HLA-A2-restricted peripheral blood cytolytic T lymphocyte response to HPV type 16 proteins E6 and E7 from patients with neoplastic cervical lesions

Evans, Cc; Bauer, Stefan; Grubert, Thomas; Brucker, Cosima; Baur, Siegfried; Heeg, Klaus; Wagner, Hermann; Lipford, Grayson B.

doi:10.1007/s002620050265

Cited by 47 publications

(54 citation statements)

References 34 publications

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“…Using a variety of restimulation protocols, HPV16 E2-, E6-and E7-specific CTLs can be detected in patients with previous (Nakagawa et al, 1997) or ongoing HPV infections (Alexander et al, 1996;Borysiewicz et al, 1996;Evans et al, 1996Evans et al, , 1997Ressing et al, 1996;Jochmus et al, 1997;Konya et al, 1997;Nimako et al, 1997). Most of this work has involved the use of selected peptides bound to the surface of various target cells to restimulate CD8 responses in vitro.…”

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confidence: 99%

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

et al. 2005

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Infection with high-risk genital human papillomavirus (HPV) types is a major risk factor for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma. The design of effective immunotherapies requires a greater understanding of how HPV-specific T-cell responses are involved in disease clearance and/or progression. Here, we have investigated T-cell responses to five HPV16 proteins (E6, E7, E4, L1 and L2) in women with CIN or cervical carcinoma directly ex vivo. T-cell responses were observed in the majority (78%) of samples. The frequency of CD4 þ responders was far lower among those with progressive disease, indicating that the CD4 þ T-cell response might be important in HPV clearance. CD8 þ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8 þ T cells are not vitally involved in disease clearance. T-cell responses were demonstrated in the majority (80%) of cervical cancer patients, but are obviously ineffective. Our study reveals significant differences in HPV16 immunity during progressive CIN. We conclude that the HPV-specific CD4 þ T-cell response should be an important consideration in immunotherapy design, which should aim to target preinvasive disease.

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confidence: 99%

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

et al. 2005

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“…14 Several studies have shown that some cervical cancer patients still retain natural CTL precursors against HPV16 E6 and E7, 11,12 suggesting that immunotherapy based on HPV16 E6/E7 vaccine(s) might be effective in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Several of these epitopes were found to stimulate CTL responses in vitro in the peripheral blood mononuclear cells of patient donors. 11,12 Recent clinical trials using E6 and E7 recombinant vaccinia virus 13 or E7-glutathione S-transferase fusion proteins 14 as vaccines resulted in the induction of specific CTLs in a portion of the evaluated patients. Both E6 and E7 have also been demonstrated to induce specific CTLs in animal studies.…”

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confidence: 99%

Interleukin-12 cDNA skin transfection potentiates human papillomavirus E6 DNA vaccine-induced antitumor immune response

Tan

Yang²,

Turner

et al. 1999

Cancer Gene Ther

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Human papillomaviruses are associated with Ͼ90% of all cases of uterine cervical tumors. The E6 and E7 oncoproteins of human papillomavirus are potentially ideal targets of immune therapy for cervical cancer, because their expression is necessary for cellular transformation. Although both E6 and E7 proteins contain numerous predicted cytotoxic T lymphocyte (CTL) epitopes that are capable of binding to human leukocyte antigens, the majority of earlier in vivo tumor rejection studies have focused on E7. We show here that gene gun-mediated skin transfection of plasmid vector encoding the nontransforming, amino-terminal half of E6 resulted in the induction of E6-specific CTL activity and tumor rejection in a murine model. The use of recombinant murine interleukin-12 (rmIL-12) as a vaccine adjuvant has been shown to result in both an enhancement and suppression of immune responses, depending upon the doses of rmIL-12 and the experimental systems used. We demonstrate here that local expression of transgenic mIL-12 at the E6 DNA vaccination site potentiated E6-specific CTL responses and increased vaccine-induced antitumor therapeutic efficacy. Our results indicate that transfection of the mIL-12 gene at the vaccination site may represent an attractive adjuvant for cancer gene immunotherapy.Key words: DNA vaccine; human papillomavirus type 16 E6; interleukin-12.C ervical cancer accounts for 15% of all cancer-related deaths and is the second leading cause of cancer deaths in women worldwide.1 Each year ϳ2,500,000 women in the United States alone are diagnosed with low-grade cervical cancer precursor.2 It has been estimated that nearly 15,000 of these individuals develop cervical cancer.3 Therefore, there is a great need to develop a safe and effective vaccine for cervical cancer. The detection of human papillomavirus (HPV) DNA in Ͼ90% of cervical tumors suggests that HPV is etiologically associated with the disease. 4 HPV type 16 is the predominant HPV DNA, being observed in 40 -60% of the cancers. 4 Two HPV16 oncoproteins, E6 and E7, are preferentially expressed in cervical cancer cells.5 These proteins are capable of inducing transformation in cells by disrupting the functions of the cellular tumor suppressors p53 and retinoblastoma.6 -8 Because E6 and E7 are retained in progressive HPV-associated cervical tumors, 5 they are potential tumor-specific targets for the immunotherapy of cervical cancer.Numerous studies indicate that E6 and E7 antigens (Ags) are immunogenic in humans. Potential cytotoxic T lymphocyte (CTL) epitopes that bind to various human histocompatibility leukocyte Ags (HLAs) have been identified within the E6 and E7 proteins.9,10 Several of these epitopes were found to stimulate CTL responses in vitro in the peripheral blood mononuclear cells of patient donors.11,12 Recent clinical trials using E6 and E7 recombinant vaccinia virus 13 or E7-glutathione S-transferase fusion proteins 14 as vaccines resulted in the induction of specific CTLs in a portion of the evaluated patients. Both E6 and E7 have also ...

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“…Numerous HPV are responsible for uterine cervical cancers, most frequently worldwide HPV-16 (4). In infected patients with high-grade cervical intraepithelial neoplasia (CIN 2/3) or invasive cervical carcinoma, blood cytotoxic T lymphocytes (CTL) directed against HPV-16 are barely detectable (5)(6)(7)(8)(9)(10), and no in situ functional studies were completed although in situ cervical cytobrush allows infiltrating lymphocytes to be obtained (11). The impairment of HPV-16 -specific CTL responses could relate to a down-regulation of MHC class I molecules on HPV-16 -infected cells (12) or to T-cell tolerance to HPV proteins (13).…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Regression of Grade 3 Vulvar Intraepithelial Neoplasia Associated with Human Papillomavirus-16–Specific CD4+ and CD8+ T-Cell Responses

Villada

Barracco²,

Ziol

et al. 2004

Cancer Research

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Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was studied in six patients affected with grade 3 vulvar intraepithelial neoplasia (VIN3, also known as bowenoid papulosis). Five of the patients presented with a chronic and persistent disease that relapsed after destructive treatments. They showed no detectable anti-HPV blood T-cell responses and no T-cell intraepidermal vulvar infiltrate containing both CD4؉ and CD8؉ lymphocytes. The last patient had a complete clearance of viral lesions, 8 months after disease onset and 2 months after electrocoagulation of <50% of the VIN3 lesions. She showed high frequency anti-E6 and anti-E7 effector blood T cells by ex vivo ELISpot-IFN␥ assay before clinical regression. Immunohistochemical study of her vulvar biopsy revealed a marked dermal infiltrate containing a majority of CD4؉ T lymphocytes and an epidermal infiltrate made up of both CD4؉ and CD8 ؉ T cells. This seems to be the first evidence of an association between spontaneous regression of VIN3 lesions and HPVspecific T-cell responses detectable in the blood. Hence, an increase of HPV-specific effector T lymphocyte responses by vaccine-based therapeutic strategies might be useful to clear the lesions in bowenoid papulosis disease.

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HLA-A2-restricted peripheral blood cytolytic T lymphocyte response to HPV type 16 proteins E6 and E7 from patients with neoplastic cervical lesions

Cited by 47 publications

References 34 publications

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

Interleukin-12 cDNA skin transfection potentiates human papillomavirus E6 DNA vaccine-induced antitumor immune response

Spontaneous Regression of Grade 3 Vulvar Intraepithelial Neoplasia Associated with Human Papillomavirus-16–Specific CD4+ and CD8+ T-Cell Responses

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