The current state of therapeutic and T cell-based vaccines against human papillomaviruses

Abstract

Human papillomavirus (HPV) is known to be a necessary factor for many gynecologic malignancies and is also associated with a subset of head and neck malignancies. This knowledge has created the opportunity to control these HPV-associated cancers through vaccination. However, despite the availability of prophylactic HPV vaccines, HPV infections remain extremely common worldwide. In addition, while prophylactic HPV vaccines have been effective in preventing infection, they are ineffective at clearing pre-existing HPV infections. Thus, there is an urgent need for therapeutic and T cell-based vaccines to treat existing HPV infections and HPV-associated lesions and cancers. Unlike prophylactic vaccines, which generate neutralizing antibodies, therapeutic, and T cell-based vaccines enhance cell-mediated immunity against HPV antigens. Our review will cover various therapeutic and T cell-based vaccines in development for the treatment of HPV-associated diseases. Furthermore, we review the strategies to enhance the efficacy of therapeutic vaccines and the latest clinical trials on therapeutic and T cell-based HPV vaccines.

Keywords: HPV E6; HPV E7; Human papillomavirus; Immunotherapy; T cell-based vaccine; Therapeutic vaccine.

Figure 1. Immune activation by therapeutic HPV vaccination

Administration of various types of therapeutic HPV vaccines leads to introduction of antigen into the body in different forms. DNA plasmids encoding antigens (HPV oncoprotein E6 and E7) can be introduced into dendritic cells through direct DNA vaccination or through infection of modified live vector vaccine. The DNA encoding antigens will be transcribed into RNA, which can also be introduced into the cell through RNA vaccination. The transcribed RNA will be further translated into antigen proteins, or long peptides, which can also be taken up by the dendritic cells through phagocytosis after protein or peptide-based vaccination. The antigen proteins or long peptides are then processed by the proteasomes into short peptides, loaded onto class one major histocompatibility complex (MHC I) inside the endoplasmic reticulum (ER) to be presented to T cell receptors (TCR) of CD8+ T cells. Alternatively, autologous dendritic or tumor cells can be collected and prepared ex vivo to express target antigen on MHC I molecules as well as the necessary co-stimulatory molecules and be vaccinated back to the body (a process called adoptive transfer) as whole cell-based vaccines for the priming of T cells. (ER – Endoplasmic Reticulum; MHC – Major Histocompatibility Complex; TCR – T Cell Receptor; E6/E7 – Human Papillomavirus E6 and E7 Protein.)

Figure 2. Generation of Passive Immunity via adoptive T cell transfer

A schematic diagram depicting the process of T cell-based vaccination. Briefly, autologous T cells are harvested from patients through PBMC collection. The T cells are non-specifically expanded (typically with CD3 and CD28 agonistic antibodies), followed by several mechanisms to induce antigen-specific T cells: 1) expanded, heterogeneous T cell population can be co-cultured with antigen pulsed feeder cells (typically dendritic cells or irradiated tumor cells) to select for antigen-specific T cells, 2) expanded T cells can be transduced with DNA encoding engineered T cell receptor that is specific to the antigen using viral vectors, and 3) expanded T cells can be transduced with DNA encoding chimeric antigen receptor that is specific to the antigen. The resulted, selected or modified T cells can then be infused back into the patient for the generation of immune responses against antigen-expressing cells.