Individualized Neoantigen Vaccine TG4050 Keeps All Treated Patients Relapse-Free at 41 Months in Resected HPV-Negative Head and Neck Cancer
核心洞察
Updated results from the randomized phase 1 TG4050.02 trial show none of 16 evaluable patients who received immediate adjuvant TG4050 relapsed at a median follow-up of 41 months.
Three of 16 patients in the watchful-waiting control arm experienced recurrence at 6, 7 and 18 months, with no additional relapses in either arm on updated analysis.
No dose-limiting toxicities or grade 3 or higher treatment-related adverse events occurred among 19 patients who received at least one TG4050 injection.
An individualized neoantigen therapeutic vaccine, TG4050, produced durable disease control in patients with resected, locally advanced, HPV-negative head and neck squamous cell carcinoma (搜索) (HNSCC), according to updated results from the randomized phase 1 TG4050.02 trial (NCT04183166) published in Nature Communications and subsequently reported by Transgene and NEC (搜索).
In the per-protocol efficacy analysis, none of the 16 evaluable patients in Arm A, who began vaccination within 1 week of randomization, had relapsed at a median follow-up of 30 months. Three of 16 patients in Arm B, assigned to watchful waiting with TG4050 available at relapse, experienced recurrence at 6, 7 and 18 months. An updated analysis at a median follow-up of 41 months confirmed no additional relapses in either arm.
"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. "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."
Trial Design and Patient Population
TG4050.02 is a multicenter, open-label, randomized phase 1/2 trial conducted across 3 sites in France and the UK. Enrolled 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.
The primary end point was safety and tolerability of TG4050. Secondary end points included feasibility and disease-free survival (DFS), with immunogenicity as an exploratory end point. No baseline features, including age, sex, tumor site, adjuvant treatment type or pathological stage, were associated with recurrence risk.
Vaccine Manufacturing and Immunogenicity
TG4050 is a modified vaccinia Ankara (MVA) viral vector-based vaccine encoding up to 30 patient-specific predicted tumor neoantigens. Vaccines were manufactured using whole-exome sequencing paired with RNA sequencing of resected tumor tissue, and an artificial intelligence system selects the predicted neoantigens. Vaccines were successfully produced for 92% of eligible patients.
Neoantigen-specific T-cell responses were detected in 73.3% (11 of 15) of patients in Arm A with available samples by ex vivo IFN-gamma ELISpot and/or peptide-MHC class I tetramer assay, with a median of 3 responding neoantigens per patient (range, 1 to 16). Vaccine-induced CD8-positive T cells had an effector memory phenotype with high expression of cytotoxic markers and ZNF683 (搜索), 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. Analysis showed the vaccine induced new immune responses while also expanding T-cell populations already present in some tumors.
Safety Profile
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 events (TRAEs). All but 1 patient (18 of 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 adverse events in Arm A included diarrhea (11.8%) and fatigue (11.8%). Long-term follow-up identified no unexpected safety findings.
Manufacturing Timelines and Combination Rationale
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. Ongoing manufacturing improvements, potentially reducing production timelines below 100 days, aim to address this challenge.
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. The authors highlighted a scientific rationale for combining TG4050 with checkpoint inhibitors, noting high PD-1 (搜索) expression in neoantigen-specific CD8-positive T cells identified by transcriptomic analysis. They also 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.
Around one-third of patients with this form of cancer experience recurrence despite surgery and postoperative treatment. A larger randomized phase 2 study is underway to evaluate immune responses and disease-free survival more rigorously.