Therapeutic Vaccination for HPV-Mediated Cancers

Abstract

Purpose of review: The goal of this narrative review is to educate clinicians regarding the foundational concepts, efficacy, and future directions of therapeutic vaccines for human papillomavirus (HPV)-mediated cancers.

Recent findings: Therapeutic HPV vaccines deliver tumor antigens to stimulate an immune response to eliminate tumor cells. Vaccine antigen delivery platforms are diverse and include DNA, RNA, peptides, proteins, viral vectors, microbial vectors, and antigen-presenting cells. Randomized, controlled trials have demonstrated that therapeutic HPV vaccines are efficacious in patients with cervical intraepithelial neoplasia. In patients with HPV-mediated malignancies, evidence of efficacy is limited. However, numerous ongoing studies evaluating updated therapeutic HPV vaccines in combination with immune checkpoint inhibition and other therapies exhibit significant promise.

Summary: Therapeutic vaccines for HPV-mediated malignancies retain a strong biological rationale, despite their limited efficacy to date. Investigators anticipate they will be most effectively used in combination with other regimens, such as immune checkpoint inhibition.

Keywords: Cancer; Human papillomavirus; Therapeutic vaccine.

Fig. 1

The intended immune response to therapeutic vaccination for HPV-mediated malignancies. The primary goal of therapeutic vaccination for cancers of HPV etiology is to initiate a cytotoxic T cell response against HPV antigens expressed on tumor cells. DC-based vaccines introduce licensed DCs that have undergone licensing and been loaded with antigen ex vivo (center panel). Peptide- or protein-based vaccines introduce peptide/protein in a form for uptake by endogenous DCs, such as a virus-like particles or liposomal carriers (left panel). DNA- and RNA-based vaccines introduce nucleic acids which are then transcribed and translated by recipient cells to produce HPV peptides or proteins (left panel). The nucleic acids can be delivered via DNA plasmids, virus-like particles, viral vectors, or bacterial vectors. The targeted cell type and mechanism of cellular entry vary with the specific vaccine formulation and route of administration. For example, DNA plasmids may be injected intramuscularly, and electroporation can be used to enhance cellular uptake. Viral vectors can enter cells by viral infection pathways. All of these will be taken up by phagocytic cells, but bacterial vectors typically target phagocytes as the cell type in which the antigenic proteins will be produced. Left panel: Antigenic peptides or proteins or DNA/RNA encoding antigenic peptides/proteins are introduced in a formulation and via a route of administration designed to activate the innate immune system and trigger DC licensing. Licensed DCs will upregulate MHCI expression, present antigenic peptides, upregulate costimulatory molecules (B7), and migrate to secondary lymphoid organs, carrying antigen with them. Center panel: In the secondary lymphoid tissues, DCs may interact with CD4 + T helper cells, resulting in a further increase in costimulatory molecule expression. CD4 + T helper cells may also provide T cell help to B cells, enhancing B cell effector functions. Licensed DCs will interact with naïve CD8 + T cells; those with appropriate T cell receptor specificity will be activated. Activated CD8 + T cells will proliferate, acquire their effector function of cytotoxicity, exit the secondary lymphoid tissues, and migrate to sites of inflammation, including tumors. Right panel: Cytotoxic T cells will infiltrate the tumor and kill tumor cells expressing their cognate antigen by releasing cytotoxic molecules that induce apoptosis