Cervical Cancer Vaccines: Recent Advances in HPV Research

Eiben, Gretchen L.; Silva, Diane M. Da; Fausch, Steven C.; Poole, I. Caroline Le; Nishimura, Michael I.; Kast, W. Martin

doi:10.1089/088282403322017866

Cited by 62 publications

(47 citation statements)

References 62 publications

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“…Anchorage-independent growth was determined by the colony formation efficiency of cells suspended in soft agar. E7WT and E7IR transformed NIH 3T3 cells were plated in triplicate dilutions (1×10 4 , 2×10 4 , and 4×10 4 ) and colonies were stained and counted after a two week incubation. Mean colony counts were determined as a function of normalized triplicates in each dilution series.…”

Section: Discussionmentioning

confidence: 99%

“…Transformed and control cells were plated in triplicate dilutions (1×10 4 , 2×10 4 , and 4×10 4 ) in 2 ml of 0.3% overlay agar and added to 6 well plates coated with 3 ml of 0.6% underlay agar. Plates were allowed to dry and were incubated at 37°C…”

Section: Soft Agar Assaymentioning

confidence: 99%

“…Of course, in this instance mutations in the p53 and pRB binding sites are essential in order to prevent vaccination induced cellular transformation. Furthermore, administration of DNA based vaccines has been shown to induce CTL to HPV antigens [4].…”

Section: Introductionmentioning

confidence: 99%

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The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors

Brinkman

Kast

2007

Vaccine

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A majority of cervical cancers are associated with HPV-16. A DNA vaccine (E7IR) was designed for prophylactic and therapeutic treatment of HPV-16+ tumors containing two repeats of the E7 gene to inactivate transformation and duplicate available epitopes. Mice were vaccinated then tumor challenged, or challenged and then immunized and monitored for tumor volume and survival. Splenocytes were utilized for in vivo CTL assays. The E7IR vaccine demonstrated decreased tumor volume and enhanced survival in prophylactic and therapeutic experiments and improved CTL mediated lysis. The E7IR vaccine shows promise in prevention of tumor formation and elimination of established tumors. KeywordsHuman Papillomavirus (HPV); DNA Vaccine; Cervical Cancer 1.IntroductionCancer of the uterine cervix is the second most common cause of cancer-related deaths in women worldwide. Approximately 510,000 new cases and 288,000 deaths are reported annually [1]. The development of cervical cancer is associated with infection with high risk types of Human Papillomaviruses (HPV). HPV is detected in 99.7% of cervical carcinomas [2], with high risks types HPV-16 and 18 accounting for nearly 70% of cervical cancer cases [3]. In contrast to many other cancers, the fact that cervical cancer is highly associated with a viral infection creates a unique opportunity for therapeutic vaccination against HPV to either prevent cervical cancer once an individual is infected or after the virus has caused cervical cancer. Integration of the viral genome into the host cell genome, a necessary step in cellular transformation, leads to the loss of some genes necessary for a productive viral life cycle and to deregulated or overexpression of the E6 and E7 oncoproteins. Because E7 has been shown to be consistently expressed in HPV-16 positive tumors, it is a logical target in HPV-16 vaccination strategies. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Preclinical studies using DNA based vaccine approaches tend to focus on enhancing presentation of HPV antigens via the MHC class I or MHC class II pathways [5]. Several different approaches have been examined including the attachment of ubiquitin to DNA constructs [6,7], targeting of tumor antigens to centrosomal compartments to enhance MHC class I presentation [8], the attachment to constructs of calreticulin to target HPV antigens to the MHC I pathway [9], optimization of codon usage for enhanced expression and presentation of HPV oncogenes [6,10,11] , utilization of modified genes to decrease the transformation capacity [12][13][14] or enhancement of intercellular s...

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Section: Discussionmentioning

confidence: 99%

Section: Soft Agar Assaymentioning

confidence: 99%

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The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors

Brinkman

Kast

2007

Vaccine

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“…The traditional detection of cervical pre-cancers by cervical cytological screening using the Papanicolaou (Pap) smear test has dramatically reduced the incidence of cervical cancer in the developed world due to early intervention with therapy. However, underdeveloped countries are unable to implement comprehensive screening-based programs, so early detection and treatment of cervical pre-cancers is very limited [5,6]. Patients who are diagnosed with early-stage disease can be treated with surgery, radiotherapy, or chemotherapy, but many patients still succumb to the disease [6,7].…”

Section: Introductionmentioning

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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“…11,12 Vaccine strategies targeting E6 and E7, using peptides, 13 proteins, 14 viral vectors 15 and plasmid DNA, 16,17 have been reported. However, there is only limited information on the CD8 1 T cell response to HPV E2.…”

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confidence: 99%

Combined prophylactic and therapeutic cancer vaccine: Enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA‐A2 mice

Qian

Dong

Pang³

et al. 2006

Intl Journal of Cancer

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We identified the strategies to induce a CTL response to human papillomavirus (HPV) 16 E2 in HLA-A2 transgenic mice (AAD). A chimeric HPV16 virus-like particle (VLP) that includes full length HPV16 E7 and E2 (VLP-E7E2) was generated. The combination of E2 and E7 has the advantage that E2 is expressed in early dysplasia and neoplasia lesions, where E7 is expressed in more advance lesions. Since T cell response to E2 is less defined, we first evaluated the strategies to enhancing CD8 1 T cell responses to HPV E7, using different combinations of immune-modulators with VLP-E7E2. Data showed that the CTL response to E7 could be significantly enhanced by coinjection of GM-CSF and antiCD40 antibodies with chimeric VLP-E7E2 without adjuvant. However, using the same combination, a low level of CD8 1 T cell response to E2 was detected. To enhance the CD81 T cell response to E2, we analyzed T cell epitopes from E2 sequence. A heterogonous prime-boost with chimeric VLP-E7E2 and E2 peptides was performed. The data showed that the priming with chimeric VLP-E7E2, followed by boosting with E2 peptides, gave a better CTL response than 2 immunizations with E2 peptides. The enhanced immunity is due to the increase of CD11c 1 and CD11c 1 CD40 1 double positive dendritic cells in mice that received immune-modulators, GM-CSF and antiCD40. Furthermore, the level of anti-L1 antibodies remains similar in mice immunized with chimeric VLP with/without immune-modulators. Thus, the data suggested that the chimeric VLP-E7E2 has a therapeutic potential for the treatment of HPV-associated CINs and cancer without diminishing VLPs potential as a prophylactic vaccine by inducing anti-L1 antibodies against free virus. ' 2006 Wiley-Liss, Inc.Key words: vaccine; HPV 16; CTL; chimeric VLP; HPV 16 E2; dendritic cells Human papillomavirus infections are associated with a spectrum of epithelial diseases from benign warts to cervical intraepithelial neoplasia (CIN) to invasive carcinoma. Almost all cervical cancers are caused by HPV infection, most often HPV16.1 Therefore, the development of effective HPV vaccines could contribute greatly to the prevention and treatment of cervical neoplasia and other diseases caused by HPV infection. Substantial advances have been made in developing HPV prophylactic vaccines based on L1 virus-like particles that induce neutralizing antibodies to L1. [2][3][4][5] In contrast, therapeutic HPV vaccines have not yet demonstrated high efficacy against cervical cancer or premalignant HPVinduced neoplasia in clinical trials.6 Humoral base vaccine is essential to eradication of HPV infection in uninfected population. However, for the population with HPV exposure, a combined prophylactic/therapeutic vaccine would be an essential development. It could promote mass immunization programs of both preadolescent and older women, many of whom have already been exposed to genital tract HPV infection. A combined vaccine could offer the best combination of immediate impact and long-term effectiveness. It will be particularly useful in dev...

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Cervical Cancer Vaccines: Recent Advances in HPV Research

Cited by 62 publications

References 62 publications

The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors

The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

Combined prophylactic and therapeutic cancer vaccine: Enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA‐A2 mice

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