Therapeutic HPV DNA vaccines

Abstract

It is now well established that most cervical cancers are causally associated with HPV infection. This realization has led to efforts to control HPV-associated malignancy through prevention or treatment of HPV infection. Currently, commercially available HPV vaccines are not designed to control established HPV infection and associated premalignant and malignant lesions. To treat and eradicate pre-existing HPV infections and associated lesions which remain prevalent in the U.S. and worldwide, effective therapeutic HPV vaccines are needed. DNA vaccination has emerged as a particularly promising form of therapeutic HPV vaccines due to its safety, stability and ability to induce antigen-specific immunity. This review focuses on improving the potency of therapeutic HPV vaccines through modification of dendritic cells (DCs) by [1] increasing the number of antigen-expressing/antigen-loaded DCs, [2] improving HPV antigen expression, processing and presentation in DCs, and [3] enhancing DC and T cell interaction. Continued improvement in therapeutic HPV DNA vaccines may ultimately lead to an effective DNA vaccine for the treatment of HPV-associated malignancies.

Fig. 1

HPV vaccination. Vaccination can be categorized into two categories: preventive and therapeutic vaccination. Preventive HPV vaccines focus on the humoral immunity. Preventive HPV vaccines deliver HPV virus-like particles (VLPs) encoding L1 and/or L2 viral capsid proteins. B cells bind to the HPV VLPs and are activated by TH2 (differentiated CD4+ T helper cells) to become plasma cells, which secrete antibodies. These neutralizing antibodies block primary HPV infection, inducing protection against HPV. Therapeutic HPV vaccination focuses more on cell-mediated immunity. Cell-mediated immunity involves the interaction between professional antigen-presenting cells, particularly dendritic cells and T cells. Dendritic cells present the MHC:peptide complex to T cells and prime naїve T cells to become effector CD4+ T cells, if presented via MHC class II, or effector CD8+ T cells, if presented via MHC class I. These effector T cells mediate therapeutic effects, with effector CD8+ T cells, also known as cytotoxic T lymphocytes (CTL) mediating antigen-specific killing of tumor cells, and effector CD4+ T cells differentiating into T helper cells to either augment CTL immune response or activate B cells to make antibodies

Fig. 2

Routes of administration for therapeutic HPV DNA vaccines. There are several routes of administration currently used for HPV DNA vaccines. They focus on enhancing antigen uptake by dendritic cells (DCs), leading to priming of CD4+ and CD8+ T cells for an enhanced immune response. 1 Gene gun is a ballistic device that delivers gold particles coated with HPV DNA directly to Langerhans cells, which are immature DCs located under the skin. 2 Intradermal administration of HPV DNA followed by laser enhances DNA uptake into DCs. 3 Intramuscular injection with encapsulated microparticles containing HPV DNA potentiates uptake of the vaccine by DCs. 4 Intramuscular injection of naked DNA vaccine followed by electroporation enhances antigen expression by the muscle cells and generates a local inflammatory response, favoring antigen uptake by DCs

Fig. 3

Strategies to enhance antigen processing and presentation through MHC class I and II pathways. There are a variety of strategies to enhance DNA vaccine potency through enhancing antigen processing and presentation. These include enhancing the transcription of MHC class I and MHC class II molecules, enhancing or bypassing antigen processing through MHC I pathway and enhancing antigen processing and presentation through MHC II pathway

Fig. 4

Employment of modified MHC class II–associated invariant chain for improving class II presentation of antigen in dendritic cells. In the endoplasmic reticulum, the major histocompatibility complex (MHC) class II–associated invariant chain (Ii) binds with MHC class II molecules and the class II-associated peptide (CLIP) region of Ii occupies the peptide-binding groove of the MHC molecule, preventing premature binding of antigenic peptides into the groove. In the endosomal/lysosomal compartments, HLA-DM facilitates the release of CLIP and CLIP is replaced by a peptide antigen. The MHC class II molecule/antigenic peptide complex is then presented on the cell surface. By replacing the CLIP region of Ii with a CD4+ T-helper epitope such as the pan human leukocyte antigen (HLA)-DR-binding epitope (PADRE), PADRE can be presented efficiently through the MHC class II pathway in dendritic cells for the stimulation of PADRE-specific CD4+ T cells. This vaccine, termed Ii-PADRE, has been shown to generate significantly greater T-cell immune responses compared to vaccination with DNA encoding unmodified Ii