Download PDF
Zentralbl Gynakol 2002; 124(11): 511-524
DOI: 10.1055/s-2002-39579
Review

© Georg Thieme Verlag Stuttgart · New York

HPV induced cervical carcinogenesis: molecular basis and vaccine development

HPV induzierte Karzinogenese der cervix uteri: molekulare Mechanismen und ImpfstoffentwicklungA. M. Kaufmann1 , C. Backsch1 , A. Schneider1 , M. Dürst1
  • 1Gynäkologische Molekularbiologie, Frauenklinik, Friedrich-Schiller-Universität Jena
Further Information

Publication History

Publication Date:
10 June 2003 (online)

    Permissions and Reprints

Zusammenfassung

Prädisponierend für die Entstehung eines Zervixkarzinoms ist die Infektion mit humanen „high-risk” Papillomviren (HPV). Es gibt nur wenige Zervixkarzinome, bei denen keine HPV DNA nachweisbar ist. Mechanismen der Immortalisierung von Epithelzellen durch Interaktion mit Tumorsuppressorgenen p53 und pRB durch virale Onkogene E6 und E7 wurden definiert. Die Progression einer HPV-infizierten Zelle zu einem malignen Phänotyp erfordert weitere genetische Veränderungen des Wirtszellgenoms. Mit dem Auftreten von chromosomalen Aberrationen kann es zur Mutation oder dem Verlust von Tumorsuppressorgenen (TSG) und zur Aktivierung und Amplifikation von Onkogenen kommen, die im Prozess der Tumorgenese involviert sind. Die Onkogenamplifikation scheint mit Ausnahme weniger Berichte allerdings in der Zervixkarzinogenese nicht bedeutsam zu sein. Demgegenüber zeigen zytogenetische und „loss of heterozygosity” LOH-Untersuchungen an CIN-Läsionen und an invasiven Zervixkarzinomen den häufigen Verlust von spezifischen chromosomalen Regionen, die auf die Lokalisation von TSG hinweisen. Genetische Veränderungen der Chromosomen 3p, 6p und 11q wurden häufig in der frühen Tumorentwicklung gefunden. Primäre invasive Karzinome zeigten zusätzliche Allelverluste an Chromosomenbereichen 6q, 17p und 18q. Als biologische Marker für die diagnostische und prognostische Einschätzung von „high-risk” HPV Infektionen und maligne Progression sind für bestimmte Fragestellungen p16INK4, p27Kip1, und NET-I/C4.8 zu nennen. Putative Seneszenzgenloci mit Relevanz für HPV-induzierte Karzinogenese sind auf Chromosomen 2, 4 und 10 lokalisiert. Gene für Telomerasesuppression werden auf den Chromosomen 3, 4, und 6 vermutet. Natürliche Immunität gegen HPV Infektionen existieren. Daher sind Immuntherapien eine attraktive Möglichkeit für die Prävention und Therapie von HPV Infektionen. Derzeit hat die Vakzinentwicklung das Stadium der klinischen Prüfung erreicht. Prophylaxe zielt auf die Induktion virus-neutralisierender Antikörper gegen Kapsidproteine. Auf Virus-ähnliche Partikel basierende Impfstoffe werden in klinischen Versuchen geprüft. Wegen der langen Verzögerungsperiode zwischen Infektion und klinischer Manifestation werden klinische Untersuchungen einer langen Zeit bedürfen, bis schlüssige Ergebnisse vorliegen. Die grundsätzliche Expression viraler und vielleicht zellulärer Gene in infizierten Epithelien und Tumorzellen bietet Zielstrukturen für therapeutische Vorgehensweisen. Dass die meisten Dysplasien spontan regredieren zeigt, dass die Virusinfektion immunogen ist. In einigen Patientinnen muss die Immunantwort durch Impfungen verstärkt werden, um effektiv zu sein. Verschiedene Strategien werden in klinischen Versuchen getestet und andere sind in präklinischer Entwicklung. Die Aufgabe wird sein, die Immunsuppression von HPV-Infizierten zu umgehen.

Schlüsselwörter

Humane Papillomaviren (HPV) - Progression - Genomveränderungen - Prophylaxe - Immuntherapie - Klinische Studien

References

  • 1 Walboomers J M, Jacobs M V, Manos M M, Bosch F X, Kummer J A, Shah K V, Snijders P J, Peto J, Meijer C J, Munoz N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.  J Pathol. 1999;  189 12-19
    Search in Google Scholar
  • 2 Stoler M H. Human papillomaviruses and cervical neoplasia: A model for carcinogenesis.  Int J Gynecol Pathol. 2000;  19 16-28
    PubMedSearch in Google Scholar
  • 3 Lorincz A T, Reid R, Jenson A B, Greenberg M D, Lancaster W, Kurman R J. Human papillomavirus infection of the cervix: Relative risk associations of 15 common anogenital types.  Obstet Gynecol. 1992;  79 328-337
    PubMedSearch in Google Scholar
  • 4 Wright W E, Shay J W. The two-stage mechanism controlling cellular senescence and immortalization.  Exp Gerontol. 1992;  27 383-389
    CrossrefPubMedSearch in Google Scholar
  • 5 Shay J W, Wright W E, Brasiskyte D, Van-der-Haegen B A. E6 of human papillomavirus type 16 can overcome the M1 stage of immortalization in human mammary epithelial cells but not in human fibroblasts.  Oncogene. 1993;  8 1407-1413
    PubMedSearch in Google Scholar
  • 6 Wu T C. Immunology of the human papillomavirus in relation to cancer.  Curr Opin Immunol. 1994;  6 746-754
    CrossrefPubMedSearch in Google Scholar
  • 7 Munger K, Phleps W C, Bubb V, Howley P M, Schlegel R. The E6 and E7 genes of human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes.  J Virol. 1989;  63 4417-4421
    PubMedSearch in Google Scholar
  • 8 Scheffner M, Werness B A, Huibregtse J M, Levine A J, Howley P M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53.  Cell. 1990;  63 1129-1136
    CrossrefPubMedSearch in Google Scholar
  • 9 Werness B A, Levine A J, Howley P M. Association of human papillomavirus types 16 and 18 E6 proteins with p53.  Science. 1990;  248 76-79
    PubMedSearch in Google Scholar
  • 10 Heilmann V, Kreienberg R. Molecular biology of cervical cancer and ist precursors.  Curr Womens Health Rep. 2002;  2 27-33
    PubMedSearch in Google Scholar
  • 11 Nevins J R. Transcriptional regulation: A closer look at E2F.  Nature. 1992;  358 375-376
    CrossrefPubMedSearch in Google Scholar
  • 12 Duensing S, Munger K. Human papillomaviruses and centrosome duplication errors: modeling the origins of genomic instability.  Oncogene. 2002;  21 6241-6248
    CrossrefPubMedSearch in Google Scholar
  • 13 Schlegel R, Wade Glass M, Rabson M S, Yang Y C. The E5 transforming gene of bovine papillomavirus encodes a small, hydrophobic polypeptide.  Science. 1986;  233 464-467
    PubMedSearch in Google Scholar
  • 14 Burkhardt A, DiMaio D, Schlegel R. Genetic and biochemical definition of the bovine papillomavirus E5 transforming protein.  EMBO J.. 1987;  6 2381-2385
    PubMedSearch in Google Scholar
  • 15 Schwarz E, Freese U K, Gissmann L, Mayer W, Roggenbruck B, Stremlau A, zur Hausen H. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells.  Nature. 1985;  314 111-114
    CrossrefPubMedSearch in Google Scholar
  • 16 Bauer-Hofmann R, Borghouts C, Auvinen E, Bourda E, Rösl F, Alonso A. Genomic cloning and characterization of the non occupied allele corresponding to the integration site of human papillomavirus type 16 DNA in the cervical cancer cell line SiHa.  Virology. 1996;  217 33-41
    CrossrefPubMedSearch in Google Scholar
  • 17 zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application.  Nature Reviews. 2002;  2 342-350
    Search in Google Scholar
  • 18 Rodriguez M I, Finbow M E, Alonso A. Binding of human papillomavirus 16 E5 to the 16 kDa subunit c (proteolipid) of the vacuolar H+-ATPase can be dissociated from the E5- mediated epidermal growth factor receptor overactivation.  Oncogene. 2000;  19 3727-3732
    CrossrefPubMedSearch in Google Scholar
  • 19 Finbow M E, Pitts J D, Goldstein D J, Schlegel R, Findlay J B. The E5 oncoprotein target: a 16-kDa channel-forming protein with diverse functions.  Mol. Carcinogen1991;  4 441-444
    PubMedSearch in Google Scholar
  • 20 Venuti A, Salani D, Poggiali F, Manni V, Bagnato A. The E5 oncoprotein of human papillomavirus type 16 enhances endothelin-1-induced keratinocyte growth.  Virol. 1998;  248 1-5
    PubMedSearch in Google Scholar
  • 21 Tsao Y P, Li L Y, Tsai T C, Chen S L. Human papillomavirus type 11 and 16 E5 repesses p21 (WafI/SdiI/CipI) gene expression in fibroblasts and keratinocytes.  J Virol. 1996;  70 7535-7539
    PubMedSearch in Google Scholar
  • 22 Seagon S, Dürst M. Genetic analysis of an in vitro model system for human papillomavirus type 16-associated tumourigenesis.  Cancer Res. 1994;  54 5593-5598
    PubMedSearch in Google Scholar
  • 23 Kim N W, Piatyszek M A, Prowse K R, Harley C B, West M D, Ho P LC, Coviello G M, Wright W E, Weinrich S L, Shay J W. Specific association of human telomerase activity with immortal cells and cancer.  Science. 1994;  266 2011-2015
    PubMedSearch in Google Scholar
  • 24 Reddel R R. The role of senescence and immortalization in carcinogenesis.  Carcinogenesis. 2000;  21 477-484
    CrossrefPubMedSearch in Google Scholar
  • 25 Backsch C, Wagenbach N, Nonn M, Leistritz S, Stanbridge E, Schneider A, Dürst M. Microcell-mediated transfer of chromosome 4 into HeLa cell suppresses telomerase activity.  Genes, Chromosomes & Cancer. 2001;  31 196-198
    PubMedSearch in Google Scholar
  • 26 Steenbergen R DM, Kramer D, Meijer C JLM, Walboomers J MM, Trott D A, Cuthert A P, Newbold R F, Overkamp W JI, Zdzienicka M Z, Snijders P JF. Telomerase suppression by chromosome 6 in a human papillomavirus type 16-immortalized keratinocyte cell line and in a cervical cancer cell line.  J Natl Cancer Inst. 2001;  93 865-872
    CrossrefPubMedSearch in Google Scholar
  • 27 Uejima H, Mitsuya K, Kugoh H, Horikawa I, Oshimura M. Normal human chromosome 2 induces cellular senescence in the human cervical carcinoma cell line SiHa.  Genes, Chromosomes & Cancer. 1995;  14 120-127
    PubMedSearch in Google Scholar
  • 28 Ning Y, Weber J L, Killary A M, Ledbetter D H, Smith J R, Pereira- Smith O M. Genetic analysis of indefinite division in human cells. evidence for a cell senescence- related gene(s) on human chromosome 4.  Proc Natl Acad Sci USA. 1991;  88 5635-5639
    PubMedSearch in Google Scholar
  • 29 Poignée M, Backsch C, Beer K, Jansen L, Wagenbach N, Stanbridge E J, Kirchmayr R, Schneider A, Dürst M. Evidence for a putative senescence gene locus within the chromosome region 10p14-p15.  Cancer Res. 2001;  61 7118-7121
    PubMedSearch in Google Scholar
  • 30 Bertram M J, Berube N G, Hang-Swanson X, Ran Q, Leung J K, Bryce S, Spurgers K, Bick R J, Baldini A, Ning Y, Clark L J, Parkinson E K, Barrett J C, Smith J R, Pereira-Smith O M. Identification of a gene that reverses the immortal phenotype of a subset of cells and is a member of a novel family of transcription factor-like genes.  Mol Cell Biol. 1999 a;  19 1479-1485
    PubMedSearch in Google Scholar
  • 31 Bertram M J, Berube N G, Swanson X H, Pereira-Smith O M. Assembly of a BAC contig of the complementation group B cell senescence gene candidate region at 4q33-q34.1 and identification of expressed sequences.  Genomics. 1999 b;  56 353-354
    CrossrefPubMedSearch in Google Scholar
  • 32 Howley P M. Papillomavirinae: The viruses and their replication.  Fields Virol. 1996;  1 2045-2076
    PubMedSearch in Google Scholar
  • 33 Shah K V, Howley P M. Papillomaviruses.  Fields Virol. 1996;  1 2077-2109
    PubMedSearch in Google Scholar
  • 34 Peitsaro P, Johansson B, Syrjänen S. Integrated human papillomavirus type 16 is frequently found in cervical cancer precursors as demonstrated by a novel quantitative real-time PCR technique.  J Clin Microbiol. 2002;  40 886-891
    CrossrefPubMedSearch in Google Scholar
  • 35 Nagao S, Yoshinouchi M, Miyagi Y, Hongo A, Kodama J, Itoh S, Kudo T. Rapid and sensitive detection of physical status of human paillomavirus type 16 DNA by quantitative real-time PCR.  J Clin Microbiol. 2002;  40 863-867
    CrossrefPubMedSearch in Google Scholar
  • 36 Luft F, Klaes R, Nees M, Dürst M, Heilmann V, Melsheimer P, von Knebel Doeberitz M. Detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR) and molecular characterization in cervical cancer cells.  Int J Cancer. 2001;  92 9-17
    CrossrefPubMedSearch in Google Scholar
  • 37 Klaes R, Woerner S M, Ridder R, Wentzensen N, Dürst M, Schneider A, Lotz B, Melsheimer P, von Knebel Doeberitz M. Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes.  Cancer Res. 1999;  59 6132-6136
    PubMedSearch in Google Scholar
  • 38 Ocadiz R, Sanceda R, Cruz M, Graef A M, Gariglio P. High correlation between molecular alterations of the c-myc oncogene and carcinoma of the uterine cervix.  Cancer Res. 1987;  47 4173-4177
    PubMedSearch in Google Scholar
  • 39 Riou G, Barrois M, Sheng Z M, Duvillard P, Lhomme C. Somatic deletions and mutations of c-Ha-ras gene in human cervical cancers.  Oncogene. 1988;  3 329-334
    PubMedSearch in Google Scholar
  • 40 Ried T, Heselmeyer-Haddad K, Blegen H ,. et al . Genomic changes defining the genesis, progression and malignancy potential in solid human tumours: a phenotype/genotype correlation.  Genes, Chromosomes & Cancer. 1999;  25 195-204
    PubMedSearch in Google Scholar
  • 41 Wistuba I I, Montellano F D, Milchgrub S, Virmani A K, Behrens C, Chen H, Ahmadian M, Nowak J A, Muller C, Minna J D, Gazdar A F. Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma.  Cancer Res. 1997;  57 3154-3158
    PubMedSearch in Google Scholar
  • 42 Kersemaekers A MF, van de Vijver M J, Kenter G G, Fleuren G J. Genetic alterations during the progression of squamous cell carcinoma of the uterine cervix.  Genes, Chromosomes & Cancer. 1999;  26 346-354
    PubMedSearch in Google Scholar
  • 43 Chung G T, Huang D P, Lo K W, Chan M K, Wong F W. Genetic lesion in the carcinogenesis of cervical cancer.  Anticancer Res. 1992;  12 1485-1490
    PubMedSearch in Google Scholar
  • 44 Rader J S, Gerhard D S, O'Sullivan M J, Li Y, Liapis H, Huettner P C. Cervical intraepithelial neoplasia III shows frequent allelic loss in 3p and 6p.  Genes, Chromosomes & Cancer. 1998;  22 57-65
    PubMedSearch in Google Scholar
  • 45 Mitra A B, Murty V V, Sigh V, Li R G, Pratap M, Sodhani P, Luthra U K, Chaganti R S. Genetic alterations for progression.  J Natl Cancer Inst. 1995;  87 742-745
    PubMedSearch in Google Scholar
  • 46 Chatterjee A, Pulido H A, Koul S, Beleno N, Perilla A, Posso H, Manusukhani M, Murty V V. Mapping of sites of putative tumour suppressor genes at 6p25 and 6p21.3 in cervical carcinoma: occurrence of allelic deletions in precancerous lesions.  Cancer Res. 2001;  61 2119-2123
    PubMedSearch in Google Scholar
  • 47 Larson A A, Liao S Y, Stanbridge E J, Cavenee W K, Hampton G M. Genetic alterations accumulate during cervical tumourigenesis and indicate a common origin for multifocal lesions.  Cancer Res. 1997;  57 4171-4176
    PubMedSearch in Google Scholar
  • 48 Evans M F, Koreth J, Bakkenist C J, Herrington C S, McGee J O'D. Allelic deletion at 11q23.3-q25 is an early event in cervical neoplasia.  Oncogene. 1998;  16 2557-2564
    CrossrefPubMedSearch in Google Scholar
  • 49 O'Sullivan M J, Rader J S, Gerhard D S, Li Y, Trinkaus K M, Gersell D J, Huettner P C. Loss of heterozygosity at 11q23.3 in vasculoinvasive and metastatic squamous cell carcinoma of the cervix.  Hum Pathol. 2001;  32 475-478
    CrossrefPubMedSearch in Google Scholar
  • 50 Heselmeyer K, Macville M, Schröck E, Blegen H, Hellström A -C, Shak K, Auer G, Ried T. Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q.  Genes, Chromosomes & Cancer. 1997;  19 233-240
    PubMedSearch in Google Scholar
  • 51 Dellas A, Torhorst J, Jiang F, Proffitt J, Schultheiss E, Holzgreve W, Sauter G, Mihatsch M J, Moch H. Prognostic value of genomic alterations in invasive cervical squamous cell carcinoma of clinical stage IB detected by comparative genomic hybridization.  Cancer Res. 1999;  59 3475-3479
    PubMedSearch in Google Scholar
  • 52 Dellas A, Torhorst J, Mihatsch M J, Moch H. Genomische Aberrationen beim invasiven Zervixkarzinom.  Geburtsh Frauenheilk. 2002;  62 458-464
    Thieme ConnectPubMedSearch in Google Scholar
  • 53 Cheung T H, Chung T K, Poon C S, Hampton G M, Wang V W, Wong Y F. Allelic loss on chromosome 1 is associated with tumour progression of cervical carcinoma.  Cancer. 1999;  86 1294-1298
    CrossrefPubMedSearch in Google Scholar
  • 54 Heselmeyer K, Schröck E, Du Manoir S, Blegen H, Shah K, Steinbeck R, Auer G, Ried T. Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix.  Proc Natl Acad Sci USA. 1996;  93 497-484
    CrossrefPubMedSearch in Google Scholar
  • 55 Krivak T C, McBroom J W, Seidman J, Venzon D, Crothers B, MacKoul P J, Rose G S, Carlson J W, Birrer M J. Abnormal fragile histidine triad (FHIT) expression in advanced cervical carcinoma: a poor prognostic factor.  Cancer Res. 2001;  61 4382-4385
    PubMedSearch in Google Scholar
  • 56 Vecchione A, Zanesi N, Trombetta G, French D, Visca P, Pisani T, Botti C, Vecchione A, Croce C M, Mancini R. Cervical dysplasia, ploidy, and human papillomavirus status correlate with loss of Fhit expression.  Clin Cancer Res. 2001;  7 1306-1312
    PubMedSearch in Google Scholar
  • 57 Su T H, Chang J G, Perng L I, Chang C P, Wie H J, Wang N M, Tsai C H. Mutation analysis of the putative tumour suppressor gene PTEN/MMAC1 in cervical cancer.  Gynecol Oncol. 2000;  76 193-199
    CrossrefPubMedSearch in Google Scholar
  • 58 Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, Breuer J, Leigh I M, Matlashewski G, Banks L. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer.  Nature. 1998;  393 229-234
    CrossrefPubMedSearch in Google Scholar
  • 59 Klaes R, Ridder R, Schaefer U, Benner A, Doeberitz M V. No evidence of p53 allele-specific predisposition in human papillomavirus-associated cervical cancer.  J Med Medicine. 1999;  77 299-302
    PubMedSearch in Google Scholar
  • 60 Lanham S, Campbell I, Watt P, Gornall R. p53 polymorphism and risk of cervical cancer.  Lancet. 1998;  352 1631
    PubMedSearch in Google Scholar
  • 61 Hildesheim A, Schiffmann M, Brinton L A, Fraumeni J F, Herrero R, Bratti M C, Schwartz P, Mortel R, Barnes W, Greenberg M, McGowan L, Scott D R, Martin M, Herrera J E, Carrington M. p53 polymorphism and risk of cervical cancer.  Nature. 1998;  396 531-532
    PubMedSearch in Google Scholar
  • 62 Van Duin M, Snijders P J, Vossen M T, Klaassen E, Voorhorst F, Verheijen R H, Helmerhorst T J, Meijer C J, Walboomers J M. Analysis of human papillomavirus type 16 E6 variants in relation to p53 codon 72 polymorphism genotypes in cervical carcinogenesis.  J Gen Virol. 2000;  81 317-325
    PubMedSearch in Google Scholar
  • 63 Cuzick J, Terry G, Ho L, Monaghan J, Lopes A, Clarkson P, Duncan I. Association between high-risk HPV types, HLA DRB1* and DQB1* alleles and cervical cancer in British women.  Brit J of Cancer. 2000;  82 1348-1352
    PubMedSearch in Google Scholar
  • 64 Serano M. The tumour suppressor protein p16INK4a. .  Exp Cell Res. 1997;  237 7-13
    CrossrefPubMedSearch in Google Scholar
  • 65 Klaes R, Friedrich T, Spitkovsky D, Ridder R, Rudy W, Petry U, Dallenbach-Hellweg G, Schmidt D, von Knebel Doeberitz M. Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri.  Int J Cancer. 2001;  92 276-284
    CrossrefPubMedSearch in Google Scholar
  • 66 Wollscheid V, Kühne-Heid R, Stein I, Jansen L, Köllner S, Schneider A, Dürst M. Identification of a new proliferation-associated protein NET-1/C4.8 characteristic for a subset of high-grade cervical intraepithelial neoplasia and cervical carcinomas.  Int J Cancer. 2002;  99 771-775
    CrossrefPubMedSearch in Google Scholar
  • 67 Huang L W, Chao S L, Hwang J L, Chou Y Y. Down-regulation of p27 is associated with malignant transformation and aggressive phenotype of cervical neoplasms.  Gynecol Oncol. 2002;  85 524-528
    CrossrefPubMedSearch in Google Scholar
  • 68 Troncone G, Vetrani A, Rosa G D, Gerbasio D, Palombini L. Cyclin dependent kinase inhibitor p27Kip1 expression in normal and neoplastic cervical epithelium.  J Clin Pathol. 1999;  52 880-887
    PubMedSearch in Google Scholar
  • 69 Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz J W, Jansen-Durr. Inactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein.  Oncogene. 1996;  13 2323-2330
    PubMedSearch in Google Scholar
  • 70 Dillner J. The serological response to papillomaviruses.  Semin Cancer Biol. 1999;  9 423-430
    CrossrefPubMedSearch in Google Scholar
  • 71 Coleman N, Birley H D, Renton A M, Hanna N F, Ryait B K, Byrne M, Taylor-Robinson D, Stanley M A. Immunological events in regressing genital warts.  Am J Clin Pathol. 1994;  102 768-774
    PubMedSearch in Google Scholar
  • 72 Bal V, McIndoe A, Denton G, Hudson D, Lombardi G, Lamb J, Lechler R. Antigen presentation by keratinocytes induces tolerance in human T cells.  Eur J Immunol. 1990;  20 1893-1897
    PubMedSearch in Google Scholar
  • 73 Jochmus-Kudielka I, Schneider A, Braun R, Kimmig R, Koldovsky U, Schneweis K E, Seedorf K, Gissmann L. Antibodies against the human papillomavirus type 16 early proteins in human sera: Correlation of anti-E7 reactivity with cervical cancer.  J Natl Cancer Inst. 1989;  81 1698-1704
    PubMedSearch in Google Scholar
  • 74 Meschede W, Zumbach K, Braspenning J, Scheffner M, Benitez-Bribiesca L, Luande J, Gissmann L, Pawlita M. Antibodies against early proteins of human papillomaviruses as diagnostic markers for invasive cervical cancer.  J Clin Microbiol. 1998;  36 475-480
    PubMedSearch in Google Scholar
  • 75 Melbye M, Palefsky J, Gonzales J, Ryder L P, Nielsen H, Bergmann O, Pindborg J, Biggar R J. Immune status as a determinant of human papillomavirus detection and its association with anal epithelial abnormalities.  Int J Cancer. 1990;  46 203-206
    PubMedSearch in Google Scholar
  • 76 Klein R S, Ho G Y, Vermund S H, Fleming I, Burk R D. Risk factors for squamous intraepithelial lesions on PAP smear in women at risk for human immunodeficiency virus infection.  J Infect Dis. 1994;  170 1404-1409
    PubMedSearch in Google Scholar
  • 77 Palefsky J M. Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus- positive men and women.  J Natl Cancer Inst Monogr. 1998;  23 15-20
    PubMedSearch in Google Scholar
  • 78 Santin A D, Hermonat P L, Ravaggi A, Chiriva- Internati M, Zhan D, Pecorelli S, Parham G P, Cannon M J. Induction of human papillomavirus-specific CD4(+) and CD8(+) lymphocytes by E7-pulsed autologous dendritic cells in patients with human papillomavirus type 16- and 18-positive cervical cancer.  J Virol. 1999;  73 5402-5410
    PubMedSearch in Google Scholar
  • 79 Hohn H, Pilch H, Gunzel S, Neukirch C, Freitag K, Necker A, Maeurer M J. Human papillomavirus type 33 E7 peptides presented by HLA-DR*0402 to tumour-infiltrating T cells in cervical cancer.  J Virol. 2000;  74 6632-6636
    CrossrefPubMedSearch in Google Scholar
  • 80 Höpfl R, Heim K, Christensen N, Zumbach K, Wieland U, Volgger B, Widschwendter A, Haimbuchner S, Müller-Holzner E, Pawlita M, Pfister H, Fritsch P. Spontaneous regression of CIN and delayed-type hypersensitivity to HPV-16 oncoprotein E7.  The Lancet. 2000;  356 1985-1986
    CrossrefPubMedSearch in Google Scholar
  • 81 Breitburd F, Kirnbauer R, Hubbert N L, Nonnenmacher B, Trin- Dinh-Desmarquet C, Orth G, Schiller J T, Lowy D R. Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection.  J Virol. 1995;  69 3959-3963
    PubMedSearch in Google Scholar
  • 82 Suzich J A, Ghim S J, Palmer-Hill F J, White W I, Tamura J K, Bell J A, Newsome J A, Jenson A B, Schlegel R. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas.  Proc Natl Acad Sci USA. 1995;  92 11553-11557
    PubMedSearch in Google Scholar
  • 83 Parr M B, Parr E L. Immunohistochemical localization of immunoglobulins A, G and M in the mouse female genital tract.  J Reprod Fertil. 1985;  74 361-370
    PubMedSearch in Google Scholar
  • 84 Thapar M A, Parr E L, Parr M B. Secretory immune responses in mouse vaginal fluid after pelvic, parenteral or vaginal immunization.  Immunology. 1990;  70 121-125
    PubMedSearch in Google Scholar
  • 85 Hagensee M E, Yaegashi N, Galloway D A. Self- assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins.  J Virol. 1993;  67 315-322
    PubMedSearch in Google Scholar
  • 86 Zhou J, Sun X Y, Davies H, Crawford L, Park D, Frazer I H. Definition of linear antigenic regions of the HPV16 L1 capsid protein using synthetic virion-like particles.  Virology. 1992;  189 592-599
    CrossrefPubMedSearch in Google Scholar
  • 87 Kirnbauer R, Booy F, Cheng N, Lowy D R, Schiller J T. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic.  Proc Natl Acad Sci USA. 1992;  89 12180-12184
    PubMedSearch in Google Scholar
  • 88 Sasagawa T, Pushko P, Steers G, Gschmeissner S E, Hajibagheri M A, Finch J, Crawford L, Tommasino M. Synthesis and assembly of virus-like particles of human papillomaviruses type 6 and type 16 in fission yeast Schizosaccharomyces pombe.  Virology. 1995;  206 126-135
    CrossrefPubMedSearch in Google Scholar
  • 89 Benyacoub J, Hopkins S, Potts A, Kelly S, Kraehenbuhl J P, Curtiss R 3  rd, De Grandi P, Nardelli-Haefliger D. The nature of the attenuation of Salmonella typhimurium strains expressing human papillomavirus type 16 virus-like particles determines the systemic and mucosal antibody responses in nasally immunized mice.  Infect Immun. 1999;  67 3674-3679
    PubMedSearch in Google Scholar
  • 90 Nardelli-Haefliger D, Roden R B, Benyacoub J, Sahli R, Kraehenbuhl J P, Schiller J T, Lachat P, Potts A, De Grandi P. Human papillomavirus type 16 virus-like particles expressed in attenuated Salmonella typhimurium elicit mucosal and systemic neutralizing antibodies in mice.  Infect Immun. 1997;  65 3328-3336
    PubMedSearch in Google Scholar
  • 91 Kirnbauer R, Chandrachud L M, O’Neil B W, Wagner E R, Grindlay G J, Armstrong A, McGarvie G M, Schiller J T, Lowy D R, Campo M S. Virus-like particles of bovine papillomavirus type 4 in prophylactic and therapeutic immunization.  Virology. 1996;  219 37-44
    CrossrefPubMedSearch in Google Scholar
  • 92 Suzich J A, Ghim S J, Palmer-Hill F J, White W I, Tamura J K, Bell J A, Newsome J A, Jenson A B, Schlegel R. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas.  Proc Natl Acad Sci USA. 1995;  92 11553-11557
    PubMedSearch in Google Scholar
  • 93 Rose R C, Lance C, Wilson S, Suzich J A, Rybicki E, Williamson A L. Oral vaccination of mice with human papillomavirus virus-like particles induces systemic virus-neutralizing antibodies.  Vaccine. 1999;  17 2129-2135
    CrossrefPubMedSearch in Google Scholar
  • 94 Harro C D, Pang Y Y, Roden R B, Hildesheim A, Wang Z, Reynolds M J, Mast T C, Robinson R, Murphy B R, Karron R A, Dillner J, Schiller J T, Lowy D R. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl.  Cancer Inst. 2001;  93 284-292
    CrossrefPubMedSearch in Google Scholar
  • 95 Plummer M HR. Potential impact of HPV vaccines: epidemiological perspectives. 18th International Papillomavirus Conference, 2000, Barcelona, Spain
  • 96 Koutsky L A, Ault K A, Wheeler C M, Brown D R, Barr E, Alvarez F B, Chiacchierini L M, Jansen K U. A controlled trial of a human papillomavirus type 16 vaccine.  N Engl J Med. 2002;  347 1645-1651
    CrossrefPubMedSearch in Google Scholar
  • 97 Evans T G, Bonnez W, Rose R C, Koenig S, Demeter L, Suzich J A, O’Brien D, Campbell M, White W I, Balsley J, Reichmann R C. A phase I study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers.  J Infect Dis. 2001;  183 1485-1493
    CrossrefPubMedSearch in Google Scholar
  • 98 Zhang L F, Zhou J, Chen S, Cai L L, Bao Q Y, Zheng F Y, Lu J Q, Padmanahba J, Hengst K, Malcom K, Frazer I H. HPV6b virus like particles are potent immunogens without adjuvant in man.  Vaccine. 2000;  18 1051-1058
    CrossrefPubMedSearch in Google Scholar
  • 99 Stoler M H, Rhodes C R, Whitbeck A, Wolinsky S M, Chow L T, Broker T R. Human papillomavirus type 16 and 18 gene expression in cervical neoplasias.  Hum Pathol. 1992;  23 117-128
    CrossrefPubMedSearch in Google Scholar
  • 100 Stoler M H, Wolinsky S M, Whitbeck A, Broker T R, Chow L T. Differentiation-linked human papillomavirus types 6 and 11 transcription in genital condylomata revealed by in situ hybridization with message-specific RNA probes.  Virology. 1989;  172 331-340
    CrossrefPubMedSearch in Google Scholar
  • 101 Crook T, Morgenstern J P, Crawford L, Banks L. Continued expression of HPV-16 E7 protein is required for maintenance of the transformed phenotype of cells cotransformed by HPV-16 plus EJ-ras.  EMBO J. 1989;  8 513-519
    PubMedSearch in Google Scholar
  • 102 Campo M S, Grindlay G J, O’Neil B W, Chandrachud L M, McGarvie G M, Jarrett W F. Prophylactic and therapeutic vaccination against a mucosal papillomavirus.  J Gen Virol. 1993;  74 945-953
    PubMedSearch in Google Scholar
  • 103 Feltkamp M C, Smits H L, Vierboom M P, Minnaar R P, de Jongh B M, Drijfhout J W, ter Schegget J, Melief C J, Kast W M. Vaccination with cytotoxic T lymphocyte-epitope-containing peptide protects against a tumour induced by human papillomavirus type 16-transformed cells.  Eur J Immunol. 1993;  23 2242-2249
    PubMedSearch in Google Scholar
  • 104 Fernando G J, Murray B, Zhou J, Frazer I H. Expression, purification and immunological characterization of the transforming protein E7, from cervical cancer-associated human papillomavirus type 16.  Clin Exp Immunol. 1999;  115 397-403
    CrossrefPubMedSearch in Google Scholar
  • 105 Lacey C J, Thompson H S, Monteiro E F, O’Neill T, Davies M L, Holding F P, Fallon R E, Roberts J S. Phase IIa safety and immunogenicity of a therapeutic vaccine, TA-GW, in persons with genital warts.  J Infect Dis. 1999;  179 612-618
    CrossrefPubMedSearch in Google Scholar
  • 106 Chen C -H, Wang T -L, Hung C -F, Pardoll D M, Wu T -C. Boosting with recombinant vaccinia increases HPV-16 E7-specific T cell precursor frequencies of HPV-16 E7-expressing DNA vaccines.  Vaccine. 2000;  18 2015-2022
    CrossrefPubMedSearch in Google Scholar
  • 107 Chen C -H, Wang T -L, Hung C -F, Yang Y, Young R A, Pardoll D M, Wu T -C. Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene.  Cancer Res. 2000;  60 1035-1042
    PubMedSearch in Google Scholar
  • 108 Chen C H, Ji H, Suh K W, Choti M A, Pardoll D M, Wu T C. Gene gun-mediated DNA vaccination induces antitumour immunity against human papillomavirus type 16 E7-expressing murine tumour metastases in the liver and lungs.  Gene Ther. 1999;  6 1972-1981
    CrossrefPubMedSearch in Google Scholar
  • 109 Ji H, Wang T -L, Chen C -H, Hung C -F, Pai S, Lin K -Y, Kurman R J, Pardoll D M, Wu T -C. Targeting HPV-16 E7 to the endosomal/lysosomal compartment enhances the antitumour immunity of DNA vaccines against murine HPV-16 E7-expressing tumours.  Hum Gene Ther. 1999;  10 2727-2740
    CrossrefPubMedSearch in Google Scholar
  • 110 Shi W, Bu P, Liu J, Polack A, Fisher S, Qiao L. Human papillomavirus type 16 E7 DNA vaccine: Mutation in the open reading frame of E7 enhances specific cytotoxic T-lymphocyte induction and antitumour activity.  J Virol. 1999;  73 7877-7881
    PubMedSearch in Google Scholar
  • 111 Greenstone H L, Nieland J D, de Visser K E, De Bruijn M L, Kirnbauer R, Roden R B, Lowy D R, Kast W M, Schiller J T. Chimeric papillomavirus virus-like particles elicit antitumour immunity against the E7 oncoprotein in an HPV16 tumour model.  Proc Natl Acad Sci USA. 1998;  95 1800-1805
    CrossrefPubMedSearch in Google Scholar
  • 112 Peng S, Frazer I H, Fernando G J, Zhou J. Papillomavirus virus-like particles can deliver defined CTL epitopes to the MHC class I pathway.  Virology. 1998;  240 147-157
    CrossrefPubMedSearch in Google Scholar
  • 113 Schafer K, Muller M, Faath S, Henn A, Osen W, Zentgraf H, Benner A, Gissmann L, Jochmus I. Immune response to human papillomavirus 16 L1E7 chimeric virus-like particles: Induction of cytotoxic T cells and specific tumour protection.  Int J Cancer. 1999;  81 881-888
    CrossrefPubMedSearch in Google Scholar
  • 114 Borysiewicz L K, Fiander A, Nimako M, Man S, Wilkinson G W, Westmoreland D, Evans A S, Adams M, Stacey S N, Boursnell M E, Rutherford E, Hickling J K, Inglis S C. A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer.  Lancet. 1996;  347 1523-1527
    CrossrefPubMedSearch in Google Scholar
  • 115 Lin K -Y, Guarnieri F G, Staveley-O ’Carroll K F, Levitsky H I, August T, Pardoll D M, Wu T -C. Treatment of established tumours with a novel vaccine that enhances major histocompatibility class II presentation of tumour antigen.  Cancer Res. 1996;  56 21-26
    PubMedSearch in Google Scholar
  • 116 Meneguzzi G, Cerni C, Kieny M P, Lathe R. Immunization against human papillomavirus type 16 tumour cells with recombinant vaccinia viruses expressing E6 and E7.  Virology. 1991;  181 62-69
    CrossrefPubMedSearch in Google Scholar
  • 117 Chen L, Ashe S, Brady W A, Hellstrom I, Hellstrom K E, Ledbetter J A, McGowan P, Linsley P S. Costimulation of antitumour immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4.  Cell. 1992;  71 1093-1102
    PubMedSearch in Google Scholar
  • 118 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
    PubMedSearch in Google Scholar
  • 119 Kast W M, Brandt R M, Drijfhout J W, Melief C J. Human leukocyte antigen-A2.1 restricted candidate cytotoxic T lymphocyte epitopes of human papillomavirus type 16 E6 and E7 proteins identified by using the processing-defective human cell line T2.  J Immunother. 1993;  14 115-120
    PubMedSearch in Google Scholar
  • 120 Ressing M E, Sette A, Brandt R M, Ruppert J, Wentworth P A, Hartman M, Oseroff C, Grey H M, Melief C J, Kast W M. Human CTL epitopes encoded by human papillomavirus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A*0201-binding peptides.  J Immunol. 1995;  154 5934-5943
    PubMedSearch in Google Scholar
  • 121 Kaufmann A M, Gissmann L, Street D, Schreckenberger C, Hunter M, Qiao L. Expression of CD80 enhances immunogenicity of cervical carcinoma cells in vitro.  Cellular Immunology. 1996;  169 246-251
    CrossrefPubMedSearch in Google Scholar
  • 122 Kaufmann A M, Gissmann L, Schreckenberger C, Qiao L. Cervical carcinoma cells transfected with the CD80 gene elicit a primary CTL response specific for HPV 16 E7 antigens.  Cancer Gene Therapy. 1997;  4 377-382
    PubMedSearch in Google Scholar
  • 123 Kather A, Ferrara A, Nonn M, Schinz M, Nieland J, Schneider A, Dürst M, Kaufmann A M. Identification of a Naturally Processed HLA-A*0201 HPV18 E7 T Cell Epitope by Tumor Cell Mediated in vitro Vaccination. Int J Cancer (in press)
  • 124 Steller M A, Gurski K J, Murakami M, Daniel R W, Shah K V, Celis E, Sette A, Trimble E L, Park R C, Marincola F M. Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7.  Clin Cancer Res. 1998;  4 2103-2109
    PubMedSearch in Google Scholar
  • 125 van Driel W J, Ressing M E, Kenter G G, Brandt R M, Krul E J, van Rossum A B, Schuuring E, Offringa R, Bauknecht T, Tamm-Hermelink A, van Dam P A, Fleuren G J, Kast W M, Melief C J, Trimbos J B. Vaccination with HPV16 peptides of patients with advanced cervical carcinoma: Clinical evaluation of a phase I-II trial.  Eur J Cancer. 1999;  35 946-952
    CrossrefPubMedSearch in Google Scholar
  • 126 Ressing M E, van Driel W J, Brandt R M, Kenter G G, de Jong J H, Bauknecht T, Fleuren G J, Hoogerhout P, Offringa R, Sette A, Celis E, Grey H, Trimbos B J, Kast W M, Melief C J. Detection of T helper responses, but not of human papillomavirus-specific cytotoxic T lymphocyte responses, after peptide vaccination of patients with cervical carcinoma.  J Immunother. 2000;  23 255-266
    PubMedSearch in Google Scholar
  • 127 Munderspach L. Wilczynski S, Roman L, Bade L, Felix J, Small LA, Kast WM, Fascio G, Marty V, Weber J. 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
    PubMedSearch in Google Scholar
  • 128 Zwaveling S, Ferreira Mota S C, Nouta J, Johnson M, Lipford G B, Offringa R, van der Burg S H, Melief C J. Established human papillomavirus type 16-expressing tumours are effectively eradicated following vaccination with long peptides.  J Immunol. 2002;  169 350-358
    PubMedSearch in Google Scholar
  • 129 Goldstone S E, Palefsky J M, Winnett M T, Neefe J R. Activity of HspE7, a novel immunotherapy, in patients with anogenital warts.  Dis Colon Rectum. 2002;  45 502-507
    CrossrefPubMedSearch in Google Scholar
  • 130 de Jong A, O’Neil T, Khan A Y, Kwappenberg K M, Chrisholm S E, Whittle N R, Dobson J A, Jack L C, St Clair Roberts J A, Offringa R, van der Burg S H, Hickling J K. Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E6E7 fusion protein vaccine.  Vaccine. 2002;  20 3456-3464
    CrossrefPubMedSearch in Google Scholar
  • 131 Thompson H S, Davies M L, Holding F P, Fallon R E, Mann A E, O’Neil T, Roberts J S. Phase I safety and antigenicity of TA-GW: A recombinant HPV6 L2E7 vaccine for the treatment of genital warts.  Vaccine. 1999;  17 40-49
    CrossrefPubMedSearch in Google Scholar
  • 132 Kaufmann A M, Nieland J, Schinz M, Gabelsberger J, Jochmus I, Gissmann L, Schneider A, Dürst M. HPV16 L1/E7 chimeric virus-like particles induce specific HLA-restricted T cells in humans after in vitro vaccination.  Int J Cancer. 2001;  92 285-293
    CrossrefPubMedSearch in Google Scholar
  • 133 Chen C H, Wu T C. Experimental vaccine strategies for cancer immunotherapy.  J Biomed Sci. 1998;  5 231-252
    CrossrefPubMedSearch in Google Scholar
  • 134 Cella M, Sallusto F, Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells.  Curr Opin Immunol. 1997;  9 10-16
    CrossrefPubMedSearch in Google Scholar
  • 135 Hart D N. Dendritic cells: Unique leukocyte populations which control the primary immune response.  Blood. 1997;  90 3245-3287
    PubMedSearch in Google Scholar
  • 136 Heufler C, Koch F, Schuler G. Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells.  J Exp Med. 1988;  167 700-705
    CrossrefPubMedSearch in Google Scholar
  • 137 Inaba K, Steinman R M, Pack M W, Ya H, Inaba M, Sudo T, Wolpe S, Schuler G. Identification of proliferating dendritic cell precursors in mouse blood.  J Exp Med. 1992;  175 1157-1167
    CrossrefPubMedSearch in Google Scholar
  • 138 Lyman S D, Jacobsen S EW. c-kit ligand and flt3 ligand: Stem/progenitor cell factors with overlapping yet distinct activities.  Blood. 1998;  91 1101-1134
    PubMedSearch in Google Scholar
  • 139 Romani N, Reider D, Heuer M, Ebner S, Kampgen E, Eibl B, Niederwieser D, Schuler G. Generation of mature dendritic cells from human blood: An improved method with special regard to clinical applicability.  J Immunol Methods. 1996;  196 137-151
    CrossrefPubMedSearch in Google Scholar
  • 140 Mayordomo J I, Zorina T, Storkus W J, Zitvogel L, Garcia-Prats M D, DeLeo A B, Lotze M T. Bone marrow-derived dendritic cells serve as potent adjuvants for peptide-based antitumour vaccines.  Stem Cells. 1997;  15 94-103
    PubMedSearch in Google Scholar
  • 141 Schoell W M, Mirhashemi R, Liu B, Janicek M F, Podack E R, Penalver M A, Averette H E. Generation of tumour-specific cytotoxic T lymphocytes by stimulation with HPV type 16 E7 peptide-pulsed dendritic cells: an approach to immunotherapy of cervical cancer.  Gynecol Oncol. 1999;  74 448-455
    CrossrefPubMedSearch in Google Scholar
  • 142 Santin A D, Hermonat P L, Ravaggi A, Chiriva-Internati M, Zhan D, Pecorelli S, Parham G P, Cannon M J. Induction of human papillomavirus- specific CD4(+) and CD8(+) lymphocytes by E7-pulsed autologous dendritic cells in patients with human papillomavirus type 16- and 18-positive cervical cancer.  J Virol. 1999;  73 5402-5410
    PubMedSearch in Google Scholar
  • 143 Nonn M, Schinz M, Zumbach K, Pawlita M, Schneider A, Dürst M, Kaufmann A M. Dendritic cell-based tumour vaccine for cervical cancer I: in vitro vaccination with recombinant protein-pulsed dendritic cells induces specific T cells to HPV16 E7 or HPV18 E7. J Cancer Res Clin Oncol (submitted 2002)
  • 144 Murakami M, Gurski K J, Marincola F M, Ackland J, Steller M A. Induction of specific CD8+ T-lymphocyte responses using a human papillomavirus-16 E6/E7 fusion protein and autologous dendritic cells.  Cancer Res. 1999;  59 1184-1187
    PubMedSearch in Google Scholar
  • 145 Santin A D, Bellone S, Gokden M, Cannon M J, Parham G P. Vaccination with HPV-18 E7-pulsed dendritic cells in a patient with metastatic cervical cancer.  N Engl J Med. 2002;  346 1752-1753
    CrossrefPubMedSearch in Google Scholar
  • 146 Ferrara A, Nonn M, Sehr P, Schreckenberger C, Pawlita M, Dürst M, Schneider A, Kaufmann A M. Dendritic cell-based tumour vaccine for cervical cancer II: results of a clinical pilot study in 15 individual patients. J Cancer Res Clin Oncol (submitted 2002)
  • 147 Hallez S, Detremmerie O, Giannouli C, Thielemans K, Gajewski T F, Burny A, Leo O. Interleukin-12-secreting human papillomavirus type 16-transformed cells provide a potent cancer vaccine that generates E7-directed immunity.  Int J Cancer. 1999;  81 428-437
    CrossrefPubMedSearch in Google Scholar
  • 148 Bubenik J, Simova J, Hajkova R, Sobota V, Jandlova T, Smahel M, Sobotkova E, Vonka V. Interleukin 2 gene therapy of residual disease in mice carrying tumours induced by HPV 16.  Int J Oncol. 1999;  14 593-597
    PubMedSearch in Google Scholar
  • 149 Chang E Y, Chen C -H, Ji H,Wang T -L, Hung K, Lee B P, Huang A YC, Kurman R J, Pardoll D M, Wu T -C. Antigen-specific cancer immunotherapy using a GM-CSF secreting allogeneic tumour cell-based vaccine.  Int J Cancer. 2000;  86 725-730
    CrossrefPubMedSearch in Google Scholar
  • 150 Moss B. Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety.  Proc Natl Acad Sci USA. 1996;  93 11341-11348
    CrossrefPubMedSearch in Google Scholar
  • 151 Kaufmann A M, Stern P L, Rankin E M, Sommer H, Nuessler V, Schneider A, Adams M, Onon T S, Bauknecht T, Wagner U, Kroon K, Hickling J, Boswell C M, Stacey S N, Kitchener H C, Gillard J, Wanders J, Roberts J St C, Zwierzina H. Safety and immunogenicity of TA-HPV, a recombinant vaccinia virus expressing modified HPV16 and 18 E6 and E7 genes, in women with progressive cervical cancer.  Clin Cancer Res. 2002;  8 3676-3685
    PubMedSearch in Google Scholar
  • 152 Davidson E, Tomlinson A, Stern P L, Dobson J, Jack L, Roberts J C, Boswell C, Hickling J, Kitchener H. A phase II trial to assess the safety, immunogenicity and efficacy of TA-HPV in patients with high grade vulvar intraepithelial neoplasia (VIN). 19th International Papillomavirus Conference, 2001, Florianopolis, Brazil
  • 153 Frazer I H, Thomas R, Zhou J, Legatt G R, Dunn L, McMillan N, Tindle R W, Filgueira L, Manders P, Barnard P, Sharkey M. Potential strategies utilised by papillomavirus to evade host immunity.  Immunol Rev. 1999;  168 131-142
    PubMedSearch in Google Scholar
  • 154 Östör A G. Natural history of cervical intraepithelial neoplasia: a critical review.  Int J Gynecol Pathol. 1993;  12 186-192
    PubMedSearch in Google Scholar
  • 155 Helmerhorst T JM, Meijer C JLM. Cervical cancer should be considered as a rare complication of oncogenic HPV infection rather than a STD.  Int J Gynecol Cancer. 2002;  12 235-236
    CrossrefPubMedSearch in Google Scholar
  • 156 Conner M E, Stern P L. Loss of MHC class I expression in cervical carcinomas.  Int J Cancer. 1990;  46 1029-1034
    PubMedSearch in Google Scholar
  • 157 Ritz U, Momburg F, Pilch H, Maeurer M J, 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
    PubMedSearch in Google Scholar
  • 158 Hazelbag S, Fleuren G J, Baelde J J, Schuuring E, Kenter G G, Gorter A. Cytokine profile of cervical cancer cells.  Gynecol Oncol. 2001;  83 235-243
    CrossrefPubMedSearch in Google Scholar
  • 159 Medema J P, de Jong J, Peltenburg L T, Verdegaal E M, Gorter A, Bres S A, Franken K L, Hahne M, Albar J P, Melief C J, Offringa R. Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumours.  Proc Natl Acad Sci USA. 2001;  98 11515-11520
    CrossrefPubMedSearch in Google Scholar

Dr. Andreas M. Kaufmann

Gynäkologische Molekularbiologie · Frauenklinik · FSU Jena

Bachstrasse 18

07743 Jena

Germany

Phone: +49/36 41/93 42 73

Fax: +49/36 41/93 42 16

Email: andreas.kaufmann@med.uni-jena.de