Potential therapeutic vaccine strategies and relevance of the immune system in uterine cervical cancer

The interaction of HPV with the immune system has been studied, but the results are still inconclusive for several reasons. Until now, we have not been able to understand the mechanisms of immune system regulation in the uterine cervix. HPV infection does not unleash an inflammatory response, and consequently an efficient and specific immune response against the virus. Moreover, an understanding of HPV infection and local immune response is indispensable for the development of new bioactive drugs and therapies for patients with both non invasive and invasive tumors, mainly for patients that do not present regression with radiotherapy or chemotherapy or in whom the tumors are surgically unresectable. The aim of this review is to provide support in understanding potential mechanisms used by the immune system to destroy neoplastic cells, comparing the immunotherapy used in cancer and discussing the possibility of developing new drugs based on these mechanisms of action.

Neoplasia; Cancer; Uterine cervical cancer; Immunotherapy; Human papillomavirus; Interferon; Cellular therapy; Immune system

[1] Parkin D.M., Pisani P., Ferlay J.: “Global cancer statistics”. Cancer J. Clin., 1999, 49, 33.

[2] Andrade J.M., Marana H.R.C.: “Tratado de Ginecologia”. Revinter, Rio de Janeiro, 1997, 1257.

[3] Murta E.F.C., Souza M.A.H., Falco V.A., Lombardi W., Borges L.S.: “Importância da infecção pelo papilomavírus humano na incidência daneoplasia intraepitelial cervical”. J. Bras. Ginec., 1997, 107, 361.

[4] Schiffman M.H.: “New epidemiology of human papillomavirus infection and cervical neoplasia”. J. Natl. Cancer Inst., 1995, 87, 1345.

[5] Munoz N.: “Human papillomavirus and cancer: the epidemiological evidence”. J. Clin. Virol., 2000, 19, 1.

[6] Murta E.F.C., Souza M.A.H., Adad S.J., Pires R.A., Matthes A.G.Z.: “Influência da idade materna do período gestacional e do número de gestaçõesna infecção pelo papilomavírus humano”. Rev. Bras. Ginec. Obstet., 1998, 20, 33.

[7] Murta E.F.C., França H.G., Carneiro M.C., Caetano M.S.S.G., Adad S.J., Sousa M.A.H.: “Câncer do colo uterino: correlação com início daatividade sexual e paridade”. Rev. Bras. Ginec. Obstet., 1999, 21, 555.

[8] Schachter J., Hill E.C., King E.B., Heilbron D.C., Ray R.M., Margolis A.J. et al.: “Chlamydia trachomatis and cervical neoplasia”. JAMA, 1982, 248, 2134.

[9] McMurray H.R., Nguyen D., Westbrook T.F., McAnce D.J.: “Biology of human papillomaviruses”. Int. J. Exp. Pathol., 2001, 82, 15.

[10] Burghardt E., Ostor A.G.: “Site and origin of squamous cervical cancer: a histomorphologic study”. Obstet. Gynecol., 1983, 62, 117.

[11] Koutsky L.A., Holmes K.K., Critchlow C.W.: “A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection”. N. Engl. J. Med., 1992, 29, 1272.

[12] Quayle A.J., Anderson D.J.: “Induction of mucosal immunity in the genital tract and prospects for oral vaccines”. Talwar G.P., Raghupathy R, Landes Biosciences, USA, 1994, 149.

[13] Kelly K.A., Walker J.C., Jameel S.H., Gray H.L., Rank R.G.: “Differential regulation of CD4 lymphocyte recruitment between the upper and lower regions of the genital tract during Chlamydia trachomatis infection”. Infect. Immun., 2000, 68, 1519.

[14] Gould D.S., Ploegh H.L., Schust D.J.: “Murine female reproductive tract intraepithelial lymphocytes display selection characteristics distinct from both peripheral and other mucosal T cells”. J. Reprod. Immunol., 2001, 52, 85.

[15] Robertson S.A., Ingman W.V., O’Leary S., Sharkey D.J., Tremellen K.P.: “Transforming growth factor beta – a mediator of immune deviation in seminal plasma”. J. Reprod. Immunol., 2002, 57, 109.

[16] Wallace P.K., Yeaman G.R., Johnson K., Collins J.E., Guyre P.M., Wira C.R.: “MHC class II expression and antigen presentation by human endometrial cells”. J. Steroid Biochem. Mol. Biol., 2001, 76, 203.

[17] Uthaisangsook S., Day N.K., Bahna S.L., Good R.A., Haraguchi S.: “Innate immunity and its role against infections”. Ann. Allergy Asthma Immunol. 2002, 88, 253.

[18] Doan T., Herd K., Street M., Bryson G., Fernando G., Lambert P., Tindle R.: “Human papillomavirus type 16 E7 oncoprotein expressed in peripheral epithelium tolerizes E7-directed cytotoxic T-lymphocyte precursors restricted through human (and mouse) major histocompatibility complex class I alleles”. J. Virol., 1999, 73, 6166.

[19] Stanley M.A.: “Immunobiology of papillomavirus infections”. J. Reprod. Immunol., 2001, 52, 45.

[20] Stern P.L., Brown M., Stacey S.N., Kitchener H.C., Hampson I., Abdel-Hady E.S. et al.: “Natural HPV immunity and vaccination strategies”. J. Clin. Virol., 2000, 19, 57.

[21] Konya J.: “Dillner, Immunity to oncogenic human papillomaviruses”. J. Adv. Cancer Res., 2001, 82, 205.

[22] Tindle R.W.: “Immune evasion in human papillomavirus-associated cervical cancer”. Nature Rev. Cancer, 2002, 2, 59.

[23] Ansel J.C., Luger T.A., Lowry D., Perry P., Roop D.R., Mountz J.D.: “The expression and modulation of IL-1 alpha in murine keratinocytes”. J. Immunol., 1988, 140, 2274.

[24] Kyo S., Inoue M., Hayasaka N., Inoue T., Yutsudo M., Tanizawa O., Hakura A.: “Regulation of early gene expression of human papillomavirus type 16 by inflammatory cytokines”. Virology, 1994, 200, 130.

[25] Dalgleish A.G., O'Byrne K.J.: “Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer”. Adv. Cancer Res., 2002, 84, 231.

[26] Cho Y.S., Kang J.W., Cho M., Cho C.W., Lee S., Choe Y.K. et al.: “Down modulation of IL-18 expression by human papillomavirus type 16 E6 oncogene via binding to IL-18”. FEBS Lett., 2001, 501, 139.

[27] Lee S.J., Cho Y.S., Cho M.C., Shim J.H., Lee K.A., Ko K.K. et al.: “Both E6 and E7 oncoproteins of human papillomavirus 16 inhibit IL-18-induced IFN-gamma production in human peripheral blood mononuclear and NK cells”. J. Immunol., 2001, 167, 497.

[28] Filippova M., Song H., Connolly J.L., Dermody T.S., Duerksen-Hughes P.J.: “The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis”. J. Biol. Chem., 2002, 277, 21730.

[29] Tjiong M.Y., van der Vange N., ter Schegget J.S., Burger M.P., ten Kate F.W., Out T.A.: “Cytokines in cervicovaginal washing fluid from patients with cervical neoplasia”. Cytokine, 2001, 14, 357.

[30] Wei L.H., Kuo M.L., Chen C.A., Cheng W.F., Cheng S.P., Hsieh F.J. et al.: “Interleukin-6 in cervical cancer: the relationship with vascular endothelial growth factor”. Gynecol. Oncol., 2001, 82, 49.

[31] Tjiong M.Y., van der Vange N., ten Kate F.J., Tjong A.H.S.P., ter Schegget J., Burger M.P. et al.: “Increased IL-6 and IL-8 levels in cervicovaginal secretions of patients with cervical cancer”. Gynecol. Oncol., 1999, 73, 285.

[32] Woodworth C.D., Simpson S.: “Comparative lymphokine secretion by cultured normal human cervical keratinocytes, papillomavirus-immortalized, and carcinoma cell lines”. Am. J. Pathol., 1993, 142, 1544.

[33] Merrick D.T., Winberg G., McDougall J.K.: “Reexpression of interleukin 1 in human papillomavirus 18 immortalized keratinocytes inhibits their tumorigenicity in nude mice”. Cell. Growth Differ., 1996, 7, 1661.

[34] al-Saleh W., Giannini S.L., Jacobs N., Moutschen M., Doyen J., Boniver J., Delvenne P.: “Correlation of T-helper secretory differentiation and types of antigen-presenting cells in squamous intraepithelial lesions of the uterine cervix”. J. Pathol., 1998, 184, 283.

[35] Tay S.K., Jenkins D., Maddox P., Hogg N., Singer A.: “Tissue macrophage response in human papillomavirus infection and cervical intraepithelial neoplasia”. Br. J. Obstet. Gynaecol., 1987, 94, 1094.

[36] Davidson B., Goldberg I., Kopolovic: “Inflammatory response in cervical intraepithelial neoplasia and squamous cell carcinoma of the uterine cervix”. J. Pathol. Res. Pract., 1997, 193, 491.

[37] Banks L., Moreau F., Vousden K., Pim D., Matlashewski G.: “Expression of the human papillomavirus E7 oncogene during cell transformation is sufficient to induce susceptibility to lysis by activated macrophages”. J. Immunol., 1991, 146, 2037.

[38] Hagari Y., Budgeon L.R., Pickel M.D., Kreider J.W.: “Association of tumor necrosis factor-alpha gene expression and apoptotic cell death with regression of Shope papillomas”. J. Invest. Dermatol., 1995, 104, 526.

[39] Malejczyk J., Majewski S., Jablonska S., Rogozinski T.T., Orth G.: “Abrogated NK-cell lysis of human papillomavirus (HPV)-16-bearing keratinocytes in patients with pre-cancerous and cancerous HPV-induced anogenital lesions”. Int. J. Cancer, 1989, 43, 209.

[40] Tay S.K., Jenkins D., Singer A.: “Natural killer cells in cervical intraepithelial neoplasia and human papillomavirus infection”. Br. J. Obstet. Gynaecol., 1987, 94, 901.

[41] Furbert-Harris P.M., Evans C.H., Woodworth C.D., DiPaolo J.A.: “Loss of leukoregulin up-regulation of natural killer but not lymphokine-activated killer lymphocytotoxicity in human papillomavirus 16 DNA-immortalized cervical epithelial cells”. J. Natl. Cancer Inst., 1989, 81, 1080.

[42] Wu R., Coleman N., Stanley M.: “Different susceptibility of cervical keratinocytes containing human papillomavirus to cell-mediated cytotoxicity”. Chin. Med. J. (Engl.), 1996, 109, 854.

[43] El-Sherif A.M., Seth R., Tighe P.J., Jenkins D.: “Quantitative analysis of IL-10 and IFN-gamma mRNA levels in normal cervix and human papillomavirus type 16 associated cervical precancer”. J. Pathol., 2001, 195, 179.

[44] Mota F., Rayment N., Chong S., Singer A., Chain B.. “The antigen-presenting environment in normal and human papillomavirus (HPV)-related premalignant cervical epithelium”. Clin. Exp. Immunol., 1999, 116, 33.

[45] Hengge U.R., Benninghoff B., Ruzicka T., Goos M.: “Topical immunomodulators-progress towards treating inflammation, infection, and cancer”. Lancet Infect. Dis., 2001, 1, 189.

[46] Banchereau J., Steinman R.M.: “Immunobiology of dendritic cells”. Nature, 1998, 392, 245.

[47] Hoffmann T.K., Muller-Berghaus J., Ferris R.L., Johnson J.T., Storkus W.J., Whiteside T.L.: “Alterations in the frequency of dendritic cells subsets in the peripheral circulatin of patients with squamous cell carcinomas of the head and neck”. Clin. Cancer Res., 2002, 8, 1787.

[48] Lissoni P., Vigore L., Ferranti R.: “Circulating dendritic cells in early and advanced cancer patients: diminished percent in the metastatic disease”. J. Biol. Regul. Homeost. Agents, 1999, 13, 216.

[49] Lissoni P., Malugani F., Bonfanti A.: “Abnormally enhanced blood concentrations of vascular endothelial growth factor (VEGF) in metastatic câncer patients and their relation to circulating dendritic cells, IL-12 and endothelin-1”. J. Biol. Regul. Homeost. Agents, 2001, 15, 140.

[50] Lespagnard L., Gancberg D., Rouas G.: “Tumor-infiltrating dendritic cells in adenocarcinomas of the breast: a study of 143 neoplasms with a correlation to usual prognostic factors and to clinical outcome”. Int. J. Cancer, 1999, 84, 309.

[51] Ambe K., Mori M., Enjogi M.: “S-100 protein-positive dendritic cells in colorectal adenocarcinomas. Distribution and relation to the clinical prognosis”. Cancer, 1989, 63, 496.

[52] Yamakawa M., Yamada K., Orui H.: “Immunohistochemical analysis of dendritic langerhans cells in thyroid carcinomas”. Anal. Cell. Pathol., 1995, 8, 331.

[53] Zeid N.A., Muller H.K.: “S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival”. Pathology, 1993, 25, 338.

[54] Buelens C., Verhasselt V., De Groote D., Thielemans K., Goldman M., Willems F.: “Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with interleukin-4 and granulocyte/macrophage-colony-stimulating factor”. Eur. J. Immunol., 1997, 27, 756.

[55] Menetrier-Caux C., Montmain G., Dieu M.C.: “Inhibition of the differentiation of dendritic cells from CD34(+) progenitorsby tumor cells: role of interleukin-6 and macrophage colony-stimulating factor”. Blood, 1998, 92, 4775.

[56] Gabrilovich D.I., Chen H.L., Girgis K.R.: “Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells”. Nat. Med., 1996, 2, 1096.

[57] Sombroek C.C., Stam A.G., Masterson A.J.: “Prostanoids play a major role çin the primary tumor-induced inhibition of dendritic cell differentiation”. J. Immunol., 2002, 168, 4333.

[58] Peguet-Navarro J., Sportouch M., Popa I., Berthier O., Schmitt D., Portoukalian J.: “Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis”. J. Immunol., 2003, 170, 3488.

[59] Adams M., Navabi H., Jasani B., Man S., Fiander A., Evans A.S. et al.: “Dendritic cell (DC) based therapy for cervical cancer: use of DC pulsed with tumour lysate and matured with a novel synthetic clinically non-toxic double stranded RNA analogue poly [I]:poly [C(12)U] (Ampligen R)”. Vaccine, 2003, 21, 787.

[60] Mayodormo I., Zorina T., Storkus W.J., Zitvogel L., Celluzzi C., Falo L.D.: “Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic anti-tumour immunity”. Nat. Med., 1995, 1, 1297.

[61] Jefford M., Maraskovsky E., Cebon J., Davis I.D.: “The use of dendritic cells in cancer therapy”. Lancet Oncol., 2001, 2, 343.

[62] Coleman N., Birley H.D.L., Renton A.M., Hanna N.F., Ryait B.K., Byrne M.: “Immunological events in regressing genital warts”. Am. J. Clin. Pathol., 1994, 102, 768.

[63] Nakagawa M., Stites D.P., Farhat S., Sisler J.R., Moss B., Kong F. et al.: “Cytotoxic T-lymphocyte responses to E6 and E7 proteins of human papillomavirus type 16: relationship to cervical intraepithelial neoplasia”. J. Infect Dis., 1997, 175, 927.

[64] Nakagawa M., Stites D.P., Patel S., Farhat S., Scott M., Hills N.K. et al.: “Persistence of human papillomavirus type 16 infection is associated with lack of cytotoxic T-lymphocyte response to the E6 antigens”. J. Infect. Dis., 2000, 182, 595.

[65] Bontkes H.J., de Gruijl T.D., van den Muysenberg A.J., Verheijen R.H., Stukart M.J., Meijer C.J. et al.: “Human papillomavirus type 16 E6/E7-specific cytotoxic T lymphocytes in women with cervical neoplasia”. Int. J. Cancer , 2000, 88, 92.

[66] Nimako M., Fiander A., Wilkinson G.W.G., Borysiewicz L.K., Man S.: “Human papillomavirus-specific cytotoxic T lymphocytes in patients with cervical intraepithelial neoplasia grade III”. Cancer Res., 1997, 57, 4855.

[67] Adams M., Borysiewicz L., Fiander A., Man S., Jasani B., Navabi H. et al.: “Clinical studies of human papilloma vaccines in pre-invasive and invasive cancer”. Vaccine, 2001, 19, 2549.

[68] Ressing M.E., van Driel W.J., Brandt R.M., Kenter G.G., de Jong J.H., Bauknecht T. et al.: “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.

[69] Stark G.R., Kerr I.M., Williams B.R., Silverman R.H., Schreiber R.D.: “How cells respond to interferons”. Annu. Rev. Biochem., 1998, 67, 227.

[70] De Marco F., Manni V., Guaricci N., Muller A., Marcante M.L.: “Induction of apoptotic cell death by IFNbeta on HPV-16 transformed human keratinocytes”. Antiviral Res., 1999, 42, 109.

[71] Woodworth C.D., Lichti U., Simpson S., Evans C.H., DiPaolo J.A.: “Leukoregulin and gamma-interferon inhibit human papillomavirus type 16 gene transcription in human papillomavirus-immortalized human cervical cells”. Cancer Res., 1992, 52, 456.

[72] Fontaine V., van der Meijden E., ter Schegget J.: “Inhibition of human papillomavirus-16 long control region activity by interferon-gamma overcome by p300 overexpression”. Mol. Carcinog., 2001, 31, 27.

[73] Murta E.F., Tavares Murta B.M.: “Successful pregnancy after vaginal cancer treated with interferon”. Tumori, 2004, 90, 247.

[74] Koromilas A.E., Li S., Matlashewski G.: “Control of interferon signaling in human papillomavirus infection”. Cytokine Growth Factor Rev., 2001, 12, 157.

[75] Li S., Labrecque S., Gauzzi M.C., Cuddihy A.R., Wong A.H., Pellegrini S. et al.: “The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha”. Oncogene, 1999, 18, 5727.

[76] Hiscott J., Pitha P., Genin P., Nguyen H., Heylbroeck C., Mamane Y. et al.: “Triggering the interferon response: the role of IRF-3 transcription factor”. J. Interferon Cytokine Res., 1999, 19, 1.

[77] 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.

[78] Cintorino M., Tripodi S.A., Romagnoli R., Ietta F., Ricci M.G., Paulesu L.: “Interferons and their receptors in human papillomavirus lesions of the uterine cervix”. Eur. J. Gynaecol. Oncol., 2002, 23, 145.

[79] Pao C.C., Lin C.Y., Yao D.S., Tseng C.J.: “Differential expression of cytokine genes in cervical cancer tissues”. Biochem. Biophys. Res. Commun., 1995, 214, 1146.

[80] Arany I., Goel A., Tyring S.K.: “Interferon response depends on viral transcription in human papillomavirus-containing lesions”. Anticancer Res., 1995, 15, 2865.

[81] Fyfe G., Fisher R., Rosenberg S.A.: “Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy”. J. Clin. Oncol., 1995, 13, 688.

[82] Geertsen P.F., Hermann G.G., von der Maase H.: “Treatment of metastatic renal cell carcinoma by continuous intravenous infusion of recombinant interleukin-2: a single-center phase II study”. J. Clin. Oncol., 1992, 10, 753.

[83] Maraninchi D., Blaise D., Viens P.: “High-dose recombinant interleukin-2 and acute myeloid leukemias in relapse”. Blood, 1991, 78, 2182.

[84] Wollenberg B., Kastenbauer J., Mundl H., Schaumberg J., Mayer A., Andratschke M. et al.: “Gene therapy-phase I trial for primary untreated head and neck squamous cell cancer (HNSCC) UICC stage II-IV with a single intratumoral injection of hIL-2 plasmids formulated in DOTMA/Chol”. Hum. Gene Ther., 1999, 10, 141.

[85] Golab J., Zagozdzon R.: “Antitumor effects of interleukin-12 in pre-clinical and early clinical studies [review]”. Int. J. Mol. Med., 1999, 3, 537.

[86] Mule J.J., Marcus S.G., Yang J.C.: “Clinical applications of IL-6 in cancer therapy”. Res. Immunol., 1992, 143, 777.

[87] Schuler M., Peschel C., Schneller F.: “Immunomodulator and hematopoietic effects of recombinant human interleukin-6 in patients with advanced renal cell cancer”. J. Interferon Cytokine Res., 1996, 16, 903.

[88] Prendiville J., Thatcher N., Lind M.: “Recombinant human interleukin-4 (rhu IL-4) administered by the intravenous and subcutaneous routes in patients with advanced cancer: phase I toxicity study and pharmacokinetic analysis”. Eur. J. Cancer, 1993, 29, 1700.

[89] Vokes E.E., Figlin R., Hochster H.: “A phase II study of recombinant human interleukin-4 for advanced or recurrent non-small cell lung cancer”. Cancer J. Sci. Am., 1998, 4, 46.

[90] Margolin R., Aronson F.R., Sznol M.: “Phase II studies of recombinant human IL-4 in advanced renal cancer and malignant melanoma”. J. Immunother., 1994, 15, 147.

[91] Tishelr M., Shoenfeld Y.: “BCG immunotherapy – from pathophysiology to clinical practice”. Expert Opin. Drug Saf., 2006, 2, 225.

[92] Joudi F.N., Smith B.J., O’Donnell M.A.: “Final results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer”. Urol. Oncol., 2006, 24, 344.

[93] Pronzato P., Vaira F., Vigani A., Losardo P., Bertelli G.: “Biochemical modulation of 5-fluorouracil with methotrexate in advanced colorectal cancer patients pretreated with adjuvant 5-fluorouracil and leucovorin”. Anticancer Res., 1995, 15, 2679.

[94] Engell H.C., Ulrich K.: “Cyclophosphamide and 5-fluoracil in the treatment of inoperable tumors”. Ugeskr. Laeg., 1966, 128, 325.

[95] Herrera-Ornelas L., Sweeney K., Petrelli N., Mittelman A., Rao U., Prado-Alcala E.: “Long survival after ovarian and hepatic metastasis from carcinoma of the large bowel: report of a case”. J. Surg. Oncol., 1984, 27, 196.

[96] Vermas S., Quirt I., McCready D., Bak K., Charette M., Iscoe N.: “Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma”. Cancer, 2006, 106, 1431.

[97] Glimelius B., Dahl O., Cedermak B., Jakobsen A., Bentzen S.M., Starkhammar H. et al.: “Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group”. Acta Oncol., 2005, 44, 904.

[98] Grillo-López A., White C., Varns C.: “Overview of the clinical developmentof rituximab: first monoclonal antibody approved for the treatment of lymphoma”. Semin. Oncol., 1999, 26, 66.

[99] Grillo-Lopez A.J., Hedrick E., Rashford M., Benyunes M.: “Rituximab: ongoing and future clinical development”. Semin. Oncol., 2002, 29, 105.

[100] Baselga J.: “Herceptin alone and in combination with chemotherapy in the treatment of HER-2-positive metastatic breast cancer: pivotal trials”. Oncology, 2001, 61, 14.

[101] Tagliaferri P., Caraglia M., Budillon A., Marra M., Vitale G., Viscomi C. et al.: “New pharmacokinetic and pharmacodynamic tools for interferon-alpha (IFN-alpha) treatment of human cancer”. Cancer Immunol. Immunother., 2005, 54, 1.

[102] Stevanovic S.: “Identification of tumor-associated T-cell epitopes for vaccine development”. Nature Rev. Cancer, 2002, 2, 514.

[103] Qin Z., Richter G., Schuler T., Ibe S., Cao X., Blankensterin T.: “B cells inhibit induction of T-cell-dependent tumor immunity”. Nature Med., 1998, 4, 627.

[104] Pinilla-Ibarz J., May R.J., Korontsvit T., Gomez M., Kappel B., Zakhaleva V. et al.: “Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein”. Leukemia, 2006, 20, 2025.

[105] Parmiani G., De Filippo A., Pilla L., Castelli C., Rivoltini L.: “Heat shock proteins gp96 as immunogens in cancer patients”. Int. J. Hyperthermia, 2006, 22, 223.

[106] Thurner B., Haendle I., Roder C.: “Vaccination with mage-3A1 Peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma”. J. Exp. Med., 1999, 190, 1669.

[107] Mackensen A., Herbst B., Chen J.L.: “Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34 (+) hematopoietic progenitor cells”. Int. J. Cancer, 2000, 86, 385.

[108] Murphy G.P., Tjoa B.A., Simmons S.J.: “Infusion of dendritic cells pulsed with HLA-A2-specific prostate-specific membrane antigen peptides: a phase II prostate cancer vaccine trial involving patients with hormone-refractory metastatic disease”. Prostate, 1999, 38, 73.

[109] Neves A.R., Ensina L.F., Anselmo L.B., Leite K.R., Buzaid A.C., Camara-Lopes L.H., Barbuto J.A.: “Dendritic cells derived from metastatic cancer patients vaccinated with allogeneic dendritic cell-autologous tumor cell hybrids express more CD86 and induce higher levels of interferon-gamma in mixed lymphocyte reactions”. Cancer Immunol. Immunother., 2005, 54, 61.

[110] Santin A.D., Bellone S., Palmieri M., Ravaggi A., Romani C., Tassi R. et al.: “HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities”. Gynecol. Oncol., 2006, 100, 469.

[111] Soper D.: “Reducing the health burden of HPV infection through vaccination”. Infec. Dis. Obstet. Gynecol., 2006, 14, 1.

[112] Griffiths P.D.: “Anticipating full benefits from the new papillomavirus vaccines”. Rev. Med. Virol., 2007, 17, 1.

[113] Schiller J.T., Lowy D.R.: “Prospects for cervical cancer prevention by human papillomavirus vaccination”. Cancer Res., 2006, 66, 10229.

[114] Festi D., Sandri L., Mazzella G., Roda E., Sacco T., Staniscia T. et al.: “Safety of interferon beta treatment for chronic HCV hepatitis”. World J. Gastroenterol., 2004, 10, 12.

[115] Brandacher G., Winkler C., Schroecksnadel K., Margreiter R., Fuchs D.: “Antitumoral activity of interferon-gamma involved in impaired immune function in cancer patients”. Curr. Drug Metab., 2006, 7, 599.

[116] Manns M.P., Wedemeyer H., Cornberg M.: “Treating viral hepatitis C: efficacy, side effects, and complications”. Gut, 2006, 55, 1350.