Immune cell-based therapy shows no significant benefits for tumor response or survival in HNSCC trialsImmune cell therapy shows limited promise for head and neck cancer

BACKGROUND: Although immune cell-based therapy (ICT) has demonstrated activity in other malignancies, its clinical outcomes in head and neck squamous cell carcinoma (HNSCC), particularly beyond nasopharyngeal carcinoma (NPC), remain underexplored, despite NPC accounting for 13.5% of HNSCC cases. METHODS: ICT trials in HNSCC were included in systematic review (n = 38); 4 case reports and 4 mixed solid tumor studies with ≤ 3 patients with HNSCC were excluded (n = 8), leaving 30 studies for meta-analysis. RESULTS: Thirty trials (953 patients), comprising 3 randomized, 1 nonrandomized, and 26 single-arm studies, were included. All randomized trials were conducted in NPC using distinct autologous ICT platforms showing no significant ICT benefits for tumor response, adverse events (AEs) ≥ grade 3, and survival outcomes. The only nonrandomized trial in non-nasopharyngeal HNSCC reported longer median survival; however, reconstructed hazard ratios lacked statistical significance. Across the 26 single-arm trials (13 NPC and 13 non-nasopharyngeal HNSCC trials), pooled rates were as follows: complete response, 11%; objective response rate, 22%; disease control rate, 56%; and AEs ≥ grade 3, 12%. Single-arm NPC studies were dominated by EBV-directed T-cell platforms (10/13), whereas non-nasopharyngeal HNSCC studies used heterogeneous ICT platforms. CONCLUSIONS: Sparse randomized evidence for ICT using different autologous platforms in HNSCC remains confined to NPC and demonstrated no clear survival benefit. In non-nasopharyngeal HNSCC, evidence remains limited to single-arm data with heterogeneous platforms. These data support the need for next-generation engineered ICT trials across all HNSCCs, particularly prioritizing randomized trials in non-nasopharyngeal HNSCC. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ID: CRD420261276992.