Despite impressive progress in prevention and therapy of premalignant and malignant dysplasia the worldwide burden of cancer is relatively unchanged. Supplementation of the therapeutic arsenal by immunotherapeutic methods would have the potential to make a significant impact. Dysplastic lesions and cancer of the cervix show strong association with human papillomaviruses (HPV), as do tumours of other mucosal epithelia like squamous cell carcinoma of the head and neck. Such tumours are distinct from most other malignancies in that they harbour foreign antigens derived from the virus. The expression of viral oncogenes is necessary to maintain the cancerous phenotype. Therefore, these antigens are unique to the tumour and very attractive targets for ‘proof of concept’ studies in the development of therapeutic vaccinesshowing the general applicability of tumour vaccination and prove the correlation of immune response and clinical response. To date numerous clinical trials have been performed with candidate vaccines predominantly for cervical cancer and its precursors. Although a naturally induced anti-HPV T cell response in patients can be shown, the success of therapeutic vaccines has so far been limited. This can probably be attributed to immunosuppression, immunoselection and immunoediting of the tumour cells and other, mostly unknown, factors of the individual contributing to the failure of autonomous clearance of the infection. Overriding this failure, reversing immunosuppression and application in early stages of the disease are the key tasks for future development of therapeutic vaccines. This review will summarize the basis and recent developments of therapeutic vaccines and discuss obstacles that hinder their success.

Keywords:
Human papillomavirus, Immunotherapy, Therapeutic vaccine, Immunomodulation, Clinical trials, immunoevasion, Cervical cancer, Squamous cell carcinoma, head and neck
1.
Munoz N, Bosch FX, de Sanjose S, et al: Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518–527.
2.
Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–19.
3.
Bosch FX, Manos MM, Munoz N, et al: Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995;87:796–802.
4.
Herrero R, Castellsague X, Pawlita M, et al: Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003;95:1772–1783.
5.
Koutsky L: Epidemiology of genital human papillomavirus infection. Am J Med 1997;102:3–8.
6.
Giuliano AR, Harris R, Sedjo RL, Baldwin S, Roe D, Papenfuss MR, Abrahamsen M, Inserra P, Olvera S, Hatch K: Incidence, prevalence, and clearance of type-specific human papillomavirus infections: the Young Women’s Health Study. J Infect Dis 2002;15:462–469.
7.
Moscicki AB: Conservative management of adolescents with abnormal cytology and histology. J Natl Compr Canc Netw 2008;6: 101–106.
8.
Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, Rush BB, Glass AG, Schiffman M: The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005;97:1072–1079.
9.
Ritz U, Momburg F, Pilch H, Huber C, Maeurer MJ, Seliger B: Deficient expression of components of the MHC class I antigen processing machinery in human cervical carcinoma. Int J Oncol 2001;19:1211–1220.
10.
Zehbe I, Voglino G, Delius H, Wilander E, Tommasino M: Risk of cervical cancer and geographical variations of human papillomavirus 16 E6 polymorphisms. Lancet 1998;352:1441–1442.
11.
Zehbe I, Wilander E, Delius H, Tommasino M: Human papillomavirus 16 E6 variants are more prevalent in invasive cervical carcinoma than the prototype. Cancer Res 1998;58:829–833.
12.
Berumen J, Ordoñez RM, Lazcano E, Salmeron J, Galvan SC, Estrada RA, Yunes E, Garcia-Carranca A, Gonzalez-Lira G, Madrigal-de la Campa A: Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study. J Natl Cancer Inst 2001;93:1325–1330.
13.
Lee K, Magalhaes I, Clavel C, Briolat J, Birembaut P, Tommasino M, Zehbe I: Human papillomavirus 16 E6, L1, L2 and E2 gene variants in cervical lesion progression. Virus Res 2008;131:106–110.
14.
Seedorf K, Krämmer G, Dürst M, Suhai S, Röwekamp WG: Human papillomavirus type 16 DNA sequence. Virology 1985;145:181–185.
15.
Yamada T, Manos MM, Peto J, Greer CE, Munoz N, Bosch FX, Wheeler CM: Human papillomavirus type 16 sequence variation in cervical cancers: a worldwide perspective. J Virol 1997;71:2463–2472.
16.
Lambropoulos AF, Agorastos T, Foka ZJ, Chrisafi S, Constantinidis TC, Bontis J, Kotsis A: Methylenetetrahydrofolate reductase polymorphism C677T is not associated to the risk of cervical dysplasia. Cancer Lett 2003;191:187–191.
17.
Zoodsma M, Nolte IM, Te Meerman GJ, De Vries EG, Van der Zee AG: HLA genes and other candidate genes involved in susceptibility for (pre)neoplastic cervical disease. Int J Oncol 2005;26:769–784.
18.
Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E: Obsetric outcomes after conservative treatments for intraepithelial or early invasive cervical lesions. Lancet 2006;367:489–498.
19.
Parkin DM: The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030–3044.
20.
Future II Study Group: Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–1927.
21.
Harper DM, Franco EL, Wheeler CM, et al: Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247–1255.
22.
Paavonen J, Jenkins D, Bosch FX, et al: Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007;369:2161–2170.
23.
Hildesheim A, Herrero R, Wacholder S, et al: Effect of human papillomavirus 16/18 L1 virus-like particle vaccine among young women with preexisting infection: a randomized trial. JAMA 2007;298:743–753.
24.
Fakhry C, D’Souza G, Sugar E, et al: Relationship between prevalent oral and cervical human papillomavirus infections in human immunodeficiency virus-positive and -negative women. J Clin Microbiol 2006;44:4479–4485.
25.
Mashberg A: Head and neck cancer. N Engl J Med 1993;328:1783; author reply 1784.
26.
Vokes EE, Weichselbaum RR, Lippman SM, et al: Head and neck cancer. N Engl J Med 1993;328:184–194.
27.
Parkin DM, Bray F, Ferlay J, et al: Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.
28.
Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 2001;51:15–36.
29.
Jones AS, Morar P, Phillips DE, et al: Second primary tumors in patients with head and neck squamous cell carcinoma. Cancer 1995;75:1343–1353.
30.
Leemans CR, Tiwari R, Nauta JJ, et al: Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor. Cancer 1994;73:187–190.
31.
Argiris A, Eng C: Epidemiology, staging, and screening of head and neck cancer. Cancer Treat Res 2003;114:15–60.
32.
Kreimer AR, Clifford GM, Boyle P, et al: Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467–475.
33.
Syrjanen S: Human papillomavirus (HPV) in head and neck cancer. J Clin Virol 2005;32(suppl 1):S59–S66.
34.
Gillison ML, Shah KV: Human papillomavirus-associated head and neck squamous cell carcinoma: mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers. Curr Opin Oncol 2001;13:183–188.
35.
Gillison ML, Lowy DR: A causal role for human papillomavirus in head and neck cancer. Lancet 2004;363:1488–1489.
36.
Gillison ML, Koch WM, Capone RB, et al: Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709–720.
37.
Smith EM, Summersgill KF, Allen J, et al: Human papillomavirus and risk of laryngeal cancer. Ann Otol Rhinol Laryngol 2000;109:1069–1076.
38.
Hobbs CG, Sterne JA, Bailey M, et al: Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol 2006;31:259–266.
39.
Mork J, Lie AK, Glattre E, et al: Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001;344:1125–1131.
40.
Schwartz SM, Daling JR, Doody DR, et al: Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 1998;90:1626–1636.
41.
Zumbach K, Kisseljov F, Sacharova O, et al: Antibodies against oncoproteins E6 and E7 of human papillomavirus types 16 and 18 in cervical-carcinoma patients from Russia. Int J Cancer 2000;85:313–318.
42.
Smith EM, Ritchie JM, Summersgill KF, et al: Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004;108:766–772.
43.
Kreimer AR, Alberg AJ, Daniel R, et al: Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 2004;189:686–698.
44.
Gillison ML, Koch WM, Shah KV: Human papillomavirus in head and neck squamous cell carcinoma: are some head and neck cancers a sexually transmitted disease? Curr Opin Oncol 1999;11:191–199.
45.
Fakhry C, Gillison ML: Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006;24:2606–2611.
46.
Cruz IB, Snijders PJ, Steenbergen RD, et al: Age-dependence of human papillomavirus DNA presence in oral squamous cell carcinomas. Eur J Cancer B Oral Oncol 1996;32B:55–62.
47.
Smith EM, Ritchie JM, Summersgill KF, et al: Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst 2004;96:449–455.
48.
Licitra L, Perrone F, Bossi P, et al: High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006;24:5630–5636.
49.
zur Hausen H: Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2:342–350.
50.
Fakhry C, Westra WH, Li S, et al: Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100:261–269.
51.
Ritchie JM, Smith EM, Summersgill KF, et al: Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer 2003;104:336–344.
52.
Hafkamp HC, Manni JJ, Speel EJ: Role of human papillomavirus in the development of head and neck squamous cell carcinomas. Acta Otolaryngol 2004;124:520–526.
53.
Pintos J, Franco EL, Black MJ, et al: Human papillomavirus and prognoses of patients with cancers of the upper aerodigestive tract. Cancer 1999;85:1903–1909.
54.
Albers A, Abe K, Hunt J, et al: Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 2005;65:11146–11155.
55.
Hoffmann TK, Arsov C, Schirlau K, et al: T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. Int J Cancer 2006;118:1984–1991.
56.
Brinkman JA, Hughes SH, Stone P, et al: Therapeutic vaccination for HPV induced cervical cancers. Dis Markers 2007;23:337–352.
57.
de Jong A, van der Burg SH, Kwappenberg KM, et al: Frequent detection of human papillomavirus 16 E2-specific T-helper immunity in healthy subjects. Cancer Res 2002;62:472–479.
58.
Welters MJ, de Jong A, van den Eeden SJ, et al: Frequent display of human papillomavirus type 16 E6-specific memory T-helper cells in the healthy population as witness of previous viral encounter. Cancer Res 2003;63:636–641.
59.
Garcia-Hernandez E, Gonzalez-Sanchez JL, Andrade-Manzano A, et al: Regression of papilloma high-grade lesions (CIN 2 and CIN 3) is stimulated by therapeutic vaccination with MVA E2 recombinant vaccine. Cancer Gene Ther 2006;13:592–597.
60.
Molling JW, de Gruijl TD, Glim J, et al: CD4(+)CD25(hi) regulatory T-cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia. Int J Cancer 2007;121:1749–1755.
61.
Stanley MA: Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp Dermatol 2002;27:571–577.
62.
Schreckenberger C, Kaufmann AM: Vaccination strategies for the treatment and prevention of cervical cancer. Curr Opin Oncol 2004;16:485–491.
63.
Muderspach L, Wilczynski S, Roman L, et al: A phase I trial of a human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive. Clin Cancer Res 2000;6:3406–3416.
64.
Roman LD, Wilczynski S, Muderspach LI, et al: A phase II study of Hsp-E7 (SGN-00101) in women with high grade cervical dysplasia. Gynecol Oncol 2007;106:558–566.
65.
Einstein MH, Kadish AS, Burk RD, et al: Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III. Gynecol Oncol 2007;106:453–460.
66.
Palefsky JM, Berry JM, Jay N, et al: A trial of SGN-00101 (HspE7) to treat high-grade anal intraepithelial neoplasia in HIV-positive individuals. AIDS 2006;20:1151–1155.
67.
Derkay CS, Smith RJ, McClay J, et al: HspE7 treatment of pediatric recurrent respiratory papillomatosis: final results of an open-label trial. Ann Otol Rhinol Laryngol 2005;114:730–737.
68.
Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, Offringa R, van der Burg SH, Melief CJ: Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients shows low toxicity and robust immunogenicity. Clin Cancer Res 2008;14:169–177.
69.
Welters MJ, Kenter GG, Piersma SJ, Vloon AP, Löwik MJ, Berends-van der Meer DM, Drijfhout JW, Valentijn AR, Wafelman AR, Oostendorp J, Fleuren GJ, Offringa R, Melief CJ, van der Burg SH: Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res 2008;14:178–187.
70.
Müller M, Zhou J, Reed TD, et al: Chimeric papillomavirus-like particles. Virology 1997;234:93–111.
71.
Schäfer K, Müller M, Faath S, et al: Immune response to human papillomavirus 16 L1E7 chimeric virus-like particles: induction of cytotoxic T cells and specific tumor protection. Int J Cancer 1999;81:881–888.
72.
Kaufmann AM, Nieland J, Schinz M, et al: HPV16 L1E7 chimeric virus-like particles induce specific HLA-restricted T cells in humans after in vitro vaccination. Int J Cancer 2001;92:285–293.
73.
Kaufmann AM, Nieland JD, Jochmus I, et al: Vaccination trial with HPV16 L1E7 chimeric virus-like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3). Int J Cancer 2007;121:2794–2800.
74.
Kaufmann AM, Stern PL, Rankin EM, et al: Safety and immunogenicity of TA-HPV, a recombinant vaccinia virus expressing modified human papillomavirus (HPV)-16 and HPV-18 E6 and E7 genes, in women with progressive cervical cancer. Clin Cancer Res 2002;8:3676–3685.
75.
Fiander AN, Tristram AJ, Davidson EJ, et al: Prime-boost vaccination strategy in women with high-grade, noncervical anogenital intraepithelial neoplasia: clinical results from a multicenter phase II trial. Int J Gynecol Cancer 2006;16:1075–1081.
76.
Nonn M, Schinz M, Zumbach K, et al: Dendritic cell-based tumor vaccine for cervical cancer I: in vitro stimulation with recombinant protein-pulsed dendritic cells induces specific T cells to HPV16 E7 or HPV18 E7. J Cancer Res Clin Oncol 2003;129:511–520.
77.
Ferrara A, Nonn M, Sehr P, et al: Dendritic cell-based tumor vaccine for cervical cancer II: results of a clinical pilot study in 15 individual patients. J Cancer Res Clin Oncol 2003;129:521–530.
78.
Santin AD, Bellone S, Palmieri M, et al: Human papillomavirus type 16 and 18 E7-pulsed dendritic cell vaccination of stage IB or IIA cervical cancer patients: a phase I escalating-dose trial. J Virol 2008;82:1968–1979.
79.
Bergmann C, Strauss L, Wieckowski E, Czystowska M, Albers A, Wang Y, Zeidler R, Lang S, Whiteside TL: Tumor-derived microvesicles in sera of patients with head and neck cancer and their role in tumor progression. Head Neck 2008;31:371–380.
80.
Albers AE, Ferris RL, Kim GG, Chikamatsu K, DeLeo AB, Whiteside TL: Immune responses to p53 in patients with cancer: enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites. Cancer Immunol Immunother 2005;54:1072–1081.
81.
Schaefer C, Kim GG, Albers A, Hoermann K, Myers EN, Whiteside TL: Characteristics of CD4+ CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer 2005;92:913–920.
82.
Rosenberg SA, Yang JC, Sherry RM, et al: Inability to immunize patients with metastatic melanoma using plasmid DNA encoding the gp100 melanomamelanocyte antigen. Hum Gene Ther 2003;14:709–714.
83.
Miller AM, Ozenci V, Kiessling R, Pisa P: Immune monitoring in a phase 1 trial of a PSA DNA vaccine in patients with hormone-refractory prostate cancer. J Immunother 2005;28:389–395.
84.
Ohlschlager P, Pes M, Osen W, et al: An improved rearranged Human Papillomavirus Type 16 E7 DNA vaccine candidate (HPV-16 E7SH) induces an E7 wildtype-specific T cell response. Vaccine 2006;24:2880–2893.
85.
Lu Y, Zhang Z, Liu Q, et al: Immunological protection against HPV16 E7-expressing human esophageal cancer cell challenge by a novel HPV16-E6/E7 fusion protein based-vaccine in a Hu-PBL-SCID mouse model. Biol Pharm Bull 2007;30:150–156.
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