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A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1\/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade \u22653 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    effector T cells. T cell receptor \u03b2-chain (TCR\u03b2) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV\u2019s mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. 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T.U.M. currently serves, or at any point in the past has served, on advisory and\/or data safety monitoring boards for Rockefeller University, Regeneron, AbbVie, Merck, Bristol-Meyers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, DrenBio, Glenmark, Simcere, Surface, G1 Therapeutics, NGM Bio, DBV Technologies, Arcus, Fate, Ono, Larkspur, Avammune and Astellas and has research grants from the National Institutes of Health (National Cancer Institute), the Cancer Research Institute, Regeneron, Genentech, Bristol-Myers Squibb, Merck and Boehringer Ingelheim. E.J.G. has served as a member of scientific advisory boards for AbbVie, Abbott Diagnostics, Aligos, Arbutus, Arrowhead, Assembly, Avalia, ClearB Therapeutics, Dicerna, Enanta, Gilead Sciences, GlaxoSmithKline, Intellia, Janssen, Merck, Novartis, Genentech-Roche, Vaccitech, Ventorx, Vir Biotechnology and Virion Therapeutics. He is a speaker for AbbVie, Abbott Diagnostics, Gilead Sciences and Intellia. R.P.-L., J.Y., N.C., S.R., J.P., A.P.-P. and N.Y.S. are either current or previous Geneos employees. A.P.-P. and N.Y.S. are listed as inventors on several pending applications related to the vaccine platform presented in this study. D.H.S. and L.T.K. have no disclosures to report. E.J.F. is on the scientific advisory board of Viosera Therapeutics\/Resistance Bio and is a consultant for Mestag Therapeutics and Merck. E.M.J. has received personal fees from Achilles, Dragonfly, the Parker Institute for Cancer Immunotherapy, the Cancer Prevention and Research Institute of Texas, Surge, HDT Bio, Neuvogen, NeoTx, Mestag and Medical Home Group. She has research grants from Lustgarten, Genentech, Bristol-Meyers Squibb and Break Through Cancer outside the submitted work. She receives other support from Abmeta and Adventris. G.B., J.L. and J.N. are full-time employees of Personalis, Inc. I.C. has a consultant role with Geneos; she has served as an advisor and\/or a member of the data safety review board for Coherus, Exscientia AI, Riboscience and the University of Utah Therapeutic Accelerator Hub. J.T.C. is a paid statistical consultant for Geneos Therapeutics. D.B.W. has received grant funding, participates in industry collaborations, has received speaking honoraria and has received fees for consulting, including serving on scientific review committees. Remunerations received by D.B.W. include direct payments and equity\/options. D.B.W. also discloses the following associations with commercial partners: Geneos (consultant\/advisory board), AstraZeneca (advisory board, speaker), Inovio (board of directors, consultant), BBI\/Sumitomo Dainippon (advisory board), Flagship (consultant), Pfizer (advisory board) and Advaccine (consultant).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}