The promise of combining cancer vaccine and checkpoint blockade for treating HPV-related cancer

Abstract

Human papillomavirus (HPV)-associated intraepithelial neoplasia or cancers are ideal candidates for cancer immunotherapy since HPV oncoproteins, such as E6 and E7 proteins of high-risk HPVs, could be utilized as foreign antigens. In HPV-associated cancers as well as nonviral cancers, the cancer cells may evade host immunity through the expression of immune checkpoint molecules, downregulation of human leukocyte antigen, and activation of immune regulatory cells. Because of these immune suppressive mechanisms, HPV therapeutic vaccines have shown little efficacy against HPV-associated cancers, although they have shown efficacy in treating HPV-associated intraepithelial neoplasias. Recently, checkpoint blockade emerged as a promising new treatment for solid cancers; however, these therapies have shown only modest efficacy against HPV-associated cancers. Here we reviewed literature analyzing a combinatory therapy using an immune checkpoint inhibitor and an HPV therapeutic vaccine for treating HPV-associated cancers to compensate for shortfalls of each monotherapy. Complimentary modes of T cell activation would be deployed; as vaccines would directly stimulate the T cells, while checkpoint inhibitors would do so by releasing inhibition. Some promising studies using animal models and early human clinical trials raised a possibility that such combinations may be efficacious in regressing HPV-associated cancers. Epitope spreading (the phenomenon in which non-targeted antigens become new targets of immune response) may play a critical role mechanistically. Currently ongoing studies will shed light as to whether such combination therapy would indeed be a promising new treatment paradigm. Current and future studies must also determine the adverse effect profile of such a combination treatment.

Keywords: Cervical cancer; Checkpoint blockade; Human papillomavirus; Immunotherapy; Therapeutic vaccine.

Figure 1.. Possible mechanisms of cancer vaccines and checkpoint blockade in therapy of HPV-related cancer.

In lymph nodes, vaccine-targeted T cells are activated after priming of antigen presenting cells (APCs) such as dendritic cells (DCs) pulsed HPV antigens (A). After disruption in cancer cells by vaccine-targeted T cells, non-vaccine-targeted antigens (e.g. neoantigens) are released resulting in epitope spreading (B). DCs phagocyting non-vaccine-targeted antigens prime another T cell clone (C). Formation of oligoclonal T cell in HPV-related cancer by PD-1 or PD-L1 blockade. If PD-1 are expressed on vaccine-targeted T cells and nonvaccine-targeted T cells, these cells will be activated by PD-1 or PD-L1 blockade followed by expansion of T cell clone in tumor (D).