TG4050, a Modified Vaccinia Ankara (MVA) viral vector–based individualized neoantigen therapeutic vaccine encoding up to 30 patient-specific predicted tumor neoantigens, demonstrated encouraging clinical activity as adjuvant monotherapy in patients with resected, locally advanced, HPV-negative head and neck squamous cell carcinoma (HNSCC), according to findings from the randomized phase 1 TG4050.02 trial (NCT04183166) published in Nature Communications.1
Regarding safety outcomes, no dose-limiting toxicities (DLTs) were observed in the safety population of 19 patients who received at least 1 TG4050 injection. No patients experienced grade 3 or higher treatment-related adverse effects (TRAEs). All but 1 patient (n = 18/19, 94.7%) reported grade 1 or 2 TRAEs; the most common were injection site reactions, occurring in 94.1% of patients at grade 1 and 23.5% at grade 2 in Arm A. Other grade 1 AEs in Arm A included diarrhea (11.8%) and fatigue (11.8%).
In the per-protocol efficacy analysis, none of the 16 patients in Arm A (immediate vaccination within 1 week of randomization) experienced a relapse at a median follow-up of 30 months, while 3 of 16 patients in Arm B (watchful waiting, with TG4050 available at relapse) experienced a relapse at 6, 7, and 18 months. An updated analysis at a median follow-up of 41 months confirmed no additional relapses in either arm. No baseline features, including age, sex, tumor site, adjuvant treatment type, or pathological stage were associated with recurrence risk.
“Out of 16 evaluable patients treated immediately with TG4050, none relapsed after 2 years, whereas 3 of 16 patients [randomly assigned] to the control arm experienced disease recurrence,” Christian Ottensmeier, MD, professor of experimental oncology at the University of Liverpool and The Clatterbridge Cancer Centre NHS Foundation Trust, wrote with study coinvestigators in the publication.1 “Even though the sample size and number of relapses is too small to conclude on TG4050 efficacy, these results are encouraging and warrant further investigation of the role of TG4050 in preventing tumor recurrence in the currently ongoing randomized phase [2] part of the study.”
TG4050.02 is a multicenter, open-label, randomized phase 1/2 trial conducted across 3 sites in France and the UK. Patients had newly diagnosed, locally advanced, HPV-negative, resectable stage III or IV oropharyngeal, laryngeal, hypopharyngeal, or oral cavity HNSCC with an ECOG performance status of 0 or 1. After surgery and adjuvant radiotherapy with or without cisplatin, patients were randomly assigned upon confirmation of complete response by imaging 3 months post-treatment. Thirty-three patients were randomly assigned between January 2021 and April 2023, including 17 to Arm A and 16 to Arm B. TG4050 vaccines encoding each patient’s unique neoantigens were manufactured using whole-exome sequencing paired with RNA sequencing of resected tumor tissue; vaccines were successfully produced for 92% of eligible patients.
The primary end point of the study was the safety and tolerability of TG4050. Secondary end points included feasibility and disease-free survival (DFS). Immunogenicity was an exploratory end point.
Neoantigen-specific T cell responses were detected in 73.3% (n = 11/15) of patients in Arm A with available samples by ex vivo IFN-γ ELISpot and/or peptide-MHC class I tetramer assay, with a median of 3 responding neoantigens per patient (range, 1-16). Vaccine-induced CD8-positive T cells had an effector memory phenotype with high expression of cytotoxic markers and ZNF683, a regulator of tissue-resident memory T cell differentiation and persisted at detectable levels up to 24 months, 1 year after the last TG4050 dose.
The authors noted that approximately 19.7% of screened patients experienced a relapse before the 3-month manufacturing cut-off and were unable to receive TG4050, a challenge that ongoing manufacturing improvements, potentially reducing production timelines below 100 days, aim to address.
Two recent phase 3 trials provide the clinical backdrop for these data: KEYNOTE-689 (NCT03765918), in which perioperative pembrolizumab (Keytruda) improved event-free survival in locally advanced HNSCC, and GORTEC 2018-01 NivoPostOp (NCT03544736), in which post-operative nivolumab (Opdivo) improved DFS among those with esophageal cancer.2,3 The authors highlighted strong scientific rationale for combining TG4050 with checkpoint inhibitors, noting high PD-1 expression in neoantigen-specific CD8-positive T cells identified by transcriptomic analysis. Additionally, they observed that durable disease control was not achieved when 2 patients in Arm B received TG4050 at relapse, suggesting that monotherapy in advanced disease may require synergistic combination strategies.
References
- Ottensmeier C, Delord JP, Lalanne A, et al. A viral-based individualized neoantigen vaccine as adjuvant treatment in resected head and neck squamous cell carcinoma: a randomized phase I trial. Nat Commun. 2026;17:9863. doi:10.1038/s41467-026-76667-1
- Uppaluri R, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer. N Engl J Med. 2025;393(1):37-50. doi:10.1056/NEJMoa2415434
- Hjortland G, Aasand K, Kumar T, et al. Safety and feasibility of irradiation and nivolumab in esophageal cancer – a phase I/II study. Ann Oncol. 2023;43(suppl 1):S46-S47. doi:10.1016/j.annonc.2023.04.149
