Cancer neoantigens as potential targets for immunotherapy

Abstract

AbstractImmune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programed cell death protein 1 (PD-1) or its ligand PD-L1 have increased the survival and cure rates for patients with many cancer types in various disease settings. However, only 10–40% of cancer patients benefited from these ICIs, of whom ~ 20% have treatment interruption or discontinuation due to immune-related adverse events that can be severe and even fatal. Current efforts in precision immunotherapy are focused on improving biomarker-based patient selection for currently available ICIs and exploring rationale combination and novel strategies to expand the benefit of immunotherapy to more cancer patients. Neoantigens arise from ~ 10% of the non-synonymous somatic mutations in cancer cells, are important targets of T cell-mediated anti-tumor immunity for individual patients. Advances in next generation sequencing technology and computational bioinformatics have enable the identification of genomic alterations, putative neoantigens, and gene expression profiling in individual tumors for personal oncology in a rapid and cost-effective way. Among the genomic biomarkers, defective mismatch DNA repair (dMMR), microsatellite instability high (MSI-H) and high tumor mutational burden (H-TMB) have received FDA approvals for selecting patients for ICI treatment. All these biomarkers measure high neoantigen load and tumor antigenicity, supporting the current development of neoantigen-based personalized cancer vaccines for patients with high TMB tumor. Several studies have shown neoantigen vaccines are feasible, safe and have promising clinical activity in patients with high TMB tumors in both metastatic and adjuvant settings. This review summarizes the emerging data and technologies for neoantigen-based personalized immunotherapy.