Personalized Immunotherapy Targeting the Cancer Mutanome

Recent advances in DNA sequencing have revealed substantial mutational heterogeneity across tumors, which presents an enormous challenge for designing effective treatments. Although the majority of mutations have proven difficult to target pharmacologically, the exquisite sensitivity and specificity of the adaptive immune system offers a promising therapeutic alternative. Mutant proteins can give rise to novel T cell epitopes (called neoantigens) that are presented on the surface of tumor cells by the major histocompatibility complex. While the existence of neoantigens has been appreciated for decades, next-generation sequencing (NGS) has enabled rapid, systematic identification of neoantigens and corresponding T cell responses in patients treated with conventional and immune-based therapies. Herein, we review the characteristics of tumor neoantigens and the methods and challenges related to their identification. We discuss several recent clinical studies in which NGS data have been used to identify mutation-reactive T cells, culminating in vaccine and cell therapy trials in which neoantigens have been deliberately targeted. Improvements in DNA sequencing have revealed the complexity of human tumors, but these advances also provide a promising new pathway toward personalized immunotherapy.