Immunotherapy for cervical cancer: Research status and clinical potential

Abstract

The high-risk types of human papillomavirus (HPV) have been found to be associated with most cervical cancers and play an essential role in the pathogenesis of the disease. Despite recent advances in preventive HPV vaccine development, such preventive vaccines are unlikely to reduce the prevalence of HPV infections within the next few years, due to their cost and limited availability in developing countries. Furthermore, preventive HPV vaccines may not be capable of treating established HPV infections and HPV-associated lesions, which account for high morbidity and mortality worldwide. Thus, it is important to develop therapeutic HPV vaccines for the control of existing HPV infection and associated malignancies. Therapeutic vaccines are quite different from preventive vaccines in that they require the generation of cell-mediated immunity, particularly T cell-mediated immunity, instead of the generation of neutralizing antibodies. The HPV-encoded early proteins, the E6 and E7 oncoproteins, form ideal targets for therapeutic HPV vaccines, since they are consistently expressed in HPV-associated cervical cancer and its precursor lesions and thus play crucial roles in the generation and maintenance of HPV-associated disease. Our review covers the various therapeutic HPV vaccines for cervical cancer, including live vector-based, peptide or protein-based, nucleic acid-based, and cell-based vaccines targeting the HPV E6 and/or E7 antigens. Furthermore, we review the studies using therapeutic HPV vaccines in combination with other therapeutic modalities and review the latest clinical trials on therapeutic HPV vaccines.

Figure 1. Therapeutic HPV Vaccination

This diagram provides an overview of the immunologic effects of therapeutic vaccination with live vector-based (viral/bacterial), protein or peptide-based, nucleic acid-based (DNA or RNA) vaccines or whole cell-based (tumor cell or dendritic cell) vaccines. Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) that prime T cells in vivo. After uptake of antigen, DCs migrate to secondary lymphoid organs, where they present antigen to naïve T cells and stimulate them to become 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 CD4+ T cells (T helper cells) and CD8+ cytotoxic T cells (CTLs). These CTLs mediate immune clearance by apoptosis of tumor cells while T helper cells can augment CTL immune response via CD4+ T cell help.