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IMMUNOTHERAPEUTIC STRATEGIES FOR CERVICAL SQUAMOUS CARCINOMA
CURRENT THERAPEUTIC ISSUES IN GYNECOLOGIC CANCER
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IMMUNOTHERAPEUTIC STRATEGIES FOR CERVICAL SQUAMOUS CARCINOMA Willemien J. van Driel, MD, Gemma G. Kenter, PhD, Gert Jan Fleuren, PhD, Cees J. M. Melief, PhD, and Baptist J. Trimbos, PhD
BIOLOGY AND VIRAL TRANSMISSION OF HUMAN PAPILLOMAVIRUS
Evidence that infection with human papillomavirus (HPV) is associated with carcinogenesis is provided both by epidemiologic and experimental studies. Epidemiologic studies show that the great majority of all grades of premalignant lesions of the cervix can be attributed to oncogenic HPV infection.” Analysis of the presence of specific HPV genotypes in premalignant cervical intraepithelial neoplasia and cervical carcinoma, makes it clear that the prevalence of HPV increases with the severity of the lesion, mainly because of contributions from HPVs 16 and 18.14In patients with a normal cervical cytology, the prevalence of HPV infection is age-dependent and varies from 20% in women between 20 and 25 years old to 6% in women older than 30 years.59Most grade I11 cervical intraepithelial neoplasia and a high percentage of grade I1 cervical intraepithelial neoplasia contain high-risk HPV types (primarily HPV 16 or 18), and both high- and low-risk HPV types have been observed in grade I cervical intraepithelial n e o ~ l a s i aIt. ~has ~ been shown that HPV infection fulfills a central etiologic role in the origin of cervical From the Departments of Gynecology (WJvD, GGK, BJT), Pathology (GJF),and Immunohematolog (CJMM), Leiden University Medical Center, Leiden, The Netherlands
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 13 * NUMBER 1 * FEBRUARY 1999
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squamous carcinoma ~ o r l d w i d eAmong .~ patients with cervical squamous carcinoma in western Europe, the prevalence of HPV 16-positive tumors of the cervix is reported to vary between 47% and 90%. On average, 65% of all cervical squamous carcinomas may contain HPV 16.5.45'58 Experimental evidence for immortalizing capacities resulting from HPV infection is provided by studies in which epithelial cells transfected with HPV 16 resulted in the transfected cells having an indefinite life span.66This finding tells us that only DNA fragments carrying the E6 and/or E7 genes are necessary to immortalize human ~ e l i s . ~ ~ HPVs are double-stranded circular DNA viruses with a genuine size of 8,000 kilobase. The HPV genome can be divided into three segments of unequal sizes: a long control region, which represents about 10% of the genome, and the early (E) and late (L) genes, which make up about 50% and 40% of the genome, re~pectively.~~ Two L genes, L1 and L2, code for viral capsid proteins; the E genes encode proteins that have a variety of regulatory functions. Three E genes may be important in carcinogenesis: E2, E6, and E7.38The E2 protein regulates transcription and replication of the HPV genome by encoding a regulatory protein that is involved in the regulation of the viral promoter that directs the expression of the E6 and E7 genes. E2 is capable of suppressing growth and of arresting the cell cycle, functions that correlate with the inhibition of E6 and E7 transcripts.18 HPV can be divided into low- and high-risk genital types. One of the differences between the two lies in the relatively high binding capacity of high-risk HPV E6- and E7-encoded proteins to products of tumor suppressor genes. Low-risk HPVs show no such binding. Lowrisk genital HPVs such as 1, 6 and 11 are found in common skin warts, genital warts, and condylomata acuminata, respectively. Highrisk genital HPVs such as 16, 18, 31, and 33 are found in invasive cervical carcinoma.94The E6 protein associates with the product of the p53 tumor-suppressor gene, and this association leads to the increased breakdown of the p53 protein.71,95 Normally, p53 is required for the growth arrest that follows cellular DNA damage, and inhibition or absence of this property leads to genomic in~tability.~~, 52 A common polymorphism of p53 may be an important factor in this respect. Recently, it was shown that the arginine form of p53 residue 72 is more susceptible to the E6-mediated degradation than is the proline form of p53. This renders individuals homozygous for arginine p53 seven times more susceptible to HPV-associated carcinogenesis.80The E7 protein has been associated with the product of the retinoblastoma tumor-suppressor gene, and this association alters activities of the retinoblastoma protein by activating the transcription of genes that regulate cell proliferation.2*%
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RATIONALE FOR IMMUNOTHERAPY HPV-Associated Cervical Abnormalities and TCell-Mediated lmmunoresponsiveness
Involvement of T-cell-mediated immunoresponsiveness in the defense against HPV-related cervical abnormalities is suggested by several observations. First, cervical abnormalities, including premalignant and malignant lesions, show an increased incidence in immunocompromised patients such as renal transplant recipients and patients infected with the human immunodeficiency virus.26,40, 65, 75,82, 91 Second, spontaneous regression of HPV-associated cervicovaginal infection and clearance of subsequent HPV infection have been described.36Third, immunohistochemical studies show extensive infiltrates in tumors consisting of immunocompetent cells. Downregulation of human leukocyte antigen (HLA) class I molecules occurs in the progression from premalignant cervical lesions to cervical carcinoma, and this downregulation correlates with histopathologically progressive disease.l2? 34, 93 Some associations of particular HLA alleles with increased susceptibility to, or protection from, HPV infection and cervical neoplasia have been reported, suggesting that these HLA molecules may present HPV-derived peptides to the immune system.19,79 Fourth, evidence for T-cell immunosurveillance and local adaptive immunoresponsiveness has been provided by experiments in which specific cytotoxic T-cell clones against an autologous tumor were obtained from tumor-infiltrating lymphocytes of primary cervical carcinoma^.^^ In addition, evidence for the existence of natural immunity against HPV-induced infection has been provided by the detection of virus-directed immunoresponsiveness in patients with HPV DNA-positive lesions that are not seen in healthy 63, Because early regions E6 and E7 are retained in the majority of cervical cancer cells? 78 the HPV 16 E6 and E7 proteins form attractive targets for T-cellbased immunotherapy of cervical carcinoma.
VACCINE TECHNIQUES AND CLINICAL PROSPECTS
Several types of vaccines and vaccination techniques are being researched for use in HPV and HPV-associated cervical cancers. Developmental and clinical progress of these vaccines and techniques are described below.
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Adoptive Transfer of Cytotoxic T Lymphocytes
Immunotherapy of tumors by adoptive transfer of in vitroexpanded cytotoxic T lymphocytes in combination with interleukin-2 has been successful in eradicating large human adenovirus-induced tumors established in In addition, the adoptive transfer of cytotoxic T lymphocytes raised against a subdominant HPV 16 E7 cytotoxic T-lymphocyte epitope has been successfully applied in mice against HPV 16-induced tumors, resulting in tumor e r a d i c a t i ~ n . ~ ~ So far, generation of tumor-infiltrating lymphocytes has been obtained from biopsy specimens of recurrent melanoma, breast cancer, colon cancer, and renal cell carcinoma showing autologous cytolysis. Tumor-infiltrating lymphocytes derived from metastatic lesions are more likely to display these cytolytic characteristic^.^^ Tumor-infiltrating lymphocytes with NK- or LAK-mediated killing potential not restricted to the major histocompatibility complex (MHC) have also been isolated at the tumor site of cervical carcinoma.35In addition, HPV 16 E7 peptidespecific cytotoxic T lymphocytes have been found at the tumor site and in draining lymph nodes.*l These tumor-infiltrating lymphocytes may prove to be very useful in adoptive transfer experiments and need to be investigated further. Peptide-Based Vaccines for Cervical Carcinoma
Vaccination with tumor-specific peptides may activate antigen-specific cytotoxic T lymphocytes. Because HPV 16 E6 and E7 peptides are retained in cervical cells and can be considered crucial for malignant transformation, vaccination with HPV 16 E6- or E7-derived peptides may boost the production of tumor-specific cytotoxic T lymphocytes. In vivo studies in mice have shown that successful vaccination with HPV 16 E7-derived, high-affinity MHC class I-binding peptides can induce protection against the outgrowth of an otherwise lethal challenge of 86 Cytotoxic T lymphocytes HPV 16-transformed syngeneic tumor cells.22, induced by this immunization protocol were capable of lysing peptidepulsed target cells, as well as tumor cells, in vitro. Moreover, synthetic peptides derived from two different tumor-associated antigens induced 57 Howthe regression of already established tumors in animal ever, peptide vaccination may not be harmless. Research with an adenovirus tumor model has shown that vaccination with the Ad5ElA peptide may cause tolerance instead of immunity against subsequent inoculation with Ad5ElA-expressing tumors.87,89 Such T-cell tolerance may result from the features of the peptides used for the vaccination or from the treatment scheme. The HPV 16 E7-encoded peptide is retained locally,
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whereas the Ad5ElA peptide diffuses rapidly throughout the body. The wide diffusion of the Ad5ElA peptide may result in exhaustion of cytotoxic T lymphocytes when combined with improper costimulation. In contrast, the local retention of the HPV 16 E7 peptides may explain its immunizing capacities. Tolerance may also result from the treatment scheme and mode of administration. A peptide vaccination given subcutaneously may be more effective in inducing protective cytotoxic T lymphocytes than peptides administered systemically (i.e., intraperitoneally).' To augment the peptide-specific responses, immunization with dendritic cells pulsed with E7 proteins can be more effe~tive.~, 68 Studies in mice demonstrated specific responses from cytotoxic T lymphocytes both in vitro and in vivo following vaccination of dendritic cells with HPV 16 E7 peptides. This vaccination resulted in protection against inoculation with syngeneic HPV 16-induced tumor cells.I5These findings support the importance of testing the immunization and tolerance properties of anticancer peptide vaccines and of using a proper peptide delivery method to avoid tolerance. Peptides encoded by HPV 16 E6 and E7 that are recognized by human cytotoxic T lymphocytes in a HLA-A2-restricted fashion have been identified for use in vaccinating patients with HPV 16-positive cervical carcinoma.67Recently, a phase 1-11 study was completed in patients with recurrent or residual cervical carcinoma that conventional therapy failed to control. No adverse side effects occurred in patients treated on this protocol. However, while four patients showed lymphoproliferative responses against the pan-DR helper peptide, no specific responses by cytotoxic T lymphocytes were seen against the injected HPV 16 E7 peptides. All patients had a low frequency of influenza virus-specific cytotoxic T lymphocytes and poor proliferative responses to tetanus toxoid and the purified protein derivative of Mycobacteriurn tuberculosis, indicating that these patients were seriously immunocompromised?*" Vaccination with Virus-like Particles
The assembly of the major capsid protein of papillomaviruses results in virus-like particles that lack potentially oncogenic viral proteins. This process results in the generation of neutralizing antibodies, which make virus-like particles attractive candidates for a prophylactic vac73, 74 The ability of virus-like particles to protect against HPVinduced abnormalities have been tested with models, including the cottontail rabbit papillomavirus (CRPV) animal model. The CRPV is an appropriate model because CRPV-induced disease in domestic rabbits closely mimics high-risk HPV disease, and rabbit immunity to CRPV
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has many parallels with human immunity to HPV.7 In this animal model, long- and short-term effective humoral protection against experimental papillomavirus infection was achieved following inoculation with native CRPV virus-like particles composed of L1 alone or in combination with L2.". 39 Moreover, naive rabbits were protected against inoculation with CRPV following the passive transfer of serum or immunoglobulin G from rabbits immunized with CRPV virus-like particles. These results show that neutralizing antibodies are capable of providing protectioa8 The antigenicity of injected virus-like particles can be evaluated with virus-like particle-based enzyme-linked immunosorbent assay or hemagglutination assay, tests that make it feasible to evaluate the antibody response after clinical application in humans.47,69 Using these assays, Roden et a170 showed that virus-like particle-based vaccines of HPVs 6, 11, 16,18,31,33, and 45 predominantly generate type-specific antibodies that have limited cross-protection for very closely related HPV types. Other research has explored the use of chimeric virus-like particles consisting of the L1 major capsid protein plus the entire E7 papillomavirus protein fused to the L2 minor capsid protein. This virus-like particlebased vaccine provided humoral protection and induced cellular-mediated protection against tumor injection in mice.28
Vaccination with Vectors Encoding for HPV Use of a recombinant virus vector that carries the genes for HPV 16 E6 and E7 proteins enables the production of the target antigen inside host cells and results in antigen processing and MHC class I-mediated antigen presentation. This approach induced antibody, T-cell proliferative, and cytotoxic T-lymphocyte responses to the HPV 16 E6 antigen in a mouse model using a vaccinia 29 In addition, specific activity of cytotoxic T lymphocytes against the HPV 16 E7 peptide was generated using a recombinant vaccinia virus that expressed the E6 and E7 proteins of HPVs 16 and 18.6 There is one report of a clinical trial using a recombinant vaccinia virus encoding modified forms of HPVs 16 and 18 E6 and E7 protein sequences. The poor immune status of the majority of the screened patients excluded them from obtaining this treatment. Eight patients who showed sufficient immunocompetence to clear vaccinia virus infection were included. Vaccine-specific cytotoxic Tlymphocyte activity against HPV 18 was detected in one patient, and antibodies specific for HPV 18 E7 developed in three patient^.^ Humoral immunoresponsiveness has been generated in mice using salmonella vaccine strains harboring the HPV 16 E7 but proliferative responses were not d e t e ~ t a b l eThus, . ~ ~ this approach is currently less attractive as a therapeutic vaccine for cervical abnormalities.
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DNA Vaccines
DNA vaccines utilize injection with DNA encoding for antigenic proteins. Such DNA vaccines are capable of inducing both humoral and cell-mediated immunoresponsiveness against viral proteins.92Immunization with DNA vaccines evades the use of a protein, a live replicating vector, or an attenuated version of the pathogen, but the mode and sequence of delivery of a DNA vaccine may influence the effectiveness of immune response^.'^ DNA vaccination with DNA originating from HPV is of special interest in the prevention and treatment of cervical abnormalities. In the CRPV model, injection of a DNA vaccine consisting of papillomavirus L1 resulted in the generation of antibodies against papillomavirus L1.16 Vaccinating rabbits intradermally with a DNA vaccine encoding for CRPV E6 using a gene gun resulted in E6-specific proliferative responses in peripheral blood mononuclear cells and concomitantly gave partial protection against papillomavirus-induced papilloma~.~~
EVASION OF IMMUNORESPONSIVENESS Antigen Presentation
Adequate presentation of antigens is required for optimal immunoresponsiveness. Cells capable of properly presenting antigens, i.e., antigen-presenting cells, are dendritic cells and macrophages. These professional antigen-presenting cells contain special properties to prime tumorspecific T cells in T cell-dependent areas of lymph nodes." Thus, for effective presentation of an antigen to a T cell, antigens must be released from the tumor cell and taken up by the antigen-presenting cell.31Antigens presented in the context of HLA class I molecules on neoplastic cells are subsequently recognized by the T-cell receptor. Because HLA class I molecules are often reduced or lost in premalignant and malignant lesions, tumor cells may have gained a way to escape immunosurveillance.l2, 33 This possibility is supported by the finding that reduced expression of HLA class I molecules in cervical carcinoma is associated with a decrease of CD8+ T lymphocytes between tumor cells.% Reduced expression of HLA class I molecules can enhance the susceptibility of tumor cells to lysis by natural killer cells, but a low number of natural killer cells are found in the tumor infiltrate of cervical carcinoma.MIn contrast, HLA class I1 molecules often show enhanced expression in cervical carcinoma and may thus confer the ability to present antigens to helper T lymphocytes, evoking efficient immunoresponsiveness.33~ 53
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Expression of stable MHC class I molecules on the epithelial cell membrane requires loading of the MHC class I heavy-chain/beta-2microglobulin dimer with peptide. Two transporter-associated with antigen processing (TAP) mechanisms exist, one TAP-dependent and one TAP-independent. The TAP-dependent mechanism involves the transport of peptides from the cytosol to the endoplasmic reticulum lumen via a peptide transporter encoded by the TAP1 and TAP2 genes.76,77 The TAP-independent pathway is concerned with proteolysis of signal sequences in the endoplasmic reticulum, resulting in peptides capable of binding HLA In cervical carcinoma, the expression of HLA class I molecules occurs partly concomitantly with the expression of the TAP.13,44 Loss of the TAP results in reduced levels of peptides in the endoplasmic reticulum, destabilizing HLA class I molecules and causing reduced expression of the HLA class I/peptide complex at the cell surface.62In these cases, inhibition of peptide transport by downregulation of TAP may provide tumor cells with a mechanism to reduce MHC class I expression and thus escape cytotoxic T lymphocyte-mediated recognition. This condition may be overcome by treatment of tumor cells with cytokines such as interferon-gamma, which is capable of restoring the expression of MHC class I and TAP.2o,30 In those cases where expression of HLA class I molecules and TAP do not correlate, a genetic loss of HLA genes may be responsible for the loss of HLA expression, a consequence that provides tumor cells with an additional mechanism with which to evade imm~nosurveillance.~~ To overcome these mechanisms of tumor evasion, certain adjustments to the vaccines may be beneficial. In case of peptide-based vaccination, delivery of peptides pulsed onto dendritic cells, as professional antigen-presenting cells, appears to induce strong and protective immunoresponsiveness against all available MHC classes I- and 11-binding peptides. As mentioned above, loading dendritic cells with HPV 16 E7 proteins results in adequate cellular immunoresponsiveness against inoculation with HPV 16-induced tumor and may provide a way to present tumor antigens by means of professional antigen-presenting cells.I5Antigen presentation may also be optimized by introducing costimulatory B7 (CD80, CD86) genes. For example, transfection of moderately immunogenic mouse tumor cells with the B7.1 (CD80) gene ren90 Indeed, the introduction dered these cells much more immunogenic.l0< of this costimulatory molecule elicited a primary HPV 16 E7-specific response by cytotoxic T lymphocytes in v i t r ~ Injecting .~~ patients with gynecologic (cervical or ovarian) cancer with DNA-liposome-contained HLA-A2 DNA resulted in regression of cutaneous lesions in 20% of patients, and isolated peripheral blood mononuclear cells of one patient with cervical carcinoma showed increased cytolytic activity against the
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autologous tumor. These findings show that the introduction of MHC genes might provide an additional way to augment cytolytic a~tivity?~ lmmunomodulation
Interactions between antigens presented by tumor cells or antigenpresenting cells on the one hand and effector cells on the other are promoted by the production of cytokines. T cells are important producers of cytokines, and T, cells, particularly, play a role in this respect. In general, two types of responses can be distinguished, depending on the cytokine profile.55,6o A type 1 response involves interferon-gamma and interleukin-2 and augments cytolytic activity by activating CD8+ T cells. Interferon-gamma may exploit this effect on both the cytotoxic T cells and the antigen-presenting cells in optimizing the expression of HLA class I m01ecules.~~ A type 2 response is characterized by the production of interleukins 4,5,6,9, and 10; the promotion of eosinophil maturation, activation, and survival; the facilitation of antibody production; and the protection against infection with extracellular parasites.60, Both responses exert negative feedback on each other through the production of their cytokines; therefore, it is possible that a type 2 response impedes cell-mediated immunity.55 By studying the role of costimulating factors in the process of antigen presentation (i.e., in directing the type of response), it was found that molecules of the B7 family might have a determining role. B7-1 (CD80) molecules lead to the generation of T cells that produce type 1 . cytokines, whereas B7-2 (CD86) molecules stimulate the production of type 2 cytokines by T cells.5O To optimize immunoresponsiveness by favoring the development of type 1 responses, it might be useful to add cytokines such as interferon-gamma or interleukin-2. As mentioned above, adding interferon-gamma to the vaccine enhances the susceptibility of cervical cancer cells to lysis by tumor-specific cytotoxic T lymphocytes by augmenting HLA class I expression.*l This may be achieved by periturnoral injections of biologic-response modifiers, as was shown when this procedure was used with OK432, resulting in the activation of interferon-gamma production by CD4 + cells. Vaccination with dendritic cells pulsed with the response modifier and peptide suppressed the growth of subsequent inoculation with P815 mastocytoma.M CONSIDERATIONS FOR CLINICAL APPLICATION OF HPV VACCINES
Experimental studies have provided evidence for the existence of both preventive and therapeutic effects of vaccines directed against
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HPV. In the development of these vaccines for disseminated clinical application, several factors should be considered. First, the adoptive transfer of cytotoxic T lymphocytes obtained from peripheral blood mononuclear cells or tumor-infiltrating lymphocytes in a human setting may be a costly and time-consuming procedure, because cytotoxic T lymphocytes must be patient-derived to avoid allogeneic rejection resulting from MHC polymorphism. Second, the use of HPV 16 E7 peptide-based vaccines has been shown to have both preventive and therapeutic characteristics in an animal model. Cytotoxic T-lymphocyte activity against an HPV peptide tested in a clinical phase 1-11 trial could not be detected, nor was any therapeutic effect seen; however, the detection of lymphoproliferative responses shows that vaccination with this highly immunogenic peptide emulsified in Montanide ISA 51 (a mineral oil-based adjuvant similar to incomplete Freund’s adjuvant [Seppic, Paris, France]) may induce a detectable peptide response. Not finding any HPV 16-specific cytotoxic T-lymphocyte activity may result from either a failure of the detection method and/or the immunocompromised state of the study group who received the peptide vaccination, but no side effects occurred in the study group, and the treatment was well tolerated. Results such as these stress the importance of performing clinical trials that involve patients who have a low tumor burden and who are immunocompetent. In such cases, peptide vaccination could be used as an adjuvant to the primary treatment of cervical cancer, especially since peptides are generally easy to make at low cost. In addition, the efficacy of inducing a cytotoxic T-lymphocyte response may be augmented by delivering dendritic cells pulsed with MHC class I-binding peptides. Studies investigating the feasibility of these approaches are currently in progress. A third factor to consider for wide clinical application is the use of modified viral particles. Virus-like particle-based vaccines seem attractive candidates for preventive vaccines that are capable of inducing immunity to HPV infection and the subsequent development of cervical abnormalities, or as therapeutic vaccines for already established cervical abnormalities. However, it may become too expensive to execute vaccination schemes on a large scale, especially in developing countries that have a high incidence of HPV-associated cervical abnormalities. Recombinant vaccinia virus that expresses the E6 and E7 proteins of HPVs 16 and 18 is capable of inducing vaccine-specific cytotoxic Tlymphocyte activity and antibody production, but whether the produced antibodies will have preventive activity against subsequent inoculation has not been confirmed. Despite the difficulty of detecting HPV-specific cytotoxic T-lymphocyte activity, the use of vaccinia virus seems promising and needs further evaluation to establkh its significance. A fourth consideration is the development of effective DNA vaccination as seen in the CRPV animal model. While DNA vaccines are easy
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to generate at low cost, the safety aspects for their use in humans must be examined. Injecting plasmid DNA into the genome of host cells may be potentially harmful, inducing mutagenicity or resulting in disruption of a cellular gene. Studies conducted so far have not yet detected integration after injection of plasmid DNA encoding for i n f l u e n ~ aIn .~~ addition, because anti-DNA antibodies are detected in a number of autoimmune diseases such as systemic lupus erythematosus, it remains to be established whether DNA vaccines induce anti-DNA antibodies in humans and subsequently produce autoimmune phenomena.
SUMMARY
Progress in developing preventive and therapeutic vaccines for HPV-associated diseases has been made in the last few years, but continued studies are needed to evaluate the clinical feasibility of different vaccination approaches and to determine a clinically effective and safe one. The perfect HPV vaccine will have both preventive and therapeutic capabilities, and because it is likely to be used world-wide, especially in developing countries, it must also have low production costs.
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typhimurium expressing human papillomavirus type 16 E7 epitopes inserted into hepatitis B virus core antigen. Vaccine 14:545, 1996 55. Lucey DR, Clerici M, Shearer GM: Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev 9:532, 1996 56. Mandelboim 0, Vafai E, Katz-Hillel A, et a1 Regression of established murine carcinoma metastases following vaccination with tumour-associated antigen peptides. Nat Med 1:1179, 1995 57. Mayordomo JI, Zorina T, Storkus WJ, et al: Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med 1:1297, 1995 58. Meanwell CA, Cox MF, Blackledge G , et al: HPV 16 DNA in normal and malignant cervical epithelium: Implications for the aetiology and behaviour of cervical neoplasia. Lancet 8535:703, 1987 59. Melkert PWJ, Hopman E, van den Brule AJC, et a1 Prevalence of HPV in cytomorphologically normal cervical smears, as determined by the polymerase chain reaction, is age-dependent. Int J Cancer 53919,1993 60. Mosmann TR, Coffman RL Two types of mouse helper T cell clone: Implications for immune regulation. Immunol Today 8:223, 1987 61. Mosmann TR, Sad S The expanding universe of T-cell subsets: Thl, Th2 and more. Immunol Today 17138,1996 62. Neefjes JJ, Momburg F, Hammerling GJ: Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. Science 261:769, 1993 63. Nimako M, Fiander AN, Wilkinson GWG, et al: HPV-specific CTLs in patients with cervical intraepithelial neoplasia grade 111. Cancer Res 574855, 1997 64. Paglia P, Guzman C A Keeping the immune system alerted against cancer. Cancer Immunol Immunother 46238, 1998 65. Penn I Tumor incidence in human allograft recipients. Transplant Proc 11:1047, 1979 66. Pirisi L, Yasumoto S, Feller M, et al: Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNA. J Virol 61:1061, 1987 67. Ressing ME, Sette A, Brandt RMP, et al: 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 154:5934, 1995 68. Ressing ME, van Driel WJ, Celis E, et al: Occasional memory cytotoxic T-cell responses of patients with human papillomavirus type 16-positive cervical lesions against a human leukocyte antigen-A*0201-restricted E7-encoded epitope. Cancer Res 56:582, 1996 69. Roden RBS, Hubbert NL, Kimbauer R, Breitburd F, et al: Papillomavirus L1 capsids agglutinate mouse erythrocytes through a proteinaceous receptor. J Virol69:5147,1995 70. Roden RBS, Hubbert NL, Kimbauer R, Christensen ND, et al: Assessment of the serological relatedness of genital human papillomavirus by hemagglutination inhibition. J Virol 70:3298, 1996 71. Scheffner M, Wemess BA, Huibregtse JM, et al: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129, 1990 72. Schiffman MH, Bauer HM, Hoover RN, et al: Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 85:958, 1993 73. Schiller JT, Boden RBS: Papillomavirus-like particles. Papillomavirus Report 6:121, 1995 74. Schiller JT, Lowy DR Papillomavirus-like particles and HPV vaccine development. Semin Cancer Biol 7373,1996 75. Schneider V, Kay S, Lee HM: Immunosuppression as a high-risk factor in the development of condyloma acuminatum and squamous neoplasia of the cervix. Acta Cytol 27220, 1983 76. Seliger 8, Maeurer MJ, Ferrone S TAP off-Tumors on. Immunol Today 18:292, 1997 77. Shastri N, Senvold T, Paz P: Reading with the lines: Naturally processed peptides displayed by MHC class I molecules. Curr Opin Immunol 10:137, 1998 78. Smotkin D, Wettstein FO: Transcription of HPV16 early genes in a cervical cancer
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and a cervical cancer derived cell line, and the identification of the E7 protein. Proc Natl Acad Sci USA 83:4680, 1986 Stern PL Immunity to human papillomavirus-associated cervical neoplasia. Adv Cancer Res 69:175, 1996 Storey A, Thomas M, Kalita A, et al: Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 393:229, 1998 Street D, Kaufmann AM, Vaughan A, et al: Interferon-gamma enhances susceptibility of cervical cancer cells to lysis by tumor-specific cytotoxic T cells. Gynecol Oncol 65265, 1997 Sun XW, Juhn L, Ellerbrock TV, et al: Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 3371343, 1997 Sundaram P, Tigelaar RE, Xiao W, et al: Intracutaneous vaccination of rabbits with the E6 gene of cottontail rabbit papillomavirus provides partial protection against virus challenge. Vaccine 16:613, 1998 Tamada K, Harada M, Abe K, et a1 Antitumor vaccination effect of dendritic cells can be augmented by locally utilizing Thl-type cytokines from OK432-reactiveCD4 + T cells. Cancer Immunol Immunother 46128, 1998 Tindle R, Herd K, London0 LP, et al: Chimeric hepatitis B core antigen particles containing B- and Th-epitopes of human papillomavirus type 16 E7 protein induce specific antibody and T-helper responses in immunised mice. Virology 200:547, 1994 Tindle RW, Croft S, Herd K, et al: A vaccine conjugate of "ISCAR" immunocarrier and peptide epitopes of the E7 cervical cancer-associated protein of human papillomavirus type 16 elicits specific Thl- and Th2-type responses in immunized mice in the absence of oil-based adjuvants. Clin Exp Immunol 101:265,1995 Toes REM, Blom RJJ, Offringa R, et a1 Enhanced tumor outgrowth after peptide vaccination: Functional deletion of tumor-specific CTL induced by peptide vaccination can lead to the inability to reject tumors. J Immunol 156:3911, 1996 Toes REM, Offringa R, Blom RJJ, Brandt RMP, et al: An adenovirus type 5 early region 18-encoded CTL epitope-mediating tumor eradication by CTL clones is downmodulated by an activated ras oncogene. J Immunol 1543396,1995 Toes REM, Offringa R, Blom RJJ, Melief CJM, et a1 Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction. Proc Natl Acad Sci USA 93:7855, 1996 Townsend S, Allison J: Tumor rejection after direct costimulation of CD8 + T cells by B7-transfected melanoma cells. Science 259:368, 1993 Tweddel G, Heller P, Cunnane M, et al: The correlation between HIV seropositivity, cervical neoplasia, and HPV subtypes 6/11, 16/18, 31/33/35. Gynecol Oncol 52:161, 1994 Ulmer JB, Donnelly JJ, Parker SE, et al: Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259:1745, 1993 van Driel WJ, Ressing ME, Brandt RPM, et al: Vaccination with HPV 16 peptides of patients with advanced cervical carcinoma: Clinical evaluation of a phase 1-11 trial. Submitted for publication, 1998. van Driel WJ, Tjiong MY, Hilders CGJM, et a1 Association of allele-specific HLA expression and histopathologic progression of cervical carcinoma. Gynecol Oncol 62:33, 1996 Villiers EM: Heterogeneity of the human papillomavirus group. J Virol 63:4898, 1989 Vogelstein B, Kinzler RW P53 function and dysfunction. Cell 70:523, 1992 Weinberg RA: Tumor suppressor genes. Science 254:1138,1991 Yannelli JR, Hyatt C, McConnell S, et al: Growth of tumor-infiltrating lymphocytes from human solid cancers: Summary of a 5-year experience. Int J Cancer 65413,1996
Address reprint requests to Willemien J. van Driel, MD Department of Gynecology H3-P Leiden University Medical Center P.O. Box 9600 2300 RC Leiden The Netherlands
0889-8588/99 $8.00
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IMMUNOTHERAPEUTIC STRATEGIES FOR CERVICAL SQUAMOUS CARCINOMA Willemien J. van Driel, MD, Gemma G. Kenter, PhD, Gert Jan Fleuren, PhD, Cees J. M. Melief, PhD, and Baptist J. Trimbos, PhD
BIOLOGY AND VIRAL TRANSMISSION OF HUMAN PAPILLOMAVIRUS
Evidence that infection with human papillomavirus (HPV) is associated with carcinogenesis is provided both by epidemiologic and experimental studies. Epidemiologic studies show that the great majority of all grades of premalignant lesions of the cervix can be attributed to oncogenic HPV infection.” Analysis of the presence of specific HPV genotypes in premalignant cervical intraepithelial neoplasia and cervical carcinoma, makes it clear that the prevalence of HPV increases with the severity of the lesion, mainly because of contributions from HPVs 16 and 18.14In patients with a normal cervical cytology, the prevalence of HPV infection is age-dependent and varies from 20% in women between 20 and 25 years old to 6% in women older than 30 years.59Most grade I11 cervical intraepithelial neoplasia and a high percentage of grade I1 cervical intraepithelial neoplasia contain high-risk HPV types (primarily HPV 16 or 18), and both high- and low-risk HPV types have been observed in grade I cervical intraepithelial n e o ~ l a s i aIt. ~has ~ been shown that HPV infection fulfills a central etiologic role in the origin of cervical From the Departments of Gynecology (WJvD, GGK, BJT), Pathology (GJF),and Immunohematolog (CJMM), Leiden University Medical Center, Leiden, The Netherlands
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squamous carcinoma ~ o r l d w i d eAmong .~ patients with cervical squamous carcinoma in western Europe, the prevalence of HPV 16-positive tumors of the cervix is reported to vary between 47% and 90%. On average, 65% of all cervical squamous carcinomas may contain HPV 16.5.45'58 Experimental evidence for immortalizing capacities resulting from HPV infection is provided by studies in which epithelial cells transfected with HPV 16 resulted in the transfected cells having an indefinite life span.66This finding tells us that only DNA fragments carrying the E6 and/or E7 genes are necessary to immortalize human ~ e l i s . ~ ~ HPVs are double-stranded circular DNA viruses with a genuine size of 8,000 kilobase. The HPV genome can be divided into three segments of unequal sizes: a long control region, which represents about 10% of the genome, and the early (E) and late (L) genes, which make up about 50% and 40% of the genome, re~pectively.~~ Two L genes, L1 and L2, code for viral capsid proteins; the E genes encode proteins that have a variety of regulatory functions. Three E genes may be important in carcinogenesis: E2, E6, and E7.38The E2 protein regulates transcription and replication of the HPV genome by encoding a regulatory protein that is involved in the regulation of the viral promoter that directs the expression of the E6 and E7 genes. E2 is capable of suppressing growth and of arresting the cell cycle, functions that correlate with the inhibition of E6 and E7 transcripts.18 HPV can be divided into low- and high-risk genital types. One of the differences between the two lies in the relatively high binding capacity of high-risk HPV E6- and E7-encoded proteins to products of tumor suppressor genes. Low-risk HPVs show no such binding. Lowrisk genital HPVs such as 1, 6 and 11 are found in common skin warts, genital warts, and condylomata acuminata, respectively. Highrisk genital HPVs such as 16, 18, 31, and 33 are found in invasive cervical carcinoma.94The E6 protein associates with the product of the p53 tumor-suppressor gene, and this association leads to the increased breakdown of the p53 protein.71,95 Normally, p53 is required for the growth arrest that follows cellular DNA damage, and inhibition or absence of this property leads to genomic in~tability.~~, 52 A common polymorphism of p53 may be an important factor in this respect. Recently, it was shown that the arginine form of p53 residue 72 is more susceptible to the E6-mediated degradation than is the proline form of p53. This renders individuals homozygous for arginine p53 seven times more susceptible to HPV-associated carcinogenesis.80The E7 protein has been associated with the product of the retinoblastoma tumor-suppressor gene, and this association alters activities of the retinoblastoma protein by activating the transcription of genes that regulate cell proliferation.2*%
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RATIONALE FOR IMMUNOTHERAPY HPV-Associated Cervical Abnormalities and TCell-Mediated lmmunoresponsiveness
Involvement of T-cell-mediated immunoresponsiveness in the defense against HPV-related cervical abnormalities is suggested by several observations. First, cervical abnormalities, including premalignant and malignant lesions, show an increased incidence in immunocompromised patients such as renal transplant recipients and patients infected with the human immunodeficiency virus.26,40, 65, 75,82, 91 Second, spontaneous regression of HPV-associated cervicovaginal infection and clearance of subsequent HPV infection have been described.36Third, immunohistochemical studies show extensive infiltrates in tumors consisting of immunocompetent cells. Downregulation of human leukocyte antigen (HLA) class I molecules occurs in the progression from premalignant cervical lesions to cervical carcinoma, and this downregulation correlates with histopathologically progressive disease.l2? 34, 93 Some associations of particular HLA alleles with increased susceptibility to, or protection from, HPV infection and cervical neoplasia have been reported, suggesting that these HLA molecules may present HPV-derived peptides to the immune system.19,79 Fourth, evidence for T-cell immunosurveillance and local adaptive immunoresponsiveness has been provided by experiments in which specific cytotoxic T-cell clones against an autologous tumor were obtained from tumor-infiltrating lymphocytes of primary cervical carcinoma^.^^ In addition, evidence for the existence of natural immunity against HPV-induced infection has been provided by the detection of virus-directed immunoresponsiveness in patients with HPV DNA-positive lesions that are not seen in healthy 63, Because early regions E6 and E7 are retained in the majority of cervical cancer cells? 78 the HPV 16 E6 and E7 proteins form attractive targets for T-cellbased immunotherapy of cervical carcinoma.
VACCINE TECHNIQUES AND CLINICAL PROSPECTS
Several types of vaccines and vaccination techniques are being researched for use in HPV and HPV-associated cervical cancers. Developmental and clinical progress of these vaccines and techniques are described below.
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Adoptive Transfer of Cytotoxic T Lymphocytes
Immunotherapy of tumors by adoptive transfer of in vitroexpanded cytotoxic T lymphocytes in combination with interleukin-2 has been successful in eradicating large human adenovirus-induced tumors established in In addition, the adoptive transfer of cytotoxic T lymphocytes raised against a subdominant HPV 16 E7 cytotoxic T-lymphocyte epitope has been successfully applied in mice against HPV 16-induced tumors, resulting in tumor e r a d i c a t i ~ n . ~ ~ So far, generation of tumor-infiltrating lymphocytes has been obtained from biopsy specimens of recurrent melanoma, breast cancer, colon cancer, and renal cell carcinoma showing autologous cytolysis. Tumor-infiltrating lymphocytes derived from metastatic lesions are more likely to display these cytolytic characteristic^.^^ Tumor-infiltrating lymphocytes with NK- or LAK-mediated killing potential not restricted to the major histocompatibility complex (MHC) have also been isolated at the tumor site of cervical carcinoma.35In addition, HPV 16 E7 peptidespecific cytotoxic T lymphocytes have been found at the tumor site and in draining lymph nodes.*l These tumor-infiltrating lymphocytes may prove to be very useful in adoptive transfer experiments and need to be investigated further. Peptide-Based Vaccines for Cervical Carcinoma
Vaccination with tumor-specific peptides may activate antigen-specific cytotoxic T lymphocytes. Because HPV 16 E6 and E7 peptides are retained in cervical cells and can be considered crucial for malignant transformation, vaccination with HPV 16 E6- or E7-derived peptides may boost the production of tumor-specific cytotoxic T lymphocytes. In vivo studies in mice have shown that successful vaccination with HPV 16 E7-derived, high-affinity MHC class I-binding peptides can induce protection against the outgrowth of an otherwise lethal challenge of 86 Cytotoxic T lymphocytes HPV 16-transformed syngeneic tumor cells.22, induced by this immunization protocol were capable of lysing peptidepulsed target cells, as well as tumor cells, in vitro. Moreover, synthetic peptides derived from two different tumor-associated antigens induced 57 Howthe regression of already established tumors in animal ever, peptide vaccination may not be harmless. Research with an adenovirus tumor model has shown that vaccination with the Ad5ElA peptide may cause tolerance instead of immunity against subsequent inoculation with Ad5ElA-expressing tumors.87,89 Such T-cell tolerance may result from the features of the peptides used for the vaccination or from the treatment scheme. The HPV 16 E7-encoded peptide is retained locally,
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whereas the Ad5ElA peptide diffuses rapidly throughout the body. The wide diffusion of the Ad5ElA peptide may result in exhaustion of cytotoxic T lymphocytes when combined with improper costimulation. In contrast, the local retention of the HPV 16 E7 peptides may explain its immunizing capacities. Tolerance may also result from the treatment scheme and mode of administration. A peptide vaccination given subcutaneously may be more effective in inducing protective cytotoxic T lymphocytes than peptides administered systemically (i.e., intraperitoneally).' To augment the peptide-specific responses, immunization with dendritic cells pulsed with E7 proteins can be more effe~tive.~, 68 Studies in mice demonstrated specific responses from cytotoxic T lymphocytes both in vitro and in vivo following vaccination of dendritic cells with HPV 16 E7 peptides. This vaccination resulted in protection against inoculation with syngeneic HPV 16-induced tumor cells.I5These findings support the importance of testing the immunization and tolerance properties of anticancer peptide vaccines and of using a proper peptide delivery method to avoid tolerance. Peptides encoded by HPV 16 E6 and E7 that are recognized by human cytotoxic T lymphocytes in a HLA-A2-restricted fashion have been identified for use in vaccinating patients with HPV 16-positive cervical carcinoma.67Recently, a phase 1-11 study was completed in patients with recurrent or residual cervical carcinoma that conventional therapy failed to control. No adverse side effects occurred in patients treated on this protocol. However, while four patients showed lymphoproliferative responses against the pan-DR helper peptide, no specific responses by cytotoxic T lymphocytes were seen against the injected HPV 16 E7 peptides. All patients had a low frequency of influenza virus-specific cytotoxic T lymphocytes and poor proliferative responses to tetanus toxoid and the purified protein derivative of Mycobacteriurn tuberculosis, indicating that these patients were seriously immunocompromised?*" Vaccination with Virus-like Particles
The assembly of the major capsid protein of papillomaviruses results in virus-like particles that lack potentially oncogenic viral proteins. This process results in the generation of neutralizing antibodies, which make virus-like particles attractive candidates for a prophylactic vac73, 74 The ability of virus-like particles to protect against HPVinduced abnormalities have been tested with models, including the cottontail rabbit papillomavirus (CRPV) animal model. The CRPV is an appropriate model because CRPV-induced disease in domestic rabbits closely mimics high-risk HPV disease, and rabbit immunity to CRPV
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has many parallels with human immunity to HPV.7 In this animal model, long- and short-term effective humoral protection against experimental papillomavirus infection was achieved following inoculation with native CRPV virus-like particles composed of L1 alone or in combination with L2.". 39 Moreover, naive rabbits were protected against inoculation with CRPV following the passive transfer of serum or immunoglobulin G from rabbits immunized with CRPV virus-like particles. These results show that neutralizing antibodies are capable of providing protectioa8 The antigenicity of injected virus-like particles can be evaluated with virus-like particle-based enzyme-linked immunosorbent assay or hemagglutination assay, tests that make it feasible to evaluate the antibody response after clinical application in humans.47,69 Using these assays, Roden et a170 showed that virus-like particle-based vaccines of HPVs 6, 11, 16,18,31,33, and 45 predominantly generate type-specific antibodies that have limited cross-protection for very closely related HPV types. Other research has explored the use of chimeric virus-like particles consisting of the L1 major capsid protein plus the entire E7 papillomavirus protein fused to the L2 minor capsid protein. This virus-like particlebased vaccine provided humoral protection and induced cellular-mediated protection against tumor injection in mice.28
Vaccination with Vectors Encoding for HPV Use of a recombinant virus vector that carries the genes for HPV 16 E6 and E7 proteins enables the production of the target antigen inside host cells and results in antigen processing and MHC class I-mediated antigen presentation. This approach induced antibody, T-cell proliferative, and cytotoxic T-lymphocyte responses to the HPV 16 E6 antigen in a mouse model using a vaccinia 29 In addition, specific activity of cytotoxic T lymphocytes against the HPV 16 E7 peptide was generated using a recombinant vaccinia virus that expressed the E6 and E7 proteins of HPVs 16 and 18.6 There is one report of a clinical trial using a recombinant vaccinia virus encoding modified forms of HPVs 16 and 18 E6 and E7 protein sequences. The poor immune status of the majority of the screened patients excluded them from obtaining this treatment. Eight patients who showed sufficient immunocompetence to clear vaccinia virus infection were included. Vaccine-specific cytotoxic Tlymphocyte activity against HPV 18 was detected in one patient, and antibodies specific for HPV 18 E7 developed in three patient^.^ Humoral immunoresponsiveness has been generated in mice using salmonella vaccine strains harboring the HPV 16 E7 but proliferative responses were not d e t e ~ t a b l eThus, . ~ ~ this approach is currently less attractive as a therapeutic vaccine for cervical abnormalities.
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DNA Vaccines
DNA vaccines utilize injection with DNA encoding for antigenic proteins. Such DNA vaccines are capable of inducing both humoral and cell-mediated immunoresponsiveness against viral proteins.92Immunization with DNA vaccines evades the use of a protein, a live replicating vector, or an attenuated version of the pathogen, but the mode and sequence of delivery of a DNA vaccine may influence the effectiveness of immune response^.'^ DNA vaccination with DNA originating from HPV is of special interest in the prevention and treatment of cervical abnormalities. In the CRPV model, injection of a DNA vaccine consisting of papillomavirus L1 resulted in the generation of antibodies against papillomavirus L1.16 Vaccinating rabbits intradermally with a DNA vaccine encoding for CRPV E6 using a gene gun resulted in E6-specific proliferative responses in peripheral blood mononuclear cells and concomitantly gave partial protection against papillomavirus-induced papilloma~.~~
EVASION OF IMMUNORESPONSIVENESS Antigen Presentation
Adequate presentation of antigens is required for optimal immunoresponsiveness. Cells capable of properly presenting antigens, i.e., antigen-presenting cells, are dendritic cells and macrophages. These professional antigen-presenting cells contain special properties to prime tumorspecific T cells in T cell-dependent areas of lymph nodes." Thus, for effective presentation of an antigen to a T cell, antigens must be released from the tumor cell and taken up by the antigen-presenting cell.31Antigens presented in the context of HLA class I molecules on neoplastic cells are subsequently recognized by the T-cell receptor. Because HLA class I molecules are often reduced or lost in premalignant and malignant lesions, tumor cells may have gained a way to escape immunosurveillance.l2, 33 This possibility is supported by the finding that reduced expression of HLA class I molecules in cervical carcinoma is associated with a decrease of CD8+ T lymphocytes between tumor cells.% Reduced expression of HLA class I molecules can enhance the susceptibility of tumor cells to lysis by natural killer cells, but a low number of natural killer cells are found in the tumor infiltrate of cervical carcinoma.MIn contrast, HLA class I1 molecules often show enhanced expression in cervical carcinoma and may thus confer the ability to present antigens to helper T lymphocytes, evoking efficient immunoresponsiveness.33~ 53
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Expression of stable MHC class I molecules on the epithelial cell membrane requires loading of the MHC class I heavy-chain/beta-2microglobulin dimer with peptide. Two transporter-associated with antigen processing (TAP) mechanisms exist, one TAP-dependent and one TAP-independent. The TAP-dependent mechanism involves the transport of peptides from the cytosol to the endoplasmic reticulum lumen via a peptide transporter encoded by the TAP1 and TAP2 genes.76,77 The TAP-independent pathway is concerned with proteolysis of signal sequences in the endoplasmic reticulum, resulting in peptides capable of binding HLA In cervical carcinoma, the expression of HLA class I molecules occurs partly concomitantly with the expression of the TAP.13,44 Loss of the TAP results in reduced levels of peptides in the endoplasmic reticulum, destabilizing HLA class I molecules and causing reduced expression of the HLA class I/peptide complex at the cell surface.62In these cases, inhibition of peptide transport by downregulation of TAP may provide tumor cells with a mechanism to reduce MHC class I expression and thus escape cytotoxic T lymphocyte-mediated recognition. This condition may be overcome by treatment of tumor cells with cytokines such as interferon-gamma, which is capable of restoring the expression of MHC class I and TAP.2o,30 In those cases where expression of HLA class I molecules and TAP do not correlate, a genetic loss of HLA genes may be responsible for the loss of HLA expression, a consequence that provides tumor cells with an additional mechanism with which to evade imm~nosurveillance.~~ To overcome these mechanisms of tumor evasion, certain adjustments to the vaccines may be beneficial. In case of peptide-based vaccination, delivery of peptides pulsed onto dendritic cells, as professional antigen-presenting cells, appears to induce strong and protective immunoresponsiveness against all available MHC classes I- and 11-binding peptides. As mentioned above, loading dendritic cells with HPV 16 E7 proteins results in adequate cellular immunoresponsiveness against inoculation with HPV 16-induced tumor and may provide a way to present tumor antigens by means of professional antigen-presenting cells.I5Antigen presentation may also be optimized by introducing costimulatory B7 (CD80, CD86) genes. For example, transfection of moderately immunogenic mouse tumor cells with the B7.1 (CD80) gene ren90 Indeed, the introduction dered these cells much more immunogenic.l0< of this costimulatory molecule elicited a primary HPV 16 E7-specific response by cytotoxic T lymphocytes in v i t r ~ Injecting .~~ patients with gynecologic (cervical or ovarian) cancer with DNA-liposome-contained HLA-A2 DNA resulted in regression of cutaneous lesions in 20% of patients, and isolated peripheral blood mononuclear cells of one patient with cervical carcinoma showed increased cytolytic activity against the
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autologous tumor. These findings show that the introduction of MHC genes might provide an additional way to augment cytolytic a~tivity?~ lmmunomodulation
Interactions between antigens presented by tumor cells or antigenpresenting cells on the one hand and effector cells on the other are promoted by the production of cytokines. T cells are important producers of cytokines, and T, cells, particularly, play a role in this respect. In general, two types of responses can be distinguished, depending on the cytokine profile.55,6o A type 1 response involves interferon-gamma and interleukin-2 and augments cytolytic activity by activating CD8+ T cells. Interferon-gamma may exploit this effect on both the cytotoxic T cells and the antigen-presenting cells in optimizing the expression of HLA class I m01ecules.~~ A type 2 response is characterized by the production of interleukins 4,5,6,9, and 10; the promotion of eosinophil maturation, activation, and survival; the facilitation of antibody production; and the protection against infection with extracellular parasites.60, Both responses exert negative feedback on each other through the production of their cytokines; therefore, it is possible that a type 2 response impedes cell-mediated immunity.55 By studying the role of costimulating factors in the process of antigen presentation (i.e., in directing the type of response), it was found that molecules of the B7 family might have a determining role. B7-1 (CD80) molecules lead to the generation of T cells that produce type 1 . cytokines, whereas B7-2 (CD86) molecules stimulate the production of type 2 cytokines by T cells.5O To optimize immunoresponsiveness by favoring the development of type 1 responses, it might be useful to add cytokines such as interferon-gamma or interleukin-2. As mentioned above, adding interferon-gamma to the vaccine enhances the susceptibility of cervical cancer cells to lysis by tumor-specific cytotoxic T lymphocytes by augmenting HLA class I expression.*l This may be achieved by periturnoral injections of biologic-response modifiers, as was shown when this procedure was used with OK432, resulting in the activation of interferon-gamma production by CD4 + cells. Vaccination with dendritic cells pulsed with the response modifier and peptide suppressed the growth of subsequent inoculation with P815 mastocytoma.M CONSIDERATIONS FOR CLINICAL APPLICATION OF HPV VACCINES
Experimental studies have provided evidence for the existence of both preventive and therapeutic effects of vaccines directed against
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HPV. In the development of these vaccines for disseminated clinical application, several factors should be considered. First, the adoptive transfer of cytotoxic T lymphocytes obtained from peripheral blood mononuclear cells or tumor-infiltrating lymphocytes in a human setting may be a costly and time-consuming procedure, because cytotoxic T lymphocytes must be patient-derived to avoid allogeneic rejection resulting from MHC polymorphism. Second, the use of HPV 16 E7 peptide-based vaccines has been shown to have both preventive and therapeutic characteristics in an animal model. Cytotoxic T-lymphocyte activity against an HPV peptide tested in a clinical phase 1-11 trial could not be detected, nor was any therapeutic effect seen; however, the detection of lymphoproliferative responses shows that vaccination with this highly immunogenic peptide emulsified in Montanide ISA 51 (a mineral oil-based adjuvant similar to incomplete Freund’s adjuvant [Seppic, Paris, France]) may induce a detectable peptide response. Not finding any HPV 16-specific cytotoxic T-lymphocyte activity may result from either a failure of the detection method and/or the immunocompromised state of the study group who received the peptide vaccination, but no side effects occurred in the study group, and the treatment was well tolerated. Results such as these stress the importance of performing clinical trials that involve patients who have a low tumor burden and who are immunocompetent. In such cases, peptide vaccination could be used as an adjuvant to the primary treatment of cervical cancer, especially since peptides are generally easy to make at low cost. In addition, the efficacy of inducing a cytotoxic T-lymphocyte response may be augmented by delivering dendritic cells pulsed with MHC class I-binding peptides. Studies investigating the feasibility of these approaches are currently in progress. A third factor to consider for wide clinical application is the use of modified viral particles. Virus-like particle-based vaccines seem attractive candidates for preventive vaccines that are capable of inducing immunity to HPV infection and the subsequent development of cervical abnormalities, or as therapeutic vaccines for already established cervical abnormalities. However, it may become too expensive to execute vaccination schemes on a large scale, especially in developing countries that have a high incidence of HPV-associated cervical abnormalities. Recombinant vaccinia virus that expresses the E6 and E7 proteins of HPVs 16 and 18 is capable of inducing vaccine-specific cytotoxic Tlymphocyte activity and antibody production, but whether the produced antibodies will have preventive activity against subsequent inoculation has not been confirmed. Despite the difficulty of detecting HPV-specific cytotoxic T-lymphocyte activity, the use of vaccinia virus seems promising and needs further evaluation to establkh its significance. A fourth consideration is the development of effective DNA vaccination as seen in the CRPV animal model. While DNA vaccines are easy
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to generate at low cost, the safety aspects for their use in humans must be examined. Injecting plasmid DNA into the genome of host cells may be potentially harmful, inducing mutagenicity or resulting in disruption of a cellular gene. Studies conducted so far have not yet detected integration after injection of plasmid DNA encoding for i n f l u e n ~ aIn .~~ addition, because anti-DNA antibodies are detected in a number of autoimmune diseases such as systemic lupus erythematosus, it remains to be established whether DNA vaccines induce anti-DNA antibodies in humans and subsequently produce autoimmune phenomena.
SUMMARY
Progress in developing preventive and therapeutic vaccines for HPV-associated diseases has been made in the last few years, but continued studies are needed to evaluate the clinical feasibility of different vaccination approaches and to determine a clinically effective and safe one. The perfect HPV vaccine will have both preventive and therapeutic capabilities, and because it is likely to be used world-wide, especially in developing countries, it must also have low production costs.
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