Antitumor efficacy of Venezuelan equine encephalitis virus replicon particles encoding mutated HPV16 E6 and E7 genes

Cassetti, M. Cristina; McElhiney, S; Shahabi, Vafa; Pullen, Jeffrey K.; Poole, I. Caroline Le; Eiben, Gretchen L.; Smith, Larry; Kast, W. Martin

doi:10.1016/j.vaccine.2003.07.003

Cited by 103 publications

(108 citation statements)

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“…The E7IR vaccine design attempts to resolve these challenges first by utilizing well characterized mutations that interfere with binding to the host cell Rb protein and by creating a gene coding for an artificial E7 protein that is unlikely to keep its original function through inserted and replicated sequences thus reducing the transformation capacity of the construct [17]. Another commonly utilized method to reduce the transforming capacity of the E7 oncogene has been to create epitope based vaccines typically containing a few common human epitopes [12].…”

Section: Discussionmentioning

confidence: 99%

“…The nucleotide sequence was synthesized by Entelechon (Entelechon GmbH, St. Veit-Weg 2, 93051 Regensburg) and was cloned into a PCR4 topo vector and sub-cloned into the APL023 expression vector [7]. In the a region, amino acids 21, 24, and 26 were modified from DLYCYEQ to GLYGYGQ to reduce transformation activity and enhance antigenicity [17,18]. In the b region, a split was introduced between two cystine residues at position 31 and 32 to reduce transformation activity.…”

Section: Construction Of the E7ir Vaccinementioning

confidence: 99%

“…However, although DNA vaccination appears to be a safe means to deliver HPV antigens, DNA vaccination with oncogenes still harbors the risk of transformation for the cells that receive and express the oncogenes [27,28]. Thus E7 based vaccine strategies seek to simultaneously eliminate or reduce the transforming ability and enhance the immunogenic potential of the E7 oncoprotein.The E7IR vaccine design attempts to resolve these challenges first by utilizing well characterized mutations that interfere with binding to the host cell Rb protein and by creating a gene coding for an artificial E7 protein that is unlikely to keep its original function through inserted and replicated sequences thus reducing the transformation capacity of the construct [17]. Another commonly utilized method to reduce the transforming capacity of the E7 oncogene has been to create epitope based vaccines typically containing a few common human epitopes [12].…”

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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: Construction Of the E7ir Vaccinementioning

confidence: 99%

mentioning

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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“…E6WT and E6GG 22 were obtained from GeneArt (Hilden, Germany), with codon optimization for expression in human cells, and were all cloned between the HindIII and XbaI sites of pVAX. The generation of E7SH has been described elsewhere, 23 and E6SH was constructed in a similar fashion.…”

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confidence: 99%

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Oosterhuis

Öhlschläger

Berg

et al. 2011

Intl Journal of Cancer

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To allow vaccination irrespective of HLA type, DNA vaccines encoding full-length antigens are required. However, here, we demonstrate that the immunogenicity of DNA vaccines encoding the full-length human papillomavirus (HPV) type 16 E7 and E6 proteins is highly reduced compared to vaccines encoding only the immunodominant epitope. Furthermore, the low remaining immunogenicity is essentially lost for both E7 and E6 when a nononcogenic ''gene-shuffled" variant is utilized. To address these issues, we tested whether alterations in transgene design can restore the immunogenicity of full-length and geneshuffled DNA vaccines. Remarkably, genetic fusion of E7 with tetanus toxin fragment C (TTFC) resulted in a dramatic increase in immunogenicity both for the full-length and the gene-shuffled version of E7. Moreover, the TTFC fusion vaccines were more immunogenic than a vaccine encoding a fusion of E7 and mycobacterial heat shock protein-70, which has recently been tested in a clinical trial. Interestingly, vaccination with these TTFC fusion vaccines also resulted in extremely persistent T-cell responses. The E7-specific CD8 1 T cells induced by TTFC fusion vaccines were functional in terms of IFN-c production,formation of immunological memory, in vivo cytolytic activity and tumor eradication. Finally, we show that genetic fusion with TTFC also improves the immunogenicity of a gene-shuffled E6 DNA vaccine. These data demonstrate that genetic fusion with tetanus toxin fragment C can dramatically improve the immunogenicity of full-length and gene-shuffled DNA vaccines. The DNA fusion vaccines developed here will be evaluated for the treatment of HPV-positive carcinomas in future studies.Persistent infection with ''high-risk'' human papillomavirus (HPV) genotypes is strongly associated with the development of anogenital cancers. 1,2 Of the ''high-risk'' genotypes, HPV 16 alone is known to be responsible for about half of the cervical cancer cases worldwide.3 Because persistent expression of the oncogenic HPV proteins E6 and E7 is required for carcinogenesis, these viral antigens are ideal targets for immunotherapeutic interventions. As E6 and E7 are solely expressed intracellularly, such therapeutic interventions should induce cellular immune responses to control existing HPV-induced lesions. 3,4 DNA vaccination forms an attractive approach for the induction of cellular immune responses as the DNA-encoded antigens are by definition produced intracellularly. Furthermore, DNA vaccines are safe, easy to produce, stable and do not suffer from the drawback of preexisting immunity or induction of antivector immunity. 5,6 In murine models, numerous DNA vaccines directed against either HPV 16 E6 or E7 have been tested with promising results.7-13 However, to date, the clinical translation of these approaches has met little success.14,15 Recently, we developed a novel DNA vaccination strategy named DNA tattoo vaccination that can potentially overcome this translational block. This strategy was shown to lead to the rapid induction of...

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“…CTL responses to E7 and E6 are defined and are the targets of immunoprophylactic and immunotherapeutic strategies Greenstone et al, 1998;Chen et al, 1999;Chu et al, 2000;Schirmbeck et al, 2003a;Cassetti et al, 2004;Doan et al, 2005;Yan et al, 2007). Murine models have seen a number of different HPV-associated tumour cell lines being established, which either contain the entire HPV genome (Feltkamp et al, 1993), or mimic the protein expression profile of an HPV-16-derived integrated tumour (Lin et al, 1996).…”

Section: Animal Models Used For Vaccine Developmentmentioning

confidence: 99%

Hepatitis B Surface Antigen-based Vaccines for Human Neoplastic Disease

Haigh¹

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Antitumor efficacy of Venezuelan equine encephalitis virus replicon particles encoding mutated HPV16 E6 and E7 genes

Cited by 103 publications

References 19 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

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Hepatitis B Surface Antigen-based Vaccines for Human Neoplastic Disease

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