DNA vaccines for cervical cancer: from bench to bedside

Chien-Fu Hung,T-C Wu,Ronald D Alvarez,Archana Monie

doi:10.1038/emm.2007.74

Abstract

More than 99% of cervical cancers have been associated with human papillomaviruses (HPVs), particularly HPV type 16. The clear association between HPV infection and cervical cancer indicates that HPV serves as an ideal target for development of preventive and therapeutic vaccines. Although the recently licensed preventive HPV vaccine, Gardasil, has been shown to be safe and capable of generating significant protection against specific HPV types, it does not have therapeutic effect against established HPV infections and HPV-associated lesions. Two HPV oncogenic proteins, E6 and E7, are consistently co-expressed in HPV-expressing cervical cancers and are important in the induction and maintenance of cellular transformation. Therefore, immunotherapy targeting E6 and/or E7 proteins may provide an opportunity to prevent and treat HPV-associated cervical malignancies. It has been established that T cell-mediated immunity is one of the most crucial components to defend against HPV infections and HPV-associated lesions. Therefore, effective therapeutic HPV vaccines should generate strong E6/E7-specific T cell-mediated immune responses. DNA vaccines have emerged as an attractive approach for antigen-specific T cell-mediated immunotherapy to combat cancers. Intradermal administration of DNA vaccines via a gene gun represents an efficient way to deliver DNA vaccines into professional antigen-presenting cells in vivo. Professional antigen-presenting cells, such as dendritic cells, are the most effective cells for priming antigen-specific T cells. Using the gene gun delivery system, we tested several DNA vaccines that employ intracellular targeting strategies for enhancing MHC class I and class II presentation of encoded model antigen HPV-16 E7. Furthermore, we have developed a strategy to prolong the life of DCs to enhance DNA vaccine potency. More recently, we have developed a strategy to generate antigen-specific CD4(+) T cell immune responses to further enhance DNA vaccine potency. The impressive pre- clinical data generated from our studies have led to several HPV DNA vaccine clinical trials.

Highlights

Cervical cancer is an important disease because it is the 2nd largest cause of cancer deaths in women worldwide (Parkin et al, 2005)
The identification and characterization of high-risk human papillomavirus as a necessary causal agent for cervical cancer provides a promising possibility for the eradication of HPV-related malignancies
In the development of therapeutic HPV DNA vaccines, we have focused on enhancing DNA vaccine potency and to augment vaccine-elicited T cell immune responses by: 1) increasing the number of antigen-expressing dendritic cell (DC) via gene gun; 2) improving antigen expression, processing, and presentation in DCs; and 3) enhancing DC and T cell interaction

Summary

Introduction

Cervical cancer is an important disease because it is the 2nd largest cause of cancer deaths in women worldwide (Parkin et al, 2005). It has been established that the primary factor in the development of cervical cancer is persistent infection with human papillomavirus (HPV) and HPV DNA has been detected in 99.7% of cervical cancers (Walboomers et al, 1999). More than 200 HPV genotypes have been identified and they are classified into low or high-risk types, depending on their propensity to cause cervical cancer (de Villiers et al, 2004). High-risk types, such as HPV 16 and HPV 18, are the most frequent HPV type associated with cervical cancer. High-risk HPV types are frequently associated with squamous intraepithelial lesions (SIL), called cervical intraepithelial neoplasia (CIN) precursor lesions of cervical cancer (For a review, see Roden and Wu, 2006). HPV has a circular, doublestranded DNA genome containing about 8,000 base pairs and encoding two classes of proteins: early proteins and late proteins. The early proteins regulate viral DNA replication (E1, E2), viral RNA transcription (E2), cytoskeleton reorganization (E4)

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