Recent developments in immunotherapy of cancers caused by human papillomaviruses

Abstract

A subset of oncogenic human papillomaviruses (HPVs) is the main cause of genital cancers, most importantly cervical cancer and an increasing number of head and neck cancers. Despite the availability of prophylactic vaccines against the most prevalent oncogenic HPV types, HPV-induced malignancies are still a major health and economic burden. Besides conventional treatment with surgery, chemotherapy and radiation, immunotherapy is emerging as an efficient adjuvant option. Here, we review relevant studies and ongoing clinical trials using immune checkpoint inhibitors, therapeutic vaccines, gene editing approaches and adoptive T cell therapies, with special focus on engineered TCR T cells, which are showing encouraging results and could lead to significant improvement in the treatment of HPV+-infected cancer patients.

Keywords: Engineered TCR T cells; cervical cancer; human papillomavirus; immunotherapy.

Figure 1

Immunotherapeutic approaches for the treatment of HPV‐associated cancers

Figure 2

Workflow for the identification of tumour‐specific TCR sequences and for construction of engineered TCR T cells. (A) Reactive CTLs to a specific epitope can be obtained through different strategies: (i) extraction from patients suffering from the tumour under study; (ii) immunization of transgenic mice expressing human HLA (humanized antigen presentation) with a tumour‐specific or tumour‐associated antigen; and (iii) in vitro generation of reactive CTLs by stimulation of PBMCs from healthy donors or patients. (B) The complete sequences of TCRs of reactive CTLs are identified based on entire transcriptome or single‐cell platforms. (C) The candidate TCR genes are engineered to include in tandem: TCR‐β variable (βV)–murine constant region of β chain (β‐mc)–Furin‐P2A–TCR‐α variable (αV)–murine constant region of α chain (α‐mc). Then, naïve T cells or a TCR‐α⁻β⁻ T cell line is transduced with a lentiviral vector expressing the fusion gene to generate engineered TCR T cells that are expanded for further studies. (D) The engineered TCR T cells are then characterized for antigen affinity and avidity and for functionality by in vitro and in vivo assays