Therapeutic Cancer Vaccines Combined with Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma: A Systematic Review of Clinical Evidence

Background:

Head and neck squamous cell carcinoma (HNSCC) is a recurrent cancer of the oral cavity, pharynx, and larynx, closely linked to tobacco and alcohol use and the oral microbiome [1,2]. Standard treatment relies on surgery, radiotherapy, and chemotherapy, while immune checkpoint inhibitors (ICIs) are used in advanced disease but achieve modest response rates (~15-20%) and frequent resistance [3–5]. Cancer vaccines that expand antigen-specific T cells may augment ICI efficacy by overcoming tumor immunosuppression [6,7]. This review examines current clinical evidence on such combination strategies in HNSCC.

Methods:

A systematic search of PubMed, Wiley Online Library, and ASCO publications identified clinical studies of therapeutic vaccines combined with ICIs in HNSCC, published between January 2020 and July 2025. Eligible trials reported clinical outcomes including survival, response rates, or pathologic regression.

Results:

Four studies met the inclusion criteria. In the randomized FOCUS trial, Antonia et al. found that UV1 vaccination with pembrolizumab in 78 recurrent/metastatic PD-L1+ patients achieved a 6-month progression-free survival (PFS) of 30% versus 40% with pembrolizumab alone; median overall survival (OS) was 12.6 vs 13.1 months, with lower response rates in the vaccine arm [8]. Massarelli et al. showed that ISA101 plus nivolumab in 24 HPV-16+ patients yielded an ORR of 33%, median OS 15.3 months, and durable complete responses, linked to interferon-γ gene expression [9]. In a neoadjuvant phase II study, Kim et al. reported 63.6% major pathologic response and 36.3% complete response rates with pembrolizumab, GX-188E, and GX-I7 in 11 resectable HPV+ patients [10]. Leidner et al. observed 33.3% downstaging and 83.3% two-year recurrence-free survival in six HPV-negative patients treated with Tri-Ad5 plus bintrafusp alfa [11].

Conclusions:

Vaccine–ICI combinations in HNSCC are safe and immunologically active but show inconsistent efficacy. The most encouraging results appear in HPV-positive and neoadjuvant settings, warranting larger biomarker-driven trials.