Purpose: While the incidence of smoking-related head and neck squamous cell carcinoma (HNSCC) has been declining, that of human papillomavirus (HPV)-mediated HNSCC has rapidly increased in the past decades worldwide. Despite rapid advances in therapeutics for solid tumors with novel immunotherapy and targeted therapeutic agents, no breakthroughs have yet been made in the treatment of advanced HPV+ HNSCCs. This review aims to summarize the concepts and designs, early trial results, and future directions of various HPV-targeted experimental therapeutics for HPV+ HNSCC.
Materials and methods: Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, a systemic literature search of PubMed was conducted for HPV-targeted therapeutics using the following search terms: HPV, head and neck squamous cell carcinoma, and therapy. For clinical trial data, publications, major oncology conference abstracts, and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov) information were reviewed. This review focused on the ones that are in the clinical stage and currently in active ongoing evaluation. The therapeutics not actively evaluated in HNSCC, in the preclinical stage, or terminated for further development were excluded.
Results: Diverse approaches are being actively explored to target HPV+ HNSCC, including therapeutic vaccines of various modalities, HPV-specific immune cell-activating agents, and adaptive cellular therapeutics. All these novel agents use immune-based mechanisms and target constitutively expressed oncogenic HPV E6 and/or E7 viral proteins. Most therapeutics demonstrated excellent safety but single-agent activities are only modest. Many are being tested in combination with immune checkpoint inhibitors.
Conclusion: Our review summarized various novel HPV-targeted therapeutics that are in the clinical phase for HPV+ HNSCC. Early-phase trial data suggest the feasibility and promising efficacy. Further strategies, including selecting the optimal combination and understanding and overcoming resistant mechanisms, are warranted for successful development.