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Background In the phase I trial TG4050.02 ( NCT04183166) evaluating TG4050 in resected, locally advanced HNSCC patients after (chemo)radiation, we showed that patients randomized to immediate vaccination with TG4050 had no relapse after a median follow-up of 30 months versus 3 relapses in the control arm randomized to watchful waiting.Methods Patient-specific neoantigens were predicted from sequencing of tumor material and individualized TG4050 vaccines containing up to 30 neoantigens were manufactured. Patients received weekly doses of TG4050 for 6 weeks followed by a maintenance period of one dose every 3 weeks for up to a total of 20 doses. In the control arm the same vaccination regimen was initiated at relapse in combination with standard of care. Apheresis for collection of PBMC was performed at Baseline and 9 weeks after treatment initiation. Blood samples were collected longitudinally up to one year after the end of vaccination. We quantified T cell responses to vaccination by ex vivo IFN-γ ELISpot and pMHC class I tetramer analyses. Using phenotyping, scRNAseq and TCR sequencing, we characterized the CD8 T cells specific to neoantigens and compared them to CD8 T cells specific to viral antigens in the same patient.Results Polyepitopic responses to vaccine neoantigens were detected by ex vivo IFN-γ ELISpot or pMHC class I tetramer analyses in the blood of patients from both treatment groups. These responses were maintained throughout treatment and persisted for over one year after the end of treatment. Vaccine neoantigen-specific CD8 T cells had an effector phenotype at all time-points analyzed, even after end of treatment. At the transcriptomic level, neoantigen-specific CD8 T cells resembled cells specific for the MVA vector. Both kinds of cells displayed higher expression of cytotoxic markers (GZMB, PRF1, GLNY) and markers associated with tissue-resident phenotype (ZNF683, CX3CR1) than CD8 T cells specific for CMV or influenza. TCR repertoire analysis showed that vaccine neoantigen-specific CD8 T cell responses were polyclonal and comprised both de novo responses and expansion of tumor-infiltrating T cell clones.Conclusions Together, this translational data is consistent with the model in which TG4050 induces tumor neoantigen-specific cytotoxic T cell responses that prevent tumor recurrence.Trial Registration EUCT 2023-508561-33, EudraCT 2018-003267-58, NCT04183166Ethics Approval The study protocol was approved by the appropriate local or national ethics committee for each participating center and complied with Good Clinical Practice guidelines, the principles of the Declaration of Helsinki, and local laws. All participants provided written, informed consent before taking part. France: Comité de Protection des Personnes Ile de France 5 ID: 35725 (EUCT 2023-508561-33) Initial approval on 01 Oct 2019 UK: South Central - Oxford A Research Ethics Committee ID: 19/SC/0500 (EudraCT 2018-003267-58) Initial approval on 26 Mar 2020 US: Mayo Clinic Institutional Review Boards ID: 20-007421 Initial approval on 19 Feb 2021