Immunogenicity of neoantigens from hepatocellular carcinoma patients treated with a combined radioimmunotherapy

In some cancers, patients responding to immune checkpoint inhibitors (ICI) usually harbor tumors with a higher tumor mutational burden and increased lymphocyte infiltration targeting mutation-derived neoantigens (neoAgs). In the NASIR-HCC trial, patients with hepatocellular carcinoma (HCC) received selective internal radiation therapy and the anti-PD-1 antibody Nivolumab, but many of them did not achieve clinical benefit (B). Since neoAg-based vaccination could enhance tumor infiltration and ICI responses, we studied neoAg-specific immunity in these patients and assessed whether patients with no benefit (NB) harbored sufficient immunogenic neoAgs for therapeutic vaccination. Using predicted neoAgs from 6 B and 4 NB patients, we tested immune reactivity <i>in vitro</i>. NeoAg-specific responses were detected in 75% of B and 83% of NB patients, recognizing 37% and 63% of neoAgs tested, respectively. <i>In vivo</i> immunization experiments in HLA transgenic HHD-DR1 mice using HLA-A*02.01- or HLA-DRB1*01-predicted neoAgs from four NB patients revealed responses against most neoAgs (87% and 73%, respectively), expanding the repertoire of immunogenic epitopes. Finally, polyepitopic peptide vaccination containing neoAgs from an NB patient induced stronger and broader T-cell responses compared to polyepitopic DNA vaccine. Our results demonstrate the immunogenicity of neoAgs in our cohort, supporting their potential utility in therapeutic vaccines designed to boost antitumor immunity.