Therapeutic human papillomavirus vaccines: current clinical trials and future directions

Abstract

Background: Cervical cancer is the second largest cause of cancer deaths in women worldwide. It is now evident that persistent infection with high-risk human papillomavirus (HPV) is necessary for the development and maintenance of cervical cancer. Thus, effective vaccination against HPV represents an opportunity to restrain cervical cancer and other important cancers. The FDA recently approved the HPV vaccine Gardasil for the preventive control of HPV, using HPV virus-like particles (VLP) to generate neutralizing antibodies against major capsid protein, L1. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and HPV-associated lesions. Furthermore, due to the considerable burden of HPV infections worldwide, it would take decades for preventive vaccines to affect the prevalence of cervical cancer. Thus, in order to speed up the control of cervical cancer and treat current infections, the continued development of therapeutic vaccines against HPV is critical. Therapeutic HPV vaccines can potentially eliminate pre-existing lesions and malignant tumors by generating cellular immunity against HPV-infected cells that express early viral proteins such as E6 and E7.

Objective: This review discusses the future directions of therapeutic HPV vaccine approaches for the treatment of established HPV-associated malignancies, with emphasis on current progress of HPV vaccine clinical trials.

Methods: Relevant literature is discussed.

Results/conclusion: Though their development has been challenging, many therapeutic HPV vaccines have been shown to induce HPV-specific antitumor immune responses in preclinical animal models and several promising strategies have been applied in clinical trials. With continued progress in the field of vaccine development, HPV therapeutic vaccines may provide a potentially promising approach for the control of lethal HPV-associated malignancies.

Figure 1. Therapeutic HPV vaccines and HPV progression

Microtrauma is believed to allow HPV to access basal epithelial cells. HPV infection promotes epithelial cell proliferation leading to SIL or CIN, and in some cases, progressing to invasive cervical carcinoma. This diagram provides an overview of the immunologic effects of therapeutic vaccination with live vector-based (viral/bacterial), protein or peptide-based, DNA or RNA-based or cell-based vaccines (DCs or tumor cells). DCs are the most potent professional APCs that prime T cells in vivo. DCs also migrate to secondary lymphoid organs to select and stimulate antigen-specific T cells. Thus, many therapeutic vaccine strategies have focused on targeting antigen to professional APCs, such as DCs, and enhancing antigen processing and presentation in DCs in order to augment T-cell-mediated immune responses. DCs activate the HPV-antigen-specific CTLs. These CTLs mediate immune clearance by apoptosis of virus-infected cells, thus blocking progression to cervical cancer or inducing regression of CIN lesions. APC: Antigen-presenting cell; CIN: Cervical intraepithelial neoplasia; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; HPV: Human papillomaviurs; SIL: Squamous intraepithelial lesions.