{"id":"doi:10.1038/s41591-024-02894-y","kind":"article","title":"Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial","authors":["Yarchoan M","Gane EJ","Marron TU","Perales-Linares R","Yan J","Cooch N","Shu DH","Fertig EJ","Kagohara LT","Bartha G","Northcott J","Lyle J","Rochestie S","Peters J","Connor JT","Jaffee EM","Csiki I","Weiner DB","Perales-Puchalt A","Sardesai NY"],"author_count":20,"year":2024,"published":"2024-04-07","venue":"Nature medicine","cited_by":225,"doi":"10.1038/s41591-024-02894-y","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-024-02894-y","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-024-02894-y","updated":null,"pmid":"38584166","pmcid":"PMC11031401","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC11031401/pdf","abstract":"Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). 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 ≥3 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 + and CD8 + effector T cells. T cell receptor β-chain (TCRβ) 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's mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117 .","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial\" by Yarchoan M, Gane EJ, Marron TU et al., https://doi.org/10.1038/s41591-024-02894-y, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"mrna-cancer-vaccines","name":"mRNA Therapeutics & Cancer Vaccines","domain_slug":"medicine"}],"cited_in_dossiers":[]}