Viral-based individualized neoantigen vaccine as adjuvant treatment in resected head and neck squamous cell carcinoma: immunogenicity and efficacy from a randomized Phase I trial

In approximately one third of patients, resected head and neck squamous cell carcinoma will recur. We postulated that the induction of tumor neoantigen-specific T cell responses could prevent relapse. To this end, we developed TG4050, an individualized neoantigen therapeutic vaccine encoding up to 30 patient-specific predicted tumor neoantigens delivered by a Modified Vaccinia Ankara virus viral vector. We tested TG4050 as single agent in a randomized phase I trial. We found that of 16 evaluable patients randomized to immediate vaccination with TG4050, none relapsed after a median follow-up of 30 months, while 3 relapsed in the 16 control arm patients randomized to observation and treatment with TG4050 after recurrence. Polyepitopic responses to vaccine neoantigens were detected in the blood of patients from both arms after treatment initiation. These responses were maintained throughout treatment and persisted for over one year after the last dose. Vaccine neoantigen-specific CD8+ T cells had an effector phenotype and displayed high expression of cytotoxic and tissue-resident markers. TCR repertoire analysis showed that vaccine neoantigen-specific CD8+ T cell responses were polyclonal and comprised both de novo responses and amplification of pre-existing tumor-infiltrating T cell clones. Together, this translational data is consistent with the model in which single-agent delivery of TG4050 induces long-lasting tumor neoantigen-specific cytotoxic T cell responses that prevent tumor recurrence.