Spontaneous regression of CIN and delayed-type hypersensitivity to HPV-16 oncoprotein E7

Höpfl, Reinhard; Heim, K.; Christensen, Neil D.; Zumbach, Klaus; Wieland, Ulrike; Volgger, Birgit; Widschwendter, Andreas; Haimbuchner, Sandra; Müller‐Holzner, Elisabeth; Pawlita, Michael; Pfister, Herbert; Fritsch, Peter

doi:10.1016/s0140-6736(00)03315-8

Cited by 85 publications

(65 citation statements)

References 5 publications

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“…This is in agreement with some reports (de Gruijl et al, 1996a(de Gruijl et al, , b, 1998de Jong et al, 2004), but not others, where CD4 responses have been found to be decreased in cancer (Luxton et al, , 1997Nakagawa et al, 1996;Hopfl et al, 2000;van der Burg et al, 2001;Welters et al, 2003). However, all of these studies use different methodologies and the majority used in vitro restimulation protocols.…”

Section: Human Papillomavirus-specific Immunity Is Different In Cancersupporting

confidence: 92%

“…Using either fusion proteins, panels of overlapping peptides, or virus-like particles (VLPs), CD4 responses to HPV16 E6 (Cubie et al, 1989;Strang et al, 1990;Nakagawa et al, 1996;Tsukui et al, 1996;Kadish et al, 1997Kadish et al, , 2002Welters et al, 2003;de Jong et al, 2004), E7 (Cubie et al, 1989;Strang et al, 1990;Altmann et al, 1992;Kadish et al, 1994Kadish et al, , 1997Kadish et al, , 2002de Gruijl et al, 1996ade Gruijl et al, , b, 1998Luxton et al, 1996;Nakagawa et al, 1996;Tsukui et al, 1996;Hopfl et al, 2000;van der Burg et al, 2001;Welters et al, 2003), E2 de Jong et al, 2002de Jong et al, , 2004Welters et al, 2003), E5 (Gill et al, 1998), E4 (Cubie et al, 1989;Nakagawa et al, 1996) and L1 (Strang et al, 1990;Nakagawa et al, 1996;Shepherd et al, 1996;Luxton et al, 1997;de Gruijl et al, 1999) have been demonstrated in both patient and healthy control populations. No clear pattern has yet emerged as to which of these responses, if any, might be associated with regression or progression of disease as only a limited number of prospective studies have been carried out.…”

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confidence: 99%

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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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Section: Human Papillomavirus-specific Immunity Is Different In Cancersupporting

confidence: 92%

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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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“…9,24 Our results on the possible enhancement of HPV-16 E7 induced T cell responses by local invasive procedures may shed new light on studies that indicated a relation between spontaneous regression of CIN lesions and cellular immune responses against HPV-16 E6 or E7. 9,13 For instance, in the study by Kadish et al, patients were, on average, included 2 months after abnormal cervical cytology and diagnostic biopsy.…”

Section: Discussionmentioning

confidence: 79%

Enhancement of human papilloma virus type 16 E7 specific T cell responses by local invasive procedures in patients with (pre)malignant cervical neoplasia

Visser

Baarle

Hoogeboom

et al. 2006

Intl Journal of Cancer

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It has been suggested that local invasive procedures may alter the natural course of (pre)malignant cervical disease. This could be due to partial excision of the lesions, or via induction of cellular immunity against human papillomavirus (HPV) by the local invasive procedures. We studied the influence of local invasive procedures on HPV-16 E7 specific immune responses in patients with different grades of cervical intra-epithelial neoplasia (CIN) and different stages of cervical cancer. Blood was obtained at intake and after invasive procedures from patients with CIN or cervical cancer. Antigen specific T-cell responses were measured by IFN-c ELISPOT analysis, after stimulation with recombinant HPV-16 E7 protein. As expected, HPV-16 E7 specific IFN-c T cell responses were more frequent in HPV-16 DNA positive patients compared with that in HPV-16 DNA negative patients (39/50 vs. 16/36, (p 5 0.006, v 2 test). After invasive procedures, a small number of HPV-16 DNA positive CIN patients, but a considerable proportion of HPV-16 DNA positive cervical cancer patients, showed an enhancement of T cell responses against HPV-16 E7. Induction of T cell reactivity was most pronounced in cervical cancer patients who had undergone previous invasive procedures. Both CD4 1 and CD8 1 T cells showed E7 specific IFN-c production upon in-vitro stimulation. Our study shows that invasive procedures may enhance HPV-specific cell-mediated immunity in a considerable number of patients with cervical cancer, but in only a minority of CIN patients. Our data indicate that invasive procedures should be considered as possible confounding factors when analyzing the effectiveness of therapeutic immunization studies, especially, when induction of HPV-specific immune responses is used as intermediate end-point. ' 2005 Wiley-Liss, Inc.Key words: cervical cancer; IFN-g; HPV; CD4 1 T cell; CD8 1 T cell Infection with oncogenic human papillomavirus (HPV) plays an important role in cervical carcinogenesis, and HPV DNA can be detected in 90-100% of all cervical cancers. 1,2 The majority of women infected with oncogenic HPV types do not develop cervical intraepithelial neoplasia (CIN) or cervical cancer but clear their HPV infection. The immune system plays an important role herein, as demonstrated by the observation that immunocompromised women, such as AIDS-patients, more often fail to clear an HPV infection and have an increased risk to develop cervical cancer. 3 The E6 and E7 transforming oncoproteins of HPV play a crucial role in the transformation and maintenance of the malignant phenotype, and therefore, these proteins are the ideal candidates for tumor-specific cervical cancer immunotherapy. Cytotoxic T cell (CTL) and T helper activity specific for E6 and E7 of HPV-16 and HPV-18 (the 2 most common HPV types) have been demonstrated in the peripheral blood of patients with (pre)malignant cervical neoplasia and healthy controls. [4][5][6][7][8][9][10][11][12] It has been suggested that spontaneous regression of CIN lesions might be associated with...

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“…3) One study indicated that spontaneous regression of CIN is accompanied by a delayed-hypersensitivity response to the viral E7 protein mediated by CD4 + T cells infiltrating the infected epithelium [47]. These observations support the hypothesis that, although humoral immunity induces antibody-mediated neutralization to protect the host against initial infection, cell-mediated immunity is necessary for the eradication of HPV infection and inhibition of tumor progression.…”

Section: Humoral Immune Responses and Cell-mediated Immune Responses mentioning

confidence: 70%

“…The lipid core peptide (LCP), a vaccine delivery system incorporating lipoamino acids, was used to produce vaccine candidates against HPV-16 [104]. Moyle et al demonstrated that an LCP system that incorporated the long sequence E7 [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] (known as 8Q) with CTL, T helper cell, and B cell epitopes was self-adjuvanting and reduced tumor size. This epitope was unable to prevent TC-1 tumors when delivered alone [104].…”

Section: Vaccine Deliverymentioning

confidence: 99%

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

Liu¹,

Hussein²,

Tóth³

et al. 2012

CTMC

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Cervical cancer is the second leading cause of cancer in women worldwide. Human papillomavirus (HPV) is responsible for all cases of cervical cancer. Commercial prophylactic HPV vaccines are now available, but unfortunately these vaccines have no therapeutic effect against established HPV infections. In order to accelerate the control of cervical cancer and treat established HPV infections, it is necessary to develop therapeutic vaccines to eradicate HPV by generating cell-mediated immunity against HPV infected cells. Two HPV-encoded early proteins, the E6 and E7 oncoproteins, are the preferred targets because they are consistently expressed in virtually all cervical cancer cells and are necessary for the induction and maintenance of HPV-associated disease. A variety of vaccine strategies have been employed targeting immune responses to these proteins. Peptide-based vaccines are a promising strategy for the development of therapeutic HPV vaccines because of their safety, stability, and ease of production. This review summarizes the prospects of peptidebased vaccines for the treatment of established HPV infections. We address the challenges that scientists currently face for developing peptide-based vaccines and explore feasible strategies for improving the potency of the induced immune response with the aim of treating established HPV infections.

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Spontaneous regression of CIN and delayed-type hypersensitivity to HPV-16 oncoprotein E7

Cited by 85 publications

References 5 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

Enhancement of human papilloma virus type 16 E7 specific T cell responses by local invasive procedures in patients with (pre)malignant cervical neoplasia

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

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