Journal Article

Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial

Csiki, Ildiko, Yan, Jian, Perales-Puchalt, Alfredo, Yarchoan, Mark, Bartha, Gabor, Marron, Thomas U., Weiner, David B., Cooch, Neil, Gane, Edward J., Sardesai, Niranjan Y., Lyle, John, Jaffee, Elizabeth M., Kagohara, Luciane T., Peters, Joann, Connor, Jason T., Shu, Daniel H., Perales-Linares, Renzo, Northcott, Josette, Fertig, Elana J., Rochestie, Sarah

2024

Overview

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 . Treatment of patients with advanced hepatocellular carcinoma with a personalized DNA vaccine in combination with anti-PD-1 therapy was safe and led to encouraging clinical efficacy, with immunological analyses confirming the induction of tumor antigen-specific T cell responses.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2152/1566/20 / 631/250/251/1567 / 631/250/590/1991 / 631/67/1504/1610 / 692/308/575 / Antibodies, Monoclonal, Humanized - adverse effects / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer vaccines / Carcinoma, Hepatocellular - drug therapy / CD4 antigen / CD8 antigen / Cell death / Cloning / Complementarity-determining region / Customization / Cytotoxicity / Deoxyribonucleic acid / DNA / DNA vaccines / Effectiveness / Effector cells / Hepatocellular carcinoma / Humans / Immunogenicity / Immunology / Immunotherapy / Infectious Diseases / Interleukin 12 / Kinases / Liver cancer / Liver Neoplasms - drug therapy / Lymphocytes / Lymphocytes T / Metabolic Diseases / Metastases / Molecular Medicine / Monoclonal antibodies / Neoantigens / Neurosciences / Patients / PD-1 protein / Pembrolizumab / Phenotypes / Solid tumors / T cell receptors / Targeted cancer therapy / Tumors / Vaccines / Vaccines - therapeutic use