Targeting HPV in gynaecological cancers - Current status, ongoing challenges and future directions

Abstract

Despite the success of preventive vaccination, the Human Papilloma Virus still accounts for 266,000 deaths annually, as the main causative factor of cervical, vaginal, anal, penile and oropharyngeal cancers. Human Papilloma Virus infects epithelial cells, driving tumourigenesis primarily from incorporation of DNA into the host cellular genome. Translation of two particular Human Papilloma Virus-specific oncoproteins, E6 and E7, are the key drivers of malignancy. If diagnosed early cervical, vaginal and vulval cancers have good prognosis and are treated with curative intent. However, metastatic disease carries a poor prognosis, with first-line systemic treatment providing only modest increase in outcome. Having shown promise in other solid malignancies, immune checkpoint inhibition and therapeutic cancer vaccines have been directed towards Human Papilloma Virus-associated gynaecological cancers, mindful that persistent Human Papilloma Virus infection drives malignancy and is associated with immunosuppression and lack of T-cell immunity. In this review, we discuss novel therapeutic approaches for targeting Human Papilloma Virus-driven gynaecological malignancies including vaccination strategies, use of immunomodulation, immune checkpoint inhibitors and agents targeting Human Papilloma Virus-specific oncoproteins. We also highlight the evolving focus on exciting new treatments including adoptive T-cell therapies.

Keywords: HPVE6/E7; Human Papilloma Virus; Human Papilloma Virus therapeutic vaccine; T-cell therapy; cervical cancer.

Figure 1.

HPV16 genomic organization. The early region of the HPV genome contains six open reading frames (E1, E2, E4, E5 and E7 genes). These encode proteins required for viral replication and contribute to cell transformation. The late region codes for two proteins of the viral capsid (L1 and L2). LCR, locus control region. pRb, retinoblastoma protein.

Figure 2.

E6 and E7 oncogenes. E6 binds to p53 and induces its degradation. E7 binds the Rb gene product and causes the transcription factor E2F to become unbound and free to induce the cell cycle activation/proliferation. Rb, retinoblastoma protein.