Immunotherapy for human papillomavirus-associated disease and cervical cancer: review of clinical and translational research

Abstract

Cervical cancer is the fourth most lethal women's cancer worldwide. Current treatments against cervical cancer include surgery, radiotherapy, chemotherapy, and anti-angiogenic agents. However, despite the various treatments utilized for the treatment of cervical cancer, its disease burden remains a global issue. Persistent infection of human papillomavirus (HPV) has been identified as an essential step of pathogenesis of cervical cancer and many other cancers, and nation-wide HPV screening as well as preventative HPV vaccination program have been introduced globally. However, even though the commercially available prophylactic HPV vaccines, Gardasil (Merck) and Cervarix (GlaxoSmithKline), are effective in blocking the entry of HPV into the epithelium of cervix through generation of HPV-specific neutralizing antibodies, they cannot eliminate the pre-existing HPV infection. For these reason, other immunotherapeutic options against HPV-associated diseases, including therapeutic vaccines, have been continuously explored. Therapeutic HPV vaccines enhance cell-mediated immunity targeting HPV E6 and E7 antigens by modulating primarily dendritic cells and cytotoxic T lymphocyte. Our review will cover various therapeutic vaccines in development for the treatment of HPV-associated lesions and cancers. Furthermore, we will discuss the potential of immune checkpoint inhibitors that have recently been adopted and tested for their treatment efficacy against HPV-induced cervical cancer.

Keywords: Human Papillomavirus; Immune Checkpoint Inhibitor; Immunotherapy; Therapeutics; Uterine Cervical Neoplasms; Vaccines.

Fig. 1

The structure of human papillomavirus (HPV) and its function. HPV genome is composed of 8k base pairs and divided into early and late gene. The early genome encodes E1, E2, E4, E5, E6, and E7 and the late genome encodes L1 and L2. Oncoprotein E6 and E7 degrade tumor suppressor p53 and pRb, respectively. L1 and L2 build the structure of HPV capsid protein. LCR, long control region.

Fig. 2

The mechanism of T cell stimulation and differentiation. T cell is stimulated through the complex of major histocompatibility complex T cell receptor (MHC-TCR) in the presence of antigen (signal 1). Co-stimulatory molecule is indispensible for the activation of T cell mainly through CD28 on T cell and B7 on antigen presenting cell (signal 2). Otherwise, T cell will fall into anergy state. Finally, T cell differentiation will be affected by cytokine or environmental factors (signal 3). ICAM, intercellular adhesion molecule; IL, interleukin; LFA-1, lymphocyte function-associated antigen-1; Th, T helper; OX-40, CD134.

Fig. 3

The function of immune checkpoint inhibitor in tumor. Tumor antigen is captured by dendritic cell and delivered to naïve T cell in lymph node. Normally, immune checkpoint (cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4]) on activated T cell is expressed to keep the balance of immune system. Anti-CTLA-4 antibody blocks the inhibitory signal of T cell and extends the duration of activated T cell. Programmed death ligand 1 (PD-L1) expressed on periphery tumor site prohibits activated T cell through programmed death receptor (PD-1) receptor expressed on effector T cell. Anti-PD-1 antibody eliminates the interaction of PD-1 and PD-L1 and aids to keep effector T cell activated enough to kill tumor cells. MHC, major histocompatibility complex; TCR, T cell receptor.