9
18. Frost Williams G, Green A. High incidence and regression rates of solar keratoses in a queensland community. J Invest dermatol 2000;115:273-7
19. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000;42:4-7
20. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988;1:795-7
21. Stockfleth E, Terhorst D, Braathen L, et al. On behalf of the European Dermatology Forum. Guidelines for the management of actinic keratoses. EDF. 2010.Available from: http://www.euroderm.org/images/stories/guidelines/ guideline-Management-Actinic-Keratoses-update2011.pdf
22. De Berker D, McGregor JM, Hughes BR. Guidelines for the management of actinic keratoses. Br J Dermatol 2007;156:222-30
23. Gilbody JS, Aitken J, Green A. What causes basal cell carcinoma to be the commonest cancer Aust J Public Health 1994;18:218-21
24. Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol 1994;30:774-8
25. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet 2010;375:673-85
26. McCord MW, Mendenhall WM, Parsosns JT, et al. Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys 2000;47:89-93
27. Ting PT, Kasper R, Arlette JP. Metastatic basal cell carcinoma: report of two cases and review of the literature. J Cutan med Surg 2005;9:10-15
28. Telfer NR, Colver GB, Morton CA. Guideliens for the management of basal cell carcinoma. Br J Dermatol 2008;159:35-48
29. Berman B, Amini S, Valins W, et al. Pharmacotherapy of actinic keratosis. Expert Opin Pharmacother 2009;10:3015-31
30. Ulrich M, Drecoll U, Stockfleth E. Emerging drugs for actinic keratosis. Expert Opin Emerg Drugs 2010;15:545-55
31. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012;366:2180-8
32. Szeimies RM, Karrer S, Radakovic-Fijan S, et al. Photodynamic therapy using topical methyl S-aminolevulinate compared with cryotherapy for actinic keratosis: a prospective, randomized study. J Am Acad Dermatol 2002;47:258-62
33. Bowers B, Basset-Seguin N, Colver G, et al. On behalf of the European Dermatology Forum. Guideline for the Management of basal cell carcinoma, EDF. 2006. Available from: http://www.euroderm.org/images/stories/guidelines/ guideline-Basal-Cell-Carcinoma.pdf
34. Viera MH, Amini S, Huo R, et al. Herpes simplex virus and human papillomavirus genital infections: new and investigational therapeutic options. Int J Dermatol 2010;49:733-49
35. Sauerbrei A, Deinhardt S, Zell R, et al. Testing of herpes simplex virus for resistance to antiviral drugs. Virulence 2010;1:555-7
36. Stockfleth E, Meyer T. The use of sinecatechins (polyphenon E) ointment for treatment of external genital warts. Expert Opin Biol Ther 2012;12:783-93
37. Meltzer SM, Monk BJ, Tewari KS. Green tea catechins for treatment of external genital warts. Am J Obstet Gynecol 2009;200:233; e1-7
38. Gorden KKB, Goski KS, Gibson SJ, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 2005;174:1259-68
39. Testerman TL, Gertser JF, Imbertson LM, et al. Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol 1995;58:365-72
40. Imbertson LM, Beaurline JM, Couture AM, et al. Cytokine induction in hairless mouse and rat skin after topical application of the immune response modifiers imiquimod and S-28463. J Invest Dermatol 1998;110:734-9
41. Christophers E, Meyer T. Pustular skin diseases reflect distinct innate defense pathways. Expert Rev Dermatol 2008;3:465-75
42. Lebre MC, van der Aar AMG, van Baarsen L, et al. Human keratinocytes express functional toll-like receptor 3, 4, 5, and 9. J Invest Dermatol 2007;127:331-41
43. Kollisch G, Kalali BN, Voelcker V, et al. Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes. Immunology 2005;114:531-41
44. Gibson SJ, Lindh JM, Riter TR, et al. Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists imiquimod and resiquimod. Cell Immunol 2002;218:74-86
45. Bimachu W, Gleason RM, Bulbulian BJ, et al. Transcriptional networks in plasmacytoid dendritic cells stimulated with synthetic TLR7 agonists. BMC Immunol 2007;8:26
46. Hornung V, Rothenfusser S, Britsch S, et al. 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 2002;168:4531-7
47. Bishop GA, Ramirez LM, Baccam M, et al. The immune response modifier resiquimod mimics CD40-induced B cell activation. Cell Immunol 2001;208:9-17
48. Wagner TL, Ahonen CL, Couture AM, et al. Modulation of TH1 and TH2 cytokine production with the immune response modifiers R-848 and imiquimod. Cell Immunol 1999;191:10-19
49. Ahonen CL, Gibson SJ, Smith RM, et al. Dendritic cell maturation and subsequent enhanced T cell stimulation induced with the novel synthetic immune response modifier R-848. Cell Immunol 1999;197:62-72
50. Nicholas SA, Bubnov VV, Yasinska IM, et al. Involvement of xanthine oxidase and hypoxia-inducible factor 1 in toll-like receptor 7/8-mediated activation ofcaspase 1 and interleukin 1β. Cell Mol Life Sci 2011;68:151-8
51. Caron G, Duluc D, Fremaux I, et al. Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R848 up-regulate proliferation and IFNy production by memory CD4+ T cells. J Immunol 2005;175:1551-7
52. Sallusto F, Lenig D, Fortser R, et al. Two subsets of T memory lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708-12
53. Brugnolo F, Sampognaro S, Liotta F, et al. The novel synthetic immune response modifier R-848 (resiquimod) shifts human allergen-specific CD4+ Th2 lymphocytes into IFNγ-producing cells. J Allergy Clin Immunol 2003;111:380-8
54. Meyer T, Nindl I, Schmook T, et al. Induction of apoptosis by toll-like receptor-7 agonist in tissue cultures. Br J Dermatol 2003;149(Suppl 66): 9-13
55. Vidal D, Matas-Guiu X, Alomar A. Efficacy of imiquimod for the expression ofBcl-2, Ki67, p53 and basal cell carcinoma apoptosis. Br J Dermatol 2004;151:656-62
56. Berman B, Sullivan TP, Araujo T, Nadji T. Expression of Fas-receptor on basal cell carcinomas after treatment with imiquimod 5% cream or vehicle. Br J Dermatol 2003;149(Suppl 66):59-61
57. Schon M, Bong AB, Drewniok C, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst 2003;95:1138-49
58. Lehner M, Kellert B, Proff J, et al. Autocrine TNF is critical for the survival of human dendritic cells by regulating BAK, BCL-2, and FLIPL. J Immunol 2012;188:4810-18
59. Stary G, Bangert C, Tauber M, et al. Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. J Exp Med 2007;204:1441-51
60. Kalb ML, Glaser A, Stary G, et al. TRAIL(+) human plasmacytoid dendritic cells kill tumor cells in vitro: mechanisms of imiquimod-and IFN-OŁ-mediated antitumor reactivity. J Immunol 2012;188:1583-91
61. Sauder DN, Smith MH, Senta-McMillan T, et al. Randomized, single-blind, placebo-controlled study of topical application of the immune response modulator resiquimod in healthy adults. Antimicrob Agents Chemother 2003;47:3846-52
62. Perkins H, Khodai T, Mechiche H, et al. Therapy with TLR7 agonists induces lymphopenia: correlating pharmacology to mechanism in a mouse model. J Clin Immunol 2012;32(5):1082-92
63. Szeimies RM, Bichel J, Ortonne JP, et al. A phase II dose-ranging study of topical resiquimod to treat actinic keratosis. Br J Dermatol 2008;159:205-10
64. Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004;50:714-21
65. Alomar A, Bichel J, McRae S. Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. Br J Dermatol 2007;157:133-41
66. Jorizzo J, Dinehart S, Matheson R, et al. Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head. J Am Acad Dermatol 2007;57:265-8
67. Gollnick H, Barona CG, Frank RG, et al. Recurrence rate of superficial basal cell carcinoma following successful treatment with imiquimod 5% cream: interim 2-year results from an ongoing 5-year follow-up study in Europe. Eur J Dermatol 2005;15:374-81
68. Quirk C, Gebauer K, Owens M, et al. Two-year interim results from a 5-year study evaluating clinical recurrence of superficial basal cell carcinoma after treatment with imiquimod 5% cream daily for 6 weeks. Australas J Dermatol 2006;47:258-65
69. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines of the use of photodynamic therapy for nonmelanoma skin cancer. An international consensus. J Am Acad Dermatol 2007;56:125-43
70. Stockfleth E, Christophers E, Benninghoff B, et al. Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol 2004;140:1542
71. Falagas ME, Angelousi AG, Peppas G. Imiquimod for the treatment of actinic keratosis: a meta-analysis of randomized controlled trials. J Am Acad Dermatol 2006;55:537-8
72. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007;157(Suppl 2):34-40
73. Gupta AK. The management ofactinic keratoses in the United States with topical fluorouracil: a pharmacoeconomic evaluation. Cutis 2002;70:30-6
74. Levy S, Furst K, Chern W. A pharmacokinetic evaluation of 0.5% and 5% fluorouracil topical cream in patients with actinic keratosis. Clin Ther 2001;23:901-7
75. Hanke CW, Beer KR, Stockfleth E, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol 2010;62:573-81
76. Swanson N, Abramovits W, Berman B, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 2010;62:582-90
77. Stockfleth E, Ulrich C, Meyer T, Christophers E. Epithelial malignancies in organ transplant patients: clinical presentation and new methods of treatment. Recent Results Cancer Res 2002;160:251-8
78. Brown VL, Atkins CL, Ghali L, et al. Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial. Arch Dermatol 2005;141:985-93
79. Papadavid E, Stratigos AJ, Falagas ME. Imiquimod: an immune response modifier in the treatment of precancerous skin lesions and skin cancer. Expert Opin Pharmacother 2007;8:1743-55
80. Mark KE, Corey L, Meng TC, et al. Topical resiquimod 0.01% gel decreases herpes simplex virus type 2 genital shedding: a randomized, controlled trial. J Infect Dis 2007;195:1324-31
81. Fidock MD, Souberbielle BE, Laxton C, et al. The innate immune response, clinical outcomes, and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF4878691). Clin Pharmacol Ther 2011;89:821-9
82. Hammerbeck DM, Burleson GR Schuler CJ, et al. Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats. Antiviral Res 2007;73:1-11
83. Lackenby A, Moran Gilad J, Pebody R et al. Continued emergence and changing epidemiology of oseltamivir-resistant influenza A(H1N1)2009 virus, United Kingdom, winter 2010/11. Euro Surveill 2011;16:pii 19784
84. Lee AJ, Ashkar AA. Herpes simplex virus-2 in the genital mucosa: insights into the mucosal host response and vaccine development. Curr Opin Infect Dis 2012;25:92-9
85. Tomai MA, Vasilakos JP. TLR-7 and-8 agonists as vaccine adjuvants. Expert Rev Vaccines 2011;10:405-7
86. McCluskie MJ, Cartier JL, Patrick AJ, et al. Treatment of intravaginal HSV-2 infection in mice: a comparison of CpG oligodeoxynecleotides and resiquimod (R-848). Antiviral Res 2006;69:77-85
87. Weeratna RD, Makinen SR McCluskie MJ, et al. TLR agonists as vaccine adjuvants: comparison of CpG ODN and Resiquimod (R-848). Vaccine 2005;23:5263-70
88. Gill N, Davies EJ, Ashkar AA. The role of Toll-like receptor ligands/agonists in protection against genital HSV-2 infection. Am J Reprod Immunol 2008;59:35-43
89. Gorden KK, Qiu XX, Binsfeld CC, et al. Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J Immunol 2006;177:6584-7
90. Azuley-Debby H, Edry E, Melamed D. CpG DNA stimulates autoreactive immature B cells in the bone marrow. Eur J Immunol 2007;37:1463-75
91. Kastenmüller K, Wile-Reece U, Lindsay RW, et al. Protective T cell immunity in mice following protein TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN and multiple DC subsets. J Clin Invest 2011;121:1782-96
92. Warger T, Osterloh P, Rechtsteiner G, et al. Synergistic activation of dendritic cells by combined toll-like receptor ligation induces superior CTL responses in vivo. Blood 2006;108:544-50
93. Stockfleth E, Ferrandiz C, Grob JJ, et al. Development of a treatment algorithm for actinic keratoses: a European Consensus. Eur J Dermatol 2008;18:651-9
94. Szeimies RM, Stockfleth E, Popp G, et al. Long-term follow-up of photodynamic therapy with a self-adhesive 5-aminolevulinic acid patch: 12 months data. Br J Dermatol 2010;162:410-14
95. Stockfleth E, Zwingers T, Willers C. Recurrence rates and patients assessed outcomes of0.5% 5-fluorouracil in combination with salicylic acid treating actinic keratosis. Eur J Dermatol 2012; Epub ahead of print
96. Lebwohl M, Swanson N, Lawrence MD, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012;366:1010-19